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I S S U E 88 Medicographia Vol 28, No. 3, 2006 ISSN 0243-3397 If I nhibition, H eart R ate, and C oronary A rtery D isease R. FERRARI, G. CAMPO, C. ARCOZZI, L. PELLEGRINO, G. PASANISI, AND C. CECONI, ITALY EDITORIAL IF INHIBITION: A THERAPEUTIC ADVANCE FOR PATIENTS 201 WITH CORONARY ARTERY DISEASE INHIBITION IF : UNE AVANCÉE THÉRAPEUTIQUE POUR LES PATIENTS AYANT UNE MALADIE CORONAIRE L. TAVAZZI, ITALY CURRENT TREATMENT OF STABLE ANGINA IN EUROPE: MAIN CONCLUSIONS FROM THE EURO HEART SURVEY 212 J. C. TARDIF, CANADA PROGNOSTIC VALUE OF HEART RATE IN CARDIO- 218 VASCULAR DISEASE M. J. SHATTOCK AND M. J. CURTIS, UNITED KINGDOM THE ROLE OF IF IN THE REGULATION OF HEART A. MUGELLI AND E. CERBAI, ITALY THE IF CURRENT BEYOND HEART RATE REGULATION 232 J. KJEKSHUS, NORWAY THE EFFECT OF HEART RATE REDUCTION ON SURVIVAL 238 224 RATE IN HEART FAILURE A journal of medical information and international communication from Servier N. DANCHIN AND L. SABBAH, FRANCE BENEFITS OF HEART RATE REDUCTION DURING AND I. SAVELIEVA AND A. J. CAMM, UNITED KINGDOM IF INHIBITION: SAFETY AND TOLERABILITY 245 AFTER INTERVENTIONAL TREATMENT S. STEINER AND HEART RATE AND PLAQUE DISRUPTION B. E. STRAUER, GERMANY 249 254 Contents continued overleaf... Medicographia Vol 28, No. 3, 2006 I S S U E 88 ...Contents continued from cover page If I nhibition, H eart R ate, and C oronary A rtery D isease I. SOYDAN, TURKEY / L. R. PADIAL, SPAIN / A. P. MAGGIONI AND G. LONARDO, ITALY / R. SEABRA-GOMES, PORTUGAL / J. HRADEC, CZECH REPUBLIC / C.-B. XU, CHINA / Y. SEINO, JAPAN / Y. N. BELENKOV, RUSSIA I. ELYUBAEVA, FRANCE CONTROVERSIAL QUESTION CAN WE DEFINE AN OPTIMAL HEART RATE FOR ALL PATIENTS? 258 PROCORALAN PROCORALAN: ANTIANGINAL EFFICACY THROUGH 267 AN INNOVATIVE MODE OF ACTION M. TENDERA, POLAND INTERVIEW WHAT CAN IF INHIBITION CONTRIBUTE TO THE 275 TREATMENT OF LEFT VENTRICULAR DYSFUNCTION? T. MEINERTZ, GERMANY C. DALY AND K. FOX, UNITED KINGDOM FOCUS TREATMENT STRATEGIES FOR THE STABLE ANGINA PATIENT: MORE THAN JUST THE HEART 278 UPDATE NEW EUROPEAN GUIDELINES FOR THE TREATMENT 285 OF STABLE ANGINA J. DUCRUET, LEBANON A TOUCH OF FRANCE FRANCE AND MEDICAL EDUCATION UNDER THE OTTOMAN EMPIRE 293 L. ALLORGE, FRANCE A TOUCH OF FRANCE FRENCH NATURALISTS IN THE LEVANT DURING THE OTTOMAN EMPIRE 301 E D I T O R I A L If inhibition: a therapeutic advance for patients with coronary artery disease by R. Ferrari, G. Campo, C. Arcozzi, L. Pellegrino, G. Pasanisi, and C. Ceconi, Italy ▲ Roberto FERRARI, MD, PhD Gianluca CAMPO, MD Chiara ARCOZZI, MD Luca PELLEGRINO, MD Giovanni PASANISI Claudio CECONI Research Center IRCCS Salvatore Maugeri Foundation Gussago, Brescia ITALY Address for correspondence: Professor Roberto Ferrari, Chair of Cardiology, University of Ferrara, Corso Giovecca 203, 44100 Ferrara, Italy (e-mail: [email protected]) Medicographia. 2006;28:201-211. O VER THE PAST 20 TO 30 YEARS, AN OVERALL REDUCTION IN mortality rates for cardiovascular diseases has been reported in the Western World. In the USA, long-term epidemiological studies carried out between 1950 and 1982 show a decline in cardiovascular mortality, with the year 1960 as the turning point. However, this decrease concerns in fact males as, in females, cardiovascular mortality has actually slightly increased.1 In Australia, death rates for cardiovascular disease have decreased rapidly in both men and women over the same period of time.2 In Sweden, between 1986 and 1994, the prevalence of angina, the most common symptomatic manifestation of coronary artery disease (CAD), remained unchanged in man, but declined in women.3 This decline in CAD mortality is mostly attributable to changes in behavioral factors and lifestyle and the development of appropriate treatments.4-6 However, the good news about CAD mortality is offset by the fact that CAD nevertheless remains a considerable cause of mortality and, furthermore, that there is a steady increase in its prevalence with the aging of the population. This explains why identification of new risk factors in addition to the “classic” ones, to better predict and prevent CAD, and the search for further improvements in the management of CAD, remain high on the agenda. In this context, the role of increased resting heart rate as an independent risk factor for CAD mortality, and the observed benefits of specific and exclusive heart rate reduction are being increasingly recognized by the cardiological community.7 The relationship between resting heart rate and cardiovascular risk has been demonstrated in a number of large-scale epidemiological studies, including the Chicago epidemiological study,8 the Framingham Heart Study,9 and the National Health And Nutrition Examination Survey (NHANES) I Follow-up Study.10 All reported a correlation between elevated resting heart rate and both cardiovascular and all-cause mortality. A recently published long-term follow-up study provided strong confirmation that heart rate is an independent risk factor for all-cause and cardiovascular mortality, using data from nearly 25 000 patients who underwent coronary arteriography for the presence of suspected or proven coronary artery disease.11 Patients with a resting heart rate between 77 and 82 beats per minute had a significantly higher risk of all-cause mortality (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.04-1.28) than patients with heart rate ≤62 beats per minute. These epidemiological findings are corroborated by data from clinical trials. Heart rate reduction has been reported to improve survival after myocardial infarction12 and reduce mortality in patients with congestive heart failure.13 Moreover, much of the antiischemic effect of β-blockade is eliminated by suppressing its heart rate–reducing effect by means of atrial pacing,14 a finding that emphasizes the independent role of heart rate as a risk factor, and the value of therapeutic strategies aimed at reducing it. If inhibition: a therapeutic advance for patients with CAD – Ferrari and others MEDICOGRAPHIA, VOL 28, No. 3, 2006 201 ED I T O R I A L Variations in heart rate can also affect the symptoms of CAD. For example, in stable angina, chest pain, triggered by physical or emotional stress, often induces an elevation in heart rate, which, in turn, aggravates myocardial ischemia. An increase in heart rate also precedes episodes of asymptomatic or silent myocardial ischemia. Thus, heart rate is an important therapeutic target. Principles of heart rate regulation: the role of the I f current Spontaneous electrical pacemaking activity arises in many regions of the heart, including the sinoatrial node, atrioventricular node, bundle of His, and Purkinje fibers. Under normal physiological circumstances, the intrinsic rhythm is fastest in the sinoatrial node, which therefore determines the overall heart rate. At the resting potential, the cells are hyperpolarized; the pacemaker cells at the sinoatrial node then generate a slow diastolic depolarization, which drives the membrane voltage towards a threshold level, in preparation for the next action potential. These regular action potentials propagate through the heart and trigger myocardial ventricular contraction, in other words, the heart beat. Four ionic currents act in concert to produce the spontaneous diastolic depolarization, and the following are observed: (i) the outward potassium current (IK), which was activated during the previous action potential, decays ; (ii) the time-dependent inward current If is activated; (iii) the ICaL (long-lasting) calcium current is activated; and (iv) the ICaT (transient) calcium current is activated. The If current was discovered in 1979 by DiFrancesco et al.15 These authors named it the “funny” current (If) because—funnily enough—this mixed Na+/K+ current with a net inward flow is slowly activated on hyperpolarization. The If current determines the slope of the diastolic depolarization curve toward the threshold level (approximately - 40 mV in humans), which, in turn, controls the time interval between the successive action potentials and therefore plays a central pacemaking role. The f-channels responsible for the If current are hyperpolarization-activated, cyclic nucleotide–gated (HCN) ion channels. There are four distinct isoforms of the HCN channels (HCN1 to HCN4), which vary in their properties and distribution in the different tissues.16 HCN channels are expressed in the heart, the retina, and the brain. The isoform found in the heart is the HCN4 channel. HCN4 channels are found in the sinoatrial node, where they are active. They are also found in the atrioventricular node and the Purkinje fibers, where they are not active under normal physiological conditions, but can become activated under pathological conditions such as heart failure and cardiac hypertrophy. The sinoatrial node is densely innervated by the adrenergic and cholinergic branches of the autonomic nervous system, which controls the chronotropic state of the heart. Sympathetic β-adrenergic stimulation accelerates the pacemaker, while parasympathetic cholinergic vagal stimulation slows it. Pharmacological inhibition of the If current to reduce the heart rate is clearly an attractive prospect. This is a very different target compared with the mechanism of action of conventional heart rate–reducing drugs, which can cause debilitating cardiovascular and noncardiovascular side effects. For example, β-blockers reduce the heart rate, but also have negative inotropic effects and do not preserve myocardial contractility. Their use is also limited due to contraindications, such as in patients with atrioventricular block and in asthmatics. The I f inhibitor ivabradine as a tool for specific and selective heart rate reduction The fact that β-blockade, in addition to heart rate reduction, depresses contractility and unmasks β-adrenergic coronary vasoconstriction, has prompted the search for selective If inhibitors and resulted in the development of a series of compounds endowed with that effect. The first compounds developed were alinidine, a clonidine derivative, and UL-FS 49, a benzazepinone derivative. Alinidine, however, was found to have a negative inotropic action,17 while UL-SF 49 proved to be a selective bradycardic agent, but resulted in frequent adverse events. For these reasons, those two compounds were never further developed for clinical use. The only currently available selective bradycardic agent that has been approved for clinical use is ivabradine. Ivabradine has been shown to inhibit the If current in a concentration-dependent manner in various experimental settings.18 Ivabradine is selective throughout two thirds of its If inhibition curve, while other currents become marginally affected at concentrations at which If inhibition becomes saturated. Ivabradine binds specifically to the f-channels on the intracellular side of the plasma membrane of the pacemaker cells in the sinoatrial node, thereby inhibiting the If current. This explains why, when the membrane potential is maintained at - 35mv, ie, the f-channel is maintained in the closed state, no binding is detected. In contrast, at more negative potentials, 202 MEDICOGRAPHIA, VOL 28, No. 3, 2006 If inhibition: a therapeutic advance for patients with CAD – Ferrari and others ED I T O R I A L the f-channel opens, ivabradine penetrates inside and binds to an intracellular site of the channel.16 This implies that binding of ivabradine occurs when there is an active inward ion flow across the channel itself. This can be illustrated by saying that ivabradine is “kicked into” the channel by the ion fluxes until it reaches the binding site and blocks the channel. It follows that ivabradine’s potency for inhibiting the If channel depends on the driving force of ion flow across the channel pore. This is important from a therapeutic point of view as it suggests that ivabradine is more effective at faster heart rates, in other words, when heart rate reduction is more necessary.17 The direct electrophysiological consequence of this inhibition is a reduction in the slope of the diastolic depolarization curve, leading to an increase in the time interval between successive action potentials and therefore, a decrease in heart rate.19 This has been confirmed experimentally in in vitro studies in rabbit sinoatrial node cells, using the patch-clamp technique.20 A slight inhibition of L-type Ca2+ channels (18%) was also observed with 10 µmol (60 times the therapeutic dose in the same animal blood). The relative lack of effect on L-type Ca2+ current suggests the absence of negative inotropic effect with ivabradine. Furthermore, no significant effect on Na+ or K+ currents with ivabradine is reported. Thus, all electrophysiological investigations confirm that ivabradine is a specific and selective inhibitor of the If pacemaker current. Effect of ivabradine in stable angina Chronic stable angina is the most common symptom of ischemic heart disease, affecting millions of men and women worldwide. Angina is caused by the failure of sufficient oxygen to reach the heart and meet the oxygen requirements for mitochondrial oxidation. The pathophysiological substrate is almost invariably atheromatous narrowing of the coronary artery, although other factors may be involved. The anginal episode lasts typically several minutes and is commonly triggered by an increase in heart rate and blood pressure occurring during exertion, eating, and/or stress and which is subsequently relieved by rest. Angina occurs more frequently in men; its prevalence increases with age in both genders, from 2% to 5% in men aged 45 to 54 years, to 11% to 20% in those aged 65 to 74 years, and from 0.5% to 1% in women aged 45 to 54 years, to 10% to 14% in those aged 65 to 74 years. It is estimated that, in countries where the risk of ischemic heart disease is high, the total number of people with angina may reach 30 000 to 40 000 per million of the total population. Surgical and percutaneous myocardial revascularization technics have transformed the treatment of angina. However, although revascularization offers effective symptomatic relief, it does not obviate the need for medical treatment, which remains recommended as first-line strategy to control symptoms.21 Heart rate reduction is a well-recognized target of medical therapy for angina. Slowing the heart rate not only decreases oxygen demand, but also improves myocardial perfusion by prolonging diastole. Elevated heart rate has also been accused of favoring an increase in atherogenesis and endothelial dysfunction in the coronary vessels. Furthermore, high heart rate is associated with increased arterial rigidity, reduced distensibility, and elevated pulse-wave velocity, all of which play a critical role in the process of the plaque disruption. The anti-ischemic properties of the β-blockers and some calcium antagonists rely, at least in part, on heart rate reduction. β-Blockers are the most prescribed primary therapy for angina, as, in addition to symptomatic relief, they are credited with reducing mortality and reinfarction in postinfarction patients.22 However, there is no trial-based evidence that β-blockers improve prognosis in chronic stable angina without previous infarction.23 β-Blockers act predominately by decreasing myocardial oxygen demand by reducing sympathetic drive and, as a consequence, heart rate and contractility. They are, however, contraindicated in patients with symptomatic peripheral vascular disease, brittle diabetes, decompensated heart failure, reversible airways obstruction, atrioventricular conduction defects, and severe depression. The target dose is often difficult to reach because of adverse effect such as fatigue, worsening claudication, and, in males, erectile dysfunction. In this context, ivabradine, with its pure heart rate–lowering action, is of particular interest in the pharmacological treatment of angina, and angina prevention. Its clinical development program is the largest ever conducted in stable angina, involving more than 5000 patients.24 Findings from this program showed that ivabradine had a very good safety and efficacy profile.25 The most frequently noted adverse drug reactions are visual symptoms, consisting of transient enhanced brightness in limited areas of the visual field, commonly associated with abrupt changes in light intensity. These symptoms are dose-dependent, generally mild and well tolerated, causing less than 1% of patients to withdraw from treatment. They may be related to the action of ivabradine on Ih channels, which are known to be present in the retina. If inhibition: a therapeutic advance for patients with CAD – Ferrari and others MEDICOGRAPHIA, VOL 28, No. 3, 2006 203 ED I T O R I A L ◆ Efficacy of ivabradine versus β-blocker (atenolol) The efficacy of ivabradine was confirmed in a trial vs a β-blocker (atenolol).25 The INternatIonal TrIal of the AnTianginal effects of IVabradinE compared to atenolol (INITIATIVE),25 was a 4-month randomized, double-blind, controlled multicenter study of 939 patients with stable angina, testing the noninferiority of ivabradine, 7.5 and 10 mg bid, compared with atenolol, 100 mg once daily, in terms of antianginal and anti-ischemic effects. Ivabradine increased total exercise duration by ≈1.5 min at the trough of drug activity. Ivabradine also improved time to limiting angina and time to angina onset. The increase in time to 1-mm ST-segment depression indicates that the improvement in total exercise capacity is associated with a relevant anti-ischemic effect. Thus, INITIATIVE shows that ivabradine is as effective as atenolol in the treatment of stable angina. Equivalence was demonstrated for all exercise parameters. ◆ Efficacy of ivabradine vs calcium channel blocker (amlodipine) Ivabradine’s efficacy versus a calcium channel blocker was established in a noninferiority clinical trial vs amlodipine. Ivabradine at a dose of 7.5 and 10 mg bid was compared with amlodipine 10 mg once daily during 3 months of therapy in a randomized study involving 1195 patients with chronic stable angina and documented CAD. The efficacy of ivabradine 7.5 mg bid was found to be indistinguishable from that of amlodipine 10 mg once daily for all measured bicycle exercise test parameters.26 ◆ Ivabradine in combination with nitrates or dihydropyridine calcium channel blockers Abundant evidence suggests that combination therapy may be more effective than monotherapy in the treatment of angina pectoris. Thus, the efficacy and safety of combination therapy with ivabradine have been established over 1 year in 386 patients with stable angina already treated with nitrates or dihydropyridine calcium channel blockers.27 Two different dosages of ivabradine were used: 5 and 7.5 mg bid. Ivabradine maintained heart rate reduction over the 1 year of follow-up. The number of angina attacks reported by patients was significantly reduced by the addition of ivabradine. Potential effects of ivabradine in congestive heart failure Several studies have demonstrated the efficacy of β-blockade in patients with congestive heart failure (CHF) and there is growing evidence that the impact of heart rate reduction is of particular relevance in the improvement of prognosis in this population.26,28-30 Heart rate is elevated during CHF, due to increased and persistent sympathetic overdrive, as shown by elevated plasma norepinephrine levels. Increases in heart rate are correlated with reduced heart rate variability, which is related to prognosis, especially sudden death. The heart rate–induced increase in myocardial oxygen consumption and the increased sympathetic activity are cytotoxic for the myocytes, accelerate apoptosis, and significantly contribute to pathological ventricular remodeling.31 Enhanced heart rate is also associated with increased stiffness of peripheral and central arteries, thus contributing to the loading condition of the heart. Colin et al32 examined left ventricular relaxation and contraction in response to saline infusion, ivabradine, or atenolol in an animal model of exercise-induced ischemia and stunning. Ivabradine limited the exercise-induced tachycardia without simultaneously altering the exercise-induced acceleration rate of left ventricular relaxation. In contrast, for the same level of limitation in heart rate during exercise, atenolol prevented the acceleration rate of ventricular relaxation. During exercise, ivabradine improved left ventricular wall thickening and reduced subsequent myocardial stunning, compared with saline and atenolol. This effect of ivabradine disappeared upon atrial pacing, proving that it is solely due to ivabradine's heart rate–reducing properties33 and can be linked to the improvement in myocardial contractility. Ivabradine has also been shown to improve left ventricular function in congestive heart failure and to reduce remodeling subsequent to myocardial infarction.34 In post–myocardial infarction rats, heart rate reduction with ivabradine decreased left ventricular collagen density and increased left ventricular capillary density, without modifying left ventricular weight, indicating that heart rate reduction improves left ventricular function, increases stroke volume, and preserves cardiac output. This improvement in cardiac function was related not only to heart rate reduction per se, but also to the modification of the extracellular matrix.34 These observations have been confirmed in CAD patients with left ventricular dysfunction (ejection fraction <40%), with ivabradine showing promising results.35 A clinical trial assessing the efficacy of ivabradine in patients with CAD and reduced ejection fraction is currently ongoing: the BEAUTIF UL study (MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in coronary disease and left ventricULar dysfunction).36 204 MEDICOGRAPHIA, VOL 28, No. 3, 2006 If inhibition: a therapeutic advance for patients with CAD – Ferrari and others ED I T O R I A L Conclusion Cardiovascular disease is the most important cause of morbidity and mortality worldwide, with CAD making up the majority of this burden. Patients with CAD may present with sudden death, myocardial infarction, or angina pectoris. In approximately 50% of patients, the initial presentation is angina. Angina occurs when myocardial oxygen consumption exceeds myocardial oxygen supply, and heart rate is the most important component of myocardial oxygen demand. It follows that control of resting heart rate and of exercise-induced increase in heart rate is the most important means of preventing angina. For decades, β-blockade has been the most effective treatment for the control of angina by virtue of its ability to control heart rate. Many patients, however, are unable to tolerate β-blockers or remain symptomatic in spite of β-blocker treatment. The antianginal efficacy of ivabradine, a selective and specific If inhibitor with antianginal and anti-ischemic properties, has been shown to be noninferior to that of the β-blockers and calcium channel blockers. Unlike β-blockers, ivabradine is devoid of intrinsic negative inotropic effects and does not affect coronary vasomotion. Thus, a wide range of patients with angina stand to benefit from exclusive heart rate reduction with ivabradine, including newly diagnosed stable angina patients, those with contraindications or intolerance to β-blockers, as well as those who are insufficiently controlled by β-blockers and calcium channel blockers. Heart rate also plays an important role in the development and evolution of atherosclerosis as well as in post–myocardial infarction. ❒ REFERENCES 1. Elvebark LH, Connoly DC, Malion LJ 3rd. Coronary heart disease in residents of Rochester Minnesota VII Incidence, 1950 through 1982. Mayo Clin Proc. 1986;61:896-900. 2. Management of stable angina pectoris recommendations of the task force of the European Society of Cardiology. Eur Heart J. 1997;18:391-413. 3. Glader EL, Stegmayr B. Declining prevalence of angina to middle aged men and women. A population-based study within the Northern Sweden MONICA project multinational monitoring of Trends and Cardiovascular Disease. J Intern Med.1992;246:285291. 4. Capewell S, Reaglehole R, Seddum M, McMurray J. Explanation for the decline in coronary heart disease mortality rates in Auckland, New Zeland between 1982 and 1993. Circulation.2000;102: 1511-1516. 5. D’Agostino RB, Kannel WB, McLanger AJ, Sykowski PA. Trends in CHD and risk factors at age 55-64 in the Framingham study. Epidemiology. 1989;18:567-572. 6. Australian Bureau of Statistics. Year Book Australia. Cardiovascular disease: 30th century trends. http//www2003. 7. Greenlang P, Daviglus ML, Dyer AR, et al. Resting heart rate is a risk factor for cardiovascular and non cardiovascular mortality: the Chicago Heart Association Detection project in industry. Am J Epidemiol. 1939;149:853-862. 8. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol.1980;112:736749. 9. Kannel W, Kannel C, Paffenbarger R, Cupples A. 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How does adrenaline accelerate the heart? Nature. 1979;280:235-235. 16. Di Francesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine. Drugs. 2004;64: 1757-1765. 17. Ogiwara Y, Furukawa Y, Akahane K, et al. Bradycardic effects of AQ-A 39 (falipamil) in situ and in isolated, blood-perfused dog hearts. Comparison with alinidine and verapamil. Jpn Heart J. 1988;29:849-61. 18. Ferrari R, Campo GL, Gardini E, Pasanisi G, Ceconi C. Specific and selective If inhibition: expected clinical benefits from pure heart rate reduction in coronary patients. Eur Heart J Suppl. 2005;7(suppl H):h16-h2. 19. Thollon C, Bidouard JP, Cambarrat C, et al. Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)S16257. Eur J Pharmacol. 1997;339:43-51. 20. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node If channels by Ivabradine. J Gen Physiol. 2002;120:1-13. 21. European Health for All Databases. WHO Regional office for Europe, Copenhagen, Denmark. www.euro.who.int/hfadb. 22. The β-Blocker Pooling Project Research Group. The betablocker pooling project (BBPP): subgroup findings from randomized trial in post infarction patients. Eur Heart J.1988;9:8-16. 23. Steg PG, Himbert D. Unmet medical needs and therapeutic opportunities in stable angina. Eur Heart J Suppl. 2005;7(suppl H):h7-h15. 24. Borer JS. If inhibitors as specific heart rate reducing agents. Nature Clin Pract Cardiovasc. 2004;1:103-109. 25. Tardif JC, Ford I, Tendera M, et al, on behalf of the INITIATIVE study investigators. Anti-angina and anti-ischaemic effects of the If current inhibitor ivabradine compared to atenolol as monotherapy in patients with chronic stable angina. A 4-month randomised, double-blinded multicenter, controlled non-inferiority trial. Eur Heart J. 2003;24(suppl):20. 26. Ruzyllo W, Ford IF, Tendera MT, et al on behalf of the study investigators. Anti-anginal and anti-ischaemic effects of the If current inhibitor ivabradine compared to amlodipine as monotherapies in patients with chronic stable angina. Randomised, controlled, double-blind trial. Eur Heart J. 2004;25(suppl):138. 27. Lopez-Bescos L, Filipova S, Martos R, on behalf of the study investigators. Long-term safety and anti-anginal efficacy of the If inhibition: a therapeutic advance for patients with CAD – Ferrari and others MEDICOGRAPHIA, VOL 28, No. 3, 2006 205 ÉD I T O R I A L If current inhibitor ivabradine in patients with chronic stable angina. A one-year randomized, double-blind, multicentre trial. Eur Heart J. 2004;25(suppl):138. Abstract A876. 28. Lecht P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II TRIAL. Circulation. 2001;103:1428-1433. 29. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:9-13. 30. Fox K et al. Future prospects of If inhibition in various cardiac conditions. Eur Heart J. 2005;7(suppl H):h33-h36. 31. Kjekshus J, Gullestad L. Heart rate as therapeutic target in heart failure. Eur Heart J. 1999;1(suppl H):h64-h69. 32. Colin P, Ghaleh B, Monnet X, et al. Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther. 2004;308:236-240. 33. Monnet X, Colin P, Ghaleh B, Hittinger L, Giudicelli JF, Berdeaux A. Heart rate reduction during exercise-induced myocardial ischemia and stunning. Eur Heart J. 2004;25:579-586. 34. Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate reduction induced by the selective If current inhibitor Ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation. 2004;109:16741679. 35. Jondeau G, Korewicki J, Vasiliauskas D. Effect of Ivabradine in patients with left ventricular systolic dysfunction and coronary artery disease. Eur Heart J Suppl. 2004;(suppl):25. Abstract 2687. 36. Fox K, Ferrari R, Steg PG, Forde I, on behalf of the BEAUTIFUL Steering Committee. Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular dysfunction: the BEAUTIFUL Study. Am Heart J. 2006. Submitted. Keywords: heart rate; coronary artery disease; morbidity; mortality; f-channel; If current; treatment; ivabradine Inhibition If : une avancée thérapeutique pour les patients ayant une maladie coronaire par R. Ferrari, G. Campo, C. Arcozzi, L. Pellegrino, G. Pasanisi et C. Ceconi, Italie A U COURS DES 20 À 30 DERNIÈRES ANNÉES, IL A ÉTÉ CONSTATÉ une diminution globale du taux de mortalité pour les maladies cardio-vasculaires, dans le monde occidental. Aux USA, des études épidémiologiques à long terme menées entre 1950 et 1982 montrent un déclin de la mortalité cardio-vasculaire, l’année 1960 marquant un tournant. Toutefois, cette diminution concerne en fait les hommes car, chez les femmes, la mortalité cardio-vasculaire a au contraire, légèrement augmenté 1. En Australie, les taux de mortalité cardio-vasculaire ont rapidement diminué chez les hommes comme chez les femmes pendant la même période 2. En Suède, entre 1986 et 1994, la prévalence de l’angor, manifestation symptomatique la plus courante de la maladie coronaire (MC), est restée stable chez l’homme, mais a diminué chez la femme 3. Cette diminution de mortalité coronaire est due principalement aux changements de comportement et de style de vie ainsi qu’au développement de traitements adéquats 4-6. Cependant, cette bonne nouvelle au sujet de la mortalité coronaire est contrebalancée par le fait que la MC reste néanmoins une cause considérable de mortalité et, de plus, que sa prévalence augmente régulièrement avec le vieillissement de la population. Ceci explique pourquoi l’identification des nouveaux facteurs de risque, en plus des facteurs « classiques », pour mieux prévoir et prévenir la MC, ainsi que la recherche pour les améliorations futures de la prise en charge de la maladie, demeurent une priorité. Dans ce contexte, le rôle d’une fréquence cardiaque de repos élevée comme facteur de risque indépendant de mortalité coronaire, et les bénéfices d’une réduction exclusive et spécifique de la fréquence cardiaque, sont de plus en plus reconnus par les cardiologues 7. 206 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Inhibition If : une avancée thérapeutique pour les patients ayant une maladie coronaire – Ferrari et al ÉD I T O R I A L Des études épidémiologiques de grande envergure, telles que l’étude épidémiologique de Chicago8, la Framingham Heart Study 9, et l’étude de suivi NHANES I 10 (National Health And Nutrition Examination Survey) ont démontré les liens entre la fréquence cardiaque de repos et le risque cardio-vasculaire. Toutes ont rapporté une corrélation entre une fréquence cardiaque de repos élevée et une mortalité cardio-vasculaire et globale élevée. Une étude de suivi à long terme publiée récemment a confirmé que la fréquence cardiaque est un facteur de risque indépendant pour la mortalité de toutes causes et cardio-vasculaire, grâce à des données issues d’environ 25000 patients qui ont subi une coronarographie à cause d’une MC suspectée ou prouvée 11. Les patients qui avaient une fréquence cardiaque de repos entre 77 et 82 battements par minute avaient un risque de mortalité globale significativement plus élevé (coefficient de probabilité [CP], 1,16 ; indice de confiance [IC] à 95%, 1,04-1,28) que les patients dont la fréquence cardiaque était ≤62 battements par minute. Ces résultats épidémiologiques sont confirmés par les données des études cliniques. La diminution de la fréquence cardiaque a amélioré la survie après infarctus du myocarde 12 et a réduit la mortalité des patients atteints d’insuffisance cardiaque congestive 13. De plus, une grande partie de l’effet anti-ischémique des -bloquants est éliminée quand leur effet de réduction de la fréquence cardiaque est supprimé par entraînement auriculaire 14, résultat qui souligne le rôle indépendant de la fréquence cardiaque comme facteur de risque et la valeur des stratégies thérapeutiques qui ont pour but de la réduire. Les variations de la fréquence cardiaque peuvent aussi affecter les symptômes de la MC. Par exemple, dans l’angor stable, les douleurs thoraciques, provoquées par un stress physique ou émotionnel, induisent souvent une élévation de la fréquence cardiaque, qui, à son tour, aggrave l’ischémie myocardique. Une augmentation de la fréquence cardiaque précède aussi les épisodes d’ischémie myocardique asymptomatique ou silencieuse. La fréquence cardiaque est donc une cible thérapeutique importante. Principes de régulation de la fréquence cardiaque : rôle du courant If De nombreuses régions du cœur, telles que le nœud sinusal de Keith et Flack, le nœud auriculo-ventriculaire, le faisceau de His et les fibres de Purkinje, sont source d’une activité de stimulation cardiaque électrique spontanée. Dans les conditions physiologiques normales, le rythme intrinsèque est plus rapide dans le nœud sinusal, qui détermine ainsi la fréquence cardiaque globale. Au potentiel de repos, les cellules sont hyperpolarisées ; les cellules « pacemaker » du nœud sinusal génèrent ensuite une dépolarisation diastolique lente, qui amène le voltage membranaire à un niveau seuil, prêt pour le potentiel d’action suivant. Ces potentiels d’action réguliers se propagent à travers le cœur et déclenchent la contraction ventriculaire myocardique, autrement dit, les battements cardiaques. Quatre courants ioniques agissent de concert pour produire une dépolarisation diastolique spontanée, comme suit : 1) le courant potassique sortant (I K ), activé pendant le potentiel d’action antérieur, décline ; 2) le courant If entrant dépendant du temps est activé ; 3) le courant calcium I CaL (long) est activé ; et 4) le courant calcium I CaT (transitoire) est activé. Le courant If a été découvert en 1979 par DiFrancesco et al 15. Ces auteurs l’ont appelé courant « funny » (drôle) d’où I f , parce que – curieusement – ce courant mixte Na+/K+ avec un courant net entrant est lentement activé lors de l’hyperpolarisation. Le courant If détermine la pente de la courbe de dépolarisation diastolique vers le niveau seuil (approximativement - 40 mV chez les humains) qui, à son tour, contrôle l’intervalle de temps entre les potentiels d’action successifs et ainsi joue un rôle central de stimulation cardiaque. Les canaux f responsables du courant If sont des canaux ioniques contrôlés par le nucléotide cyclique (HCN) et activé par hyperpolarisation. Il y a quatre isoformes distinctes des canaux HCN (HCN1 à HCN4), dont la propriété et la distribution varient suivant les différents tissus 16. Les canaux HCN s’expriment dans le cœur, la rétine et le cerveau. L’isoforme retrouvée dans le cœur est le canal HCN4. Les canaux HCN4 sont retrouvés dans le nœud sinusal, où ils sont actifs. Ils sont aussi retrouvés dans le nœud auriculo-ventriculaire et les fibres de Purkinje, où ils ne sont pas actifs dans les conditions physiologiques normales, mais peuvent s’activer au cours d’états pathologiques tels que l’insuffisance cardiaque et l’hypertrophie cardiaque. Le nœud sinusal est abondamment innervé par les branches adrénergiques et cholinergiques du système nerveux autonome, qui contrôle l’état chronotrope du cœur. Une stimulation sympathique -adrénergique accélère le « pacemaker », alors qu’une stimulation vagale cholinergique parasympathique le ralentit. La perspective d’une inhibition pharmacologique du courant If pour réduire la fréquence cardiaque représente est réellement attrayante. C’est un objectif très différent par rapport au Inhibition If : une avancée thérapeutique pour les patients ayant une maladie coronaire – Ferrari et al MEDICOGRAPHIA, VOL 28, No. 3, 2006 207 ÉD I T O R I A L mécanisme d’action des médicaments classiques bradycardisants, qui peuvent provoquer des effets secondaires néfastes tant cardio-vasculaires que non cardio-vasculaires. Ainsi, les -bloquants réduisent la fréquence cardiaque, mais ils ont aussi des effets inotropes négatifs et ne préservent pas la contractilité myocardique. Leur utilisation est aussi limitée à cause de leurs contre-indications, par exemple chez les patients qui ont un bloc auriculo-ventriculaire et chez les asthmatiques. Ivabradine : réduction spécifique et sélective de la fréquence cardiaque par inhibition du courant If Le fait que les -bloquants, outre la réduction de la fréquence cardiaque, diminuent la contractilité et démasquent la vasoconstriction coronaire -adrénergique, a suscité la recherche d’inhibiteurs If sélectifs, ce qui a conduit au développement d’une série de composés dotés de cet effet. Les premiers produits développés ont été l’alinidine, un dérivé de la clonidine, et l’UL-FS 49, un dérivé de la benzazépinone, doué d’une action bradycardisante sélective. Cependant, ces deux produits n’ont jamais pu être utilisés en clinique, en raison, pour l’alinidine, d’une action inotrope négative 17, et pour l’UL-SF 49, de nombreux effets secondaires. Ainsi, le seul agent bradycardisant sélectif actuellement disponible accepté en usage clinique est l’ivabradine. L’ivabradine inhibe le courant If de façon concentration-dépendante dans des circonstances expérimentales variées 18. Elle est sélective pour les deux tiers de sa courbe d’inhibition If , tandis que d’autres courants sont partiellement modifiés aux concentrations auxquelles l’inhibition If devient saturée. L’ivabradine se fixe de façon spécifique aux canaux f sur le côté intracellulaire de la membrane plasmatique des cellules « pacemakers » du nœud sinusal, inhibant ainsi le courant If . Ceci explique pourquoi, quand le potentiel de membrane est maintenu à - 35 mV, soit, quand le canal f est maintenu fermé, aucune liaison n’est détectée. Au contraire, à des potentiels plus négatifs, le canal f s’ouvre, l’ivabradine y pénètre et se lie à un site intracellulaire du canal 16. Ceci implique que la liaison de l’ivabradine intervient lorsqu’il y a un flux ionique actif entrant au travers du canal lui-même. Ceci peut être illustré en disant que l’ivabradine est « projetée vers » le canal par le flux ionique jusqu’à ce qu’il atteigne le site de liaison et bloque le canal. Il s’ensuit que la puissance de l’ivabradine pour inhiber le canal If dépend de la force d’entraînement du flux ionique à travers le pore du canal. Ceci est important au point de vue thérapeutique car cela suggère que l’ivabradine est plus efficace aux fréquences cardiaques les plus rapides, en d’autres termes, quand la réduction de la fréquence cardiaque est la plus nécessaire 17. La conséquence électrophysiologique directe de cette inhibition est une réduction de la pente de la courbe de dépolarisation diastolique, conduisant à une augmentation de l’intervalle de temps entre les potentiels d’action successifs, et donc à une diminution de la fréquence cardiaque 19. Ceci a été confirmé de façon expérimentale dans des études in vitro sur des cellules de nœud sinusal de lapin, en utilisant la technique du patch-clamp 20. On a aussi observé une légère inhibition des canaux Ca 2+ de type L (18 %) avec 10 µmol (60 fois la dose thérapeutique dans le sang du même animal). Le manque relatif d’effet sur le courant Ca 2+ de type L suggère l’absence d’effet inotrope négatif avec l’ivabradine. De plus, on n’a rapporté aucun effet significatif sur les courants Na+ et K+ avec l’ivabradine. Toutes les investigations électrophysiologiques confirment donc que l’ivabradine est un inhibiteur sélectif et spécifique du courant « pacemaker » If . Effet de l’ivabradine sur l’angor stable L’angor stable chronique est le symptôme le plus courant de la cardiopathie ischémique, affectant des millions d’hommes et de femmes dans le monde entier. L’angor est dû à l’insuffisance d’oxygène pour atteindre le cœur et pour répondre aux demandes en oxygène nécessaire à l’oxydation mitochondriale. Le substrat physiopathologique est presque invariablement un rétrécissement athéromateux de l’artère coronaire, bien que d’autres facteurs puissent être impliqués. L’épisode angoreux dure habituellement plusieurs minutes, il est généralement déclenché par une augmentation de la fréquence cardiaque et de la pression artérielle au cours d’un exercice, d’un repas, et/ou d’un stress et ultérieurement soulagé par le repos. L’angor est plus fréquent chez l’homme ; sa prévalence augmente avec l’âge dans les deux sexes. Chez l’homme, elle passe de 2 % à 5 % entre 45 à 54 ans à 11 % à 20 % entre 65 à 74 ans, et chez la femme de 0,5 % à 1 % entre 45 à 54 ans, à 10 % à 14 % entre 65 à 74 ans. Dans les pays où le risque de cardiopathie ischémique est élevé, on estime que le nombre total de personnes présentant un l’angor pourrait atteindre 30 000 à 40 000 par million de la population totale. Les techniques de revascularisation myocardique percutanées et chirurgicales ont transformé le traitement de l’an208 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Inhibition If : une avancée thérapeutique pour les patients ayant une maladie coronaire – Ferrari et al ÉD I T O R I A L gor. Cependant, bien que la revascularisation offre un soulagement symptomatique efficace, elle n’évite pas la nécessité d’un traitement médical, qui reste recommandé comme stratégie de première ligne pour contrôler les symptômes 21. La réduction de la fréquence cardiaque est une cible bien connue du traitement médical de l’angor. Ralentir la fréquence cardiaque non seulement diminue la demande en oxygène, mais améliore aussi la perfusion myocardique en prolongeant la diastole. Une fréquence cardiaque élevée a aussi été accusée de favoriser une augmentation de l’athérogenèse et de la dysfonction endothéliale dans les coronaires. De plus, une fréquence cardiaque élevée est associée à une augmentation de la rigidité artérielle, une diminution de la distensibilité et une élévation de la vélocité de l’onde de pouls, tous paramètres jouant un rôle critique dans le processus de rupture de la plaque. Les propriétés anti-ischémiques des -bloquants et de certains antagonistes calciques reposent, au moins en partie, sur la réduction de la fréquence cardiaque. Les -bloquants sont les médicaments les plus prescrits pour l’angor, car, outre le soulagement des symptômes, ils sont supposés réduire la mortalité et la récidive d’infarctus chez les patients en post-infarctus 22. Cependant, il n’y a aucune preuve basée sur des études, de l’amélioration, par les -bloquants, du pronostic de l’angor chronique stable sans infarctus antérieur 23. Les -bloquants agissent essentiellement en diminuant la demande en oxygène myocardique par réduction du tonus sympathique, et donc de la fréquence cardiaque et de la contractilité. Ils sont cependant contre-indiqués chez les patients qui ont une maladie vasculaire périphérique symptomatique, un diabète instable, une insuffisance cardiaque décompensée, une obstruction réversible des voies aériennes, des troubles de conduction auriculo-ventriculaire, et une dépression sévère. La dose cible est souvent difficile à atteindre à cause des effets indésirables tels que la fatigue, une aggravation d’une claudication et, chez les hommes, une dysfonction érectile. Dans ce contexte, l’action de diminution de la fréquence cardiaque pure de l’ivabradine est d’un intérêt particulier dans le traitement pharmacologique et la prévention de l’angor. Son programme de développement clinique est le plus important jamais conduit dans l’angor stable, comprenant plus de 5 000 patients 24. Les résultats de cette étude ont montré que l’ivabradine avait un excellent profil d’innocuité et d’efficacité 25. Les effets indésirables les plus fréquents de ce médicament sont les symptômes visuels, consistant en éclairs lumineux fugaces dans certaines aires limitées du champ visuel, associés fréquemment à des changements brutaux d’intensité lumineuse. Ces symptômes sont dose-dépendants, généralement légers et bien tolérés, entraînant, chez les patients, un nombre d’abandons du traitement inférieur à 1 %. Ils seraient liés à l’action de l’ivabradine sur les canaux h présents dans la rétine. ◆ Efficacité de l’ivabradine versus -bloquant (aténolol) L’efficacité de l’ivabradine a été confirmée dans une étude versus -bloquant (aténolol), l’étude INITIATIVE 25 (INternatIonal TrIal of the AnTianginal effects of IVabradinE) comparé à l’aténolol, une étude multicentrique contrôlée, en double aveugle, randomisée de 4 mois et comprenant 939 patients ayant un angor stable, pour vérifier la non-infériorité de l’ivabradine à 7,5 et 10 mg deux fois par jour, par rapport à l’aténolol, 100 mg une fois par jour, en termes d’effets antiangoreux et anti-ischémiques. L’ivabradine a augmenté la durée totale de l’exercice d’environ 1,5 min à la phase de concentration sérique minimale du médicament. Elle a aussi amélioré le temps de l’angor limitant et le délai d’apparition de l’angor. L’augmentation du délai d’apparition du sous-décalage du segment ST de 1 mm indique que l’amélioration de la capacité totale à l’effort est associée à un effet anti-ischémique efficace. L’étude INITIATIVE a donc montré que l’ivabradine est aussi efficace que l’aténolol dans le traitement de l’angor stable. Il en a été de même pour tous les paramètres à l’effort. ◆ Efficacité de l’ivabradine versus inhibiteurs calciques (amlodipine) L’efficacité de l’ivabradine versus un inhibiteur calcique a été établie dans une étude clinique de non-infériorité vs amlodipine. L’ivabradine à la dose de 7,5 et 10 mg deux fois par jour a été comparée à l’amlodipine 10 mg une fois par jour pendant 3 mois dans une étude randomisée comprenant 1 195 patients ayant un angor stable chronique et une maladie coronaire documentée. L’efficacité de l’ivabradine 7,5 mg deux fois par jour a été identique à celle de l’amlodipine 10 mg une fois par jour pour tous les paramètres mesurés des tests d’effort sur bicyclette 26. ◆ L’ivabradine en association aux dérivés nitrés ou aux inhibiteurs calciques dihydropyridiniques Les arguments abondent en faveur d’une plus grande efficacité des associations thérapeutiques par rapport à la monothérapie dans le traitement de l’angor. L’efficacité et l’innocuité d’une association ont donc été établies avec l’ivabradine pendant 1 an chez 386 patients ayant un angor Inhibition If : une avancée thérapeutique pour les patients ayant une maladie coronaire – Ferrari et al MEDICOGRAPHIA, VOL 28, No. 3, 2006 209 ÉD I T O R I A L stable déjà traité avec des dérivés nitrés ou des inhibiteurs calciques dihydropyridiniques 27. Nous avons utilisé deux dosages différents d’ivabradine : 5 et 7,5 mg deux fois par jour. L’ivabradine a permis une réduction de la fréquence cardiaque pendant 1 an de suivi. L’addition d’ivabradine a permis de réduire le nombre de crises d’angor rapporté par les patients. Effets potentiels de l’ivabradine dans l’insuffisance cardiaque congestive Plusieurs études ont démontré l’efficacité des -bloquants chez les patients ayant une insuffisance cardiaque congestive (ICC) et il apparaît de plus en plus que la réduction de la fréquence cardiaque participe à l’amélioration du pronostic dans cette population 26,28-30. L’élévation de la fréquence cardiaque au cours de l’ICC, comme l’ont montré les concentrations élevées de noradrénaline plasmatique, est due à une hypertonie sympathique majorée et persistante. L’accélération de la fréquence cardiaque est corrélée à une réduction de la variabilité de la fréquence cardiaque qui est liée au pronostic, en particulier la mort subite. L’augmentation de la consommation en oxygène myocardique induite par la fréquence cardiaque ainsi que l’augmentation de l’activité sympathique sont cytotoxiques pour les myocytes, accélèrent l’apoptose, et contribuent de façon significative à un remodelage ventriculaire pathologique 31. Une fréquence cardiaque plus importante s’associe aussi à une augmentation de la rigidité des artères centrales et périphériques, contribuant ainsi à l’état de surcharge du cœur. Colin et al.32 ont examiné la contraction et le relâchement ventriculaires gauches en réponse à une solution saline, à l’ivabradine ou à l’aténolol dans un modèle animal d’ischémie et de sidération induites par un effort. L’ivabradine a limité la tachycardie induite par l’effort sans altérer simultanément l’accélération de la relaxation ventriculaire gauche induite par cet effort. À l’opposé, pour un niveau identique de limitation de la fréquence cardiaque à l’effort, l’aténolol a empêché l’accélération de la relaxation ventriculaire. Pendant l’effort, l’ivabradine a diminué l’épaississement de la paroi ventriculaire gauche et réduit la sidération myocardique qui s’ensuit, par rapport à une solution saline et à l’aténolol. Cet effet de l’ivabradine a disparu à l’entraînement électrosystolique auriculaire, prouvant qu’il est uniquement dû aux propriétés bradycardisantes de l’ivabradine 33 et peut être lié à l’amélioration de la contractilité myocardique. Il a également été montré que l’ivabradine améliorait la fonction ventriculaire gauche dans l’insuffisance cardiaque congestive et réduisait le remodelage consécutif à l’infarctus du myocarde 34. Chez des rats en postinfarctus, la réduction de la fréquence cardiaque due à l’ivabradine a diminué la densité du collagène du ventricule gauche et augmenté la densité capillaire du ventricule gauche, sans modifier son poids, indiquant que le ralentissement de la fréquence cardiaque améliore la fonction ventriculaire gauche, augmente le débit systolique et préserve le débit cardiaque. Cette amélioration de la fonction cardiaque a été due non seulement à la réduction de la fréquence cardiaque en elle-même, mais aussi à la modification de la matrice extracellulaire 34. Ces observations ont été confirmées chez les patients atteints de MC avec dysfonction ventriculaire gauche (fraction d’éjection <40 %), l’ivabradine faisant preuve de résultats prometteurs 35. Une étude clinique évaluant l’efficacité de l’ivabradine chez les patients atteints de MC et ayant une fraction d’éjection réduite est actuellement en cours : l’étude BEAUTIF UL (MorBiditymortality EvAlUaTion of the If inhibitor ivabradine in coronary disease and left ventricULar dysfunction36). Conclusion La maladie cardio-vasculaire est la cause la plus importante de morbidité et de mortalité dans le monde entier, la MC représentant l’essentiel de ce fardeau. Les patients ayant une MC peuvent avoir une mort subite, un infarctus du myocarde ou un angor. L’angor est la première manifestation chez environ 50 % des patients. Il survient quand la consommation en oxygène myocardique dépasse l’apport en oxygène, la fréquence cardiaque étant le paramètre le plus important de la demande en oxygène du myocarde. Le contrôle de la fréquence cardiaque au repos et de l’accélération de la fréquence cardiaque induite par l’effort est donc le meilleur moyen de prévenir l’angor. Depuis une dizaine d’années, le traitement par -bloquants est le plus efficace pour contrôler l’angor grâce à sa capacité à contrôler la fréquence cardiaque. Cependant, de nombreux patients ne supportent pas les -bloquants ou restent symptomatiques malgré le traitement par -bloquants. L’efficacité antiangoreuse de l’ivabradine, inhibiteur If sélectif et spécifique aux propriétés antiangoreuses et anti-ischémiques, s’est montrée équivalente à celle des -bloquants et des in210 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Inhibition If : une avancée thérapeutique pour les patients ayant une maladie coronaire – Ferrari et al ÉD I T O R I A L hibiteurs calciques. Contrairement aux -bloquants, l’ivabradine est dénuée d’effets inotropes négatifs intrinsèques et ne touche pas le calibre des vaisseaux coronaires. Une grande partie des patients angoreux devrait pouvoir bénéficier de la réduction exclusive de la fréquence cardiaque par l’ivabradine, y compris les patients ayant un angor stable récemment diagnostiqué, ceux qui ont des contre-indications ou une intolérance aux -bloquants, ainsi que ceux qui sont insuffisamment contrôlés par les -bloquants et les antagonistes calciques. Le rôle joué par la fréquence cardiaque dans le développement et l’évolution de l’athérosclérose et dans le post-infarctus est également important. ❒ ✦ Inhibition If : une avancée thérapeutique pour les patients ayant une maladie coronaire – Ferrari et al MEDICOGRAPHIA, VOL 28, No. 3, 2006 211 IF I N H I B I T I O N , H E A R T R A T E , AND CORONARY ARTERY DISEASE Luigi TAVAZZI, MD, PhD IRCCS Policlinico San Matteo Division of Cardiology Pavia, ITALY Current treatment of stable angina in Europe: main conclusions from the Euro Heart Survey b y L . Ta v a z z i , I t a l y T o obtain accurate and up-to-date information concerning the presentation and clinical course of stable angina, and to evaluate how the condition is managed with particular reference to the implementation of guidelines and regional or international variations in practice, the Euro Heart Survey (EHS) Program conducted a European Survey of Stable Angina. A total of 3779 patients were enrolled in 197 centers of 35 European or Mediterranean countries: 39% had Canadian Cardiac Society class I, 49% class II, and 12% class III symptoms. Eighty-one percent of patients were taking or were recommended an antiplatelet agent, and 78% aspirin. A statin was prescribed in 48%, -blockers in 67%, and a nitrate in 61% patients. Only 27% were taking a calcium channel blocker. The majority of patients (59%) were on two or more antianginal drugs after assessment by a cardiologist, and only 13% were on no antianginal drug, 41% of patients had a coronary angiogram either performed or planned as a result of the initial assessment. Of patients with results of angiography recorded within 4 weeks of presentation, revascularization was the chosen treatment strategy for 52% of patients with significant disease, ie, >50% coronary stenosis. As for the nonprescriptions arising from contraindications, those regarding aspirin, statins, and -blockers totaled only 5%, 8%, and 10%, respectively, of the overall population. In conclusion, the Euro Heart Survey on Stable Angina is the largest contemporary study of treatment of this condition in clinical practice and shows a significant discrepancy between guidelines and practice with regard to the use of evidence-based drug and interventional therapy. Medicographia. 2006;28:212-217. (see French abstract on page 217) Keywords: epidemiology; observational research; ischemic heart disease; stable angina; treatment; angiography; guidelines; interventional therapy Address for correspondence: Prof Luigi Tavazzi, Policlinico San Matteo, Divisione di Cardiologia, IRCCS Policlinico San Matteo, P.le Golgi 2, 27100 Pavia, Italy (e-mail: [email protected]) 212 MEDICOGRAPHIA, VOL 28, No. 3, 2006 table angina is the most prevalent manifestation of coronary artery disease, occurring as an initial presentation in almost half of such patients.1,2 Despite its prevalence, in contrast to the abundance of national and international surveys of the management of acute coronary syndromes, data regarding the management of chronic stable angina are sparse and few studies document the complete sequence of investigation and treatment for this condition. Accordingly, to obtain accurate and up-to-date information concerning the presentation and clinical course of stable angina, and to evaluate how the condition is managed with particular reference to the implementation of guidelines and regional or international variations in practice, the Euro Heart Survey (EHS) Program has conducted a European Survey of Stable Angina.3,4 S Population of the Euro-Heart Survey To ensure that the population studied was representative of the stable angina population, investigators were asked to enroll consecutive newly presenting patients over a 4-to-6 week time period or until a minimum target number was enrolled. A new presentation was defined as a first-ever presentation, or new referral or re-referral, after a period of at least 1 year of not attending or consulting a cardiologist. Patients were suitable for inclusion if the cardiologist made a diagnosis, on the basis of clinical assessment, of stable angina, caused by myocardial ischemia due to coronary disease. Patients were not obliged to have documented evidence of ischemia to be included, but they did have to have stable anginal symptoms that were due to coronary disease in the opinion of the physician investigator. Patients with remote (>1 year) prior myocardial infarction were also included. Current treatment of stable angina in Europe: the Euro-Heart Survey – Tavazzi IF I N H I B I T I O N Patients were enrolled in 197 centers of 35 European or Mediterranean countries. Of the participating centers, 35% had noninvasive diagnostic facilities, 20% had noninvasive and invasive facilities, and 34% had, in addition to a catheterization laboratory, cardiac surgery facilities on-site. The majority of patients included (71%) had been referred by a primary care physician, and only 5% were referred from an emergency department for follow-up. Self-referrals accounted for 10% of the population. Details of the numbers and basic demographics of the 3779 patients enrolled are presented in Table I.3 The prevalence of diabetes and hypertension increased with increasing age with the prevalence of diabetes in the >70 year age-group (22%) and was double that in the <50 year age-group (11%), and the prevalence of hypertension rose from 45% in those <50 years of age to 71% in those >70 years of age. Overall, the prevalence of comorbidity was low. Angina class was assigned for 3472 patients, 39% had Canadian Cardiac Society class I, 49% class II, and 12% class III symptoms. The majority, 75% of patients, had symptoms for 1 year before assessment by a cardiologist. The median duration of symptoms prior to presentation to a cardiologist was 5 months and did not vary according to symptom severity. Severe heart failure symptoms (New York Heart Association [NYHA] class III or IV) were rare, occurring in 5% and 0.6% of patients, respectively. The population was overweight: three quarters had a body mass index of 25 or more, and the mean body mass index was 28±5. Mean systolic and diastolic blood pressures were 144±21 and 85±11 mm Hg, respectively. The resting ECG was abnormal in 41% of patients. An exercise ECG was performed or planned as part of initial investigation in 76% of patients, and 18% had a stress imaging test (perfusion scanning or stress echo). A coronary angiogram was performed or planned in 41%, and 64% had an echocardiogram. Medical treatment and revascularization Almost half (49%) of patients were taking aspirin before assessment by a cardiologist. Only 22% of patients were on a statin prior to assessment by the cardiologist, and even among patients with recognized hyperlipidemia only 46% were on a statin (41%) or on an alternative lipid-lowering agent.5 Patients were taking at least one antianginal drug at presentation to the cardiologist in 62% of cases and two or more in 28%. Table II 4 (next page) shows the frequency of use of secondary prevention and antianginal drugs in patients enrolled after assessment by a cardiologist. Eighty-one percent of patients were taking or were recommended an antiplatelet agent, which was aspirin in 78% of cases. A statin was prescribed in 48% of patients, β-blockers in 67%, and a nitrate in 61%. Only 27% were taking a calcium channel blocker. The majority of patients (59%) were on two or more antianginal drugs after assessment by a cardiologist, and only 13% were on no antianginal drug. The number of antianginal drugs per patient did not differ significantly between male and females, but , H E A R T RAT E , A N D Mean age y (SD) Male n (%) Diabetic n (%) Hypertensive n (%) Hyperlipidemia n (%) Current smoker n (%) Family history n (%) Peripheral vascular disease n (%) CVA or TIA n (%) Chronic respiratory disease n (%) Chronic hepatic disease n (%) Chronic renal failure n (%) Malignancy n (%) CO R O N A RY 61 2197 652 2267 1843 819 1347 267 197 313 72 54 61 AR T E RY DI S E A S E (11) (58) (18) (62) (58) (23) (43) (7) (5) (8) (2) (1) (2) Table I. Cardiovascular risk factors and comorbidities of 3779 patients enrolled in the Euro Heart Survey on stable angina. CVA, cerebrovascular accident; TIA, transient ischemic accident. Reproduced from reference 3: Daly C, Clemens F, Lopez-Sendon J, et al. The clinical characteristics and investigations planned in patients with stable angina presenting to cardiologists in Europe: from the Euro Heart Survey of Stable Angina. Eur Heart J. 2005; 26:996-1010. Copyright © 2005, Oxford University Press. did increase significantly with age up to 70 years, not beyond ( P≤ 0.002 for each decade increase in age up to 70 years). Angiotensin-converting enzyme (ACE) inhibitors were prescribed in 40% of patients overall. However, the rate of prescription was much higher, 73%, in patients with clinical signs of heart failure. In diabetic patients, ACE inhibitors were also prescribed more frequently, with 56% of patients with diabetes being recommended ACE-inhibitor therapy. SELECTED ABBREVIATIONS AND ACRONYMS 4S ACTION Scandinavian Simvastatin Survival Study A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system ASCOT Anglo-Scandinavian Cardiac Outcomes Trial CABG coronary artery bypass grafting CARE Cholesterol And Current Events EHS Euro Heart Survey EUROASPIRE II Second EUROpean Action on Secondary Prevention by Intervention to Reduce Events EUROPA EUropean trial on ReductiOn of cardiac events with Perindopril in stable coronary Artery disease GISSI-3 Gruppo Italiano per lo Studio della Soppravvivenza nell’Infarto miocardico-III HOPE Heart Outcomes Prevention Evaluation HPS Heart Protection Study Survival MDPIT Multicenter Diltiazem Post-Infarction Trial MI myocardial infarction MSMI Multicenter Study of Myocardial Ischemia NCEP-ATP II National Cholesterol Education Program–Adult Treatment Panel II PCI percutaneous coronary intervention PEACE Prevention of Events with Angiotensin-Converting Enzyme inhibition QUIET QUinapril Ischemic Event Trial TNT Treating to New Targets Current treatment of stable angina in Europe: the Euro-Heart Survey – Tavazzi MEDICOGRAPHIA, VOL 28, No. 3, 2006 213 IF I N H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY European macroregions Northern Central Western Mediterranean Aspirin Alternative antiplatelet Statin Alternative lipid lowering β-Blocker Nitrate Calcium antagonist ACE inhibitor Angiotensin receptor antagonist Oral anticoagulant Overall 85% 3% 61% 2% 68% 67% 29% 21% 5% 89% 10% 55% 6% 77% 77% 29% 61% 2% 52% 7% 30% 3% 52% 35% 18% 23% 8% 85% 13% 51% 4% 66% 61% 33% 40% 10% 78% 9% 48% 4% 67% 61% 27% 40% 6% 1% 2% 5% 2% 3% Table II. Frequency of use of secondary prevention and antianginal drugs. Reproduced from reference 4: Daly C, Clemens F, Lopez-Sendon J, et al. The initial management of stable angina in Europe, from the Euro Heart Survey. Eur Heart J. 2005;26:1011-1022. Copyright © 2005, Oxford University Press. The reasons for not prescribing secondary prevention treatments of known prognostic benefit, in particular aspirin, statins, and β-blockers, were explored by asking investigators why the drug was not recommended. In the 834 patients not recommended aspirin, specific patient contraindications accounted for only 22% of the reasons given for nonprescription. A further 45% were not prescribed aspirin because, in the opinion of the investigator, it was not indicated, and 23% had a decision regarding prescription of aspirin deferred until the results of further investigation were available. Of the 33% of patients who were not taking a β-blocker after assessment by a cardiologist, 24% had a specific contraindication to β-blockade, while in 46% of cases the investigator did not feel that β-blockade was indicated. Just one third of the population not already taking a statin was prescribed lipid-lowering therapy. Specific patient contraindications accounted for only 19% of reasons given for not prescribing a statin. In 51% of cases, statin therapy was not prescribed because in the opinion of the investigator it was not indicated, and a further 24% had a decision regarding prescription of statin deferred until the results of further investigation were available. In patients with a history of hyperlipidemia, the use of statin therapy was considerably higher, 70% to 85%, across all regions. Conservative management (medical therapy only) with all investigations completed was planned in 452 patients (12%). In all, 78% of these patients had an exercise test, 8% a stress echo, and 3% a perfusion scan. An angiogram was performed in 281 (62%). Only 161 patients, 4% of the population overall, had percutaneous coronary intervention (PCI) performed within 4 weeks of presentation, and 68 (2%) had coronary artery bypass grafting (CABG), although PCI was planned for an additional 156 (4%) of the population and CABG for a further 151 (4%). A small number of patients, 34 in total, had both procedures performed or planned within 4 weeks. In all, 501 patients had a revascularization procedure either performed or planned within 4 weeks of initial presentation. The propor214 MEDICOGRAPHIA, VOL 28, No. 3, 2006 DI S E A S E tion of men (16.9%) in the survey who had revascularization either performed within 4 weeks or planned was twice that of women. In the survey population as a whole, 1564, or 41% of patients, had a coronary angiogram either performed or planned as a result of the initial assessment, and the results of angiography were available for 799 patients overall. Of patients with results of angiography recorded within 4 weeks of presentation, revascularization was the chosen treatment strategy for 52% of patients with significant disease, ie, >50% coronary stenosis (Table III).4 Discussion Overall, the use of evidence-based medical therapy, particularly secondary prevention strategies, is far less than ideal in European patients with chronic ischemic heart disease. The treatment of stable angina has two major purposes. The first is to prevent the progression of coronary atherosclerosis and its clinical consequences—death and myocardial infarction (MI). The second is to reduce the symptoms of angina and the occurrence of ischemia. Accordingly, there are two major categories of treatment: those aimed at preventing MI and death, and those aimed at preventing angina and reducing the ischemic burden. The two categories partially overlap. The first group of drugs includes antiatherothrombotic agents, comprising antiplatelet drugs, lipid-lowering agents, and ACE inhibitors. The agents expected to be the most effective for relieving ischemia and angina are the β-blockers, Caantagonists, and nitrates. There is no evidence that any of these drugs prolongs life or reduces the incidence of MI in patients with chronic stable angina.6,7 Among the first group of drugs, antiplatelet agents of one form or another were prescribed after cardiology consultation to 81% of patients, a rate similar to the 83.9% of patients with established coronary heart disease on antiplatelet therapy in the Second EUROpean Action on Secondary Prevention by Intervention to Reduce Events (EUROASPIRE II) survey8 and somewhat less than reported in contemporary clinical trials of patients with cardiovascular disease, but the prescription rates varied by up to 50% at national level, from 94% in the UK to 44% in the Netherlands. Daily aspirin intake is recommended for all patients with coronary artery disease, unless there is a definite contraindication, such as allergy to aspirin or a history of upper gastrointestinal hemorrhage.1 The only randomized controlled trial comparing aspirin 325 mg per day with placebo showed a reduced cardiovascular mortality and morbidity with an absolute reduction of 12 additional deaths for every 1000 patients treated during a 15-month period.9 Low-dose aspirin (81 to 100 mg) is generally recommended as an inexpensive and effective way to reduce adverse clinical outcomes in chronic ischemic heart disease. Only 48% of patients enrolled in the Euro Heart Survey were prescribed statin therapy following review by a cardiologist, and this is considerably lower than desirable in a patient population with known or suspected coronary disease, and a high preva- Current treatment of stable angina in Europe: the Euro-Heart Survey – Tavazzi IF I N H I B I T I O N lence of hyperlipidemia. Statins combine lipid-lowering efficacy with significantly improved prognosis and decreased mortality. The Cholesterol And Current Events (CARE)10 and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID)11 studies showed the benefits of pravastatin in reducing cardiovascular events. The Scandinavian Simvastatin Survival Study (4S)12 and Heart Protection Study (HPS)13 provided similar evidence on behalf of simvastatin, which lowered both cholesterol and cardiovascular events, and raised high-density lipoprotein (HDL) cholesterol levels. The recently published Treating to New Targets (TNT) trial in patients with stable coronary artery disease and low-density lipoprotein (LDL) cholesterol levels <130 mg/dL14 showed that atorvastatin was effective in reducing the risk of cardiovascular events, though no reduction in overall mortality was found. The mean LDL cholesterol level in the study was 77 mg/dL with 80 mg atorvastatin and 101 mg/dL with 10 mg atorvastatin. Current guidelines recommended a target fasting LDL cholesterol level of <100 mg/dL in patients with stable coronary artery disease. The most recent National Cholesterol Education Program–Adult Treatment Panel III (NCEPATP III) directive suggests a target of <70 mg/dL for high-risk coronary artery disease patients.5 ACE inhibitors and angiotensin receptor blockers were prescribed in 46% of patients, more frequently in patients with hypertension, signs of heart failure, or diabetes. The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines issued a class I recommendation for the use of ACE inhibitors in patients with ischemic heart disease and ventricular dysfunction or diabetes.1 This was based on the results of the Heart Outcomes Prevention Evaluation (HOPE)15 trial showing that ACE inhibition (ramipril 10 mg/d) decreases cardiovascular death, myocardial infarction, and stroke in patients with, or at high risk for, vascular disease in the absence of heart failure. Particular benefit was found in diabetics. Subsequently, a large study that recruited over 13 000 patients with chronic coronary artery disease, the EUropean trial on ReductiOn of cardiac events with Perindopril in stable coronary Artery disease (EUROPA), showed that perindopril treatment was associated with a significantly decreased relative risk (-20%) of the primary composite end point of cardiovascular death, MI, or cardiac arrest.16 Benefit was apparent within 1 year and increased steadily during followup. At variance with these data, the Prevention of Events with Angiotensin Converting-Enzyme inhibition trial (PEACE) showed no benefit versus placebo from trandolapril added to optimized medical therapy in the prevention of cardiovascular death, MI, or revascularization in patients with stable ischemic heart disease.17 Overall, meta-analysis of the EUROPA, HOPE, QUinapril Ischemic Event Trial (QUIET), and PEACE studies, shows that ACE inhibition has significant benefits in ischemic heart disease, with preserved ventricular function.18 In terms of specific antianginal drugs, β-blockers and nitrates are clearly the most frequently employed in the Euro Heart Survey patients, with a , H E A R T RAT E , A N D CO AR R O N A RY T E RY DI S E A S E smaller, but not inconsequential, proportion of patients on calcium antagonists, and combination therapy is the order of the day for the majority of patients. The use of β-blockers in this study is in line with reported usage in other studies of stable coronary disease.19,20 Actually, the β-blockers have been studied extensively in hypertensive and postMI patients, but only few, small and short-lasting randomized outcome trials have been carried out in stable angina patients. Compared with placebo, β-blockers consistently induce an improvement in exertional ischemic variables. Overall, less than 2000 patients were enrolled in randomized studies havPatients revascularized according to recorded severity of CAD n Patients referred for revascularization (Total= 501) Angiogram planned/performed, but no results recorded 753 159 Angiogram performed with results recorded 799 342 0-vessel diseasea 146 3 2 1-vessel diseasea 217 93 43 2-vessel diseasea 191 96 50 a 3-vessel disease 245 150 61 Any significant CADb 653 339 52 a b Number of vessels diseased defined as number of vessels with significant coronary disease. Significant coronary disease defined as >50% stenosis of a major epicardial vessel or branch thereof. Table III. Proportion of patients referred for revascularization (either percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]); CAD, coronary artery disease. Reproduced from reference 4: Daly C, Clemens F, Lopez-Sendon J, et al. The initial management of stable angina in Europe, from the Euro Heart Survey. Eur Heart J. 2005;26:1011-1022. Copyright © 2005, Oxford University Press. ing clinical events as end points, all comparing Ca– antagonists vs β-blockers.1 During the short followups, death or MI occurred with similar rates (58 vs 62 patients). In a meta-analysis, β-blockers and Ca antagonists showed similar effects on ischemia variables: angina and time to 1-mm ST-segment depression during exercise.1 However, practice guidelines recommend that β-blockers as first-choice therapy for uncomplicated stable angina.1 Ca-antagonists are used as frequently as β-blockers, often in combination.21 Among the Ca antagonists, verapamil and diltiazem can be used as a firstline therapy in ischemic heart disease. Although a negative effect on long-term cardiovascular outcome has been reported with short-acting dihydropyridines (mainly nifedipine), long-acting formulations are safe, with decreased revascularization rates and no effect on major cardiovascular eventfree survival, as recently shown in A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system (ACTION).22 Long-acting nitrates were used in 61% of patients, a prescription rate similar to that of β-blockers and Ca-antagonists. Organic nitrates are among the oldest and most commonly used drugs for the treatment of cardiovascular disease. Nitrates have Current treatment of stable angina in Europe: the Euro-Heart Survey – Tavazzi MEDICOGRAPHIA, VOL 28, No. 3, 2006 215 IF I N H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY a rapid onset of action, lower blood pressure and cardiac filling pressures, and dilate coronary arteries. They are used to treat episodes of angina, for short-term control of blood pressure and in the treatment of pulmonary congestion. Large-scale trials in the acute and postacute infarction setting of middle-term therapy with transdermal nitroglycerin (Gruppo Italiano per lo Studio della Soppravvivenza nell’Infarto miocardico-III [GISSI-3] trial) and oral mononitrate (Fourth International Study of Infarct Survival–4 [ISIS-4] trial) failed to demonstrate a significant effect of nitrates on outcome. In a meta-analysis of 12 long-term studies of nitrates vs β-blockers and of 4 studies of nitrates vs calcium antagonists,23 no significant differences in outcome were seen even though a nonsignificant trend for a higher number of angina episodes in patients taking nitrates was observed. A posthoc analysis has been conducted on data prospectively acquired in an observational study (Multicenter Study of Myocardial Ischemia or MSMI) and a randomized trial (Multicenter Diltiazem Post Infarction Trial or MDPIT), which included patients who had recovered from an acute coronary event.24 Longterm nitrates appeared to be associated with a significantly increased mortality risk, raising concerns about the potential adverse effects of long-acting nitrate therapy in chronic coronary disease.25 Thus, 160 years after the synthesis of nitroglycerin by Ascanio Sobrero, questions about its therapeutic use remain open. As for the nonprescriptions arising from contraindications, those regarding aspirin, statins, and β-blockers totaled only 5%, 8%, and 10%, respectively, of the overall population. Accordingly, it seems that the results of trials of secondary prevention are broadly applicable to the general angina population, although contraindications to statin therapy are more frequent than might be expected after the results of studies such as HPS12 or the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),26 where a considerably smaller proportion of patients were not randomized because of contraindications. The overall revascularization rates seem very low. However, when restricted to those in whom obstructive coronary disease has been documented within 4 weeks of the initial assessment, just over REFERENCES 1. Gibbons RJ, Abrams J, Chatterjee K, et al. American College of Cardiology; American Heart Association Task Force on Practice Guidelines. Committee on the management of patients with Chronic Stable Angina ACC/AHA 2002 guideline update for the management of patients with chronic stable angina – summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2003;107:149-158. 2. Fox KE Investigation and management of chest pain. Heart. 2005;91:105-110. 3. Daly C, Clemens F, Lopez-Sendon J, et al. The clinical characteristics and investigations planned in patients with stable angina presenting to cardiologists in Europe: from the Euro Heart Survey of Stable Angina. Eur Heart J. 2005;26:996-1010. 4. Daly C, Clemens F, Lopez-Sendon J, et al. The initial management of stable angina in Europe, from the Euro Heart Survey. Eur Heart J. 2005;26:1011-1022. 5. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program 216 MEDICOGRAPHIA, VOL 28, No. 3, 2006 DI S E A S E half have been referred for, or have had, a revascularization procedure, mostly PCI. The overall number of revascularization procedures will probably rise in the survey as time progresses and more patients come to have scheduled angiography performed and analyzed. However, as the highest-risk patients on clinical and noninvasive testing were prioritized for earlier angiography, it is likely that the rate of referral for revascularization may decelerate after the first month. In any event, the revascularization rate observed in the European Heart Survey is greater than other estimates of revascularization in stable angina.27,28 Revascularization procedures are advised for patients with stable angina who do not respond adequately to optimal antianginal therapy; for those who lead an active lifestyle; for subjects with a large burden of ischemia; and for those with severe coronary artery disease,5 especially with decreased left ventricular function.6 PCI and CABG surgery relieve angina in most patients. However, compared with medical therapy, these procedures do not prolong life or reduce the incidence of MI.1,5,29 In the Euro Heart Survey, clinically appropriate reasons for referral such as severe (class III) symptoms or a positive exercise test are independently associated with 2.5-fold increase in the likelihood of referral for revascularization, but women are only half as likely to be referred for revascularization, even when other potential confounding features are adjusted for. Type of centers and prevailing national rate of angiography are also independent predictors of revascularization, reflecting the influence of service capacity and availability of on-site revascularization facilities on referral patterns.4 In centers/countries where the capacity to perform angiography promptly is sufficient, there may be a lower threshold to proceed to revascularization for fiscal as well as clinical reasons. Conclusion In conclusion, the Euro Heart Survey on Stable Angina is the largest contemporary study of treatment of this condition in clinical practice and shows a significant discrepancy between guidelines and practice with regard to the use of evidence-based drug and interventional therapy. ❒ Adult Treatment Panel III Guidelines. Circulation. 2004;110: 227-239. 6. Thadani U. Current medical management of chronic stable angina. J Cardiovasc Pharmacol Ther. 2004;9(suppl I):S11-S29. 7. Abrams J. Chronic stable angina. N Engl J Med. 2005;352: 2524-2533. 8. EUROASPIRE II study group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries; principal results from EUROASPIRE II Euro Heart Survey Programme. Eur Heart J. 2001;22:554-572. 9. Juul-Muller S, Edvarson N, Jahnmatz B, et al; SAPAT (Swedish Angina Pectoris Aspirin Trial) Group. Double blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet. 1992;340:1421-1425. 10. Sacks FM, Pfeffer MA, Moye La, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med. 1996;335:1001-1009. 11. Long term Intervention with Pravastatin in Ischemic Disease Current treatment of stable angina in Europe: the Euro-Heart Survey – Tavazzi IF I N H I B I T I O N (LIPID) study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357. 12. No authors listed. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344: 1383-1389. 13. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. 14. La Rosa JC, Grund SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435. 15. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259. 16. Fox KM, for the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised double-blind , placebo controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788. 17. Braunwald E, Domanski MJ, Fowler SE, et al, for the PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med.2004;351:2058-2068. 18. Yusuf S. ACE-inhibition in stable coronary artery disease. N Engl J Med. 2005;352:937-938. 19. Carasso S, Markiewicz W. Medical treatment of patients with stable angina pectoris referred for coronary angiography: failure of treatment or failure to treat. Clin Cardiol. 2002;25:436-441. 20. Herlitz J, Brorsson B, Werko L. Factors associated with the use of various medications amongst patients with severe coro- , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E nary artery disease. SECOR/SBU Project Group. J Intern Med. 1999;245:143-153. 21. Klein WW, Jackson G, Tavazzi L. Efficacy of monotherapy compared with combined antianginal drugs in treatment of chronic stable angina: a meta-analysis. Coron Artery Dis.2002;13:427-436. 22. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of longacting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet. 2004;364:849-857. 23. Heidenreich PA, McDonald KM, Hastie T, et al. Meta-analysis of trial comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA. 1999;281:1927-1936. 24. Nakamura Y, Moss AJ, Brown MW, et al, for the Multicenter Myocardial Ischemia Research Group. Long-term nitrate use may be deleterious in ischemic heart disease: a study using the databases from two large-scale postinfarction studies. Am Heart J. 1999;138:577-585. 25. Gori T, Parker JD. Nitrate tolerance: a unifying hypothesis. Circulation. 2002;106:2510-2513. 26. Severs PS, Dalhof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Lancet. 2003;361:1149-1158. 27. Wittels E, Haty J, Gotto A, Medical costs of coronary artery disease in the United States. Am J Cardiol. 1990;65:432-440. 28. Miller T, Roger V, Hodge D, et al. Gender differences and temporal trends in clinical characteristics, stress test results and use of invasive procedures in patients undergoing evaluation for coronary disease. J Am Coll Cardiol. 2001;38:690-697. 29. Task Force of the European Society of Cardiology. Management of stable angina pectoris: recommendations of the Task Force of the European Society of Cardiology. Eur Heart J.1997;18: 394-413. TRAITEMENT ACTUEL DE L’ANGOR STABLE EN EUROPE : PRINCIPALES CONCLUSIONS DE L’EURO HEART SURVEY L e programme Euro Heart Survey (EHS) a conduit une étude européenne sur l’angor stable afin d’obtenir des informations précises et de pointe concernant la présentation et l’évolution clinique de l’angor stable, et pour évaluer la prise en charge de cette pathologie en fonction des recommandations officielles et les variations régionales ou internationales dans la pratique courante. Un total de 3 779 patients a été inclus dans 197 centres de 35 pays européens ou méditerranéens : 39 % avaient des symptômes de classe I de la Canadian Cardiac Society, 49 % de classe II et 12 % de classe III. Quatrevingt-un pour cent des patients prenaient ou devaient prendre un antiagrégant plaquettaire, et 78 % de l’aspirine. Une statine était prescrite chez 48 % des patients, un -bloquant chez 67 % et un dérivé nitré chez 61 %. Seulement 27 % prenaient un inhibiteur calcique. La majorité des patients (59 %) prenait deux médicaments antiangoreux ou plus prescrits par un cardiologue, et seulement 13 % n’en prenaient pas. Chez 41 % d’entre eux une coronarographie était soit prévue soit réalisée après l’évaluation initiale. Cinquante-deux pour cent des patients dont la coronarographie effectuée moins de 4 semaines après leur présentation dans l’étude montrait une atteinte significative (sténose coronaire >50 %), ont bénéficié d’une revascularisation. Les prescriptions d’aspirine, de statines, et de -bloquants n’ont concerné que respectivement 5 %, 8 % et 10 % de la population globale, les absences de prescriptions relevant des contreindications. En conclusion, l’Euro Heart Survey sur l’angor stable est la plus grande étude contemporaine de traitement de cette pathologie en pratique clinique et montre une discordance significative entre les recommandations et la pratique quant à l’utilisation des médicaments agréés et des traitements interventionnels. ✦ Current treatment of stable angina in Europe: the Euro-Heart Survey – Tavazzi MEDICOGRAPHIA, VOL 28, No. 3, 2006 217 IF I N H I B I T I O N , H E A R T R A T E , AND CORONARY ARTERY DISEASE he total number of heart beats in a lifetime remains fairly constant across species and there exists an inverse relationship between resting heart rate and life expectancy.1 Epidemiological studies have addressed the issue of the importance of heart rate in healthy humans.2-12 The association between resting heart rate and mortality has been observed in patients with hypertension, with metabolic syndrome, and in the elderly.13-18 However, there was, until recently, little information on the prognostic value of resting heart rate in patients with coronary artery disease (CAD). Heart rate reduction is the cornerstone of antianginal therapy. In addition to the beneficial effects of heart rate reduction for prevention of angina, a lower heart rate is also associated with a more favorable prognosis in patients with CAD. This issue is clinically important because it may support the relevance of testing the effect of lowering heart rate to reduce cardiovascular mortality and morbidity. Experimental and clinical studies have already suggested that heart rate reduction may improve coronary endothelial function and atherosclerosis.19-29 We recently reported the results of a study that evaluated the relationship between resting heart rate and future cardiovascular events in a large population of patients with suspected or proven CAD with an extended follow-up.30 T Jean-Claude TARDIF, MD, FRCPC, FACC Department of Medicine Montreal Heart Institute Montreal, CANADA Prognostic value of heart rate in cardiovascular disease b y J . C . Ta r d i f , C a n a d a Heart rate and cardiovascular mortality and morbidity in patients with coronary artery disease eart rate reduction is highly desirable for the treatment of angina. An association between resting heart rate and mortality has been observed in patients with hypertension, with metabolic syndrome, and in the elderly. However, the prognostic value of heart rate in patients with stable coronary artery disease (CAD) was until recently less known. We assessed the relationship between resting heart rate at baseline and cardiovascular mortality and morbidity, while adjusting for risk factors. A total of 24 913 patients with suspected or proven CAD from the Coronary Artery Surgery Study (CASS) registry were studied for a median follow-up of close to 15 years. All-cause and cardiovascular mortality and cardiovascular rehospitalizations were increased with increasing heart rate (P<0.0001). When compared with the reference group, patients with resting heart rate ≥83 bpm at baseline had a significantly higher risk for total mortality (hazard ratio [HR], 1.32; confidence interval [CI], 1.19-1.47; P<0.0001), and cardiovascular mortality (HR, 1.31; CI, 1.15-1.48; P<0.0001) after adjustment for multiple clinical variables. When comparing patients with heart rates between 77-82 bpm and ≥83 bpm with patients with a heart rate ≤62 bpm, the hazard ratios for time to first cardiovascular rehospitalization were 1.11 and 1.14 (P<0.001 for both). Resting heart rate is a simple measurement with prognostic implications. High resting heart rate is a predictor for total and cardiovascular mortality independent of other risk factors in patients with CAD. H Medicographia. 2006;28:218-223. (see French abstract on page 223) Keywords: heart rate; angina; coronary artery disease; cardiovascular mortality; prognosis; risk factor Address for correspondence: Jean-Claude Tardif, MD, Research Center, Montreal Heart Institute, 5000 Belanger Street E, Montreal H1T 1C8, Canada (e-mail: [email protected]) 218 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Our study focused on the 24 913 patients included in the Coronary Artery Surgery Study (CASS) registry undergoing coronary arteriography for the presence of suspected or proven CAD. A detailed description of CASS has been published elsewhere.31 Baseline resting heart rate was obtained manually at enrollment with radial pulse measurement during 60 seconds with the patient in the sitting position. The variables evaluated in CASS have been previously described in detail.30 Median duration of follow-up (and interquartile range) was 14.7 years (9.0-16.1 years). The date of enrollment was that of the initial angiographic evaluation. Annual clinical follow-up was mandatory for all patients in the registry. Additional information was obtained for all patients in the registry who suffered a “coronary event.” The CASS follow-up requirements for various situations designated as “coronary events” included the following: ◆ If a patient experienced a myocardial infarction (MI), all relevant information, including electrocarSELECTED BCAPS BMI CAD CASS MI ABBREVIATIONS AND ACRONYMS Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study body mass index coronary artery disease Coronary Artery Surgery Study myocardial infarction Prognostic value of heart rate in cardiovascular disease – Tardif IF I N Age (years) Males (%) Total cholesterol (mg/dL) a BMI (kg/m2) NDCV EF (%) Hypertension (%) Diabetes mellitus (%) Cigarette smoking Presently Formerly Sedentary (%) β-Blockers (%) Antiplatelets (%) Diuretics (%) Lipid-lowering drugs (%) H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY ≤62 (bpm) 63-70 (bpm) 71-76 (bpm) 77-82 (bpm) ≥83 (bpm) Overall P-value 54.8±8.9 79.2 227.1±47.0 25.8±3.6 1.6±1.1 60.5±13.5 35.7 9.6 53.5±9.2 77.4 231.3±50.0 25.8±3.6 1.5±1.1 59.5±14.6 38.6 9.9 53.0±9.2 75.3 230.6±50.0 25.7±3.7 1.4±1.1 59.3±15.2 41.8 11.0 52.8±9.3 74.0 232.9±50.6 25.8±3.8 1.4±1.1 59.0±16.1 44.2 11.0 52.1±9.6 71.6 232.5±53.8 26.0±4.2 1.4±1.1 58.1±17.6 49.5 12.5 <0.001 <0.001 <0.001 0.03 <0.001 <0.001 <0.001 <0.001 26.7 49.6 37.5 69.5 6.3 20.1 3.6 31.6 44.4 35.7 52.2 6.1 21.5 4.4 33.5 41.4 34.1 40.5 6.6 23.2 4.8 35.1 40.2 33.2 33.3 6.8 24.5 4.2 39.2 36.9 33.4 26.4 7.1 29.1 4.3 DI S E A S E <0.001 <0.001 <0.001 0.23 <0.001 0.06 Continuous variables are expressed in mean ± one SD. Categorical variables are represented as relative frequences. bpm, beats per min. Differences between different heart rate quintiles at baseline were assessed using χ2 test for categorical variables and one-way ANOVA for continuous variables. a Total cholesterol was not available in 20% of patients and was not included in multivariable analyses. Table I. Baseline characteristics divided by resting heart rate quintiles (n= 24 913 patients). Abbreviations: BMI, body mass index; EF, ejection fraction; NDCV, number of diseased coronary vessels. Adapted from reference 30: Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974. Copyright © 2005, Oxford University Press. diograms (ECGs) and the results of enzyme studies, was obtained regardless of whether the patient was hospitalized. ◆ Detailed reports of hospitalizations for any cardiac event or stroke were collected if the period of hospitalization exceeded 5 days. ◆ If a patient was hospitalized for coronary angiography or cardiac surgery, a specific description of the hospitalization and the procedures performed was obtained. ◆ If a patient died, a detailed report of the circumstances of death was filled out. The baseline demographic and clinical characteristics of the 24 913 patients included in this study are presented in Table I.30 The mean age was higher in the lower heart rate quintiles. The proportion of males was larger than females in all groups, with women having a trend toward a higher resting heart rate. There were higher proportions of dyslipidemics, smokers, hypertensives, and diabetic patients in the higher quintiles. The ejection fraction was lower in patients with a high heart rate at baseline. Patients in the higher heart rate quintiles received less treatment with β-blockers and were treated more often with diuretics. There were no significant differences between the different quintiles with regard to body mass index (BMI) and use of antiplatelets or lipid-lowering drugs. In order to summarize the independent variables and to better understand their relationship to heart rate, descriptive statistics are presented by heart rate quintiles. Quintiles were chosen according to the resting heart rate distribution in the general sample population: heart rate 1, <62; heart rate 2, 63-70; heart rate 3, 71-76; heart rate 4, 77-82; and heart rate 5, >83 bpm. Prognostic value of heart rate in cardiovascular disease – Tardif After adjusting the multivariable Cox proportional hazard model for age, sex, diabetes, hypertension, cigarette smoking, left ventricular ejection fraction, number of clinically significant diseased coronary vessels, type of recreational activity, and concomitant treatments (including β-blockers), patients with resting heart rate between 77 and 82 bpm had a significantly higher risk for total mortality (hazard ratio [HR], 1.16; (99% confidence interval [CI], 1.04-1.28). This effect was even larger for patients with a resting heart rate ≥83 bpm, with a HR of 1.32 (CI, 1.19-1.47, Figure 1, next page).30 The multivariable Cox proportional hazard model for cardiovascular mortality was adjusted for the same covariates as for overall mortality plus body mass index (BMI). A high resting heart rate (≥83 bpm), was a strong predictor of cardiovascular mortality (HR,1.31; CI, 1.15-1.48). Age, hypertension, diabetes, BMI, current smoking, and number of clinically significant diseased coronary vessels remained strongly associated with cardiovascular (CV) death. Ejection fraction and treatment with diuretics showed a protective effect. Figure 130 shows the adjusted cumulative survival curves for cardiovascular mortality by highest and lowest quintiles of resting heart rate. There was also a marked difference in time to first cardiovascular rehospitalization between the two highest heart rate quintiles and the other groups. When comparing patients with heart rates between 77-82 bpm and ≥83 bpm with patients with a heart rate of ≤62 bpm, the hazard ratios for time to first rehospitalization due to any cardiovascular event were, respectively, 1.11 (CI, 1.00-1.24) and 1.14 (CI, 1.02-1.27)(P-values <0.0001 for both) (Figure 2).30 MEDICOGRAPHIA, VOL 28, No. 3, 2006 219 IF I N H I B I T I O N , H RAT E A R T E , A N D CO R O N A RY AR T E RY DI S E A S E Adjusted survival curves for overall mortality by RHR quintiles 1.0 1.0 RHR in quintiles: 0.8 0.7 0.9 Cumulative survival ≤62 bpm 63-70 bpm 71-76 bpm 77-82 bpm ≥83 bpm 0.9 Cumulative survival Adjusted survival curves for CV mortality by RHR quintiles 0.8 0.7 0.6 0.6 0.5 0.5 0.00 5.00 10.00 15.00 20.00 0.00 Years after enrollment 5.00 10.00 15.00 20.00 Years after enrollment Figure 1. Left panel. Survival curves for overall mortality, by resting heart rate (RHR) quintiles, adjusted for age, gender, hypertension, diabetes mellitus, cigarette smoking, clinically significant coronary vessel disease, ejection fraction, recreational activity, treatment with antiplatelets, diuretics, β-blockers, and lipid-lowering drugs. Right panel. Survival curves for cardiovascular mortality, by resting heart rate quintiles, adjusted as in left panel, plus for body mass index. Adapted from reference 30: Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974. Copyright © 2005, Oxford University Press. Adjusted survival curves for time to rehospitalization due to any CV cause 1.0 1.00 RHR in quintiles: 0.8 0.7 0.99 Cumulative survival ≤62 bpm 63-70 bpm 71-76 bpm 77-82 bpm ≥83 bpm 0.9 Cumulative survival Adjusted survival curves for time to first rehospitalization due to congestive heart failure 0.98 0.97 0.6 0.96 0.5 0.95 0.00 2.00 4.00 6.00 8.00 Time to first CV rehospitalization since enrollment 0.00 2.00 4.00 6.00 8.00 Time to first CHF rehospitalization since enrollment Figure 2. Left panel. Survival curves for time to rehospitalization due to any cardiovascular cause, by resting heart rate (RHR) quintiles, adjusted for age, gender, hypertension, diabetes mellitus, cigarette smoking, clinically significant coronary vessel disease, ejection fraction, recreational activity, treatment with antiplatelets, diuretics, β-blockers, and lipid-lowering drugs. The green and black lines are superimposed. Right panel. Survival curves for time to first rehospitalization due to congestive heart failure, by resting heart rate quintiles, adjusted as in left panel (minus for cigarette smoking). Adapted from reference 40: Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104:1477-1482. Copyright © 2001, American Heart Association. A high resting heart rate was also an independent predictor of time to first rehospitalization due to angina and CHF. The association between heart rate and total mortality held true in all analyzed subgroups: men vs women, old (>65 years) vs young, diabetics vs nondiabetics, hypertensives vs normotensives, BMI >27 or <27, those with ejection fraction >50% or <50%, and patients treated with β-blockers vs those without such treatment (Figure 3).30 220 MEDICOGRAPHIA, VOL 28, No. 3, 2006 It might be argued that in subjects with ischemic heart disease a higher heart rate might reflect some degree of left ventricular dysfunction. According to this view, the higher mortality rate among subjects with tachycardia would be caused by the underlying systolic dysfunction. However, heart rate was an important predictor of all-cause and cardiovascular mortality both in subjects with and without left ventricular dysfunction. The better prognosis of the subjects with lower heart rates was not simply due Prognostic value of heart rate in cardiovascular disease – Tardif H I B I T I O N to a protective effect of β-blockers, because the predictive value of heart rate for mortality persisted in the subjects not treated with this class of agents. Another important finding of this study is that the predictive power of heart rate for mortality was observed both in men and women. A gender-related difference in the association between heart rate and mortality has been found in some studies conducted either in elderly subjects32 or in patients with myocardial infarction.33 In particular, in most studies, a high heart rate appeared to be a weak predictor of death from CAD in women. Data from our study in patients with stable CAD indicates that a higher heart rate can also be deleterious in women. Heart rate and pathophysiology of coronary artery disease A high heart rate is a major determinant of myocardial ischemia, because it leads to both greater myocardial oxygen consumption (MVO2 ) and decreased myocardial perfusion, the latter because of the shortening in the duration of diastole. The likelihood of the occurrence of an ischemic episode increases at higher baseline heart rates. With a baseline heart rate less than 60 bpm, the likelihood of occurrence of ischemic episodes with heart rate acceleration was 8.7%, while at rates in excess of 90 bpm, the likelihood increased to 18.5%.34 An increased heart rate has also been found to be an independent risk factor for cardiovascular morbidity and mortality in the general population,2,7,8 in elderly subjects,18 in hypertensive cohorts,13 and in patients with myocardial infarction.35 The relationship between reduction in heart rate and decrease in mortality has been well established with β-blockers, especially after myocardial infarction, and in patients with heart failure.36-39 As far as these β-blocker trials are concerned, the magnitude of the effect on mortality was closely correlated with the degree of reduction in heart rate.36,37 Experimental and clinical evidence suggests that sustained elevations in heart rate may play a direct role in the pathogenesis of coronary atherosclerosis. Heart rate was significantly correlated with the severity and progression of atherosclerosis on coronary angiography among men who had developed myocardial infarction at a young age.27,28 Accelerated atherogenesis resulting from increased heart rate may be due to both mechanical and metabolic factors. Increased vascular wall stress may contribute to endothelial injury, potentially promoting the complex cascade of events leading to increased atherosclerosis. Experimental data have also demonstrated that a reduction in heart rate can delay the progression of coronary atherosclerosis in monkeys.20,25 Beere et al20 showed that male cynomolgus monkeys subjected to sinus node ablation or those with innately low heart rates had significantly less coronary atherosclerosis than animals with higher heart rates. These observations are supported by results from the Beta-Blocker CholesterolLowering Asymptomatic Plaque Study (BCAPS) randomized trial, which have shown that a β-blocker reduced the rate of progression of carotid intima- Prognostic value of heart rate in cardiovascular disease – Tardif , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E Subgroup analysis on total mortality HR (95% CI) for one SD heart rate (12.4 bpm) increment IF I N 1.30 1.20 1.10 1.00 0.90 0.80 % ics ics % rs rs rs rs 7 7 es es en en M om cke cke yea yea nsiv nsiv >50 <50 bet bet I >2 I <2 a a i i te ote EF F W -Blo -blo 65 65 M M r E D nd B B e β < > β LV LV o e Hyp orm e o N N Ag Ag N Subgroups Figure 3. Subgroup analyses on total mortality for a 1-SD increment in heart rate (12.4 bpm). Abbreviations: BMI, body mass index; LVEF, left ventricular ejection fraction. Adapted from reference 30: Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26: 967-974. Copyright © 2005, Oxford University Press. media thickness in asymptomatic patients.29 More recently, a high heart rate has also been associated with an increased risk of coronary plaque disruption.40 In this retrospective angiographic study evaluating patients who underwent two coronary angiograms within 6 months, logistic regression analysis identified positive associations between plaque disruption and a mean heart rate >80 beats/ min. This association again indicates that hemodynamic forces may play a critical role in the process of plaque disruption (Table II).30 A further study41 has shown that a high heart rate is strongly associated with increased arterial rigidity, reduced vascular distensibility, and elevated pulse-wave velocity, characteristics that are all associated with an increased risk of myocardial infarction and cardiac death. In addition, a retrospective study has examined the relationship between bradycardia and the development of coronary collateral vessels visible on angiography in patients with obstructive CAD. Pa- LV mass >270 g HR mean >80 bpm β-Blocker use Wall thickness IVS PPF ACE-inhibitors Statins OR (95% CI) P-value 4.92 (1.83-13.25) 3.19 (1.15-8.85) 0.32 (0.13-0.88) 1.68 (0.57-9.91) 1.81 (0.67-4.90) 0.51 (0.19-1.34) 0.42 (0.16-1.22) 0.02 0.02 0.02 0.06 0.07 0.06 0.06 Table II. Heart rate as a predictor of coronary plaque rupture. Multivariate analysis of predictors of coronary plaque disruption. ACE, angiotensin-converting enzyme. Abbreviations: IVS, interventricular septum; PPF, fractional pulse pressure. Adapted from reference 30: Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974. Copyright © 2005, Oxford University Press. MEDICOGRAPHIA, VOL 28, No. 3, 2006 221 IF I N H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E tel and coworkers observed that a larger number of patients with heart rates <50 beats/min had developed collateral vessels (potentially decreasing the ischemic burden) compared with control patients with heart rates >60 beats/min, (P<0.001). The presence of collaterals was independent of the history of angina or the use of β-blockers.42 Finally, a high heart rate may reflect an imbalance of the autonomic nervous system and may therefore be a marker of sympathetic overactivity.43-45 Some investigators have hypothesized that many of the risk factors (hypertension, diabetes, dyslipidemia, smoking and sedentariness) are also related to sympathetic overactivity.45-47 In summary, studies have shown that a high resting heart rate is a strong predictor of total and cardiovascular mortality in healthy populations as well as in patients with suspected or proven coronary artery disease. Patients with resting heart rate above 77 bpm are also prone to more rehospitalizations for cardiovascular reasons, independently of major risk factors when compared with patients with lower resting heart rates. Resting heart rate is a simple measurement with important prognostic implications that should no longer be neglected in risk flowcharts. ❒ REFERENCES 1. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol. 1997;30:1104-1106. 2. Ferrari R. Prognostic benefits of heart rate reduction in cardiovascular disease. Eur Heart J. 2003;5(suppl G):G10-G14. 3. Kannel WB. Heart rate and cardiovascular mortality. The Framingham Study. Am Heart J. 1987;113:1489-1494. 4. Reunanen A. Heart rate and mortality. J Intern Med. 2000;247: 231-239. 5. Mensink GB, Hoffmeister H. The relationship between resting heart rate and all-cause, cardiovascular and cancer mortality. Eur Heart J. 1997;18:1404-1410. 6. Benetos A. Influence of heart rate on mortality in a French population. Hypertension. 1999;33:44-52. 7. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. 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VALEUR PRONOSTIQUE DE LA FRÉQUENCE CARDIAQUE DANS LA MALADIE CARDIO-VASCULAIRE U ne réduction de la fréquence cardiaque est éminemment souhaitable dans le traitement de l’angor. Une association entre fréquence cardiaque de repos et mortalité a été observée chez les patients hypertendus ayant un syndrome métabolique et chez les personnes âgées. Cependant, la valeur pronostique de la fréquence cardiaque chez les patients ayant une maladie coronaire (MC) stable était jusqu’à maintenant moins connue. Nous avons évalué les rapports entre la fréquence cardiaque initiale de repos et la morbidité et la mortalité cardio-vasculaires, en les ajustant pour les facteurs de risque. Au cours d’un suivi d’environ 15 ans, nous avons étudié un total de 24 913 patients issus du registre de la CASS (Coronary Artery Surgery Study) ayant une MC prouvée ou suspectée. La mortalité cardio-vasculaire et de toutes causes ainsi que les réhospitalisations cardio-vasculaires étaient augmentées en cas de fréquence cardiaque élevée (p<0,0001). Comparés au groupe de référence, les patients dont la fréquence cardiaque initiale de repos était au moins de 83 bpm avaient un risque significativement plus élevé de mortalité globale (coefficient de probabilité [CP], 1,32 ; intervalle de confiance [IC], 1,19-1,47 ; p<0,0001), et de mortalité cardiovasculaire (CP, 1,31 ; IC, 1,15-1,48 ; p<0,0001) après ajustement pour les nombreuses variables cliniques. En comparant les patients ayant une fréquence cardiaque entre 77-82 bpm et d’au moins 83 bpm à ceux dont la fréquence cardiaque est inférieure ou égale à 62 bpm, les CP se rapportant au moment de la première réhospitalisation cardio-vasculaire étaient de 1,11 et 1,14 (p < 0,001 pour les deux). La fréquence cardiaque de repos est une mesure simple avec des implications pronostiques. Une fréquence cardiaque de repos élevée est un facteur prédictif de mortalité globale et cardio-vasculaire indépendante des autres facteurs de risque chez les patients présentant une MC. ✦ Prognostic value of heart rate in cardiovascular disease – Tardif MEDICOGRAPHIA, VOL 28, No. 3, 2006 223 IF I N H I B I T I O N , H E A R T R A T E , AND CORONARY ARTERY DISEASE n mammals, the heart rate is determined by the sinoatrial (SA) node pacemaker located in the right atrium. Nodal cells express a unique array of ion channels/currents — at least ten ionic currents have been described—whose combined effect on the diastolic membrane potential results in spontaneous depolarization (pacemaker depolarization) thus determining the rhythmic activity of the nodal cell. One of these—named the “funny current” (If) because of its electrophysiological peculiarities—is the subject of much recent interest, as its pharmacological inhibition results in heart rate reduction of significant, but limited extent, free of associated negative inotropic effects, with potential therapeutic benefits in cardiovascular diseases such as angina and heart failure. ▲ I Michael J. SHATTOCK, PhD Michael J. CURTIS, PhD Cardiovascular Division King’s College, St Thomas’ Hospital London, UNITED KINGDOM The role of If in the regulation of heart rate by M. J. Shattock and M. J. Curtis, United Kingdom T he mammalian heart rate is determined by the sinoatrial (SA) node pacemaker located in the right atrium. Nodal cells express a unique array of ion channels that make their diastolic membrane potential spontaneously depolarize (pacemaker depolarization). When a threshold is reached this triggers a propagating action potential. Sinoatrial pacemaker cells set the heart rate because their depolarizations arise at a rate faster than those of other spontaneously active cells in the heart (eg, atrioventricular node cells, Purkinje fibers, etc). The generation of the diastolic depolarization and of the SA nodal action potential involves at least 10 different ion currents. Thus, channel-selective drugs may be limited by a physiological reserve that makes the node hard to stop. However, the nodal firing rate can be exquisitely influenced by small changes in small currents. This is because SA nodal cells lack the large timeindependent background potassium current (IK1 ) present in most other cardiac cells and have a correspondingly high input impedance. This feature of nodal cells means small changes in the small pacemaker current If can significantly affect heart rate. If has been suggested to be the primary physiological regulator of SA nodal response to neurohormonal stimulation. The role of If in regulating heart rate and the natural redundancy of many currents contributing to the overall action potential means that ivabradine, which inhibits If , achieves pharmacological heart rate slowing with an extent limited to a safe maximum by the physiological reserve. Medicographia. 2006;28:224-231. (see French abstract on page 231) Keywords: sinoatrial node; heart rate; pacemaker; ion current; action potential; HCN-channel; ivabradine Address for correspondence: Professor Michael J. Shattock, Cardiovascular Division, King’s College, St Thomas’ Hospital, London SE1 7EH, UK (e-mail: [email protected]) 224 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Electrophysiology of heart rate regulation ◆ The origin and the importance of heart rate The origin of the heart beat is the sinoatrial (SA) node.1 The SA node sets the rate of the heart by generating spontaneous electrical activity (depolarization). Depolarization spreads wave-like from the SA node, first through the atrial muscle, which responds by contracting and ejecting blood into the ventricles. The wave of depolarization then meets the atrioventricular node, where its velocity is temporarily slowed. As the wave enters the adjacent cardiac tissues, the bundle of His and then the Purkinje fiber system, its velocity speeds greatly. The Purkinje fibers impinge first on the apex of the ventricles, then the base, meaning that depolarization passes into the ventricles in a coordinated manner, resulting in the ejection of blood via the great vessels. The pacemaker therefore controls the rate, but not the coordination, of cardiac contraction. The pacemaker controls cardiac output by two means. It controls the rate of ejection of blood by the ventricles, and it also controls the volume of blood ejected per beat by controlling the duration of diastole. Slowing the rate allows longer for the ventricles to fill with venous blood, which not only provides more blood for ejection per beat, but also increases the force of each beat via the Starling mechanism. Thus, along with the intrinsic properties of the cardiac muscle itself, the SA node is the key location of control of cardiac output, with the heart rate it sets being the tool of this control. The basis of this control is the underlying electrophysiology of the SA node cells. This is determined in part by the ion channels expressed by SA node cells, and in part by the anatomy of the node. ◆ Location and structure of the mammalian SA node The SA node is a small tear-drop–shaped cluster of cells located at the junction of the superior vena cava, the inferior vena cava, and the crista terminalis in the right atrium.2 It may vary in length from 7 to 20 mm3,4 in the human heart. The node is comprised of different types of specialized cells that exhibit pacemaker activity to a greater or lesser degree (depending on location) together with atrial The role of If in the regulation of heart rate – Shattock and Curtis IF I N H I B I T I O N myocytes and a large amount of connective tissue. The latter varies with species3 and age5 and can make up between 50% and 90% of the node. This mixture of tissue gives the node its characteristic properties that include spontaneous electrical activity of a coordinated nature, and of sufficient electrical strength to propagate away and into the rest of the heart, and at a rate sufficient to overdrive and capture any latent pacemaker activity that may reside elsewhere in the heart (eg, in the atrioventricular node).1 Depolarization spreads from the SA node as a broad wavefront anteriorly and obliquely towards the crista terminalis then changes direction and propagates toward the atrioventricular node.1 There is a region of immeasurably slow conduction located close to the leading pacemaker site. This block zone prevents depolarization from propagating directly to the septum which, for efficient cardiac pumping activity, requires to be activated later. The net effect is that the wave of atrial depolarization and resultant contraction begins at the top of the chamber, thereby directing the movement of atrial blood down toward the atrioventricular valve, with the block zone preventing an arrhythmic loop of propagation, ie, reentry of the wave of depolarization from the atrium back into the SA node. , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E the node.1,7 The smaller P cells have a more positive resting membrane potential and a slower rate of diastolic depolarization than the larger peripheral cells.7 When diastolic depolarization reaches threshold, the resultant action potential in the smaller cells has a slower rate of upstroke (+dV/dt) than that of surrounding cells. This is because P cells express fewer Na channels than their neighbors, meaning that the upstroke of their action potential is determined primarily by the voltage-dependent opening of Ca channels. Towards the periphery of the node, the larger cells express increasing amounts of Na channels, giving rise to steep and tall action potentials (Figure 1 B).7 When studied in the laboratory, isolated peripheral nodal cells display a faster rate of diastolic pacemaker depolarization and a greater resultant spontaneous beating rate than they ever achieve in situ—most likely as a consequence of an increase in the pacemaker current If. In situ, however, the electrotonic coupling of these cells to their A Small cell — central? Slower upstroke (I Ca ) – lower peak potential 0 mV ◆ Microanatomy of the SA node 2,6 Cells within the SA node vary in size and shape. The central nodal cells (sometimes called P cells) are the site of the primary pacemaker. These cells are small (5-10 µm in diameter and 25-30 µm long), spindle-shaped, poorly differentiated, contain few myofilaments or mitochondria, and have highly convoluted membranes containing many caveolae. Cells in the remainder of the node vary between P cell type and surrounding atrial cell type in shape and structure, cells becoming larger, having a clear myofilament structure, and containing more mitochondria the closer they are located to the periphery of the node.1,2,6 Interspersed between these cells are a third type of cell termed “spider” cells. These are clearly identifiable if the node is disaggregated in a laboratory.6 The role of these spider cells is uncertain, but it is speculated that they play a role equivalent to that of the Purkinje fibers in the ventricles, since their extensive “dendritic” structure and their large surface-to-volume ratio may facilitate rapid conduction of the wave of depolarization generated by P cells and facilitate electrical coupling between nodal cells and the surrounding atrial region. ◆ Cellular electrophysiology of individual nodal cells The hallmark property of the majority of nodal cells is a pacemaker depolarization, which is a progressive positive shift in membrane potential that occurs during diastole (Figure 1 A).7 The rate of change of membrane potential sets the heart rate. However, the overall shape of the action potential varies between the different cell types within the node. This is the result of differences in cell shape and differences in ion channel expression between cells in The role of If in the regulation of heart rate – Shattock and Curtis –50 mV Slower pacemaker depolarization and more positive takeoff potential B Longer action potential Less negative minimum diastolic potential Large cell — peripheral? Faster upstroke – (increased I Na ) – higher peak potential 0 mV –50 mV Shorter action Faster pacemaker potential potential – increased I f More negative minimum diastolic potential 500 ms Figure 1. Spontaneous action potentials recorded from two cells isolated from rabbit sinoatrial node. (A) Recording from a small cell (22 pF) assumed to be from the center of the node. (B) Recording from a large cell (57.5 pF) assumed to be from the periphery of the node. Traces are reproduced from reference 7: Honjo H, Boyett MR, Kodama I, Toyama J. Correlation between electrical activity and the size of rabbit sino-atrial node cells. J Physiol. 1996;463:795-808. Copyright © 1996, Cambridge University Press. MEDICOGRAPHIA, VOL 28, No. 3, 2006 225 IF I N H I B I T I O N , H E A R T RAT E , CO A N D R O N A RY AR T E RY ✪ Low CI- Low NA+ ★ ✪ RA Reproduced from reference 1: Boyett MR, Honjo H, Kodama I. The sinoatrial node: a heterogeneous pacemaker structure. Cardiovasc Res. 2000;47:658-687. Copyright © 2000, Elsevier Science BV. 4-AP ✪ ✪ SEP Low CA2+ ✪ Low temperature High K+ ✪ ACh ✪ ✪ ✪ ✪ Nif ✪ Adr CT 1 mm IVC A Ventricular myocyte Outward current Small current –120 – 80 –40 40 Membrane potential (mV) High resting permeability to K sets membrane potential near Inward current – 85 mV B –120 –80 –40 Small effect on Em Sinoatrial node cell Outward current Small current – 50 – 25 25 50 Membrane potential (mV) Big effect on Em Inward current Figure 3. Illustration of the differences in current-voltage (I-V) relationships for the steady-state background current in ventricular myocytes and sinoatrial nodal cells. (A) Representation of the steady-state I-V relationship for IK1 in ventricular cells showing it intersecting the voltage axis at the resting membrane potential. The K+ conductance of the resting membrane is high (ie, the slope of the I-V relationship is steep) such that a small current exerts only a small effect on membrane potential (see inset). (B) Shows the lack of IK1 in the sinoatrial node cell gives a shallow steadystate I-V relationship (ie, low conductance, high impedance), and hence a small current can induce a large change in membrane voltage (see inset). The data in (B) are redrawn from reference 11: Noma A, Nakayama T, Kurachi Y, Irisawa H. Resting K conductances in pacemaker and non-pacemaker heart cells of the rabbit. Jpn J Physiol. 1984;34:245-254. Copright © 1984, Center for Academic Publications Japan. 226 MEDICOGRAPHIA, VOL 28, No. 3, 2006 S E A S E Figure 2. Pacemaker shifts in the rabbit SA node. The node is represented as the tear-drop–shaped structure bounded by the right atrium (RA) , crista terminalis (CT), inferior (IVC) and superior (SVC) vena cavae, and the intraatrial septum (SEP). Ach, acetylcholine; Adr, adrenaline; 4-AP, 4-aminopyridine; Nif, nifedipine. SVC E-4031 DI neighbors tends to slow pacemaker rate1 and hence in the intact node, the P cells in the center of the node set the basal heart rate. At least 10 ionic currents have now been shown to contribute to the SA node action potential.8,9 However, Irisawa et al (1993) have pointed out that only two currents are required to produce rhythmic activity in nodal cells—a time-independent outward current and the Ca inward current (ICa ).10 This indicates that on a cellular level the pacemaking of individual nodal cells is hard to stop due to the natural redundancy that multiple currents confer. In addition, across the node the variation in cell shape and ion channel expression within the node provides an additional pacemaking safety factor. The node can respond to changes in its physiological, pharmacological, and physical environment by allowing the primary pacemaker site to “wander” according to prevailing conditions and how these affect the function of different ion channels in various regions of the node.1 Figure 2 shows the estimated location of the primary pacemaker site within the SA node and how this may shift in response to different stimuli.1 This demonstrates how different areas of the node are more or less dependent on different ion channels and illustrates the fail-safe nature of the node in which no single ion channel or region is solely responsible for the initiation of excitation. Importantly, the large number of ion channels that contribute to pacemaking, together with the variation in their expression, means that hormones, neurotransmitters, and drugs that activate or inhibit individual ion channels are less likely to arrest or overstimulate the node. Instead they will shift the primary pacemaker site to a different region of the node where the targeted channel plays a lesser role.1 This therefore confers a functional safety factor making heart rate more stable and more resistant to extrinsic influences than it would be if fewer channels determined pacemaker depolarization, and did so homogenously throughout the node. The practical outcome of this is that although drugs may affect heart rate, the maximum extent to which they can do this is often limited by the inherent physiological reserve conferred by the diversity of nodal ion channel expression. An exception to this rule is acetylcholine, which can cause total sinus arrest at high concentrations—although the explanation for this is that acetylcholine can affect several different SA node ionic currents (involved in both repolarization and depolarization). This reinforces a key point — selective drugs acting on the SA node are the drugs with the desirable property of having a safe (limited) maximum effect. The role of If in the regulation of heart rate – Shattock and Curtis IF I N H I B I T I O N The importance of I f in heart rate control ◆ The importance of input-impedance in regulat- ing the effects of small currents The passive electrical properties of SA node cells make their electrophysiology and pharmacology very different from that of other parts of the heart. In ventricular cells, the resting membrane potential is set primarily by the predominant K current that operates during diastole. The ventricular sarcolemma is highly permeable to K ions because the only ion channel that is appreciably open during diastole is the inwardly rectifying K channel (IK1). This high resting permeability of the cell membrane to K and the differences in intracellular and extracellular K concentrations generate a diastolic membrane potential of approximately --85 mV. The relationship between current flow and voltage is described by Ohm’s Law (Voltage = Current Resistance; or V= IR). Because the cell generates both inward and outward currents (ie, “alternating currents”) we use the term impedance rather than resistance. Figure 3 A shows the relationship for the resting membrane of a ventricular myocyte and IK1. This current-voltage relationship crosses the voltage axis at the resting membrane potential (ie around --85 mV) and, because the membrane is very permeable to K at these voltages, the slope of this relationship is steep (ie, conductance is high). Thus, at around --85 mV, where the impedance (resistance) of the membrane is low, the opening of any other channel, generating a small inward current in this example, gives rise to only a small effect on membrane voltage (Figure 3 A inset). This makes the resting potential of a ventricular cell inherently stable and protects the cell against inappropriate depolarization and arrhythmias—a useful feature for ventricular cells. In contrast, SA node cells lack IK1. Therefore (Figure 3 B),11 according to Ohm’s Law, the SA node cell’s impedance is ≈30 times that of a ventricular myocyte11,12 (ie, the slope of the currentvoltage relationship is much shallower). A small change in current in an SA node cell can thus result in a large change in membrane potential (Figure 3 B inset). Thus, the diastolic membrane potential of SA node cells is inherently unstable and very small changes in current can profoundly influence diastolic depolarization rate (heart rate). However, hormones and neurotransmitters of the autonomic nervous system utilize the numerous ion channels that can be opened and closed during diastole in the SA node, resulting in highly dynamic yet powerfully stable control of a variable heart rate, as a consequence of the high-input impedance. ◆ Characteristics of If If is an unusual inward current, first described by Brown et al,13 that is activated by hyperpolarization of the SA node cell. In 1979, a hyperpolarizationactivated inward current was viewed as so peculiar that it was termed the “funny” current — If. Subsequently, other functionally similar currents, generated by structurally related channels, have been identified in neuronal and retinal cells and have been termed hyperpolarization-activated currents, Ih.14 The role of If in the regulation of heart rate – Shattock and Curtis , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E Figure 4 shows the principal characteristics of If. If can be carried by a mixture of Na and K ions (although Na is the major carrier under physiologic conditions) and has all the features necessary to be a primary pacemaker current in the heart.15,16 Thus, If is an inward (depolarizing) current that is activated by hyperpolarization (negative membrane potentials of --50 mV, as seen throughout diastole in the SA node cell) (Figure 4 A). It will therefore cause sustained depolarization during diastole, contributing to diastolic “pacemaker” depolarization. The size A 500 ms 0 mV –45 mV –55 mV –65 mV –70 –75 mV B –45 –55 500 pA –65 –75 500 ms Figure 4. Spontaneous action potentials recorded from an isolated sinatrial nodal cell (A) and the hyperpolarization-activated (If) current recorded in response to voltage-clamp steps (B). The dotted lines in (A) indicate the voltages of the clamp-steps shown in (B). This illustrates that, in this case, the diastolic depolarization phase of the action potential goes from around --60 mV to around --50 mV in about 150 ms. Note: the slow activation kinetics of the currents shown in panel (B) mean that, at these voltages, the activation of If is relatively small after 150 ms. Redrawn from reference 16: Baruscotti M, DiFrancesco D. Pacemaker channels. Ann N Y Acad Sci. 2004;1015:111-121. Copyright © 2004, New York Academy of Sciences. of the current is increased by β-receptor stimulation, and inhibited by acetylcholine.13,15 Likewise, in isolated SA node cells, β-receptor stimulation increases, and acetylcholine slows, the rate of SA node cell diastolic depolarization (Figure 5A, next page).15 If the steady state activation of If is plotted against membrane potential (Figure 5 B),17 at --60 mV, only approximately 23% of channels are activated. However, in the presence of a β-agonist, this value is increased by 87%. The reason for this is that the channel is activated by cAMP, which is increased by β-agonism, via an intracellular cascade involving adenylyl cyclase. Conversely, acetylcholine activates muscarinic receptors, leading to inhibition of this cascade and the opposite effect on If activation. Because acetylcholine inhibits If at concentrations MEDICOGRAPHIA, VOL 28, No. 3, 2006 227 IF I N H I B I T I O N , H E A R T RAT E , A N D CO AR R O N A RY T E RY ACh (3 nM) Iso (10 nM) 20 mV Panel (A) is redrawn from reference 15: DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993;55:455-472. Copyright © 1993, Annual Reviews. Panel (B) is redrawn from reference 17: Accili EA, Robinson RB, DiFrancesco D. Properties and modulation of If in newborn versus adult cardiac SA node. Am J Physiol. 1997;272:H1549-1552. Copyright © 1997, American Physiological Society. 100 ms B testinal peptide (VIP),19 thyroid hormone (T3),20 and nitric oxide.21 Other endogenous inhibitors of If also exist, including by neuropeptide Y and adenosine.22 If current is mediated by a channel that is a member of the hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel family (Figure 6).16,23 In the SA node, 80% of the If current is derived from a channel encoded primarily by the HCN4 isoform.24-26 If current density and the expression of HCN4 channels are both greatest in cells at the periphery of the SA node and least in cells from the center.27-29 100% Iso (10 nM) Fraction of channels activated Control 87% increase ACh (3 nM) 23% 70% decrease mV –100 –50 0% 0 ◆ Effect of selective inhibition of If on heart rate Although it is anticipated from single-cell studies and from theory that drug modulation of If may alter heart rate, the likely magnitude of the effect in vivo of a selective If -inhibiting drug has been a subject of controversy.30-33 This is because the SA node action potential during diastole varies between approximately --60 mV at its most negative to approximately --55 mV, and this takes place over a period of approximately 200 ms (Figure 4 A) and that under these conditions, If is slow to activate and its amplitude is small (up to only 40 pA) (Figure 4 B). However, as described above, the design of the SA node is such that even such small currents can clearly influence heart rate. 20 times lower than those required to affect other (potassium) currents involved in pacemaking, it has been argued that If is the primary target via which acetylcholine slows heart rate under physiological conditions.18 However, it should be noted that acetylcholine can effect sinus arrest at higher concentrations (eg, during the vasovagal reflex), yet If inhibition (even 100% inhibition) merely slows heart rate to a modest extent, implying that, at high concentrations, acetylcholine slows heart rate in vivo by mixed actions on a number of ion channels. Other endogenous activators of If include vasoactive in- β-Receptor stimulation via Gs proteins + + 1 2 3 S E A S E Figure 5. Effect of β-receptor and muscarinic-receptor stimulation on (A) spontaneous action potentials recorded from an isolated SA nodal cell, and (B) the steady-state activation curve for If . Isoprenaline (Iso) accelerates and acetylcholine (ACh) slows the spontaneous rate of an isolated sinoatrial node cell by altering the rate of diastolic depolarization. The shaded area in both panels indicates the diastolic voltage range from --45 to --70 mV. Panel (B) shows that at --60 mV only 23% of the available channels are activated. However, the fraction of channels available increases by 87% in respose to isoprenaline (10 nM) or decreases by 70% in response to ACh (3 nM). Control A DI 4 + 5 + + + Muscarinic receptor stimulation via Gi proteins 6 His321 Adenylate cyclase H+ CN NH2 COOH 228 MEDICOGRAPHIA, VOL 28, No. 3, 2006 BD cA M P Figure 6. Diagram showing the stylized structure of the HCN channel. The monomeric channel protein channel consists of six transmembrane segments.16 The intact channel appears to assemble as a tetramer and evidence suggests that this may involve a heteromeric mixture of different HCN isoforms. The S4 domain contains 10 regularly spaced charged residues that form the voltage sensor and this domain moves in the outward direction upon depolarization. The S5-S6 loop forms the channel pore and contains a conserved GYG sequence typical of K-permeable channels. The intracellular carboxy terminal contains a cyclic nucleotide binding domain (CNBD), which activates the channel when bound to cAMP. Hence, modulation of cytoplasmic cAMP concentration following G-protein coupled receptor stimulation, can modulate channel activity. Histidine 321 confers the pH sensitivity of this channel with acidosis inhibiting channel opening.23 The role of If in the regulation of heart rate – Shattock and Curtis IF I N H I B I T I O N Cardiomyocytes from mice with a homozygote deletion of the gene encoding HCN4 beat at a rate 40% below that of controls.34 This would appear to indicate that If contributes to pacemaker function, but is not the sole determinant of heart rate. This is supported by both pharmacological experiments in isolated node cells (Figure 7 A, B) and computer simulations of nodal function (Figure 7 C). The effect of inhibiting If with ivabradine in an isolated SA nodal cell is shown in Figure 7. A low concentration of ivabradine may evoke a modest rate reduction in isolated SA node cells (Figure 7A) with the effect mediated entirely on diastolic depolarization (no change in action potential shape),16 an effect contrasting with that of β-antagonists, verapamil, and diltiazem, which affect pacemaking and SA node cell action potential shape. A higher concentration (3 µM) of ivabradine reduces If by ≈78% (Figure 7 B). Figure 7 C shows a computer simulation (Cellular Open Resource; COR—Oxford University),35 which predicts that, as in the recorded data of Figure 7 B, under steady state conditions, complete inhibition of If will reduce SA node rate by approximately 20% to 30% in an isolated cell. The absence of If in HCN4-deficient hearts not only lowers their basal heart rate, but also abolishes their response to an elevation of intracellular cAMP, suggesting that If may be exclusively responsible for the chronotropic effect of β-adrenoceptor agonism.34 This observation is particularly important because it may allow If inhibition not only to cause potentially therapeutic lowering of basal heart rate, but may also limit the tachycardic response to β-receptor stimulation. ◆ Therapeutic effects of If inhibition While the contribution of If to pacemaking in isolated cells under laboratory conditions has been the subject of debate, what is beyond doubt is that drugs reported to be specific and selective inhibitors of If do slow heart rate in man. For example, ivabradine reduces heart rate by 10-15 bpm in clinical studies,36 over a blood range of concentrations (0.3-3 µM) known to be sufficient, in separate isolated tissue studies, to achieve potent and relatively selective inhibition of If.37 Given that such agents clearly slow heart rate, what therapeutic advantage might this present? It has long been speculated that reducing heart rate may have benefit in a variety of conditions, in angina,38 heart failure,39 and even cancer.40 However, a high heart rate may not represent a causal factor itself in disease since it may be secondary to a high sympathetic tone. The latter may be a consequence of the disease, with the underlying cause being heart rate–independent. In addition, the successful therapeutic goal of reducing sympathetic tone by the use of β-blockers is not itself a selective method of slowing heart rate since variables in addition to heart rate are regulated by sympathetic tone, including some of the variables, such as heart size and blood vessel wall thickness, that contribute to cardiac and vascular remodeling in heart failure and hypertension. Nevertheless, with the working hypothesis that selective (sympathetic-independent) heart rate low- The role of If in the regulation of heart rate – Shattock and Curtis , H E A R T A RAT E , A N D CO R O N A RY AR T E RY DI S E A S E Ivabradine (0.3 µM) Control 20 mV 100 ms B +5 mV –35 mV –70 mV Ivabradine (0.3 µM) 200 pA Control 2s C Control Complete inhibition of I f 20 mV 500 ms Figure 7. Effects of inhibition of If on spontaneous action potentials from an sinoatrial (SA) node cell (A), and current recorded in a voltage-clamped SA node cell (B), and a computer model of the SA node action potential (C). (A) Ivabradine (0.3 µM) slows the spontaneous rate of an isolated SA node cell by slowing the diastolic depolarization phase without affecting the shape of the subsequent action potential. (B) Ivabradine (3 µM) inhibits If in a voltage-clamped isolated SA node cell. (C) Complete inhibition of If in a computer-simulated model of the SA node action potential using the Cellular Open Resource program developed by Noble and colleagues35 slows, but does not abolish, repetitive activity. Panels (A) and (B) are redrawn from reference 16: Baruscotti Baruscotti M, DiFrancesco D. Pacemaker channels. Ann N Y Acad Sci. 2004;1015:111-121. Copyright © 2004, New York Academy of Sciences. ering is a potentially viable therapeutic mechanism, the pharmaceutical industry has synthesized and begun to develop several selective bradycardic agents that lower heart rate without the associated negative inotropic effects encountered with use of β-antagonists or verapamil and diltiazem.41 These agents include alinidine, zatebradine, and ivabradine, some of which are sometimes referred to as specific bradycardic agents (although “selective” would be a more appropriate term since β-antagonists, verapamil, and diltiazem are all “specific” bradycardic agents in that they act directly on the SA node). Figure 8 A (next page) shows the relationship between ivabradine concentration and inhibition of If , while Figure 8B37 shows a dose-titration study in MEDICOGRAPHIA, VOL 28, No. 3, 2006 229 IF I N H I B I T I O N , H E A R T A RAT E , A N D CO R O N A RY AR T E RY I f inhibition (%) 100 50 IC50 = 2.210–6 M 0 10–8 10–7 10–6 10–5 10–4 Concentration of ivabradine (M) HR (bpm) B 75 60 45 Ivabradine dose (mg bid) 30 0 D0 10 15 20 D7 D14 D21 Figure 8. Dose-dependent effects of ivabradine on If (A) and heart rate (B). (A) Dose-response curve for steady-state inhibition of If measured in a rabbit sinoatrial node cell paced at 6 Hz with a 1.8-s voltage-clamp step from --30 mV to --100 mV. (B) Effects of ivabradine on heart rate from a dose-titration study in which ivabradine concentration was incrementally increased every 7 days from control (0) to 20 mg (bid). Panel (A) is redrawn from reference 37: Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol. 1996;118:1051-1057. Copyright © 1996, Nature Publishing Group. REFERENCES 1. Boyett MR, Honjo H, Kodama I. The sinoatrial node: a heterogeneous pacemaker structure. Cardiovasc Res. 2000;47:658687. 2. Bleeker WK, Mackaay AJ, Masson-Pevet M, Bouman LN, Becker AE. Functional and morphological organization of the rabbit sinus node. Circ Res. 1980;46:11-22. 3. Opthof T. The mammalian sinoatrial node. Cardiovasc Drugs Ther. 1988;1:573-597. 4. Opthof T, Coronel R. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res. 2000;45:175-176. 5. Shiraishi I, Takamatsu T, Minamikawa T, Onouchi Z, Fujita S. Quantitative histological analysis of the human sinoatrial node during growth and aging. Circulation. 1992;85:2176-2184. 6. Verheijck EE, Wessels A, van Ginneken AC, et al. Distribution of atrial and nodal cells within the rabbit sinoatrial node: models of sinoatrial transition. Circulation. 1998;97:1623-1631. 7. Honjo H, Boyett MR, Kodama I, Toyama J. Correlation between electrical activity and the size of rabbit sino-atrial node cells. J Physiol. 1996;463:795-808. 8. Shattock MJ. The initiation of the heart beat. Eur Heart J. 1999;1:H11-H17. 9. Boyett MR, Harrison SM, Janvier NC, McMorn SO, Owen JM, Shui Z. A list of vertebrate cardiac ionic currents: Nomenclature, properties, function and cloned equivalents. Cardiovasc Res. 1996;32:455-481. 10. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the 230 MEDICOGRAPHIA, VOL 28, No. 3, 2006 DI S E A S E patients where the dose of ivabradine has been increased stepwise from 5 to 20 mg bid. The peak heart rate–lowering effect is a 30% fall in heart rate and this occurs with 10 mg (bid) and does not increase with further dose increments. This is in accord with the in vitro and simulation data shown in Figure 7C, suggesting that even complete inhibition of If will not cause severe bradycardia or sinus arrest. Earlier we introduced the concept of the importance of If in mediating the chronotropic response to sympathetic stimulation. At the cellular level, an increase in beating rate and frequency of depolarization can influence drug action via the “use-dependence” of the drug’s action. However, although ivabradine is a use-dependent open-state If channel inhibitor,37 its negative chronotropic effect in the human is similar at rest and during exercise.36 This implies that either the use-dependence is insufficient to make the drug tachycardia-selective, or that its use-dependent extra effect on pacemaking during tachycardia is surmounted uncompetitively by other factors altered by the tachycardia. In much the same way, selective inhibitors of the inward rectifying potassium channel in ventricular myocardium do not show use-dependent effects on ventricular repolarization in vivo despite showing usedependent inhibiting effects on the relevant channel in the laboratory, owing to a tachycardia-induced increase in the size of a current associated with a separate potassium channel, which opposes the drug’s effect on repolarization, and is not inhibited by the drug.42,43 Conclusion Targeting If appears to produce a bradycardic effect of significant, but limited extent in the human heart. This has the potential to provide benefit in several cardiovascular diseases without the concomitant scope for adverse effects encountered with other nonselective bradycardic agents that also affect autonomic function and vascular tone. ❒ sinoatrial node. Physiol Rev. 1993;73:197-227. 11. Noma A, Nakayama T, Kurachi Y, Irisawa H. Resting K conductances in pacemaker and non-pacemaker heart cells of the rabbit. Jpn J Physiol. 1984;34:245-254. 12. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sinoatrial node. Physiol Rev. 1993;73:197-227. 13. Brown HF, DiFrancesco D, Noble SJ. How does adrenaline accelerate the heart? Nature. 1979;280:235-236. 14. Pape HC. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu Rev Physiol.1996; 58:299-327. 15. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993;55:455-472. 16. Baruscotti M, DiFrancesco D. Pacemaker channels. Ann N Y Acad Sci. 2004;1015:111-121. 17. Accili EA, Robinson RB, DiFrancesco D. Properties and modulation of If in newborn versus adult cardiac SA node. Am J Physiol. 1997;272:H1549-1552. 18. DiFrancesco D, Ducouret P, Robinson RB. Muscarinic modulation of cardiac rate at low acetylcholine concentrations. Science. 1989;243:669-671. 19. Chang F, Yu H, Cohen IS. Actions of vasoactive intestinal peptide and neuropeptide Y on the pacemaker current in canine Purkinje fibers. Circ Res. 1994;74:157-162. 20. Renaudon B, Lenfant J, Decressac S, Bois P. Thyroid hormone increases the conductance density of f-channels in rabbit sino- The role of If in the regulation of heart rate – Shattock and Curtis IF I N H I B I T I O N atrial node cells. Receptors Channels. 2000;7:1-8. 21. Musialek P, Lei M, Brown HF, Paterson DJ, Casadei B. Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, If . Circ Res. 1997;81:60-68. 22. Zaza A, Rocchetti M, DiFrancesco D. Modulation of the hyperpolarization-activated current If by adenosine in rabbit sinoatrial myocytes. Circulation. 1996;94:734-741. 23. Zong X, Stieber J, Ludwig A, Hofmann F, Biel M. A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2. J Biol Chem. 2001;276:6313-6319. 24. Ishii TM, Takano M, Xie LH, Noma A, Ohmori H. Molecular characterization of the hyperpolarization-activated cation channel in rabbit heart sinoatrial node. J Biol Chem.1999;274:1283512839. 25. Shi W, Wymore R, Yu H, et al. Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res. 1999;85:e1-e6. 26. Moosmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem. 2001;268:1646-1652. 27. Kreitner D. Electrophysiological study of the two main pacemaker mechanisms in the rabbit sinus node. Cardiovasc Res. 1985;19:304-318. 28. Nikmaram MR, Boyett MR, Kodama I, Suzuki R, Honjo H. Variation in effects of Cs+, UL-FS-49, and ZD-7288 within sinoatrial node. Am J Physiol. 1997;272:H2782-2792. 29. Efimov IR, Nikolski VP, Rothenberg F, et al. Structure-function relationship in the AV junction. Anat Rec A Discov Mol Cell Evol Biol. 2004;280:952-965. 30. Vassalle M. The pacemaker current If does not play an important role in regulating SA node pacemaker activity. Cardiovasc Res. 1995;30:309-310. 31. DiFrancesco D. The pacemaker current If plays an important role in regulating SA node pacemaker activity. Cardiovasc Res. 1995;30:307-308. 32. Noma A, Morad M, Irisawa H. Does the “pacemaker current” RÔLE , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E generate the diastolic depolarization in the rabbit SA node cells? Pflugers Arch. 1983;397:190-194. 33. Boyett MR, Kodama I, Honjo H, Arai A, Suzuki R, Toyama J. Ionic basis of the chronotropic effect of acetylcholine on the rabbit sinoatrial node. Cardiovasc Res. 1995;29:867-878. 34. Stieber J, Herrmann S, Feil S, et al. The hyperpolarizationactivated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc Natl Acad Sci U S A. 2003;100:15235-15240. 35. Garny A, Kohl P, Noble D. Cellular Open Resource (COR): a public CellML based environment for modelling biological function. Int J Bif Chaos. 2003;13:3579-3590. 36. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823. 37. Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol. 1996;118:1051-1057. 38. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974. 39. Tavazzi L. Heart rate as a therapeutic target in heart failure? Eur Heart J. 2003;5:G15-G18. 40. Benetos A, Thomas F, Safar ME, Bean KE, Guize L. Should diastolic and systolic blood pressure be considered for cardiovascular risk evaluation: a study in middle-aged men and women. J Am Coll Cardiol. 2001;37:163-168. 41. Borer JS. Drug Insights: If inhibitors as specific heart-rate reducing agents. Nat Clin Pract Cardiovasc Med.2004;1:103-109. 42. Jurkiewicz NK, Sanguinetti MC. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res. 1993;72:75-83. 43. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol.1990;96:195-215. DU COURANT IF DANS LA RÉGULATION DE LA FRÉQUENCE CARDIAQUE L a fréquence cardiaque des mammifères est déterminée par le nœud sinoauriculaire (SA), pacemaker situé dans l’oreillette droite. Les cellules nodales expriment une série remarquable de canaux ioniques qui provoquent la dépolarisation spontanée de leur potentiel membranaire diastolique (dépolarisation pacemaker) à l’origine du déclenchement et de la propagation d’un potentiel d’action lorsqu’un seuil est atteint. Les cellules du pacemaker SA règlent la fréquence cardiaque car leur dépolarisation survient plus rapidement que celles des autres cellules cardiaques à activité spontanée (par exemple, les cellules du nœud auriculo-ventriculaire, les fibres de Purkinje, etc). Au moins 10 courants ioniques (ou canaux) différents sont mis en jeu dans la dépolarisation diastolique et le potentiel d’action du nœud SA. Il semble que les molécules agissant de façon sélective sur ces canaux soient limitées par une réserve physiologique qui rend difficile l’arrêt du nœud. En revanche, il peut suffire de très légères modifications des courants faibles pour exercer une influence marquée sur le taux de décharge nodal, car les cellules du nœud SA ne possèdent pas de grand courant potassique (IK1) de fond indépendant du temps, contrairement à la plupart des autres cellules cardiaques, et elles ont une impédance d’entrée proportionnellement élevée. Ces caractéristiques des cellules nodales expliquent que de légers changements du faible courant pacemaker If peuvent influer significativement sur la fréquence cardiaque. L’hypothèse a été émise que le courant If était le régulateur physiologique primaire de la réponse nodale SA à la stimulation neurohormonale. Le rôle du courant If dans la régulation de la fréquence cardiaque ainsi que la redondance naturelle des nombreux courants participant au potentiel d’action global permettent à l’action inhibitrice de l’ivabradine sur le courant If , de ralentir pharmacologiquement la fréquence cardiaque en toute sécurité sans dépasser la limite imposée par la réserve physiologique. ✦ The role of If in the regulation of heart rate – Shattock and Curtis MEDICOGRAPHIA, VOL 28, No. 3, 2006 231 IF I N H I B I T I O N , H E A R T R A T E , AND CORONARY ARTERY DISEASE he pacemaker current If is a mixed voltageand cyclic nucleotide–gated cation current that activates upon hyperpolarization; it represents a prominent depolarizing current in cardiac cells that show spontaneous electrical activity (see 1 for review). In the mammalian cardiac sinus node, the pacemaker current If plays a pivotal role in the generation of the diastolic depolarization of pacemaker cells and thus in the physiological control of heart rate.1 If is typically found in the specialized cells of the conduction system, eg, in sinoatrial node cells and Purkinje fibers, which possess a well-defined diastolic depolarization phase. In these cells it is thought to mediate the β-adrenergic control of heart rate via its direct modulation by cAMP. The molecular correlates of native pacemaker channels are the HCN (hyperpolarization-activated, cyclic nucleotide–gated) channels. Four HCN channels underlie the native If : the subtype assembly that produce If specific for different cells and tissues throughout the organism is yet unknown. Three isoforms are present in the heart (HCN1, HCN2, HCN4) with varying expression levels in different cardiac regions: in the sinoatrial node, HCN4 appears to be the predominant isoform in all species.2 The study of f-channels in nonpacemaker cardiac cells has long been disregarded for at least two reasons: (i) the assumption that If expression should be confined only to the sinus node and other parts of the conduction system endowed of automaticity; (ii) the lack of molecular assays (genes encoding for f-channels have been cloned only recently). A large amount of experimental data, initially only from electrophysiological studies, and subsequently from molecular studies, have now convincingly demonstrated that the pacemaker current If and HCN channels are also present in nonpacemaker tissues. The hypothesis that the “pacemaker” current could be present in diseased ventricular cells was advanced for the first time by one of us (A. M.) as a result of speculations on the possible electrophysiological basis for the diastolic depolarization phase observed between driven action potentials that a young researcher had recorded from papillary muscles isolated from the hypertrophied hearts of senescent hypertensive rats.3 The presence of a diastolic depolarization phase was surprising and unexpected since, by definition, the membrane potential of cells of the working myocardium does not change during diastole. Two facts excluded that the observation could be due to an experimental ▲▲ ▲ T Alessandro MUGELLI, MD, FESC Elisabetta CERBAI, PhD Professors of Pharmacology Center of Molecular Medicine CIMMBA Department of Preclinical and Clinical Pharmacology Firenze, ITALY The If current beyond heart rate regulation by A. Mugelli and E. Cerbai, Italy he role of the If pacemaker current in the generation and modulation of the sinus node pacemaker activity has been amply described. In sinoatrial node cells and in neonatal cardiomyocytes, If contributes significantly to spontaneous diastolic depolarization. However, If is present not only in primary and subsidiary pacemakers, but also in nonautomatic cardiac tissue. Electrophysiological and molecular data collected over the last 10 years demonstrated that f-channels are also present in nonpacemaker cardiomyocytes. In cardiac hypertrophy and in heart failure, If current densities and/or mRNA levels of its molecular correlate (ie, hyperpolarization-activated cyclic nucleotide-gated [HCN] channels) are increased compared with controls. Similar, but limited data have been reported in atrial fibrillation. Expression and/or overexpression of f-channels in nonpacemaker cells are one of the consequences of the process of cardiac remodeling and it has been suggested that this phenomenon may represent an arrhythmogenic mechanism in heart failure, a condition associated with high risk for sudden cardiac death. However, it remains controversial whether If overexpression plays a role in the increased propensity of arrhythmias in diseased states, as If current activation is obtained at more negative potentials in working myocardium than in pacemaker cells. The availability of selective f-channel inhibitors such as ivabradine will help in the near future to assess the potential arrhythmogenic role of If in heart disease. T Medicographia. 2006;28:232-237. (see French abstract on page 237) Keywords: pacemaker channel; atrial myocyte; ventricular myocyte; heart failure; I f inhibitor; electrophysiological remodeling; arrhythmia Address for correspondence: Alessandro Mugelli, MD, Professor of Pharmacology, Center of Molecular Medicine CIMMBA, Department of Preclinical and Clinical Pharmacology, Viale G. Pieraccini 6, 50139 Firenze, Italy (e-mail: [email protected]) 232 MEDICOGRAPHIA, VOL 28, No. 3, 2006 SELECTED 5-HT Ang II ANP AT1 HCN LVH SHR β-AR ABBREVIATIONS AND ACRONYMS serotonin angiotensin II atrial natriuretic peptide angiotensin II type 1 receptor hyperpolarization-activated cyclic-nucleotide–gated (channel) left ventricular hypertrophy spontaneously hypertensive rat β-adrenoceptor The If current beyond heart rate regulation – Mugelli and Cerbai IF I N H I B I T I O N artifact: first, the diastolic phase was, as expected, completely flat in the recordings that had been obtained from papillary muscles isolated from normal hearts and studied under similar experimental conditions. Second, and most important, the diastolic depolarization phase was dose-dependently steepened by β-adrenoceptor (βAR) stimulation with isoprenaline, to such an extent that spontaneous action potentials were easily generated in the hypertrophied ventricular tissue.3 Since the number and affinity of βARs were not altered,3 we postulated that the sensitivity to catecholamines and the presence of a diastolic depolarization phase were due to electrophysiological alterations (eg, the presence of delayed afterdepolarizations) caused by cardiac hypertrophy. This is what we wrote in the paper submitted to the Journal of Molecular and Cellular Cardiology (published in July 1994), but we immediately planned a series of experiments to test the hypothesis that the diastolic depolarization could be due to the atypical occurrence of the pacemaker current in diseased ventricular tissue. In a very short time, Elisabetta Cerbai was able to record a current having the characteristics of If in left ventricular myocytes isolated from the hypertrophied heart of hypertensive rats; we were able to publish its characterization in the December 1994 issue of the Journal of Physiology.4 This is how the story of If beyond heart rate control started. This article will review the present knowledge concerning: (i) the presence of If in nonpacemaker cardiac tissue such as atrial and ventricular myocytes in physiological and pathological conditions; (ii) the characteristics of If functionality in pathological conditions focusing on studies performed in failing hearts; and (iii) the possible clinical implications of the presence of If in ventricular myocytes and of its pharmacological blockade. I f and atrial myocytes The existence of If in fibers from the human atrial appendage was reported more than 20 years ago in abstract form.5 If was then characterized in isolated human atrial myocytes isolated from atrial appendages excised during corrective cardiosurgery by several groups6 who also studied its modulation by neurotransmitters.7,8 The role and contribution of If to atrial electrogenesis remains controversial since there is a large variability in current amplitude from cell to cell,7 and, furthermore, the current activates at voltages that are more negative than the physiological diastolic potential of atrial cells.8 The observation that stimuli likely involved in the genesis of atrial arrhythmias like serotonin (5-HT) were able to shift the activation curve of If toward more positive potentials,9 suggested that under certain circumstances If could be implicated in atrial arrhythmias.10 When f-channel mRNA was reported to increase in human atrial specimens isolated from patients with atrial fibrillation,11 the question of whether If overexpression might play a role in the increased propensity of arrhythmias in diseased states became compelling. Irrespective of the role of If in atrium The If current beyond heart rate regulation – Mugelli and Cerbai , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E under normal conditions, the problem was to determine whether pathological conditions and/or activation of specific intracellular pathways by neurohumoral signals could amplify or modify the properties of the If current constitutively present in atrial myocytes, giving it an important role in the genesis of atrial arrhythmias. Among the many different signals, serotonin and atrial natriuretic peptide (ANP) are peculiar to the human atrium and have been investigated in our laboratory. The 5-HT4 receptor subtype is present in the atrium of large animals, including humans, and is not present in the ventricle.12,13 Their stimulation increases cAMP. ANP is synthesized and stored as prohormone in granules localized in human atrial myocytes.14 Upon atrial distension, ANP is released from its stores and may interact with specific membrane-bound receptors having guanylyl cyclase (GC) activity localized in atrial myocytes.14 Thus, their stimulation increases intracellular cGMP. Both 5-HT and ANP increase If in human atrial myocytes8; the effect is concentration-dependent and occurs at concentrations likely reached upon local release of 5-HT by platelet aggregation or of ANP by cell stretching. Furthermore, the effects of 5-HT and ANP are likely additive due to the involvement of two distinct pathways: activation of adenylate cyclase by 5-HT, which increases cAMP levels,9,15 and cGMP-dependent inhibition of phosphodiesterases by ANP, which further enhances intracellular cAMP.15 These results support the view that under specific conditions If could influence cell excitability and predispose to the occurrence of atrial arrhythmias. However, recent unpublished data16 obtained in human atrial appendages excised during cardiac surgery from patients in sinus rhythm or with chronic atrial fibrillation do not indicate any physiological or molecular overexpression of f-channels in this setting, suggesting that the process of electrophysiological remodeling in chronic atrial fibrillation does not involve If . Thus, the role of If present in human atrial myocytes remains controversial and should be clarified by further in vitro and in vivo studies. I f and ventricular myocytes If is abundantly expressed in ventricular myocytes during fetal and neonatal life.17-19 If is also detected early during differentiation in murine beating myocytes derived from embryonic stem cells.20 Obviously, during the process of electrophysiological maturation toward the adult ventricular phenotype, these cells at some time point lose their capacities of generating spontaneous activity. This phenomenon is associated with a progressive reduction in If current expression both in mouse and rat ventricles.17,18 In our experience, the If current occurs in all ventricular myocytes early after birth, but is only present in 50% after 2 weeks and in 30% at 4 weeks of age; at this age the amplitude of If is much smaller than in newborn rats.17 In the adult animal, as expected, If is not present (Figure 1, next page). These changes are part of the normal process of electrophysiological maturation, which in rat ventricular myocytes is characterized by a progressive MEDICOGRAPHIA, VOL 28, No. 3, 2006 233 IF I N H I B I T I O N , H E A R T 2 days RAT E , A N D CO R O N A RY 2 weeks AR T E RY 2 months 0 mV –40 200 ms 0 – 70 pA 0 0 –90 –500 –110 500 ms Figure 1. If expression during aging. Representative recordings of action potentials and corresponding hyperpolarization-activated currents obtained in ventricular myocytes isolated from 2-day-old, 2-week-old, and 2-month-old rat hearts. shortening of the action potential duration (Figure 1) largely due to an increase in the potassium outward current Ito , which is the main current controlling cell repolarization in the rat heart. During cardiac hypertrophy, the action potential duration of rat ventricular myocytes is progressively prolonged as the severity of hypertrophy increases and this is largely due to a decrease in the repolarizing current Ito .21 Interestingly enough, while ventricular expression of Ito is reduced, the ventricular myocytes can reexpress If during adult life in certain pathophysiological conditions. In fact, a striking upregulation of If expression has been observed in ventricular myocytes in a variety of animal models of cardiac hypertrophy and failure4,22-24; in those circumstances, If seems to resume its “fetal” role, and a diastolic depolarization phase can be detected in ventricular preparations3 or in cardiomyocytes isolated from the hypertrophied ventricle.4 Figure 2 summarizes the changes occurring in If expression in ventricular cardiomyocytes during the life span of the rat, in physiological or in pathological conditions. Disappearance of If in ventricular myocytes during early development occurs while Hypertrophic factors If expression (pS/pF) Pathological overexpression Physiological expression 2 days 15 days Neonate 1 mo 2 mo 12 mo Adult 24 mo Old Figure 2. Lifetime changes in If density under physiological and pathological conditions. Each bar represents the density of If recorded in ventricular myocytes isolated from the heart of rats of different ages under physiological or pathological conditions (hypertrophic factors such as angiotensin II). The horizontal arrow indicates the density physiologically present in the working myocardium of the adult animal; under those conditions, If does not have any functional role. 234 MEDICOGRAPHIA, VOL 28, No. 3, 2006 DI S E A S E cell size increases, as postnatal cellular growth develops. During pathophysiological hypertrophy, both cell size and If density increase. Thus, If is expressed independently of the cell dimensions, ie, a larger cell has not necessarily a larger current. It is rather If density (ie, amplitude normalized to cell size, thus excluding the contribution of cellular hypertrophy) that is directly related to the severity of cardiac hypertrophy caused by pressure overload.22 Cardiac hypertrophy, as occurs in the normal process of aging, is not a sufficient stimulus for the reexpression of the current.22 Consequently, it appears that it is not the cellular growth per se that triggers this phenomenon, but other factors are involved (hypertrophic factors, as shown in Figure 2 ). Overexpression of If has been detected in all animal models of cardiac hypertrophy/failure tested so far, as well as in human failing hearts. The extent of the increase in If density is not homogeneous in the different pathological conditions. In order to better appreciate the relative importance of the phenomenon in the different settings, the proportional increase observed in ventricular myocytes isolated from diseased hearts was compared with normal controls. The values were corrected for cell size, since the degree of cellular hypertrophy may affect the absolute value of the current: consequently, current amplitude is normalized with respect to membrane capacitance, an index of cell size, and then expressed as current density.25 If density was increased more than twofold in left ventricular myocytes isolated from the hearts of rats with severe cardiac left ventricular hypertrophy (LVH) caused by pressure overload. The increase was even larger in the rats with signs of heart failure caused by pressure overload; a large overexpression was also present in rats with chronic myocardial infarction (Figure 3). Increased If density was linearly correlated with the degree of hypertrophy,22 and changes in expression levels were most pronounced in the cardiac regions with highest overload,24,26 suggesting that the remodeling process is likely to affect the level of channel expression directly. That the etiology of the disease is important for the degree of If overexpression is supported by data obtained in failing human ventricles from transplanted patients.27,28 As shown in Figure 3, If density was greater in ischemic cardiomyopathy than in idiopathic dilated cardiomyopathy.29 A correlation with the severity of cardiac disease was obviously impossible since all patients were affected by terminal heart failure. Furthermore, studies in human preparations have the usual limitations due to individual variability, chronic or acute therapies, paucity of human samples, difficulties in cell isolation, etc. Despite these obvious limitations, the difference seems to be real and is supported by a different voltage dependence among the If activation curves in ischemic cardio-myopathy versus control hearts. A modification of the level of protein expression does not explain differences in the activation curves; instead, it could be that, in diseases, HCN isoforms (which have different intrinsic properties30) coassemble to form channels with different electrophysiological characteristics. The If current beyond heart rate regulation – Mugelli and Cerbai IF I N H I B I T I O N NS ICM Man DCM PMI-HF PO-HF Rat Severe LVH Mild LVH 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 I f overexpression , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E Figure 3. Ventricular If expression is increased in cardiomyopathies. Each point represents the ratio between current density measured in ventricular cardiomyocytes from rat or human diseased hearts, and respective controls; confidence intervals (95%) are omitted for the sake of clarity. Mild LVH, Severe LVH: relative increase of If in rats with mild or severe left ventricular hypertrophy caused by aortic banding23 or long-lasting pressure overload,22 respectively. PO-HF, PMI-HF: relative increase of If in rats with overt heart failure, resulting from uncompensated hypertrophy due to pressure-overload22 or following a myocardial infarction due to coronary ligation,24 respectively. DCM, ICM: relative increase in If in patients undergoing cardiac transplantation for terminal dilated or ischemic cardiomyopathy, respectively.29 For all conditions, the relative increase in If density was statistically significant versus controls, that is, normo-tensive rats, sham-operated rats, or nondiseased donor hearts not transplanted for technical reasons, with the exception of DCM patients (NS: not significant). To date, the molecular basis of If overexpression in human heart failure remains largely unknown. A 3-fold increase in mRNA coding for HCN4 was reported in end-stage failing human hearts.31 Recent unpublished work demonstrated an increased expression of HCN2 and HCN4 at both mRNA and protein levels in samples obtained from transplanted patients with ischemic cardiomyopathy.32 A recent paper reports for the first time detailed singlechannel analysis of heterologously expressed HCN isoforms and native human If, demonstrating that recombinant HCN isoforms differ profoundly in their single-channel properties.33 Activation of single HCN/If channels was observed at potentials more positive than previously reported in whole-cell experiments, which strongly indicates a potential role of these channels for arrhythmogenesis. On the whole, these observations support a potential role of HCN/If for the arrhythmogenesis of working myocardium under pathological conditions.33 Further support for this view is derived by considering the effects of the sympathetic activation: by increasing intracellular cAMP levels, β-adrenergic stimulation increases the degree of If activation, the current becoming faster and of larger amplitude.34 Since maximum current amplitude does not change, the net result is a rightward shift of the If activation curve, ie, at the same potential there is a larger degree of current activation. This effect is particularly intriguing in view of the potential arrhythmogenic role of If in heart failure: in a setting of enhanced sympathetic drive, If is more likely to be arrhythmogenic in the working myocardium. I f and cardiac remodeling Overexpression of cardiac HCN channels in ventricular myocytes represents an example of the process of cardiac remodeling, a general phenomenon occurring in heart failure, which basically consists in the reexpression of fetal proteins.35 It is well known that the renin-angiotensin system plays a pivotal role in ventricular remodeling.36 The chronic activation of the system, as it occurs in many cardiovascular diseases, results in an overproduction of angiotensin II (Ang II), whose plasmatic and/or tis- The If current beyond heart rate regulation – Mugelli and Cerbai sue levels are increased. Ang II promotes a variety of cellular responses within the myocardium: myocyte and fibroblast growth, collagen deposition, myocytic apoptosis, etc. Directly or indirectly, these effects are mediated by the stimulation of type 1 Ang II receptors, AT1.37-39 Although the signaling pathways switching off/on If expression in nonpacemaker cardiac cells are largely unknown, the reninangiotensin system seems to play a pivotal role. In fact, chronic administration of AT1 blockers (losartan or irbesartan) to old spontaneously hypertensive rats (old SHR) not only reduces cardiac hypertrophy, but also hampers If overexpression.40,41 The effects on If are summarized in Figure 4: irbesartantreated SHRs show a smaller If density than control WKY Nontreated old SHR 0 gf (pS/pF) 0 20 40 pA/pF –5 Nontreated SHR IRBE-treated SHR 0 pA/pF –5 IRBE-treated old SHR 0 1000 ms 0 V1/2 (–mV) 90 Figure 4. Effect of treatment with irbesartan (IRBE) on If measured in left ventricular myocytes of 18-month-old spontaneously hypertensive rats (old SHR). Typical recordings of the current (left panels) evoked by applying a train of hyperpolarizing steps, from --60 to --130 mV. Specific current conductance (gf) and voltage of half maximal activation (V1/2) are reported for both treated and nontreated SHR. The dotted line represents the mean values of gf and V1/2 in age-matched normotensive Wistar-Kyoto rats (WKY), statistically different from nontreated SHR. Modified from reference 41: Cerbai E, De Paoli P, Sartiani L, Lonardo G, Mugelli A. Treatment with irbesartan counteracts the functional remodeling of ventricular myocytes from hypertensive rats. J Cardiovasc Pharmacol. 2003;41:804-812. Copyright © 2003, Lippincott Williams & Wilkins. MEDICOGRAPHIA, VOL 28, No. 3, 2006 235 IF I N H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY rats (nontreated old SHR). Under these experimental conditions, irbesartan exerted a slight, although significant, antihypertensive effect; similar results were, however, obtained with losartan at doses that did not affect blood pressure.40 The right part of Figure 4 shows that the effect of AT1 blockers (angiotensin-receptor blockers, ARBs) was due to a reduction in maximal specific conductance of If (gf) toward values similar to those obtained in agematched Wistar-Kyoto rats; the properties of the channel such as the voltage of half maximal activation (V1/2) are not modified by the disease or by the treatment. These data obviously do not imply a unique or a direct role of Ang II in regulating HCN transcription; in fact a relevant role is also played by other Gq-protein agonists (such as endothelin-1 or norepinephrine).42 However, the data suggest the following consideration: if some of the beneficial effects of ARBs on patients with heart failure, (eg, reduction in risk of sudden death) are due to their effect on If , it is possible to speculate that selective blockers of If could have an even larger beneficial effect in such patients. I f inhibitors in nonpacemaker cells The data presented so far strongly suggest that If might indeed contribute to arrhythmogenesis in diseases characterized by If overexpression such as hypertrophy and heart failure, and clearly indicate a potential therapeutic role of specific If blockers in REFERENCES 1. Baruscotti M, Bucchi A, DiFrancesco D. Physiology and pharmacology of the cardiac pacemaker (“funny”) current. Pharmacol Ther. 2005;107:59-79. 2. Marionneau C, Couette B, Liu J, et al. Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart. J Physiol (Lond). 2005;562:223-234. 3. Barbieri M, Varani K, Cerbai E, et al. Electrophysiological basis for the enhanced cardiac arrhythmogenic effect of isoprenaline in aged spontaneously hypertensive rats. J Mol Cell Cardiol.1994; 26:849-860. 4. Cerbai E, Barbieri M, Mugelli A. Characterization of the hyperpolarization-activated current, If , in ventricular myocytes isolated from hypertensive rats. J Physiol (Lond).1994;481:585-591. 5. Carmeliet E. Existence of pacemaker current If in human atrial appendage fibres. J Physiol (Lond). 1984;357:125P. Abstract. 6. Heidbuchel H, Vereecke J, Carmeliet E. The electrophysiological effects of acetylcholine in single human atrial cells. J Mol Cell Cardiol. 1987;19:1207-1219. 7. Thuringer D, Lauribe P, Escande D. A hyperpolarization-activated inward current in human myocardial cells. J Mol Cell Cardiol. 1992;24:451-455. 8. Porciatti F, Pelzmann B, Cerbai E, et al. The pacemaker current If in single human atrial myocytes and the effect of beta-adrenoceptor and A1-adenosine receptor stimulation. Br J Pharmacol. 1997;122:963-969. 9. Pino R, Cerbai E, Calamai G, et al. Effect of 5-HT4 receptor stimulation on the pacemaker current If in human isolated atrial myocytes. Cardiovasc Res. 1998;40:516-522. 10. Opthof T. The membrane current If in human atrial cells: implications for atrial arrhythmias. Cardiovasc Res. 1998;38:537540. 11. Lai LP, Su MJ, Lin JL, et al. Measurement of funny current If channel mRNA in human atrial tissue: correlation with left atrial filling pressure and atrial fibrillation. J Cardiovasc Electrophysiol. 1999;10:947-953. 12. Kaumann AJ. 5-HT4-like receptors in mammalian atria. J Neural Transm Suppl. 1991;34:195-201. 13. Blondel O, Gastineau M, Dahmoune Y, Langlois M, Fischmeister R. Cloning, expression, and pharmacology of four human 5-hydroxytryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus. J Neurochem. 1998;70: 236 MEDICOGRAPHIA, VOL 28, No. 3, 2006 DI S E A S E modifing pathological automaticity. However, studies exploring whether, in diseased states, If overexpression can lead to spontaneous diastolic depolarizations in working myocardium in vivo are lacking. The availability of bradycardic agents, which act by specifically blocking the f-channel,43 will certainly contribute to clarify the role of If overexpression in the working myocardium. Conclusions Molecular identification of HCN subunits and their functional/molecular detection in cardiac nonpacemaker tissues have drawn novel and unforeseen attention to pacemaker channels beyond heart rate control. In heart failure, hypertrophy, and atrial fibrillation, If current densities and/or mRNA levels of HCN channels are increased compared with controls. Experimental data supporting a potential arrhythmogenic role of If in the working myocardium under pathological conditions are stronger for heart failure. The clinical implication of these findings is that If overexpression may predispose ventricular myocytes of the failing heart to enhanced automaticity and to arrhythmias. Selective f-channels inhibitors, such as ivabradine, by blocking If in ventricular myocytes, could possibly reduce the risk of sudden death in patients with heart failure. ❒ The original work was supported by grants from the Ministry of Education University and Research and from Telethon. 2252-2261. 14. Venugopal J. Cardiac natriuretic peptides — hope or hype? J Clin Pharm Ther. 2001;26:15-31. 15. Lonardo G, Cerbai E, Casini S, et al. Atrial natriuretic peptide modulates the hyperpolarization-activated current If in human atrial myocytes. Cardiovasc Res. 2004;63:528-536. 16. Belus A, Piroddi N, Tesi C, et al. Molecular and mechanical changes in human chronic atrial fibrillation: a comparison with remodeling in heart failure. Proceedings of the International Meeting Atrial Fibrillation 2005. CEPI Publisher; 2005:1-2. 17. Cerbai E, Pino R, Sartiani L, Mugelli A. Influence of postnatal-development on If occurrence and properties in neonatal rat ventricular myocytes. Cardiovasc Res. 1999;42:416-423. 18. Yasui K, Liu W, Opthof T, et al. If current and spontaneous activity in mouse embryonic ventricular myocytes. Circ Res.2001; 88:536-542. 19. Robinson RB, Yu H, Chang F, Cohen IS. Developmental change in the voltage-dependence of the pacemaker current, If, in rat ventricle cells. Pflugers Arch. 1997;433:533-535. 20. Abi-Gerges N, Ji GJ, Lu ZJ, Fischmeister R, Hescheler J, Fleischmann BK. Functional expression and regulation of the hyperpolarization activated non-selective cation current in embryonic stem cell-derived cardiomyocytes. J Physiol (Lond). 2000; 523:377-389. 21. Cerbai E, Barbieri M, Li Q, Mugelli A. Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages. Cardiovasc Res. 1994; 28:1180-1187. 22. Cerbai E, Barbieri M, Mugelli A. Occurrence and properties of the hyperpolarization-activated current If in ventricular myocytes from normotensive and hypertensive rats during aging. Circulation. 1996;94:1674-1681. 23. Stilli D, Sgoifo A, Macchi E, et al. Myocardial remodeling and arrhythmogenesis in moderate cardiac hypertrophy in rats. Am J Physiol Heart Circ Physiol. 2001;280:H142-H150. 24. Fernandez-Velasco M, Goren N, Benito G, Blanco-Rivero J, Bosca L, Delgado C. Regional distribution of hyperpolarizationactivated current If and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts. J Physiol (Lond). 2003;553: 395-405. The If current beyond heart rate regulation – Mugelli and Cerbai IF I N H I B I T I O N 25. Cerbai E, Sartiani L, De Paoli P, Mugelli A. Isolated cardiac cells for electropharmacological studies. Pharmacol Res. 2000; 42:1-8. 26. Sartiani L, De Paoli P, Stillitano F, et al. Functional remodeling in post-myocardial infarcted rats: Focus on beta-adrenoceptor subtypes. J Mol Cell Cardiol. 2006;40:258-266. 27. Cerbai E, Pino R, Porciatti F, et al. Characterization of the hyperpolarization-activated current, If, in ventricular myocytes from human failing heart. Circulation. 1997;95:568-571. 28. Hoppe UC, Jansen E, Sudkamp M, Beuckelmann DJ. Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts. Circulation. 1998;97: 55-65. 29. Cerbai E, Sartiani L, DePaoli P, et al. The properties of the pacemaker current If in human ventricular myocytes are modulated by cardiac disease. J Mol Cell Cardiol. 2001;33:441-448. 30. Biel M, Schneider A, Wahl C. Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc Med. 2002; 12:206-213. 31. Borlak J, Thum T. Hallmarks of ion channel gene expression in end-stage heart failure. FASEB J. 2003;17:1592-1608. 32. Lonardo G, Stillitano F, Zicha S, Cerbai E, Mugelli A, Nattel S. Molecular basis of funny current If in normal and failing human heart. Circulation. 2004;110:III-129. Abstract. 33. Michels G, Er F, Khan I, Sudkamp M, Herzig S, Hoppe UC. Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias. Circulation. 2005;111:399-404. 34. Cerbai E, Pino R, Rodriguez ML, Mugelli A. Modulation of the pacemaker current If by β-adrenoceptor subtypes in ventricular myocytes isolated from hypertensive and normotensive rats. LE , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E Cardiovasc Res. 1999;42:121-129. 35. Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999;79:215-262. 36. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II–mediated cardiovascular and renal diseases. Pharmacol Rev. 2000;52:11-34. 37. Sadoshima J, Izumo S. Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res. 1993;73:413-423. 38. Kajstura J, Cigola E, Malhotra A, et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol. 1997;29:859-870. 39. Henegar JR, Schwartz DD, Janicki JS. ANG II-related myocardial damage: role of cardiac sympathetic catecholamines and beta-receptor regulation. Am J Physiol Heart Circ Physiol. 1998; 275:H534-H541. 40. Cerbai E, Crucitti A, Sartiani L, et al. Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes. Cardiovasc Res. 2000; 45:388-396. 41. Cerbai E, De Paoli P, Sartiani L, Lonardo G, Mugelli A. Treatment with irbesartan counteracts the functional remodeling of ventricular myocytes from hypertensive rats. J Cardiovasc Pharmacol. 2003;41:804-812. 42. Stillitano F, DePaoli P, Sartiani L, Paola R, Mugelli A, Cerbai E. A molecular basis for HCN channel over-expression. Eur Heart J. 2003;24:131. 43. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs.2004;64:1757-1765. COURANT IF AU-DELÀ DE LA RÉGULATION DE LA FRÉQUENCE CARDIAQUE L e rôle du courant « pacemaker » If dans la génération et la modulation de l’activité stimulatrice du nœud sinusal a été largement décrit. Dans les cellules du nœud sino-auriculaire et les cardiomyocytes néonataux, le courant If contribue de façon significative à la dépolarisation diastolique spontanée. Cependant, ce courant est présent non seulement dans les cellules « pacemaker » primaires et accessoires mais aussi dans les tissus cardiaques non automatiques. Les données électrophysiologiques et moléculaires regroupées des 10 dernières années ont démontré que les canaux f sont également retrouvés dans les cardiomyocytes non « pacemaker ». Au cours de l’hypertrophie cardiaque et de l’insuffisance cardiaque, les densités de courant If et/ou les taux d’ARNm de ses corrélats moléculaires (par ex., les canaux contrôlés par l’acide nucléotide cyclique activé par hyperpolarisation [HCN]) sont augmentées par rapport aux témoins. Des résultats identiques mais limités ont été retrouvés dans la fibrillation auriculaire. L’expression et/ou la surexpression des canaux f dans les cellules « non pacemaker » est une des conséquences du remodelage cardiaque et ce phénomène pourrait représenter un mécanisme arythmogène dans l’insuffisance cardiaque qui est associée à un risque élevé de mort subite cardiaque. Cependant, le rôle joué par une surexpression du courant If dans l’augmentation de la tendance aux arythmies dans les états pathologiques est controversé, l’activation du courant If étant obtenue à des potentiels plus négatifs dans le myocarde à l’effort que dans les cellules « pacemaker ». L’existence d’inhibiteurs sélectifs de canaux If comme l’ivabradine permettra dans un futur proche d’évaluer le rôle arythmogène potentiel du courant If dans la maladie cardiaque. ✦ The If current beyond heart rate regulation – Mugelli and Cerbai MEDICOGRAPHIA, VOL 28, No. 3, 2006 237 IF I N H I B I T I O N , H E A R T R A T E , AND CORONARY ARTERY DISEASE John KJEKSHUS, MD Department of Cardiology Rikshospitalet University of Oslo Oslo, NORWAY The effect of heart rate reduction on survival in heart failure by J. Kjekshus, Norway everal studies have shown that elevated resting heart rate carries an increased risk of cardiovascular morbidity and mortality. More than 60 years ago, Levy et al demonstrated that sustained tachycardia (>100 beats per minute) was associated with higher cardiovascular mortality as compared with subjects with normal heart rate.1 The study was followed by epidemiological studies on healthy humans, confirming their findings and extending the implications of elevated heart rate to all-cause mortality.2 This relationship has been demonstrated in patients with stable coronary artery disease, hypertension, diabetes mellitus, and acute myocardial infarction.3-7 Although the association between heart rate and incidence of coronary events is blunted after adjustment for multiple risk factors, the independent relationship with cardiovascular death and, especially, with sudden death, is S H eart rate reduction protects the failing heart, resulting in long-term improvement in myocardial function and clinical prognosis. A meta-analysis of heart failure trials suggests that heart rate reduction by -blocker treatment is associated with a parallel reduction in mortality. Although the mechanisms of the benefits resulting from heart rate–reducing treatments are not clearly defined, reduction in oxygen requirements and an increase in myocardial perfusion duration are the most likely contributors. Metabolic protection of the failing myocardium accounts for long-term benefit and improved neurohormonal balance. Ivabradine, which acts specifically on the sinoatrial node by inhibiting the If pacemaker current, has been shown to result in longterm improvement in left ventricular function and to reduce plasma levels of norepinephrine, as well as improving intrinsic myocardial structure, in a rat model, and is currently being tested in heart failure patients. Medicographia. 2006;28:238-244. (see French abstract on page 244) Keywords: heart rate; heart failure; myocardial function; prognosis; -blocker; ivabradine; meta-analysis Address for correspondence: Prof John Kjekshus, University of Oslo, Department of Cardiology, Rikshospitalet Sognvannsveien 20, Oslo 0027 Norway (e-mail: [email protected]) 238 MEDICOGRAPHIA, VOL 28, No. 3, 2006 particularly impressive.8 Heart rate is also an independent marker of rehospitalization for cardiovascular disease, including angina, stroke, and heart failure. Some studies have suggested a gender difference. However, these studies included few women and no older women. Heart disease in women occurs late in life. When elderly women are included, higher heart rates (>90 beats per minute) were clearly associated with increased risk over 3 years of follow up, after adjustments were made for age, cardiovascular risk factors, physical activity, and pulmonary function.9 Clinical data have been difficult to evaluate because of the retrospective nature of most of these studies, lack of standardized protocols for recording heart rate, and different background therapies. Most studies have used baseline heart rate taken from ECG recordings. However, single recordings compare with the average heart rate obtained during 24-hour ECG recordings despite marked diurnal variations.10,11 Regulation of resting heart rate The spontaneous cycling of the action potential in the sinoatrial node is determined by several specialized ionic channels. The most important one of these regulates the If current, which determines the slope of diastolic depolarization, and the intrinsic heart rate. Heart rate variation is regulated by the autonomic balance between the sympathetic and the vagal nervous system, which acts directly on the sinus node. This balance is modulated by baroreceptor activity, the cardiorespiratory center in the brain, and receptors in the lungs. An increase in heart rate induced by pacing is directly related to an increase in myocardial oxygen consumption.12 During exercise, this relationship shifts upward due to inotropic stimulation of the myocardium and increased oxygen requirement in excess of that determined by heart rate alone. The effect of heart rate reduction on survival in heart failure – Kjekshus H I B I T I O N Clinical interactions with heart rate Several intrinsic and extrinsic factors are known to modulate heart rate. In general, elevated resting heart rate is associated with smoking, low physical activity, type B behavior, hypertension, atherogenic lipoprotein pattern, increased body mass index, insulin insensitivity, and impaired glucose tolerance.6 Elevated resting heart rate is closely associated with indices of the metabolic syndrome. The driving mechanism of this syndrome seems to be a general sympathetic overactivity with increased release of catecholamines.6 The induced constriction of resistance and conduction vessels and enhanced βreceptor activity contribute to insulin resistance and impaired glucose uptake. The increase in arterial stiffness enhances pulse pressure and the reflected waveform from the periphery, results in a higher systolic pressure load on the left ventricle. Elevated leptin levels influence cardiovascular prognosis and have also been demonstrated to be directly related to increased heart rate in the denervated heart.13 This may explain that in patients with high heart rate and hypertension there is an association between heart rate and cardiovascular death in univariate analysis, but that this is blunted when adjustments are made for concurrent cardiovascular risk factors. A relationship between heart rate and morbidity and mortality can also be demonstrated in individuals with body mass index lower than 25, suggesting a role for heart rate that is also independent of the metabolic syndrome. The risk of a given heart rate level has been examined in several studies. The average heart rate from 24-hour ambulatory ECGs was studied prospectively in 1311 men and women older than 60 years and was used to define the risk.10 After controlling for other risk factors, the probability of developing new coronary events was 1.14 for an increment of 5 beats per minute. In a French study in 19 306 healthy subjects undergoing routine examination and followed for 20 years, heart rate in quartiles was a significant predictor of all-cause mortality in men.14 The relative risk for cardiovascular death after adjustment for age and other risk factors was 1.35, 1.44, and 2.18, respectively, in heart rate quartiles 2, 3, and 4 compared with quartile 1. Heart failure and heart rate Heart failure is characterized by an increase in resting heart rate and chronotropic incompetence during exercise. Heart rate is increased partly due to chronic activation of the sympathetic nervous system and partly due to permanent withdrawal of vagal nervous activity.15,16 Vagal withdrawal is identified by blunting of vagal reflexes and reduced heart rate variability in response to respiratory cycling.17 The relationship between heart rate and mortality is different from that in non–heart failure patients. The heart rate mortality curve in heart failure is J-shaped with a trend for increased mortality for resting heart rates below 50 and a steep increase for heart rates above 80. This relationship may be , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E blunted in patients with the most severe heart failure, probably reflecting confounding and more complex compensatory hemodynamic and metabolic effects caused by a reduction of cardiac output and coronary perfusion pressure. Coronary flow, which is restricted to the diastole because of compression of the myocardium during systole, may be compromised in the failing heart because of decreased coronary intra-arterial diastolic (perfusion) pressure and elevation of diastolic ventricular pressure, which is transformed into extramural compression of intramyocardial vessels, especially in 60 PROFILE 40 XAMOTEROL PROMISE 20 Change in mortality (%) IF I N VHeFT (prazosin) 0 VHeFT (HDZ/ISDN) CIBIS –20 BHAT GESICA –40 –60 NOR TIMOLOL SOLVD ANZ CONSENSUS US CARVEDILOL MOCHA –80 –100 –18 –16 –14 –12 –10 –8 –6 –4 –2 0 2 4 6 8 10 Figure 1. Relationship between changes in heart rate and mortality in studies on chronic heart failure. Adapted from reference 31: Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator-beta-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation. 1995;92:212-218. Copyright © 1995, American Heart Association, Inc. the subendocardial areas.18,19 Elevated ventricular filling and reduced perfusion pressure preferentially cause subendocardial ischemia, both at very low and high heart rates. Increased neurohumoral activity further deteriorates changes in myocardial oxygen supply and demand ratio. The functional consequences on the myocardium are directly related to the subendocardial blood flow per beat.20 Elevation of inflammatory cytokines and endotoxins also contribute to worsening heart failure. Furthermore, due to increased oxygen requirement and shortened diastole there is a marked increase in coronary flow velocity, which increases shear stress in the conduction vessels. This may explain the association between elevated heart rate and atherosclerosis observed in experimental and clinical studies.21,22 High coronary flow velocity may also cause increased risk of coronary plaque rupture.23 The compensatory mechanisms in heart failure probably add to the overall risk in severe heart failure and may therefore mask the impact of heart rate alone. Heart failure treatment, which improves outcome, is usually associated with reduction in heart rate; conversely, unadapted treatment tends to increase the heart rate (Figure 1).24 The effect of heart rate reduction on survival in heart failure – Kjekshus MEDICOGRAPHIA, VOL 28, No. 3, 2006 239 IF I N H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY Effect of heart rate reduction Drugs that reduce heart rate may have a beneficial effect on outcome primarily by reducing myocardial oxygen requirements and prolonging left ventricular diastole duration. This reverses the mismatch between myocardial oxygen requirement and perfusion in the ischemic myocardium.18-20 Selective heart rate reduction with ivabradine has been shown to exert an anti-ischemic effect, as demonstrated by improved contractility of the stunned myocardium.25 Addition of a β-blocker, however, also decreases myocardial contractility due to its negative inotropic effect, with additional reduction in myocardial oxygen requirements. In exercising dogs, Table I. β-Blocker studies: relationship btween heart rate and cardiovascular mortality in heart failure. N, number of patients in each treatment group; n, number of deaths; %, percent mortality. Follow-up (months) Project Year β-Blocker BHAT MDC CIBIS I ANZHF MOCHA PRECISE US Carvedilol CIBIS II 1986 1993 1994 1995 1996 1996 1996 1999 MERIT-HF 1999 Propranolol Metoprolol tartrate Bisoprolol Carvedilol Carvedilol Carvedilol Carvedilol Bisoprolol Metoprolol succinate Bucindolol Carvediol Carvedilol Metoprolol tartrate vs carvedilol Nebivolol BEST 2001 CAPRICORN 2001 COPERNICUS 2001 COMET 2003 SENIORS 2005 S E A S E The beneficial effect of β-blocker treatment in reducing morbidity and mortality has been extended to patients with heart failure, and its effects in symptomatic heart failure with low ejection fraction are now well established.31-33 Most β-blockers seem to confer cardioprotective effects during heart failure, except β-blockers with intrinsic mimetic effects.34 However, the mechanism of benefit in heart failure is more complex than in patients with normal ventricular function and not completely understood. Animal experiments have demonstrated that heart failure induced by constant pacing cannot be prevented by β-blockade.35 Conversely, ischemia in hearts with fixed coronary artery stenosis is highly dependent on heart rate.35,36 β-Blockade in β-Blocker Placebo Resting HR N n % N 25 15 23 6 6 6 6.5 15.6 78.6 90 82.5 76 83 84 83 81 365 189 321 208 84 145 398 1320 67 38 67 18.4 20 20.9 13 15.5 11 7.6 31 7.8 228 17.3 346 194 320 207 261 133 696 1327 12 6 6 4.5 22 3.2 156 11.8 12 82.4 2001 217 1990 145 7.3 24 15.6 10.4 81 77.3 83 1354 984 1133 449 33 151 15 190 16.8 1354 975 1156 411 30 116 12 130 11.2 58 81 1518 600 40 1511 512 34 21 79 1061 99 9.3 1067 76 7.1 heart rate reduction and negative inotropy by βblockade have been shown to equally contribute to the reduction in myocardial oxygen consumption during exercise, although the gain in diastolic perfusion time was smaller following β-blocker treatment compared with selective sinus node inhibition.26 There is also evidence that heart rate reduction improves endothelial function and prevents atherosclerosis21,22,27 and may induce angiogenesis, increase coronary reserve and improve myocardial function.28 Heart rate reduction is therefore clearly helpful in preventing all ischemic states. Several drugs have been shown to cause a major reduction in heart rate in patients with heart failure: β-blockers, calcium-blockers, thalidomide, amiodarone, and ivabradine, whose actions we now describe. ◆ -Blockers Reduction of heart rate by β-blockade in patients with coronary artery disease is cardioprotective and confers a proportionate reduction in mortality.29 The Norwegian timolol trial was the first to demonstrate that patients with enlarged hearts benefited from treatment, as confirmed by a reduction in cardiovascular death, especially sudden cardiac death.30 240 MEDICOGRAPHIA, VOL 28, No. 3, 2006 DI 11 n % 46 13.3 25 12.9 53 16.6 heart failure tends to reactivate vagal activity and normalize the autonomic balance, and provide additional protection against sudden arrhythmic death.37 Vagal stimulation during β-blockade ensures further reduction in heart rate that benefits the ischemic myocardium.38 The initial effect of β-blockade is a transient depression of left ventricular ejection fraction followed by an increase of 4% to 7%. The improvement is accompanied by a reduction in atrial peptides.39,40 Long-term treatment results in a slight, but inconsistent, depression of circulating norepinephrine and peripheral sympathetic nervous activity,41 but this may well be secondary to the improvement in hemodynamics. The nonselective β-blocker carvedilol elicits slightly greater effects than the β1-selective β-blocker metoprolol at conventional dosing regimens. The reduction in β1-receptor density during heart failure has been considered as a protective adaptation to the elevated sympathoadrenergic activation. Selective and nonselective β-blockade (including by carvedilol) tend to restore receptor density, which, in the setting of heart failure and myocardial ischemia, may be counterproductive. The relationship between heart rate and cardiovascular mortality in heart failure is more complex The effect of heart rate reduction on survival in heart failure – Kjekshus H I B I T I O N E A R T 40 RAT E , A N D CO R O N A RY AR T E RY DI S E A S E Placebo: r=0.65, P=0.02 β-Blockade: r=0.37, P=0.20 Annualized mortality due to the effects of heart failure on myocardial and peripheral hemodynamics. It is likely that there is a limit below which a drop in perfusion pressure and an increase in diastolic ventricular pressure become critical for further reduction in heart rate, but this lower level has not been properly defined. Most studies have excluded patients with heart rates lower than 60 to 68 beats per minute. Some studies have included patients with resting heart rates as low as 50 beats per minute, yet observing an overall improvement in outcome (Table I). Although few βblocker studies have been designed to titrate the effect of these drugs according to heart rate levels, studies have demonstrated that the heart rate reduction is dose-dependent. However, the sensitivity to β-blocker treatment changes according to the degree of heart failure. In the MEtoprolol controlled-release Randomized Intervention Trial in Heart Failure (MERIT-HF), patients sensitive to a low dose (<100 mg) had similar reduction in heart rate and mortality as in patients who tolerated higher doses (>100 mg).42 In order to examine the effects of heart rate on mortality, a retrospective analysis was performed of all available prospective trials in patients with symptomatic heart failure and ejection fraction below 35% to 40%,31-33;42-53 who had been randomized to a β-blocker or placebo. In all trials, mortality data and resting heart rate at baseline and on treatment were available. The β-blockers used in these trials were propranolol (1), metoprolol tartrate (1), metoprolol succinate (1), bisoprolol (2), carvedilol (6), and metoprolol tartrate vs carvedilol (1) (Table I). A total of 22 618 patients were included. They were followed for periods ranging between 6 to 58 months. Most of the trials included only patients with heart rate above 69 beats /minute. The average heart rate in the trials varied from 73 to 90 beats per minute. When heart rate at baseline was related to annualized mortality, a significant correlation was observed for placebo recipients, but not for β-blocker users (Figure 2). The latter was shifted downward, showing a significant improvement for β-blocker use in almost all studies. The correlation line for β-blocker–treated patients was less steep, suggesting a difference in efficacy between patients with low and high heart rates (Figure 2). The lines seem to converge at a heart rate around 60 beats per minute, suggesting that this may be a lower limit for effect. This is in accordance with previous studies and suggests that lower heart rates may have detrimental hemodynamic consequences on myocardial perfusion during heart failure.52 Because there is no prospective heart-rate reduction outcome trial in terms of vital end points, a retrospective analysis was carried out using the findings from all available outcome studies on βblocker use in heart failure. By taking the difference between the heart rates observed on treatment with placebo and β-blocker in each trial and relating the difference to the observed risk reduction in mortality, a significant relationship was observed (Figure 3). This suggests that some of the improvements associated with β-blockers are due to their effect on heart rate. At heart rates higher than 70 , H 30 20 10 0 70 75 80 85 90 95 Resting heart rate Figure 2. Results from heart failure outcome studies, comparing average resting heart rate and mortality for β-blocker treated (open circles) and placebo-treated patients (closed circles) from each trial. beats per minute, the slope suggests that for each reduction of 5 beats there is a 10% reduction in mortality. This observation is in accordance with a similar analysis from the Cardiac Insufficiency Bisoprolol Study (CIBIS II).54 The difficulties in the past in demonstrating a quantitative relationship between heart rate reduction and mortality may be due to the fact that none of the larger trials defined heart rate as a treatment goal. On the contrary, low heart rates alone were often given as a reason for withdrawing patients from the studies, even when patients were asymptomat- 100 r=0.59, P=0.027 Mortality reduction (%) IF I N 75 50 25 0 0 5 10 15 20 ∆ Heart rate Figure 3. Effect of β-blocker treatment in heart failure studies. Relationship between differences in heart rate and mortality reduction for each trial. ic.54,55 Heart rate reduction alone cannot explain all the benefits observed in heart failure trials. Due to the wide variation among trial results, the heart rate effect probably explains no more than 35% of the total effect. β-Blockers have an independent effect by blocking sympathetic stimulation and its toxic effects on the myocytes.56 The long-term reversal of remodeling and 5% to 8% increase in ejection fraction relative to placebo following treatment results in secondary improvement in hemodynamics. Although acute β-blocker treatment is associated with The effect of heart rate reduction on survival in heart failure – Kjekshus MEDICOGRAPHIA, VOL 28, No. 3, 2006 241 IF I N H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY an increase in circulating norepinephrine, longterm studies have demonstrated that continued treatment causes reversal, with less release of myocardial norepinephrine. This strongly suggests that the effect of β-blockers is not directly related to the acute reduction in heart rate, but rather to longterm protection of stunned myocardium, or to ancillary effects during heart failure, which are not directly reflected by the reduction in heart rate, for instance by reduction in renin or free fatty acids. ◆ Thalidomide Thalidomide has recently generated a certain amount of interest in the context of heart failure because of its immunomodulatory properties. It has been tested in a placebo-controlled study of patients with New York Heart Association (NYHA) class II and III heart failure, and ejection fractions <40%.57 Thalidomide 200 mg qd on top of β-blocker treatment increased the ejection fraction by 7% during 12 weeks of follow up. There was no change in the placebo group. This change was accompanied by a significant reduction in heart rate from 66 to 56, ie, an average reduction of 11 beats per minute. No change was observed in the placebo group. The reduction in heart rate with thalidomide on top of β-blocker treatment may involve stimulation of vagal activity and improve myocardial function due to its beneficial myocardial oxygen-saving effect. However, the relatively high number of adverse effects, fatigue, and constipation, may limit its use in clinical practice. DI S E A S E Both sudden death and progressive heart failure death were reduced compared with placebo. In patients with resting heart rates below 90 beats per minute, amiodarone did not alter heart rate or survival. The effect of amiodarone 180 mg/day was evaluated in 13 patients intolerant to β-blockade vs 9 controls.59 All subjects were in heart failure class III or IV. The heart rate dropped from 81 to 65 beats per minute at 1 and 3 months, respectively. This was associated with a significant reduction in brain natriuretic peptide and atrial natriuretic peptide and a significant improvement in fractional shortening. Two large prospective studies with amiodarone in patients with left ventricular dysfunction demonstrated improved survival in patients treated with β-blockers.60 A retrospective analysis demonstrated that addition of carvedilol in patients already receiving or not receiving amiodarone resulted in a similar increase in left ventricular ejection fraction after 3 months of treatment in both groups.61 Heart rate was reduced by 15 beats per minute irrespective of treatment group, demonstrating that the effects of amiodarone and carvedilol on heart rate and ejection fraction are additive. ◆ Amiodarone Amiodarone reduces heart rate by inhibiting the automaticity of the sinus node and through a noncompetitive antiadrenergic action. Heart rate may be reduced by 5 to 12 beats per minute depending on baseline heart rate. In a substudy of the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) study,58 in which the impact of amiodarone on mortality was investigated in 516 patients with severe congestive heart failure and ejection fraction <35%, heart rate reduction was examined during 6 months of follow-up. In patients with resting heart rate >90 beats per minute, amiodarone reduced heart rate by 12.7 beats per minute and overall mortality was reduced to 38.4% compared with 62.4% in control patients. ◆ Ivabradine Ivabradine is a new class of selective heart rate–lowering agents acting specifically on the sinoatrial node by inhibiting the If pacemaker current. In a rat model of heart failure, long-term heart rate reduction with ivabradine improved left ventricular systolic function and reduced plasma levels of norepinephrine throughout the 90 days of follow up.62 The long-term improvement in left ventricular systolic function was also associated with a reduction in collagen deposition and increased capillarity. In a study in congestive heart failure, ivabradine reduced heart rate in man by 14 and 19 beats per minute at the highest dose (10 mg/day) and produced a dose-dependent improvement in exercise tolerance.63 In a more recent trial, ivabradine (at 7.5 mg and 10 mg) compared favorably with atenolol (100 mg) with respect to exercise tolerance.64 Transient visual symptoms (the majority of which were phosphenes), were reported in 15% of the patients at the highest dose. Further investigation of the role of ivabradine in heart failure patients is currently under way. ❒ REFERENCES 1. Levy RL, White PD, Stroud WD,Hillman CC. Transient tachycardia. Prognostic significance alone and in association with transient hypertension. JAMA. 1945;129:585-588. 2. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol. 1980;112:736749. 3. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987; 113:1489-1494. 4. Hjalmarson A, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol. 1990; 65:547-553. 5. Gillman MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J.1993;125:1148-1154. 6. Palatini P, Casiglia E, Pauletto P, Staessen J, Kaciroti N, Julius S. 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Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284:H676-H682. 27. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Lowdose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation. 2001;103:1721-1726. 28. Lei L, Zhou R, Zheng W, Christensen LP, Weiss RM, Tomanek RJ. Bradycardia induces angiogenesis, increases coronary reserve, and preserves function of the postinfarcted heart. Circulation. 2004;110:796-802. 29. Kjekshus J. Heart rate reduction—a mechanism of benefit? Eur Heart J. 1987;8(suppl L):115-122. 30. Gundersen T. Influence of heart size on mortality and reinfarction in patients treated with timolol after myocardial infarction. Br Heart J. 1983;50:135-139. 31. Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator-beta-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation. 1995;92:212-218. 32. MERIT-HF Investigators. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353: 2001-2007. 33. CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13. 34. Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet. 1990;336:1-6. 35. Spinale FG, Johnson WS, Wang Y, et al. Direct effects of chronic beta-adrenergic receptor blockade on left ventricular and myocyte function in a model of tachycardia-induced congestive heart failure. J Card Fail. 1996;2:311-318. 36. Guth BD, Heusch G, Seitelberger R, Ross J Jr. Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs. Circ Res.1987;60:738-746. 37. Parker GW, Michael LH, Hartley CJ, Skinner JE, Entman ML. Central beta-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs. Circ Res. 1990;66:259-270. 38. Kjekshus JK, Blix AS, Grottum P, Aasen AO. Beneficial effects , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E of vagal stimulation on the ischaemic myocardium during betareceptor blockade. Scand J Clin Lab Invest. 1981;41:383-389. 39. de Groote P, Delour P, Lamblin N, et al. Effects of bisoprolol in patients with stable congestive heart failure. Ann Cardiol Angeiol (Paris). 2004;53:167-170. 40. Packer M, Antonopoulos GV, Berlin JA, Chittams J, Konstam MA, Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Am Heart J. 2001;141:899-907. 41. Rahman MA, Hara K, Daly PA, Wigle ED, Floras JS. Reductions in muscle sympathetic nerve activity after long-term metoprolol for dilated cardiomyopathy: preliminary observations. Br Heart J. 1995;74:431-436. 42. Wikstrand J, Hjalmarson A, Waagstein F, et al. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol. 2002;40:491-498. 43. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357:1385-1390. 44. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med.1996; 334:1349-1355. 45. Packer M, Colucci WS, Sackner-Bernstein JD, et al. Doubleblind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation. 1996;94:2793-2799. 46. Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation. 1996;94:2807-2816. 47. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344: 1651-1658. 48. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344:1659-1667. 49. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;90:1765-1773. 50. Lechat P, Escolano S, Golmard JL, et al. Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency BIsoprolol Study (CIBIS). Circulation. 1997;96(7):2197-2205. 51. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet. 1993;342:1441-1446. 52. Chadda K, Goldstein S, Byington R, Curb JD. Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation. 1986;73:503-510. 53. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215-225. 54. Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation. 2001;103:1428-1433. 55. Gullestad L, Wikstrand J, Deedwania P, et al. What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). J Am Coll Cardiol. 2005;45:252-259. 56. Sabbah HN. Biologic rationale for the use of beta-blockers in the treatment of heart failure. Heart Fail Rev. 2004;9:91-97. 57. Gullestad L, Ueland T, Fjeld JG, et al. Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a doubleblind, placebo-controlled study. Circulation. 2005;112:34083414. 58. Nul DR, Doval HC, Grancelli HO, et al. Heart rate is a marker of amiodarone mortality reduction in severe heart failure. The GESICA-GEMA Investigators. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina-Grupo de Estudios Multicentricos en Argentina. J Am Coll Cardiol. 1997;29:11991205. 59. Takemura K, Yasumura Y, Hirooka K, et al. Low-dose amiodarone for patients with advanced heart failure who are intolerant of beta-blockers. Circ J. 2002;66:441-444. 60. Kennedy HL. Beta-blocker prevention of proarrhythmia and proischemia: clues from CAST, CAMIAT, and EMIAT. Cardiac Ar- The effect of heart rate reduction on survival in heart failure – Kjekshus MEDICOGRAPHIA, VOL 28, No. 3, 2006 243 IF I N H I B I T I O N , H E A R T RAT E , A N D rhythmia Suppression Trial. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial. European Myocardial Infarct Amiodarone Trial. Am J Cardiol. 1997;80:1208-1211. 61. Macdonald PS, Keogh AM, Aboyoun C, Lund M, Amor R, McCaffrey D. Impact of concurrent amiodarone treatment on the tolerability and efficacy of carvedilol in patients with chronic heart failure. Heart. 1999;82:589-593. 62. Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular function and intrinsic myocardial CO R O N A RY AR T E RY DI S E A S E structure in congestive heart failure. Circulation. 2004;109:16741679. 63. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823. 64. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:25292536. EFFET DE LA RÉDUCTION DE LA FRÉQUENCE CARDIAQUE SUR LA SURVIE DANS L’INSUFFISANCE CARDIAQUE L a réduction de la fréquence cardiaque protège le cœur défaillant, en améliorant à long terme la fonction myocardique et le pronostic clinique. Une métaanalyse d’études sur l’insuffisance cardiaque suggère que la réduction de la fréquence cardiaque par un traitement -bloquant s’associe à une réduction parallèle de la mortalité. Bien que le mécanisme des avantages issus de la réduction de la fréquence cardiaque ne soit pas clairement défini, la réduction de la demande en oxygène et l’augmentation de la durée de perfusion myocardique en sont les acteurs les plus probables. La protection métabolique du myocarde défaillant assure un bénéfice à long terme et l’amélioration de l’équilibre neurohormonal. L’ivabradine, actuellement à l’essai chez des patients insuffisants cardiaques, agit de façon spécifique sur le nœud sinoauriculaire en inhibant le courant pacemaker If . Dans un modèle de rat, il a été montré qu’elle améliorait la fonction ventriculaire gauche à long terme, réduisait les concentrations plasmatiques de norépinéphrine et améliorait la structure myocardique intrinsèque. ✦ 244 MEDICOGRAPHIA, VOL 28, No. 3, 2006 The effect of heart rate reduction on survival in heart failure – Kjekshus IF I N H I B I T I O N , H E A R T R A T E , AND CORONARY ARTERY DISEASE umerous epidemiologic data have shown a close link between resting heart rate and long-term outcomes, particularly long-term mortality. Conceptually, lowering the heart rate might prove particularly beneficial in patients undergoing myocardial revascularization procedures. Indeed, a lower heart rate in circumstances of potential myocardial ischemia may decrease myocardial oxygen consumption and increase myocardial blood supply during diastole, thereby limiting the risk or the degree of myocardial ischemia. Few studies, however, have analyzed the impact of heart rate on outcomes during or after myocardial revascularization procedures. ▲ N Nicolas DANCHIN, MD Laurent SABBAH, MD Hôpital Européen Georges Pompidou Paris, FRANCE Benefits of heart rate reduction during and after interventional treatment by N. Danchin and L. Sabbah, France V ery few data are available regarding the relationship between heart rate and outcomes in patients undergoing myocardial revascularization. In patients undergoing coronary artery bypass surgery, a higher heart rate presages higher in-hospital mortality in patients who have long stays in the intensive care unit. Decreasing heart rate might prove beneficial in patients undergoing off-pump coronary artery surgery, by preventing myocardial ischemia in the territories awaiting revascularization. There is no evidence that heart rate is a predictor of outcome in patients undergoing percutaneous coronary interventions. In contrast, in patients with acute coronary syndromes, elevated heart rate is a predictor of poor outcomes independently of the use of angioplasty. In a registry of patients with ST-segment elevation myocardial infarction treated by primary angioplasty, heart rate >90 beats/minute was an independent predictor of early mortality. Finally, heart rate was found to be an independent correlate of 1-year mortality in patients with cardiogenic shock participating in the SHOCK trial (SHould we emergently revascularize Occluded Coronaries or cardiogenic shocK). There is a sound theoretical basis to suggest that lowering heart rate in patients treated by myocardial revascularization, particularly in situations of hemodynamic instability, might achieve a clinical benefit with an agent such as ivabradine, which lowers heart rate without affecting myocardial contractility. Clinical trials, however, are needed to confirm this hypothesis. Medicographia. 2006;28:245-248. (see French abstract on page 248) Keywords: heart rate; coronary angioplasty; coronary artery bypass surgery; percutaneous coronary intervention; If current inhibitor Address for correspondence: Prof Nicolas Danchin, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15, France (e-mail: [email protected]) Benefits of heart rate reduction during and after interventional treatment – Danchin and Sabbah Coronary artery bypass surgery The role of heart rate as a predictor of untoward events in patients undergoing coronary artery bypass grafting (CABG) has very seldom been assessed. In a study of 2417 patients undergoing CABG (with or without concomitant valvular surgery), Mathew et al assessed predictors of the occurrence of postoperative atrial fibrillation.1 A total of 27% patients developed atrial fibrillation postoperatively. A precardiopulmonary bypass heart rate of more than 100 beats per minute was found to be an independent predictor of subsequent atrial fibrillation (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.002.55), along with older age, male sex, history of atrial fibrillation or congestive heart failure, and several perioperative parameters. During on-pump CABG, the question of heart rate is obviously not raised. Conversely, off-pump CABG can be facilitated by a slower heart rate. Initially, surgeons used medications such as verapamil to lower the heart rate, although stabilizers render such measures less necessary nowadays.2 New techniques, such as on-pump CABG on a beating heart are advocated by some, and here again, a lower heart rate might prove helpful to the surgeons. Very few data are available regarding the prognostic significance of heart rate after CABG. In a series of 183 patients with a prolonged stay (at least 10 consecutive days) in the intensive care unit after CABG, Hartz et al analyzed factors associated with 60-day mortality.3 Overall, patients with a prolonged stay in the intensive care unit had a more severe clinical profile than patients with a shorter stay. Using a multivariate logistic regression model, the authors found that 7 variables were independently associated with an increased risk of 60-day mortality. Decreased cardiac index, urine output, and PaCO2 SELECTED ABBREVIATIONS AND ACRONYMS CABG coronary artery bypass grafting COMMIT ClOpidrogel and Metoprolol in Myocardial Infarction Trial GRACE Global Registry of Acute Coronary Events PCI percutaneous coronary intervention SHOCK SHould we emergently revascularize Occluded Coronaries or cardiogenic shocK MEDICOGRAPHIA, VOL 28, No. 3, 2006 245 IF I N H I B I T I O N , H RAT E A R T E , A N D CO R O N A RY AR T E RY were predictors of higher mortality. Likewise, increased pulmonary artery wedge pressure, blood urea nitrogen, and positive end-expiratory pressure were associated with an increased risk of death. Finally, increased heart rate was a predictor of increased 60-day mortality. On average, heart rate measured on day 9 following surgery was 102±17 beats/minute; the odds ratio for 60-day mortality for an increase of 1 standard deviation in heart rate (17 beats per minute) was 2.85. This study, however, could not determine whether increased heart rate was only a consequence of a more severe cardiac (and general) condition and therefore a kind of innocent bystander, or whether increased heart rate per se was a true and independent risk factor for mortality, or both. Of note, a similar association between increased heart rate and in-hospital mortality had been observed previously in patients hospitalized in intensive care units for other reasons than CABG.4 Following successful CABG, the response of 100 Survival (%) Heart rate ≤90 90 80 Heart rate >90 P=0.02 70 0 Figure 1. One-year survival in patients treated by primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Data from the French USIC 2000 registry. 90 180 270 360 Days heart rate to a mental stress administered 6 months after surgery and its correlation with subsequent cardiovascular events over the next 3 years was studied in a series of 521 patients included in the Post Coronary Artery Bypass Grafting biobehavioral study.5 Unexpectedly, events were more frequent in the patients who had the smallest changes in heart rate and systolic blood pressure during the mental stress test. The role of the change in heart rate in response to the stress test, however, was no longer significant in multivariate analyses. Percutaneous coronary intervention The technique of percutaneous transluminal coronary intervention (PCI) has changed considerably over the past 15 years. From a rather cumbersome procedure, with prolonged balloon inflations leading to nearly constant (though usually transient) myocardial ischemia, interventions currently performed, mainly because of the widespread use of coronary stents, require only very brief periods of myocardial ischemia, as inflation times are usually only 10 to 20 seconds long. In a study comparing changes in outcomes during PCI in patients with multivessel coronary artery disease from the early to the mid-1990s (the period corresponding to the regular use of coronary stents), heart rate did not 246 MEDICOGRAPHIA, VOL 28, No. 3, 2006 DI S E A S E appear to be a determinant of hospital outcome.6 Conversely, increased heart rate is an important and independent determinant of outcome in patients with acute coronary syndromes. In patients with either ST-segment elevation or non–ST-elevation acute coronary syndromes, the Global Registry of Acute Coronary Events (GRACE) probably represents the largest series of patients in whom prognostic factors were sought.7,8 Both in-hospital mortality and 6-month mortality were analyzed. Regarding hospital mortality, in a population of 11 389 patients of whom 35% had ST-segment elevation, each 30-beat/minute increase in presentation heart rate was accompanied by a 20% increase in early mortality (OR, 1.20; 95% CI, 1.10-1.40).7 Similar figures were found in two cohorts of 15 007 and 7638 patients in whom 6-month mortality was analyzed.8 Of these populations, approximately 30% were treated by PCI during their hospital stay, and 5% underwent CABG. Six-month postdischarge mortality was increased by 30% for each 30-beat/ minute increment in admission heart rate (OR, 1.3; 95% CI, 1.23-1.47). This important prognostic significance of initial heart rate was independent of other significant predictors, and in particular of the use of PCI, suggesting that increased heart rate has a deleterious prognostic impact in patients undergoing PCI as well as in those without such procedures. In a smaller registry of 2320 patients with acute myocardial infarction, 83% of whom had ST-segment elevation myocardial infarction, and representing 83% of patients admitted for acute myocardial infarction in France over a 1-month period in 2000, an admission heart rate >90 beats/minute was associated with an OR of 1.69 (95% CI, 1.11-2.59) for 5-day mortality and an OR of 1.76 (95% CI, 1.2212.5) for in-hospital mortality.9 We specifically analyzed the influence of baseline heart rate in the 411 patients who had undergone primary PCI at the acute stage (within 24 hours of symptom onset). One-year mortality was significantly higher in patients whose heart rate on admission was >90 beats per minute (18% versus 9%, P=0.02) (Figure 1). Using Cox multivariate analysis, increased heart rate on admission remained a significant and independent predictor of 1-year mortality (OR, 2.16; 95% CI, 1.04-4.51; P=0.04). We also repeated the analysis in the 1318 patients who had undergone PCI at any time during the hospital stay. Here again, an admission heart rate >90 beats per minute was associated with increased 1-year mortality (14% versus 7%, P=0.003). Cox multivariate analysis, however, did not show an independent prognostic value for elevated heart rate, when potential confounders were included in the multivariable model. The specificity of cardiogenic shock The SHOCK (SHould we emergently revascularize Occluded Coronaries or cardiogenic shocK) trial randomized patients with cardiogenic shock at the acute stage of myocardial infarction to revascularization or conventional strategy of initial medical stabilization. The prognostic significance of ECG Benefits of heart rate reduction during and after interventional treatment – Danchin and Sabbah IF I N H I B I T I O N findings obtained on a recording obtained within 12 hours of the onset of shock was analyzed.10 One hundred and twenty-two patients died within 1 year of randomization. Heart rate was 106±20 beats/ minute in nonsurvivors versus 95±24 beats/minute in survivors (P<0.01). Several other electrocardiographic variables appeared related to 1-year survival and included QRS duration and sum of ST-segment depression in all leads. Multivariate analysis showed that elevated heart rate was an independent predictor of mortality (hazard ratio [HR] 1.12; 95% CI, 1.02-1.23, for each 10-beat/minute increase); only 3 other baseline indicators were related to outcome (Table I). Potential role of selective I f current inhibitors From the aforementioned data, a medication capable of lowering heart rate without affecting left ventricular function would be of benefit in several situations. In patients undergoing beating-heart CABG, lowering heart rate during the intervention would render the task of the surgeon slightly easier, but the main benefit of heart rate reduction during the intervention would be a reduction in myocardial ischemia during the procedure in the territories awaiting revascularization. The potential role of heart rate reduction in patients with a difficult postoperative course is less easy to determine and will require specific studies. In patients undergoing elective PCI, there is no evidence that a specific action on heart rate would improve the outcome of the procedure. Conversely, as increased heart rate is an important predictor of mortality in patients with acute coronary syndromes treated by PCI, medications such as ivabradine may prove particularly helpful. In the recently reported ClOpidrogel and Metoprolol in Myocardial Infarction Trial (COMMIT),11 early administration of metoprolol did not improve early outcomes, in particular mortality. Interestingly, metoprolol administration was accompanied by a decreased rate of reinfarction and ventricular fibrillation, which was counterbalanced by an increase in cardiogenic shock. Overall, the administration of a β-blocker appeared beneficial in patients with signs of heart failure on admission, but deleterious in those with signs of hemodynamic instability. This suggests that the beneficial effect of the β-blocker in terms of heart rate reduction is counterbalanced by its depressant effect on left ventricular function. In such situations, the capacity to decrease heart rate without altering cardiac contractility would be REFERENCES 1. Mathew JP, Parks R, Savino JS, et al. Atrial fibrillation following coronary artery bypass graft surgery: predictors, outcomes, and resource utilization. Multi Center Study of Perioperative Ischemia Research Group. JAMA. 1996;276:300-306. 2. Buffolo E, Branco JNR, Gerola LR, et al. Off-pump myocardial revascularization: critical analysis of 23 years’ experience in 3,866 patients. Ann Thorac Surg. 2006;81:85-89. 3. Hartz A, Guse C. Kayser K, Kuhn E, Johnson D. Use of postoperative information to predict mortality rates for patients who have long stays in the intensive care unit after coronary artery bypass grafting. Heart Lung. 1998;27:22-30. , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E particularly useful. Also, in patients with cardiogenic shock treated by primary percutaneous transluminal coronary angioplasty (PTCA), the use of sympathomimetic agents such as dobutamine or dopamine, as well as the use of an intra-aortic balloon pump, is usually warranted. In clinical practice, the increase in heart rate observed during cardiogenic shock, and aggravated by dobutamine, limits the efficacy of aortic counterpulsation (which acts Variable Hazard ratio 95% confidence interval P value Age (for 5-year increase) 1.15 1.05-1.25 0.007 Pulmonary capillary wedge pressure (for 5–mm Hg increase) 1.14 1.00-1.30 0.042 Heart rate (for 10 beats/ minute increase) 1.12 1.02-1.23 0.020 Sum of ST-segment depression by treatment group interaction: - Revascularization - Medical stabilization 1.02 0.81 0.97-1.08 0.73-0.91 0.828 <0.001 Table I. Multivariate analysis determining independent correlates of one-year mortality in patients with cardiogenic shock in the SHould we emergently revascularize Occluded Coronaries or cardiogenic shocK (SHOCK) randomized trial. Adapted from reference 10: White HD, Palmeri ST, Sleeper LA, et al; SHOCK trial investigators. Electrocardiographic findings in cardiogenic shock, risk prediction, and the effects of emergency revascularization: results from the SHOCK trial. Am Heart J. 2004;148:810-817. Copyright © 2004, Elsevier Inc. essentially by improving diastolic hemodynamics). Therefore, the combined use of heart rate-controlling medications might prove particularly helpful, provided these medications do not cause further impairment in left ventricular function, which is precisely the case with If current inhibitors such as ivabradine.12 Experimental evidence from a rat model of myocardial stunning caused by a sequence of ischemia reperfusion indicates that concomitant use of dobutamine and ivabradine avoids the tachycardia generated by dobutamine, without impairing mean arterial pressure or the recovery of left ventricular wall thickening and left ventricular fractional shortening obtained with dobutamine (V. Richard, personal communication). Overall, specific heart rate reduction may provide additional therapeutic benefits during myocardial revascularization procedures, particularly in difficult circumstances, such as acute myocardial infarction or myocardial infarction complicated by cardiogenic shock. ❒ 4. Knaus WA, Wagner D, Zimmerman JE, et al. The APACHE III prognostic system: risk prediction of hospital mortality for critically ill hospitalized adults. Chest. 1991;100:1619-1636. 5. Herd JA, Hoogwerf BJ, Barton F, et al. Heart rate and blood pressure responses to mental stress and clinical cardiovascular events in men and women after coronary artery bypass grafting: the Post Coronary Artery Bypass Graft (post-CABG) biobehavioral study. Am Heart J. 2003;146:273-279. 6. Danchin N, Angioi M, Cador R, et al. Changes in immediate outcome of percutaneous transluminal coronary angioplasty in multivessel coronary artery disease in 1990 to 1991 versus 1994 Benefits of heart rate reduction during and after interventional treatment – Danchin and Sabbah MEDICOGRAPHIA, VOL 28, No. 3, 2006 247 IF I N H I B I T I O N , H E A R T RAT E , A N D to 1995. Am J Cardiol. 1997;79:1389-1391. 7. Granger CB, Goldberg RJ, Dabbous O, et al. Predictors of hospital mortality in the Global Registry of Acute Coronary Events. Arch Intern Med. 2003;163:2345-2363. 8. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome. Estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291:2727-2733. 9. Hanania G, Cambou JP, Guéret P, et al, for the USIC 2000 Investigators. Management and in-hospital outcome of patients with acute myocardial infarction admitted to intensive care units at the turn of the century: results from the French nationwide USIC 2000 registry. Heart. 2004;90:1404-1410. CO R O N A RY AR T E RY DI S E A S E 10. White HD, Palmeri ST, Sleeper LA, et al; SHOCK trial investigators. Electrocardiographic findings in cardiogenic shock, risk prediction, and the effects of emergency revascularization: results from the SHOCK trial. Am Heart J. 2004;148:810-817. 11. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Early intravenous then oral metoprolol in 45 582 patients with acute myocardial infarction: randomised, placebo-controlled trial. Lancet. 2005;366:16221632. 12. Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation. 2004;109:1674-1679. AVANTAGES DE LA RÉDUCTION DE LA FRÉQUENCE CARDIAQUE AU COURS ET AU DÉCOURS D’UN TRAITEMENT INTERVENTIONNEL L es résultats disponibles concernant les rapports entre la fréquence cardiaque et l’évolution des patients ayant subi une revascularisation myocardique sont peu nombreux. Après un pontage coronaire, une fréquence cardiaque plus élevée présage d’une mortalité à l’hôpital plus élevée chez les patients restant longtemps en soins intensifs. La diminution de la fréquence cardiaque pourrait être utile chez les patients subissant une chirurgie coronaire à cœur battant, en prévenant une ischémie myocardique dans les territoires en attente de revascularisation. Aucune donnée ne permet d’avancer que la fréquence cardiaque est un facteur prédictif de l’évolution chez les patients subissant une chirurgie coronaire percutanée. À l’inverse, chez les patients présentant des syndromes coronaires aigus, une fréquence cardiaque élevée permet de prévoir une évolution défavorable indépendamment de l’angioplastie. Dans un registre de patients ayant eu un infarctus du myocarde avec sus-décalage du segment ST traité d’emblée par angioplastie, une fréquence cardiaque supérieure à 90 battements par minute était un facteur prédictif indépendant de mortalité précoce. Finalement, chez les patients ayant eu un choc cardiogénique et participant à l’étude SHOCK (SHould we emergently revascularize Occluded Coronaries or cardiogenic shocK), la fréquence cardiaque était associée de façon indépendante à une mortalité à 1 an. De solides arguments théoriques prédisent que l’ivabradine – un produit capable de diminuer la fréquence cardiaque sans affecter la contractilité du myocarde – entraînerait un bénéfice clinique chez des patients ayant subi une revascularisation myocardique, et ce tout particulièrement dans les situations d’instabilité hémodynamique. Cette hypothèse doit cependant être confirmée par des études cliniques. ✦ 248 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Benefits of heart rate reduction during and after interventional treatment – Danchin and Sabbah IF I N H I B I T I O N , H E A R T R A T E , AND CORONARY ARTERY DISEASE t has been many years since the last new antianginal drug with a novel mechanism of action was introduced. Ivabradine has recently been approved for the treatment of angina in patients in normal sinus rhythm when β-blockers are contraindicated or not tolerated. Ivabradine slows the heart rate, at rest and during exercise, by inhibiting the If —or “pacemaker”—current in sinus node pacemaker cells. This is believed to be the only mechanism by which it exerts an antianginal effect. The action of ivabradine is highly selective in that, at therapeutic plasma concentrations, the drug does not affect cardiac contraction or cardiac conduction. The drug does not reliably slow heart rate during atrial fibrillation, atrial flutter, or other atrial tachycardias. Similarly the drug cannot slow heart rate in patients who are dependent on cardiac pacemakers. Thus, it is therapeutically useful only in those patients whose heart rate is controlled by the sinus node. β-Blockers have been shown to reduce mortality in post-myocardial infarction patients with significant coronary artery disease. They are therefore preferred to ivabradine at the present time provided that they are not contraindicated, and that they are well tolerated and clinically effective. Ivabradine shares with β-blockers the major mode of action of inducing significant heart rate reduction, but does not have many of the side effects provoked by β-blockers, such as the aggravation of asthma, chronic obstructive airways disease, and peripheral vascular disease. Ivabradine has been subject to an extensive program of development that involved over 5000 patients, of whom approximately 3000 received ivabradine. It has proven to be an extremely effective antianginal agent.1 ▲▲ ▲ I Irina SAVELIEVA, MD A. John CAMM, MD St George’s University of London London, UNITED KINGDOM If inhibition: safety and tolerability by I. Savelieva and A. J. Camm, United Kingdom A lthough the If (“funny”) current is a major ion channel mechanism modulating sinus node pacemaker action potential, full If inhibition cannot lower the heart rate by more than 30% since pacemaker potential is comodulated by some ten other channel mechanisms, all of which continue to operate independently. This in-built plateau accounts for both the tolerability and controlled efficacy of ivabradine, the selective and specific If inhibitor recently approved for the treatment of angina in patients with sinus rhythm in whom -blockers are either contraindicated or poorly tolerated. Ivabradine provides the essential benefits of -blockers without their major side effects. It is therapeutically useful only in patients whose heart rate is controlled by the sinus node. Registration studies in some 3000 patients have shown that it slows the heart at rest and during exercise without affecting contraction or conduction. It neither impairs left ventricular function, even in patients with depressed myocardial contractility, nor endangers those with bundle-branch block. Because the bradycardic effect of ivabradine is proportional to the resting heart rate, such that the effect tends to plateau as heart rate reduces, extreme sinus bradycardia leading to withdrawal of the drug is uncommon and was reported in less than 1% of patients. The QT interval is expectedly prolonged with the reduction in heart rate, but after appropriate correction for heart rate, and in direct comparisons of the QT interval when the influence of the heart rate was controlled by atrial pacing, no significant effect of ivabradine on ventricular repolarization duration was demonstrated. Less than 1% of patients withdrew from treatment because of visual symptoms. Further safety and tolerability data will rapidly accrue in postmarketing studies, while the purpose of the ongoing placebo-controlled MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIF UL) study in 10 000 patients is to elucidate the impact of ivabradine on coronary end points in angina patients with left ventricular systolic dysfunction. Medicographia. 2006;28:249-253. (see French abstract on page 253) Keywords: ivabradine; electrophysiological effect; left ventricular function; QT interval; safety; adverse event; visual effect Address for correspondence: Prof A. John Camm, Division of Cardiac & Vascular Sciences, St George’s University of London, Cranmer Terrace, London SW17 ORE, UK (e-mail: [email protected]) If inhibition: safety and tolerability – Savelieva and Camm Fundamental properties of ivabradine The If or “funny” current is an important myocyte transmembrane current carried by potassium and sodium ions, which flows through a hyperpolarization-activated, cyclic nucleoside–gated (HCN) channel, thereby contributing to the rate of spontaneous slow diastolic depolarization of the sinus node. However, complete inhibition of the If current results in a maximum heart rate reduction of 30% to 40%. In experimental and clinical studies, ivabradine exhibited a dose-response that plateaued at higher dosages, and a use-dependent effect on heart rate.2 This occurs because the pacemaker potential is modulated by several (at least 10) ion channel mechanisms, including the L- (long-lasting) and T- (transient) types of calcium currents. At concentrations seen with a supratherapeutic dose of 10 mg twice daily (mean Cmax of ≈0.1 µM) in humans, ivabradine is highly selective for the If current, with no effect on L- and T-type calcium currents.3 Binding of ivabradine to HCN channels is restricted to the open channel state and the drug–channel interaction is controlled by the balance between open and closed states. Ivabradine does not interact with β-adrenergic or muscarinic receptors. MEDICOGRAPHIA, VOL 28, No. 3, 2006 249 IF I N H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY Ivabradine inhibited IKr with an IC50 of 4.9 µM, which is approximately 75-fold higher than mean total plasma Cmax and 250-fold higher when considering the unbound fraction in patients treated with ivabradine 7.5 mg bid, well beyond the 30-fold value considered as an adequate threshold for safety. In canine His-Purkinje fibers, there was no action potential duration prolongation up to 10 µM (150fold the total concentration in patients treated with 7.5 mg bid) at stimulation rates of 60 and 40 bpm. It is therefore extremely unlikely that ivabradine will prove to have any direct effect on the duration of the QT interval, although it will be prolonged due to the bradycardia induced by the drug.4 Experimental studies using a chronic heart failure model in rats have demonstrated that ivabradine effectively reduced heart rate, decreased left ventricular systolic diameter, and improved myocardial contractility, probably due to its ability to shift the ventricular systolic pressure-volume curve leftwards and reduce collagen accumulation.5 Ivabradine does not affect vascular relaxation and has been shown to produce an antihypertrophic effect on the aorta in rats with spontaneous hypertension.6 Clinical investigations ◆ Cardiac electrophysiology The electrophysiological effects of ivabradine have been assessed in patients undergoing diagnostic electrophysiological studies.7 The drug induces a heart-rate–lowering effect and a small, but significant, increase in the sinus node recovery time and a trend towards an increase in the sinoatrial conduction time. The effects of ivabradine on atrioventricular (AV) nodal function are controversial. There is either no effect on AV nodal refractoriness and conduction (AH interval), including Wenckebach periodicity, or a small and probably clinically insignificant increase. This small effect is certainly inadequate to slow the heart rate effectively during atrial fibrillation and it is unlikely to cause any clinical degradation of AV nodal conduction or induce higher degrees of AV block. Similarly, the drug appears to have no effect on intraventricular conduction (HV interval). Thus, it can be safely administered to patients with preexisting bundle-branch block. Ivabradine does not cause any increase in ventricular refractoriness when assessed at identical rates before and after drug administration.8 Similarly, the QT interval is not prolonged when the heart rate is held constant by atrial pacing. However, the measured QT interval is prolonged when sinus bradycardia is induced by the drug. Correcting for heart rate, using traditional correction formulas, results in QTcB reduction with the Bazett formula (overcorrection) and QTcF prolongation (undercorrection) with the Fridericia formula. Plotting the predrug measured QT value against its corresponding RR interval suggests that the correct regression exponent value is 0.38 for the population of patients in the ivabradine development program whose ECG data were measured in a central laboratory. When this “population correction” was applied to the ondrug data, the QTcP showed no prolongation.9 250 MEDICOGRAPHIA, VOL 28, No. 3, 2006 DI S E A S E The mean changes from baseline in the population-corrected QT (QTcP) consisted of small changes in either direction that never exceeded +1.4 ms in the ivabradine group, never attained statistical significance within a treatment group, and showed a good agreement between different ECG safety sets for each ivabradine treatment group. Concerning QT changes in individual patients, only 1 patient out of 1140 (0.1%) in the ivabradine group and 1 patient out of 91 patients (1.1%) in the atenolol group had a QTcP value >500 ms in the middle-term ECG safety set. The measured QT interval during sinus bradycardia is prolonged and this prolongation may be substantial at low heart rates. The possible arrhythmogenic effect of such prolongation, which is also seen with β-blockers, is uncertain because ivabradine does not oppose the effect of catecholamines. In order to explore this further, the complete data set was interrogated with respect to ventricular tachycardia. Two episodes of polymorphic tachycardia were noted in patients treated with ivabradine. However, in a direct comparison between amlodipine and ivabradine in patients at high risk of torsades de pointes, more ventricular tachycardia was seen with amlodipine (19.4 per 100 patient-years than with ivabradine (11.7 patient-years). ◆ Effects on left ventricular function During its development, ivabradine was not systematically administered to patients with heart failure, and left ventricular function was not routinely measured before and during exposure to the drug. However, limited studies are available that demonstrate that ivabradine does not impair left ventricular function even in patients with depressed myocardial contractility. Although acute dosing with ivabradine does reduce sinus rate, it does not impair left ventricular function.10 Also, using nuclear angiography, it was demonstrated in patients with coronary disease, left ventricular dysfunction (ejection fraction <45%), and New York Heart Association (NYHA) class II heart failure, that treatment with ivabradine 10 mg bid led to an decrease in left ventricular end-diastolic volume, especially in patients with a very low ejection fraction (<35%), whereas no such favorable effect was seen with placebo.11 Clinical evidence The data presented in the following sections are taken from the European Public Assessment Report (EPAR).12 Ivabradine is associated with two principal adverse events, both of which are predictable from the pharmacodynamic properties of the drug. Sinus bradycardia and visual symptoms are due to If and Ih channel inhibition, respectively (Table I). ◆ Sinus bradycardia At a dose of ivabradine of 5 or 7.5 mg bid, sinus bradycardia occurred in 3.2% of the population compared with 5.1% of a control group treated with atenolol. In the placebo- and amlodipine-treated groups, sinus bradycardia occurred in 1.0% and 1.7%, respectively. There was no report of severe If inhibition: safety and tolerability – Savelieva and Camm IF I N System organ class Preferred term H I B I T I O N , H RAT E A R T Ivabradine (5 or 7.5 mg bid) (N=1651) PY=635.2 E , CO A N D Placebo (N=313) PY=64.7 R O N A RY AR T E RY Atenolol (N=408) PY=184.4 DI S E A S E Amiodipine (N=404) PY=95.5 n % PY n % PY n % PY n % PY Eye disorders Visual disturbance NOS 281 270 17.0 16.4 44.24 42.51 10 9 3.2 2.9 15.46 13.91 39 27 9.6 6.6 21.15 14.64 19 18 4.7 4.5 19.90 18.85 Cardiac disorders Sinus bradycardia Ventricular extrasystoles Angina pectoris aggravated Angina unstable Atrioventricular block 1st-degree Myocardial ischemia Palpitations Supraventricular extrasystoles Atrial fibrillation Myocardial infarction Ventricular tachycardia Supraventricular tachycardia 296 53 50 33 33 23 19 15 15 15 13 11 8 17.9 3.2 3.0 2.0 2.0 1.4 1.2 0.9 0.9 0.9 0.8 0.7 0.5 46.60 8.34 7.87 5.20 5.20 3.62 2.99 2.36 2.36 2.36 2.05 1.73 1.26 29 3 4 6 1 3 3 0 4 1 1 0 1 9.3 1.0 1.3 1.9 0.3 1.0 1.0 0.0 1.3 0.3 0.3 0.0 0.3 44.82 4.64 6.18 9.27 1.55 4.64 4.64 0.00 6.18 1.55 1.55 0.00 1.55 62 21 5 7 1 8 6 1 2 2 2 0 0 15.2 5.1 1.2 1.7 0.2 2.0 1.5 0.2 0.5 0.5 0.5 0.0 0.0 33.62 11.39 2.71 3.80 0.54 4.34 3.25 0.54 1.08 1.08 1.08 0.00 0.00 53 7 11 4 5 2 2 3 2 5 3 0 2 13.1 1.7 2.7 1.0 1.2 0.5 0.5 0.7 0.5 1.2 0.7 0.0 0.5 55.50 7.33 11.52 4.19 5.24 2.09 2.09 3.14 2.09 5.24 3.14 0.00 2.09 sinus bradycardia (<40 beats/minute) with ivabradine 5 mg bid and it occurred in only 0.5% with ivabradine 7.5 mg bid compared with 1.7% with atenolol. Less than 1% of patients treated with ivabradine withdrew because of sinus bradycardia. It is important to note that during the development of ivabradine, coadministration with β-blockers or rate-limiting calcium antagonists was not allowed. Generally, patients were excluded from participation if the resting heart rate was less than 50 beats/ minute. When analysis is restricted to patients with a resting heart rate equal to or more than 50 beats/ minute, fewer than 0.3% patients treated with ivabradine 5 or 7.5 mg bid developed sinus bradycardia. Arrhythmias were uncommon in association with ivabradine-induced sinus bradycardia. In a comparison with amlodipine, atrial arrhythmias occurred in 1.0% of ivabradine-treated patients and 1.7% of ivabradine-treated patients with a heart rate less than 50 beats/minute and 1.2% of all patients treated with amlodipine. In the same dataset, ventricular tachycardia occurred in 2.1% of all ivabradinetreated patients and 2.3% of patients with bradycardia. Ventricular tachycardia was seen in 2.5% of amlodipine-treated patients. Sinus bradycardia was generally well tolerated. Sinus bradycardia less than 45 beats/minute was associated with dizziness in 5.7 per 100 years of patient exposure (patient-years), syncope in none, fatigue in 2.8 patient-years and dyspnea in 1.4 patient-years. Comparable figures with atenolol were 6.5 patient-years for dizziness and syncope, and 19.4 patient-years for both dyspnea and fatigue. atenolol, and 4.5% of amlodipine-treated patients, probably because of the detailed consent and information forms that were provided to patients participating in these trials. The major symptom (phosphenes) consisted of transient enhanced brightness in a limited area of the visual field (88.9%); occasionally blurred vision was reported (8.9%). The symptoms were usually triggered by sudden changes of illumination and generally occurred within 2 months of treatment initiation. They tended to resolve spontaneously during continued treatment (76%) and always disappeared when treatment was discontinued. Most patients did not find these symptoms worrisome and less than 1% withdrew because of them. Studies of driving ability, using a simulator, showed that visual symptoms did not have a significant effect. No long-term retinal pathology has been associated with the use of ivabradine. ◆ Visual symptoms ◆ Atrial fibrillation Ivabradine is not intended for use in patients with long-term atrial fibrillation, but its effect in patients with paroxysmal atrial fibrillation must be understood. This is particularly important since sinus bradycardia might favor the induction of atrial fibrillation (AF). There was no evidence for a deleterious effect of ivabradine in patients with AF, and patients with AF were successfully converted to sinus rhythm by either amiodarone or DC cardioversion while treated with ivabradine, without evidence for excessive bradycardia on return to sinus rhythm. In patients with paroxysmal atrial fibrillation (PAF), ivabradine did not demonstrate any prevention of symptomatic PAF attacks and did not increase the rate of PAF attacks in comparison to placebo. The occurrence of visual symptoms (16.4% overall) was dose-dependent: 13.8% at 5 mg bid and 18.1% at 7.5 mg bid. It is important to note that such symptoms occurred in controlled trials in 2.9% of placebo-treated patients, 6.6% of patients receiving ◆ Safety in high-risk patients Patients with left ventricular hypertrophy or with factors associated with left ventricular dysfunction and in the pooled set of patients at risk of arrhyth- If inhibition: safety and tolerability – Savelieva and Camm Table I. Emergent visual and cardiac adverse events reported by at least 0.5% of patients exposed to ivabradine 5 or 7.5 mg bid in the Overall Oral Safety set. PY, patient-years.12 MEDICOGRAPHIA, VOL 28, No. 3, 2006 251 IF I N H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E Ivabradine is an antianginal agent with a novel mechanism of action — If current inhibition. Full block of the If current should only reduce the heart rate by 30% and the effect tends to plateau because this mechanism is only one of many responsible for the currents that depolarize the sinus node. Also, this mechanism slows heart rate in proportion to the resting heart rate. In animal models, ivabradine improves rather than worsens left ventricular function. Clinical electrophysiological testing has demonstrated that the effects of ivabradine are largely limited to the sinus node, although there may be a small nonsignificant depressant effect on AV conduction. Atrial and ventricular refractoriness are unaltered by ivabradine. Ivabradine has no effect on ventricular repolarization when assessed at identical heart rates before and during drug treatment or if appropriately corrected for the change in heart rate induced by ivabradine. However, ivabradine does lead to prolongation of the QT interval due to sinus bradycardia—the relevance of this is unclear, although very little ventricular tachycardia had been noted in patients treated with this agent. Ivabradine has two primary pharmacological actions that may provoke adverse effects. One is Ih inhibition, leading to visual phenomena, which are usually transient and trivial. They do not appear to lead to any permanent pathology and have no effect on intricate skills such as driving. The other is If inhibition, which leads to sinus bradycardia that is usually well tolerated and is not associated with the aggravation of other arrhythmias. The effect of ivabradine on coronary end points such as unstable angina, acute myocardial infarction, and sudden cardiac death appears not to be worse than other treatments, but no formal trial has been conducted to establish this. Currently, the BEAUTIFUL trial, a large study in which 10 000 patients are randomized between treatment with ivabradine or placebo, is under way in patients with coronary disease and depressed left ventricular function. The safety profile of ivabradine appears to be highly satisfactory. Increased clinical experience with ivabradine—now that the drug is approved for use in patients with normal sinus rhythm in whom β-blockers are either contraindicated or not tolerated — will also allow its safety profile to be more fully defined. ❒ REFERENCES 1. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K; INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536. 2. DiFrancesco, D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757-1765. 3. Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol. 1996;118:1051-1057. 4. Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP. Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49. Br J Pharmacol. 1994;112:37-42. 5. Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation. 2004;109:1674-1679. 6. Albaladejo P, Carusi A, Apartian A, Lacolley P, Safar ME, Benetos A. Effect of chronic heart rate reduction with ivabradine on carotid and aortic structure and function in normotensive and hypertensive rats. J Vasc Res. 2003;40:320-328. 7. Camm AJ, Lau CP. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Drugs. 2003;4: 83-89. 8. Savelieva I, Jones S, Dougal K, Malik M, Camm AJ Non-invasive Electrophysiological Study of Ivabradine (NESI) in patients with dual chamber pacemakers: effects on ventricular repolarization. J Am Coll Cardiol. 2006;47:27A. Abstract. 9. Savelieva I, Camm AJ. Comparison of the effects of a selective If current inhibitor ivabradine and atenolol on the QT interval in patients with coronary artery disease. Heart Rhythm. 2005;2: S145-S146. Abstract. 10. Manz M, Reuter M, Lauck G, Omran H, Jung W. A single intravenous dose of ivabradine, a novel If inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology. 2003;100:149-155. 11. Jondeau G, Korewicki J, Vasiliauskas D. Effect of ivabradine in patients with left ventricular systolic dysfunction and coronary artery disease. Eur Heart J. 2004;25:491. Abstract. 12. European Public Assessment Report (EPAR). Ivabradine hydrochloride–stable angina pectoris. Scientific discussion. EMEA 2005. mia, were analyzed to assess potential adverse effects of ivabradine in these “at-risk” subsets. These additional analyses in high-risk patients demonstrated that there was no evidence of an increased frequency of coronary or arrhythmic events as compared with amlodipine either in patients at risk of coronary events or at risk of arrhythmias. ◆ Coronary events No trial has yet been conducted to evaluate whether treatment with ivabradine may lead to a reduction in acute coronary events such as acute coronary syndrome (aggravation of angina, unstable angina, and acute myocardial infarction), revascularization, or sudden cardiac death. Many patients awaiting coronary revascularization in countries with long waiting lists for such procedures were entered into the trials of angina treatment with ivabradine. In the development program, ivabradine 5 mg bid or 7.5 mg bid was associated with worsening angina in 2%, unstable angina in 2%, and acute myocardial infarction in 0.8%. Very similar figures were noted in placebo-, amlodipine- and atenolol-treated groups of patients. No rebound effect was seen when patients were discontinued from treatment with ivabradine. Cardiac deaths occurred in 1.6% of the patients collated in the pooled 1 year studies of ivabradine. This is comparable to the death rate in similar patients treated with other antianginal agents. Thus, there does not appear to be a greater incidence of coronary events in association with ivabradine. A large clinical trial (MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction [BEAUTIF UL]) is currently under way to specifically compare such outcomes in patients with coronary artery disease and poor left ventricular function. Summary and conclusions 252 MEDICOGRAPHIA, VOL 28, No. 3, 2006 If inhibition: safety and tolerability – Savelieva and Camm IF I N H I B I T I O N INHIBITION IF : , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E SÉCURITÉ D’EMPLOI ET TOLÉRANCE e courant If (où la lettre « f » représente le terme « funny » en anglais, en raison des caractéristiques « étranges » de ce courant) est un des courants ioniques majeurs impliqués dans la modulation du potentiel d’action « pacemaker » du nœud sino-auriculaire. De façon remarquable, l’inhibition complète de ce courant ne réduit pas la fréquence cardiaque en-dessous d’un seuil limite de 30%, le potentiel « pacemaker » étant sous le contrôle de pas moins d’une dizaine d’autres courants ioniques, qui tous continuent de fonctionner de façon indépendante. Ce seuil inhérent au système rend compte à la fois de la bonne tolérance et de l’efficacité contrôlée d’une molécule comme l’ivabradine, un inhibiteur sélectif et spécifique du courant If , récemment approuvée dans le traitement de l’angor à rythme sinusal chez les patients pour lesquels les -bloquants sont soit contre-indiqués, soit mal tolérés. L’ivabradine assure les mêmes bénéfices essentiels que les -bloquants, tout en étant libre des effets secondaires majeurs associés à ces derniers. Leur efficacité est limitée aux patients dont le cœur reste sous le contrôle du nœud sino-auriculaire. Les études d’enregistrement menées chez quelque 3000 patients ont montré que l’ivabradine ralentissait le cœur tant au repos qu’à l’effort, sans modifier la contractilité ou la conduction du myocarde. L’ivabradine n’altère pas les fonctions ventriculaires gauches, même chez les patients ayant une contractilité myocardique diminuée, et son emploi est sans inconvénient en cas de bloc de branche. Puisque l’effet bradycardisant de l’ivabradine est proportionnel à la fréquence cardiaque de repos, de telle sorte que son effet tend vers un plateau à mesure que la fréquence cardiaque diminue, une bradycardie sinusale extrême motivant l’arrêt du médicament est rare et n’a été rapportée que chez moins de 1% des patients. De façon prévisible, l’intervalle QT augmente avec la réduction de la fréquence cardiaque, mais aucun effet significatif de l’ivabradine sur la durée de la repolarisation ventriculaire n’a été mis en évidence après correction des données pour la fréquence cardiaque et dans les comparaisons directes de l’intervalle QT lorsque l’influence de la fréquence cardiaque est contrôlée par entraînement auriculaire. Les abandons de traitement en raison de symptômes visuels ne concernent que moins de 1 % des patients. Les études de pharmacovigilance devraient rapidement compléter les données sur la tolérance et la sécurité d’emploi. L’étude contrôlée versus placebo BEAUTIF UL (MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), actuellement en cours chez 10 000 patients, vise à determiner l’impact de l’ivabradine sur les événements coronaires chez les patients ayant un angor avec dysfonction ventriculaire systolique. L ✦ If inhibition: safety and tolerability – Savelieva and Camm MEDICOGRAPHIA, VOL 28, No. 3, 2006 253 IF I N H I B I T I O N , H E A R T R A T E , CORONARY ARTERY DISEASE ▲ AND Stephan STEINER, MD Bodo Eckehard STRAUER, MD Department of Medicine Division of Cardiology, Pneumology, and Angiology University Hospital Düsseldorf Düsseldorf, GERMANY Heart rate and plaque disruption by S. Steiner and B . E . S t r a u e r, G e r m a n y he total number of heartbeats during lifetime remains fairly constant across species and there exists an inverse relationship between resting heart rate and life expectancy.1 In patients with coronary artery disease, resting heart rate is a predictor of total and cardiovascular mortality, which is independent of other risk factors, eg, left ventricular dysfunction.2 Today, a large body of evidence substantiates the hypothesis that tachycardia is not only a marker of other cardiovascular risk factors, but that increased frequency of cardiac beats directly causes mechanical cardiovascular damage.3 There is also growing evidence that heart rate is T laque disruption plays a central role in the pathogenesis of acute coronary syndromes (unstable angina pectoris, myocardial infarction) and sudden cardiac death, and promotes the progression of atherosclerosis. The structural defect allows circulating blood from the lumen of the artery to come into contact with subendothelial components of the plaque. Thrombi develop in places where the continuity of the plaque’s fibrous cap is disrupted by fissures or where the endothelial lining is eroded. The risk of coronary plaque disruption is determined by two main factors: plaque composition and wall stress. According to Laplace’s law, the latter is determined by systolic arterial pressure, vessel diameter, and wall thickness. This may explain the fact that the majority of the plaques that produce acute coronary syndromes are not severely stenotic. In coronary artery disease, an elevated heart rate is also a predictor of mortality, independent of other risk factors. There is evidence that a resting heart rate higher than 85 beats/min causes mechanical cardiovascular damage and promotes progression of atherosclerosis. Moreover, tachycardia may contribute to plaque disruption. In this context, heart rate reduction is a promising therapeutic approach in view of reducing the risk of acute coronary syndromes and delaying the progression of atherosclerosis. P Medicographia. 2006;28:254-257. Pathogenesis of plaque disruption Plaque rupture is multifactorial in nature (Figure 1). Two factors predominate in contributing to the risk of plaque disruption: plaque composition and the mechanical forces that develop within the plaque. Other contributing factors such as elevated whole blood viscosity (shear stress) or platelet activation will not be discussed in this review. (see French abstract on page 257) Keywords: acute coronary syndrome; myocardial infarction; sudden cardiac death; atherosclerosis; plaque; heart rate; therapy Address for correspondence: Stephan Steiner, MD, Department of Medicine, Division of Cardiology, Pneumology, and Angiology, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany (e-mail: [email protected]) 254 MEDICOGRAPHIA, VOL 28, No. 3, 2006 significantly related to the severity and progression of atherosclerosis and may contribute to plaque disruption.4 Plaque disruption is the most common condition underlying acute coronary syndromes and the progression of coronary atherosclerosis. The resulting structural defect allows circulating blood from the lumen of the artery to come into contact with subendothelial components of the plaque. Thrombi develop in places where the continuity of the plaque’s fibrous cap is disrupted by fissures or where the endothelial lining is eroded.5 Cardiovascular events are more likely caused by artery occlusion by thrombi (≈60%) rather than by obliteration of the arterial lumen by atheroma. Interestingly, it has been shown that the majority of plaques that produce acute coronary syndromes are not severely stenotic, since 60% of all cardiac events occur as a result of stenoses with only 60% lumen reduction.6 It follows that the development of more effective therapeutic strategies requires the precise identification of the factors contributing to plaque weakening and destabilization. ◆ Plaque morphology Plaque disruption takes two forms, erosion, where the endothelium becomes denuded, and rupture, where the fibrous cap is torn through the underlying lipid core. It is estimated that 25% of thrombi responsible for sudden cardiac death are due to endothelial erosion, and the remainder to plaque disruption.7 Morphologically, vulnerable plaques are characterized by a high lipid content and an in- Heart rate and plaque disruption – Steiner and Strauer IF I N H I B I T I O N creased number of macrophage-derived foam cells.3 A study of atherectomy specimens obtained from patients with coronary syndromes showed an association between the amount of inflammatory cells present and the severity of the underlying clinical syndrome. The authors conclude that disruption of the integrity of the plaque is initiated by the degrading effects of inflammatory products on the extracellular matrix.8 Furthermore, in plaques prone to rupture, there is an increased rate of formation of metalloproteinase enzymes, (eg, collagenase) that degrade components of the protective matrix.9,10 Hayashi and coworkers observed the culprit lesions in patients with acute myocardial infarction by coronary angiography and intravascular sonography. They report that patients with eroded plaque lesions have smaller infarctions than those with ruptured plaque lesions, suggesting that an eroded plaque is less potently thrombogenic than a ruptured plaque.11 Although this review focuses on the contribution of heart rate to coronary plaque disruption, it should be considered that mechanisms leading to plaque stabilization play a major role in reducing the risk of plaque disruption. In this context, the study by Takano et al (2003), which looked at the effects of statin therapy on plaque morphology, should be mentioned. Based on angioscopic findings, the authors reported on the changes in coronary plaques induced by atorvastatin in humans, and suggested that statin therapy leads to coronary plaque stabilization.12 ◆ Mechanical stress The mechanical forces that develop in the plaque are associated with the composition of the individual atheroma and geometrical parameters. The typical asymmetrical geometry in atherosclerotic vessels with eccentric stenosis imposes an increased mechanical stress on the plaque, especially at the margin of the fibrous cap near an adjacent plaquefree segment of the coronary artery wall.13 According to Laplace’s law, circumferential stress depends on blood pressure and the vessel radius and is inversely related to the thickness of the vessel wall. Therefore, mild and moderate lesions are more likely to rupture than severe ones.14 It is well known that arterial hypertension in response to physical or emotional stress contributes to the risk of myocardial infarction, especially in patients with aneurysms and those with coronary artery disease and mild-to-moderates stenosis. Furthermore, there is a marked association between plaque disruption and left ventricular mass.4 This could be explained in part by a potential association between increased left ventricular muscle mass and coronary atherosclerosis, probably due to changes in wall architecture and arterial wall thickness.15 Furthermore, left ventricular hypertrophy precludes the existence of increased blood pressure values. In summary, there is evidence that blood pressure control as well as regression of left ventricular hypertrophy are necessary to prevent plaque disruption. In the following, the contribution of tachycardia to mechanical stress is discussed. Heart rate and plaque disruption – Steiner and Strauer , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E Tachycardia and mechanical stress Heart rate is an important determinant of myocardial oxygen consumption and may affect myocardial perfusion. Therefore, an elevated heart rate can induce silent myocardial ischemia or angina pectoris symptoms. Moreover, tachycardia is positively correlated with arterial blood pressure.16 Several studies have shown that β-blockers reduce the inInternal triggers ◆ Mechanical forces (blood pressure, heart rate) ◆ Platelet activity ◆ Whole-blood viscosity ◆ Endothelial dysfunction ACS Plaque composition ◆ Atherosclerosis PLAQUE RUPTURE/ EROSION ◆ Lipid accumulation ◆ Inflammation ◆ Cap degradation ◆ Myocardial infarction ◆ Unstable angina pectoris SCD Atherosclerosis External triggers ◆ Physical exertion ◆ Emotional stress cidence of angina pectoris symptoms in patients with coronary artery disease,17-19 especially after myocardial infarction.17 That this action does not simply result from the effects of β-blockers on sympathetic overactivity was demonstrated by Borer et al20 in a recent placebo-controlled study using the If current inhibitor ivabradine, a novel selective heart rate–lowering agent that acts specifically on the sinus node without any effect on the blood pressure or the sympathetic nerve system. In this study, heart rate reduction with ivabradine resulted in a dose-dependent reduction in angina pectoris symptoms and an increase in exercise capacity. Beyond its deleterious effect on myocardial perfusion, elevated heart rate has also been implicated in the progression of atherosclerosis,21 both in animal studies and in patients with coronary artery disease. Beere et al22 examined the effect of sinus node ablation on the progression of atherosclerosis in cynomolgus monkeys. All animals were fed an atherogenic diet for 6 months. The authors found that the mean degree of stenosis was lower in animals with low resting heart rate. Several pathophysiological links exist between tachycardia, atherosclerosis, and cardiovascular events (Table I). An Figure 1. Triggers of plaque disruption. Plaque disruption may trigger acute coronary syndromes or sudden cardiac death. Furthermore, plaque disruption promotes progression of atherosclerosis. Abbreviations: ACS, acute coronary syndromes; SCD, sudden cardiac death. ◆ Low physical fitness Table I. Pathophysiological links between tachycardia and cardiovascular morbidity/mortality. ◆ Reduced cardiac reserve ◆ Increased arterial wall stress ◆ Plaque disruption ◆ Hypertension ◆ Decreased threshold for arrhythmias ◆ Sympathetic overactivity Adapted from reference 25: Palatini P. Elevated heart rate as a predictor of increased cardiovascular morbidity. J Hypertens. 1999;17:S3-S10. Copyright © 1999, Lippincott Williams & Wilkins. MEDICOGRAPHIA, VOL 28, No. 3, 2006 255 H I B I T I O N , H E A R T RAT E , A N D CO R O N A RY AR T E RY elevated heart rate exposes susceptible regions to a greater number of oscillations in flow direction over time. As every heart contraction is associated with flexion stress caused by axial bending and stretching of the coronary arteries,23 this phenomenon may be accentuated in patients with hypertensive heart disease.24 Furthermore, tachycardia results in an increase in total time spent in systole because of the shortening of diastolic time. The resulting hemodynamic wall stress may perturb intercellular junctions and favor the ingress of atherogenic particles.25 Increased heart rate also favors the mechanical perturbation of the atheromatous plaque by foreshortening and twisting of large epicardial arteries during systole, thereby contributing to plaque disruption.26 In conclusion, elevated heart rate is not only a marker of sympathetic activity, but a cardiovascular risk factor per se. Although there are no objective data for establishing normal limits for heart rate, a resting heart rate higher than 80 to 85 beats/min should not be considered normal.2,4,27 Therapeutic approaches to preventing plaque disruption due to tachycardia As mentioned above, elevated heart rate is associated with higher cardiovascular mortality and is thought to contribute to mechanical stress and plaque rupture. Therefore, reduction of heart rate appears to be a promising therapeutic approach to preventing plaque disruption. Table II lists the drugs that have a heart rate-lowering action. ◆ β-Blockers (eg, sotalol) ◆ Nondihydropyridine calcium channel blockers (benzothiazepines, eg, diltiazem; phenylalkylaminases, eg, verapamil) ◆ Antiarrhythmic agents (class I, eg, propafenone, Table II. Pharmacological strategies for heart rate reduction. flecainide) DI S E A S E ➤ ➤ IF I N Figure 2. Coronary arteriography of the right coronary artery (72-year-old male), showing plaque disruption, a cause of acute coronary syndrome (ACS). but their use is contraindicated in patients with coronary artery disease because of their proarrhythmogenic effects.28,29 Finally, a new promising class is that of the If inhibitors, with ivabradine now being available for clinical use. Pacemaker activity involves the interplay between several ionic currents—chief among which is the If current—that influence the spontaneous diastolic depolarization of the sinoatrial node. Ivabradine is a selective inhibitor of the If current as it significantly inhibits the If current and reduces the rate of the spontaneous action potential, resulting in heart rate reduction.30 Because of its specific effect on the If current, there are no side effects such as bronchoconstriction (as with β-blockers) or negative inotropic effects (as with β-blockers or calcium channel blockers). Further studies are needed to evaluate the expected benefits of ivabradine in terms of reducing the risk of plaque disruption and, consequently, of improving the outcome of coronary artery disease. ◆ Selective and specific If inhibitors (ivabradine) β-Blockers slow the heart rate probably via a reduction in sympathetic activity. Data published by Heidland et al4 suggest that β-blockers diminish the risk of coronary plaque rupture. Nevertheless, although there is robust evidence that these agents improve long-term prognosis after myocardial infarction,17,18 their use is limited by contraindications (eg, asthma) or reduced patient compliance because of side effects like weakness, lethargy, fatigue, and sexual dysfunction. In addition, the β-blockers may worsen the symptoms of peripheral vascular disease. Calcium channel blockers (verapamil, diltiazem) can also be used to decrease the heart rate and reduce angina pectoris symptoms in coronary artery disease, but here again, restrictions exist because of their negative inotropic effects in patients with heart failure. Some antiarrhythmic agents, such as flecainide or propafenone, are able to reduce the heart rate, 256 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Clinical manifestations of plaque disruption Plaque disruption has a broad spectrum of clinical presentations, ranging from asymptomatic resolution, which is reported in up to 22% of the patients who die from noncardiac causes,31 to refractory ischemia, myocardial infarction, or death. Approximately 90% of cases of nonfatal myocardial infarction and many cases of sudden cardiac death are caused by the rupture of a coronary atherosclerotic plaque.23 Most patients who survive a plaque rupture experience some form of chest pain or dyspnea. Remarkably, the characteristics of the chest pain are variable, and its severity predicts neither outcome nor angiographic findings.32,33 A less severe reduction in coronary blood flow resulting from mural thrombosis provides a starting-point for subsequent stenotic lesions34,35 because of organization and incorporation in the vessel wall. Alternatively, the thrombus may embolize downstream, resulting in myocardial ischemia. Angiography can rapid- Heart rate and plaque disruption – Steiner and Strauer IF I N H I B I T I O N ly establish the diagnosis of plaque disruption. In acute coronary syndromes, there may be a complete thrombotic occlusion of the vessel. In addition to that, some typical angiographic findings are suggestive of plaque disruption4: eccentric lesions with overhanging edges or irregular borders, and filling defects indicative of thrombus formation or ulcerations (Figure 2). In some patients, the diagnosis of plaque disruption may be established by intracoronary ultrasound. In summary, in coronary artery REFERENCES 1. Levine HJ. Resting heart rate and life expectancy. J Am Coll Cardiol. 1997;30:1104-1106. 2. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974. 3. Palatini P. Heart rate: a strong predictor of mortality in subjects with coronary artery disease. Eur Heart J. 2005;26:943-945. 4. Heidland UE Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104:1477-1482. 5. Falk A, Burke AP, Tang AJ, et al. Coronary plaque erosion without rupture into a lipid core. Circulation. 1996;93:1354-1363. 6. Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild to moderate coronary artery disease? Circulation. 1988; 78:1157-1166. 7. Berlowitz M, Brown D. The clinical manifestation of plaque rupture. In: Brown D, ed. Cardiovascular Plaque Rupture. New York, NY: Marcel Dekker; 2002: 191-213. 8. Becker A, van der Wahl A. The role of inflammation in plaque rupture. In: Brown D, ed. Cardiovascular Plaque Rupture. New York, NY: Marcel Dekker; 2002: 63-84. 9. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92: 657-671. 10. Libby P. Molecular basis of the acute coronary syndromes. Circulation. 1995;91:2844. 11. Hayashi T, Kiyoshima T, Matsuura M, et al. Plaque erosion in the culprit lesion is prone to develop a smaller myocardial infarction size compared with plaque rupture. Am Heart J. 2005;149: 284-290. 12. Takano M, Mizuno K, Yokoyama S, et al. Changes in coronary plaque color and morphology by lipid lowering therapy with atorvastatin: serial evaluation by coronary angioscopy. J Am Coll Cardiol. 2003;42: 680-686. 13. Chen GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions: a structural analysis with histopathologic correlation. Circulation. 1993;87:1179-1187. 14. Moreno P, Shah P, Falk E. Determinants of rupture of atherosclerotic coronary lesions. In: Willich A, Muller J, eds. Triggering of Acute Coronary Syndromes: Implications for Prevention. Dordrecht, The Netherlands: Kluwer Academic Publishers; 1996. 15. Roman MJ, Pickering TG, Schwartz JE, et al. Relation of arterial structure and function to left ventricular geometric patterns in hypertensive adults. J Am Coll Cardiol.1996;28:751-756. 16. Palatini P. Exercise hemodynamics in the normotensive and the hypertensive subject. Clin Sci. 1994; 87:275-287. 17. European Society of Cardiology. Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J. 1997;18:394-413. 18. Kjekshus JK. Importance of heart rate in determining betablocker efficacy in acute and long-term myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F. 19. Lechat P. Beta blocker treatment in heart failure. Role of heart rate reduction. Basic Res Cardiol. 1998; 93:148-155. 20. Borer JS, Fox K, Jaillon P, et al. Antianginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double blind, multicentered, placebo-controlled trial. Circulation. 2003;107: 817-823. 21. Persiki A, Olsson G, Landou C, et al. Minimum heart rate and coronary atherosclerosis: independent relations to global severity and heart rate of progression of angiographic lesions in men with myocardial infarction at a young age. Am Heart J. 1992;123:609-616. 22. Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science.1984;226:180-182. 23. Davies MJ, Thomas AC. Plaque fissuring—the cause of myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J. 1985;53:363-373. Heart rate and plaque disruption – Steiner and Strauer , H E A R T RAT E , A N D CO R O N A RY AR T E RY DI S E A S E disease, an elevated heart rate is a predictor of mortality, independent of other risk factors. There is evidence that a resting heart rate higher than 85 beats/min causes mechanical cardiovascular damage and promotes progression of atherosclerosis. Moreover, tachycardia may contribute to plaque disruption. In this context, heart rate reduction is a promising therapeutic approach in order to reduce the risk of acute coronary syndromes and delay the progression of atherosclerosis. ❒ 24. Schannwell CM, Steiner S, Strauer BE. Hypertensive microvascular disease. Herz. 2005;30:26-36. 25. Palatini P. Elevated heart rate as a predictor of increased cardiovascular morbidity. J Hypertens. 1999; 17:S3-S10. 26. Borer J. Drug insight: If inhibitors as specific heart-rate-reducing agents. Nat Clin Pract. 2004;1: 103-109. 27. Palatini P. Heart rate as a risk factor for atherosclerosis and cardiovascular mortality: the effect of antihypertensive drugs. Drugs. 1999;57:713-724. 28. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1989;324: 781-788. 29. Rude RK, Ryzen E. Ventricular fibrillation during antiarrhythmic drug therapy. N Engl J Med. 1989;320: 537-538. 30. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs.2004;64:1757-1765. 31. Davies MF, Bland JM, Hangartner JR, Angelini A, Thomas AG. Factors influencing the presence or absence of acute coronary artery thrombi in sudden ischemic death. Eur Heart J. 1989; 10:203-208. 32. Calvin JE, Klein LW, Vandenberg BJ, et al. Risk stratification in unstable angina. Prospective evaluation of the Braunwald classification. JAMA. 1995;273: 136-144. 33. Hultgren HN Peduzzi P. Relation of severity of symptoms to prognosis in stable angina pectoris. Am J Cardiol.1984;54:988993. 34. Mann J Davies MJ. Mechanism of progression in native coronary artery disease: role of healed plaque disruption. Heart.1999; 82:265-268. 35. Ge J, Haude M, Görke G, et al. Silent healing of spontaneous plaque disruption demonstrated by intracoronary ultrasound. Eur Heart J. 1995;16:1149-1151. FRÉQUENCE CARDIAQUE ET RUPTURE DE LA PLAQUE D’ATHÉROME L a rupture de la plaque d’athérome joue un rôle central dans la pathogenèse des syndromes coronaires aigus (angor instable, infarctus du myocarde) et dans la mort subite cardiaque, et favorise la progression de l’athérosclérose. L’altération structurale permet au sang circulant venant de la lumière de l’artère de rentrer en contact avec les composés sous-endothéliaux de la plaque. Des thrombus se développent là où la continuité du manchon fibreux de la plaque est fissurée ou là où la membrane endothéliale est érodée. Deux principaux facteurs favorisent le risque de rupture de la plaque coronaire : la composition de la plaque et la contrainte pariétale. Selon la loi de Laplace, celle-ci est déterminée par la pression artérielle systolique, le diamètre du vaisseau et l’épaisseur pariétale. Ceci peut expliquer le fait que la majorité des plaques qui induisent un syndrome coronaire aigu n’engendre pas de sténose sévère. Une fréquence cardiaque élevée est aussi, dans la maladie coronaire, un facteur prédictif de mortalité, indépendant des autres facteurs de risque. Il est établi qu’une fréquence cardiaque au repos supérieure à 85 battements par minute provoque une altération cardio-vasculaire mécanique et favorise la progression de l’athérosclérose. La tachycardie pourrait en outre contribuer à la rupture de la plaque. Dans ce contexte, la réduction de la fréquence cardiaque est une approche thérapeutique prometteuse pour diminuer le risque de syndrome coronaire aigu et retarder la progression de l’athérosclérose. ✦ MEDICOGRAPHIA, VOL 28, No. 3, 2006 257 C O N T R O V E R S I A L Q U E S T I O N Can we define an optimal heart rate for all patients? 1 ◆ I. Soydan, Turkey The quicker you run, the faster you tire! (Turkish proverb) ince the beginning of time (Big Bang), everything in the universe is in continuous change from a less probable status (order) to a more probable status (entropy, chaos). However this rule applies only to closed systems without any exchange of materials with the outside, and not to living organisms and machines exchanging materials with the external world, which evolve toward an increasingly improbable status (more order). Thus, living creatures and machines (created by living beings) go the opposite way to the rest of the universe, though ultimately, they must brutally reckon with the general law of entropy — in other words, die or break down, respectively. Does this imply that the universe exacts retribution for this “unruly” behavior of living beings and machines? If such is the case, high-speed machines will become out of order in a shorter amount of time than slower machines, and living creatures with a higher metabolic rate will live less long than those with a lower metabolic rate. Assuredly, the universe, or nature, is far more likely to be “neutral” than I have implied above, yet it is intriguing that, if we look at things from a cardiological standpoint, nature, much rather than retribution, seems in fact to have afforded a certain extent of protection to the beating heart. Thus, the rate of beating of a heart released from the control of the autonomic nervous system (as in the case of complete denervation) ranges between 90 to 110 beats/min, which is higher than the physiological resting heart rate. The so-called autonomic rate of the heart is higher than the normal resting rate due to the predominance of vagal tone over sympathetic tone under resting conditions. The question of why nature has chosen to restrain heart rate via higher control centers is interesting to ad- S Inan SOYDAN, MD Ege University Faculty of Medicine Chief of Cardiology Department Bornova/Izmir TURKEY (e-mail: [email protected]) REFERENCES 1. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104:1477-1482. 2. Nagatsu M, Spinale FG, Koide M, et al. Bradycardia and the role of beta-blockade in the amelioration of left ventricular dysfunction. Circulation. 2000;101:653-659. 3. Antman EM: ST-elevation myocardial infarction: management. In: Braunwald’s Heart Disease, 7th ed. 2005;2(chap 47): 1167-1226. 258 MEDICOGRAPHIA, VOL 28, No. 3, 2006 dress. Currently, generation of 60 to 100 impulses per minute by the sinus node and beating of the heart at this rate is accepted as normal. This is quite a wide range and even alterations of the rate within this range may significantly affect mortality and morbidity. However, a threshold level above which a linear relation between the increased risk and elevated heart rate can be observed has not been established yet. Therefore, the same reasoning may be applied to heart rate as is to ideal blood pressure and serum cholesterol levels: until a specific threshold has been confirmed, the rule of thumb is by which we go is “the lower, the better!” Theoretically, a slower heart rate relieves hemodynamic stress by decreasing the heart’s oxygen consumption and workload, thus providing significant benefits in ischemic heart disease. In patients with heart failure, slowing of the heart rate—taking care not to weaken the contractions—in addition to the above benefits, also provides favorable effects through an increase in diastolic filling. The validity of these hypotheses has been confirmed in several trials. In addition, -blocker treatment has a proven protective effect and heart rates over 80 beats/min have been associated with the facilitation of coronary plaque rupture.1 Nagatsu et al found the greatest benefits of -blockers in patients with a heart rate greater than 80 beats/ min.2 On the other hand, during treatment of ST-segment elevation myocardial infarction (STEMI), a heart rate below 60 beats/min with subsequent IV injections of a -blocker is used as a criterion.3 Currently, we don’t have any objective evidence to set a definite threshold for heart rate as for blood pressure and serum cholesterol levels. However, trials in the general population4 and in hypertensive individuals5 suggest a heart rate of 80 to 85 beats/ min as a reasonable cutoff level between high and normal heart rate. ❒ 4. Palatini P. Heart rate as a risk factor for atherosclerosis and cardiovascular mortality: the effect of antihypertensive drugs. Drugs. 1999;57:713-724. 5. Gillman MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J. 1993:125:1148-1134. Can we define an optimal heart rate for all patients? CO 2 ◆ N T R O V E R S I A L QU E S T I O N L. R. Padial, Spain Normal heart rate he normal heart rate (HR) is considered to be between 60 and 100 beats/min; however, the precise range is between 43 and 93 beats/min for men and 52 and 94 beats/min for women.1 Normal sinus rhythm originates in the sinoatrial node, situated in the crista terminalis region, and the location of the primary pacemaker can move among groups of cells within this region. Interestingly, sinoatrial node automaticity seems to arise from a changing balance of positive inward and negative outward currents that favor depolarization and repolarization, respectively. The maximal diastolic potential of normal sinus cells is about -60 mV, a voltage that inactivates most sodium channels, and therefore the major inward current is primarily a slow calcium current. A time-dependent decrease in an outward current of potassium flux (IK ) and a small inward potassium current (If ) promote pacemaker activity.2 T Luis Rodríguez PADIAL, MD Cardiac Unit Hospital Virgen de la Salud Toledo, SPAIN (e-mail: [email protected]) Determinants of heart rate The activity of the sinus node is regulated by the nervous system and an intrinsic HR can be obtained by denervating the sinus node with atropine and propranolol. The intrinsic heart rate is a function of age and can be determined by the equation 117.2 – (0.53 age).3 In a normal patient, the metabolic needs of the body are the major determinants of HR. Every heart beat impulses a volume of blood (stroke volume) and a given amount of oxygen (oxygen pulse) to the periphery. Peripheral cells extract this oxygen, producing an arteriovenous difference of O2 . The oxygen cost of performing work depends on the work rate, given that as the work rate increases so do the oxygen needs. Furthermore, for obese patients there is an extra cost for performing work of 5.8 mL of O2 /min/kg body weight.4 The beating heart consumes much energy itself (30 kg of ATP every day), and therefore, slowing the heart rate by 10 beats/min would result in a saving of 5 kg of ATP every day,5 which is very important in ventricular dysfunction and coronary artery disease. Although, the heart must beat at a rate able to supply the metabolic needs of the body, the relationship appears to be more complex given that some data suggest that HR controls the body’s metabolic activity through modulation of endothelial activity by shear stress. REFERENCES 1. Spodick DH, Raju P, Bishop RL, Rifkin RD. Operational definition of normal sinus heart rate. Am J Cardiol. 1992;69: 1245-1246. 2. Schuessler RB. Abnormal sinus node function in clinical arrhythmias. J Cardiovasc Electrophysiol. 2003;14:215-217. 3. Jose AD, Taylor RR. Autonomic blockade by propranolol and atropine to study intrinsic myocardial function in man. J Clin Invest. 1969;48:2019-2031. 4. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Principles of exercise testing and interpretation. Including pathophysiology and clinical applications. Philadephia, Pa: Lippincott Williams & Wilkins; 2005:168. Can we define an optimal heart rate for all patients? Heart rate with activity HR increases with exercise. The maximum HR achievable declines with age, while no consistent differences have been found between men and women or among different types of exercise. The most common formula for predicting peak HR is 200 -- age (years), with a standard deviation of 10 beats/min. In a given individual, a consistent relationship exists between oxygen consumption (VO2 ) and HR during exercise, and the quotient of the VO2 and HR is the O2 pulse. An exercise response with a higher VO2 /HR than predicted in the normal state indicates better than average cardiorespiratory function, whereas a response with a lower VO2 /HR indicates poorer than average cardiorespiratory function; in this case, there is a higher HR response to a given VO2 . The HR reserve or difference between predicted and observed peak heart rate should be zero in a normal person, but frequently it is a positive number due to several causes such as normal population variability, poor motivation, medications (-blockers), or disease (eg, heart, peripheral vascular, lung, endocrine, or musculoskeletal disease). Optimal heart rate A decrease in HR produces a significant increase in the length of diastole, which has a positive impact on patients with several cardiac diseases (coronary artery disease, mitral stenosis, hypertrophic or restrictive cardiomyopathy, constrictive disease, or hypertensive left ventricular diastolic dysfunction). The increase in diastole duration promotes myocardial perfusion and ventricular filling when these are restricted, as in coronary stenosis or diastolic dysfunction. Taking all of this into consideration, there must be an optimal heart rate for each patient, depending on his/her age, coronary anatomy, diastolic function, metabolic demands, and comorbidities. The lowest HR that accomplishes all these needs must be the optimal for a given patient, as the heart will consume less energy itself. Since it is difficult to determine all these factors clinically in a given patient, in my opinion the best approach would be to obtain a HR of around 60 to 70 beats/min, which has been shown to convey a better prognosis both in patients with coronary artery disease,6 the most prevalent illness, and in the normal population.7 ❒ 5. Ferrari R, Campo G, Gardini E, Pasanisi G, Ceconi C. Specific and selective If inhibition: expected clinical benefits from pure heart rate reduction in coronary patients. Eur Heart J. 2005;7:H16-H21. 6. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26: 967-974. 7. Mensink GBM, Hoffmeister H. The relationship between resting heart rate and all-cause, cardiovascular and cancer mortality. Eur Heart J. 1997;18:1404-1410. MEDICOGRAPHIA, VOL 28, No. 3, 2006 259 CO 3 N T R O V E R S I A L ◆ QU E S T I O N A. P. Maggioni and G. Lonardo, Italy large body of clinical studies has demonstrated a strong association between elevated resting heart rate (HR) and life expectancy: the lower the HR, the better the cardiovascular and general outcome. These findings were observed many years ago in the general population,1-4 then confirmed by other more recent studies 5-7 and in specific groups of patients such as the elderly,8 those with hypertension,9,10 myocardial infarction,11,12 diabetes mellitus,13 and those having undergone coronary artery bypass graft surgery (CABG).14 This large body of evidence has suggested that control of HR would probably improve the prognosis of patients suffering from coronary artery disease (CAD), but also from other cardiovascular disturbances, and would decrease the risk of overall cardiovascular mortality. Indeed, some drugs helpful in cardiovascular disorders, currently considered as drugs of first choice by international guidelines, exert their beneficial effect through their HR-lowering capability, although this is not their primary or only mechanism of action. Two typical examples are the -blockers 11,15 and the nondihydropyridine calcium antagonists,16 while other calcium antagonists, such as nifedipine, which elicit adrenergic stimulation and then increase more than reduce HR, might have harmful effects.17 However, if an ideal HR exists for any patient, it would certainly be difficult to achieve it by administrating drugs that act only indirectly on HR. Therefore, a “pure” HR-lowering drug would be of great value in evaluating the benefit of HR reduction per se, in specific populations of patients, regardless of age, sex, and clinical status. Furthermore, this “pure” HR-lowering effect should not be associated with alterations of electrophysiological parameters, negative inotropism, or reduction of blood pressure. Ivabradine answers this description and is the most selective and specific HRlowering molecule to date. It is already approved in some countries as a new therapeutic option for controlling stable angina. Ivabradine acts by selectively inhibiting the I f current, which plays a crucial role in generating and controlling HR. Anti-ischemic and antianginal effects of ivabradine have been demonstrated versus placebo in a large double-blind, randomized, dose-ranging clinical trial, involving 360 patients with stable angina and documented CAD.18 Furthermore, a second large clinical trial, INITIATIVE (INternatIonal Trial of the AntTianginal effects of IVabradinE compared to atenolol), compared the efficacy of ivabradine and atenolol in 939 patients with stable angina pectoris followed for 4 months, and found that ivabradine was at least as effective as atenolol.19 These data highlight the importance of good HR control in stable angina, and it is relatively easy to hypothesize that such control would also be of benefit in other clinical conditions, such as left ventricular dysfunction, heart failure, or vascular diseases, as an alternative and/or complementary choice to calcium antagonists, and/or -blockers. However, the still open question is “Can we define an optimal HR for all patients?” Answering this specific question is not easy. Results of recent studies show that, in the general population, the HR-mortality relationship is J-shaped, with the best HR being between 60 and 69 beats/min.5 Instead, in elderly people,8 the HR-mortality relationship is J-shaped, with the safest HR being between 60 and 89 beats/min. In patients with acute myocardial infarction, the HR-mortality relationship is also J-shaped, the safest range of HR lying between 50 and 60 beats/min.11,12 On the contrary, in patients with hypertension10 or in CABG patients,14 there is a cutoff for the safest HR, around 79 to 80 beats/ min. Pooled together, all these data seem to imply that the best rest HR would be around 60 to 65 beats/min, but the findings merely suggest, without proving, an epidemiological association. This does not mean that a reduction of HR to these levels, artificially obtained with a drug, is definitely associated with a patient outcome improvement. This concept must be proven by specific studies. Clinical trials testing pure HRlowering drugs as a new approach to the treatment of some cardiovascular disorders such as CAD or heart failure are in progress in large populations of patients. The results of these studies will be available in coming years. They should provide important information that could help better define the optimal HR, and indicate how to achieve it, in patients suffering from cardiovascular disorders. ❒ REFERENCES 1. Hjalmarson A, Remme W, eds. Sinus Node Inhibitors: A New Concept in Angina Pectoris. New York, NY: Springer Verlag; 1991. 2. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol. 1980; 112:736-749. 3. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologic Followup Study. Am Heart J. 1991;121(1 pt 1):172-177. 4. Kannel WB, Kannel C, Paffenbarger RS, Jr Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113:1489-1494. 5. Fujiura Y, Adachi H, Tsuruta M, et al. Heart rate and mortality in a Japanese general population: an 18-year follow-up study. J Clin Epidemiol. 2001;54:495-500. 6. Greenland P, Daviglus ML, Dyer AR, et al. Resting heart rate is a risk factor for cardiovascular and noncardiovascular mortality: the Chicago Heart Association Detection Project in Industry. Am J Epidemiol. 1999;1149:853-862. 7. Seccareccia F, Pannozzo F, Dima F, et al. Heart rate as a predictor of mortality: the MATISS Project. Am J Public Health. 2001;91:1258-1263. 8. Chang M, Havlik RJ, Corti MC, et al. Relation of heart rate at rest and mortality in the Women’s Health and Aging Study. Am J Cardiol. 2003;92:1294-1299. 9. Gillman MW, Kannel WB, Belanger A, et al. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J. 1993;125:1148-1154. 10. Palatini P, Thijs L, Staessen JA, et al. Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med. 2002; 162:2313-2321. A ▲ Aldo Pietro MAGGIONI, MD Giuseppe LONARDO, PhD Centro Studi ANMCO Via La Marmora 34 50121 Florence ITALY (e-mail: [email protected]) 260 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Can we define an optimal heart rate for all patients? CO 11. Hjalmarson A, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol. 1990;65:547-553. 12. Zuanetti G, Mantini L, Hernandez-Bernal F, et al. Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: insights from the GISSI-2 study. Eur Heart J. 1998;19(suppl F):F19-F26. 13. Singh N. Diabetes, heart rate, and mortality. J Cardiovasc Pharmacol Ther. 2002;7:117-129. 14. Fillinger MP, Surgenor SD, Hartman GS, et al. The association between heart rate and in-hospital mortality after coronary artery bypass graft surgery. Anesth Analg. 2002;95:1483-1488. 15. Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic 4 ◆ N T R O V E R S I A L QU E S T I O N heart failure in CIBIS II trial. Circulation. 2001;103:1428-1433. 16. Calcium channel antagonists: friend or foe in postinfarction patients? Am J Hypertens. 1996;9(12 pt 2):172S-176S. 17. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;92:1326-1331. 18. Borer JS, Fox K, Jaillon P, et al. Antianginal and anti-ischemic effects of ivabradine, an If Inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823. 19. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536. R. Seabra-Gomes, Portugal igher heart rate has long been considered a major independent risk factor for cardiovascular death, particularly sudden death.1,2 Heart rate has a predictive value for mortality after myocardial infarction3 and in older hypertensive patients.4 In atrial fibrillation, recent data suggest that an initial rate-control strategy is associated with better prognosis than just by controlling the rhythm.5 Even with the knowledge that increased heart rate will increase myocardial oxygen consumption and metabolic demand, and with ample evidence that higher heart rates will impact on prognosis of the general population as well as of those with cardiovascular disease, defining an optimal heart rate for all patients seems an impossible task. In the clinical setting, patients should be considered individually and each doctor should bear responsibility for what he/she considers the best treatment options for their patients. This is probably one of the main reasons why guidelines fail to be consistent with the experience of practicing doctors’, and are not as widely followed as we would like them to be. Heart rate increases with daily activities and in physiologic situations. Anxiety, any type of stress (particularly occupational and emotional), exertion (mainly in obese and sedentary people), heavy smoking, etc, will increase heart rate, often without the individual noticing it. Once heart rate–related high blood pressure is diagnosed, or when there is a suspicion of coronary artery disease due to the appearance of symptoms on exertion, lowering the heart rate is usually the first step to consider. The information gathered from blood pressure ambulatory monitoring or from the ischemic threshold for angina as indicated by electrocardiographic changes on a treadmill exercise test, will usually guide us to the best heart rate for that particular individual or patient. -Blockers are the first-line treatment for controlling heart rate in coronary artery disease (CAD), with the advantage that they reduce blood pressure and myocardial oxygen requirements as well as increasing coronary perfusion by a longer diastolic filling H Ricardo SEABRA-GOMES MD, PhD Instituto do Coração Ava Prof Dr Reinaldo dos Santos n° 27 2794-006 Carnaxide PORTUGAL (e-mail: [email protected]) Can we define an optimal heart rate for all patients? time. -Blockers may not be ideal in the first-line control of hypertension, but they will certainly continue to be used in hypertensive patients when lowering of heart rate is considered important.6 Calcium channel blockers, such as diltiazem or verapamil, have been, so far, the only, albeit weaker, alternative for those patients who do not tolerate -blockers, and there is evidence of their benefits after myocardial infarction, provided there is no associated heart failure or depressed left ventricular function. Newcomers, particularly ivabradine with its specific inhibitory effects on the hyperpolarization-activated I f current, which do not alter myocardial contractility or coronary vasomotion, will certainly represent the best alternative to -blockers for the required heart rate reduction.7,8 The question of the existence of an ideal heart rate in a given patient is even more relevant if there is an established diagnosis of coronary artery disease and if coronary revascularization procedures (percutaneous coronary interventions [PCI] or coronary artery surgery [CABG]), are used to improve symptoms or ischemia. If angina, dyspnea, or extensive myocardial defects detected by perfusion scans can be related to heart rate, then control of heart rate to a specific threshold is mandatory. The medical treatment of CAD is now well established, and consists of antiplatelet drugs, statins, -blockers, angiotensin-converting enzyme inhibitors, nitrates, and metabolic agents.9 Heart rate is a variable that can be measured accurately and reproducibly. We can ask the patient to adjust the dose of -blocker to a resting heart rate of 40 to 50 beats/min, if tolerated, as well as to an exercise heart rate limited by the onset of symptoms and/or signs of ischemia or significant increases in blood pressure. The available evidence supports the concept that lower heart rate has significant prognostic implications.10 Lowering the heart rate is important for therapeutic purposes in CAD patients, but is equally important in the prevention of cardiovascular events in high-risk populations. -Blockers are the only pharmacological agents MEDICOGRAPHIA, VOL 28, No. 3, 2006 261 CO N T R O V E R S I A L QU E S T I O N able to significantly reduce the heart rate, but their wider use is hampered by poor tolerability in a large number of patients. There is thus a compelling need for an alternative and equally efficient drug with better tolerance, and ivabra- dine may be the one. The optimal heart rate for all patients is the lowest one that each patient can obtain by the use of heart-rate–lowering drugs, without significant side effects, and maintaining the best possible quality of life. ❒ REFERENCES 1. Kannel W, Kannel C, Paffenbarger R, Cupples A. Heart rate and cardiovascular mortality: the Framingham study. Am Heart J. 1987;113:1489-1494. 2. Jouven X, Zureik M, Desnos M, et al. Resting heart rate as a predictive risk factor for sudden death in middle-age men. Cardiovasc Res. 2001;50:373-378. 3. Kjekshus J. Importance of heart rate in determining betablocker efficacy in acute and long-term myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F. 4. Palatini P, Thijs L, Staessen JA, et al. Predictive value of clinical and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med. 2002; 162:2313-2321. 5. Testa L, Biondi-Zoccai GGL, Russo AD, et al. Rate-control vs rhythm-control in patients with atrial fibrillation: a metaanalysis. Eur Heart J. 2005;26:2000-2006. 6. Lindholm LH, Carlberg B, Samuelsson O. Should -blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005;366:1545-1553. 7. Fox K. Ivabradine—a selective and specific I f inhibitor: efficacy and safety in stable angina. Eur Heart J. 2003;5(suppl G): G36-G45. 8. Ferrari R, Campo G, Gardini E, et al. Specific and selective If inhibition: expected clinical benefits from pure heart rate reduction in coronary patients. Eur Heart J. 2005;7(suppl H): H16-H21. 9. Steg PG, Himbert D. Unmet medical needs and therapeutic opportunities in stable angina. Eur Heart J. 2005;7(suppl H): H7-H15. 10. Singh BN. Increased heart rate as a risk factor for cardiovascular disease. Eur Heart J. 2003;5(suppl G):G3-G9. 5 ◆ J. Hradec, Czech Republic ormal heart rate (HR) is generally defined as a sinus rhythm of 60 to 100 beats/min, with some textbooks giving a range of 60 to 90 beats/min; in healthy individuals, resting HR usually ranges between 70 and 80 beats/min. However, there are no objective data determining the normal range of resting HR, or even optimal HR. Generally, a normal HR is one providing for adequate resting cardiac output and responding adequately to cardiac and extracardiac (eg, nerve stimulation) factors. Heart rate is modulated by a host of factors including physical activity, psychogenic and emotional factors, temperature, breathing, sympathetic and parasympathetic tone and their balance, baroreceptor activity, thyroid hormones, and many others. In the Framingham Heart Study, 90% of subjects had resting HR of 60 to 90 beats/min; HR <60 beats/min was present in approximately 5% of individuals, as was HR >90 beats/min.1 Heart rate >100 beats/min is defined as tachycardia, while HR <60 beats/min is bradycardia. A number of large epidemiological prospective observational cohort studies have clearly shown that resting HR is an independent risk factor for total, cardiovascular, and coronary mortality (for reference, see 2). There is an almost linear significant correlation between resting HR and mortality. The risk of death in subjects with HR >90 beats/min is about three times that in those with HR <60 beats/min. The relationship between HR and both total and cardiovascular mortality applies equally to healthy individuals, hypertensives, patients with metabolic syndrome, stable coronary heart disease, post– myocardial infarction, and chronic heart failure. The correlation is applicable to both genders, N Jaromir HRADEC MD, PhD, FESC Professor of Medicine 3rd Department of Internal Medicine 1st Faculty of Medicine and General University Hospital Charles University, Prague CZECH REPUBLIC (e-mail: [email protected]) 262 MEDICOGRAPHIA, VOL 28, No. 3, 2006 although it is somewhat weaker in women, and is independent of age and race. The increase in total and cardiovascular mortality in relation to the increase in resting HR remains significant and clinically relevant even when adjusted to all established risk factors of atherosclerosis. It is thus almost certain that it can be generalized to the population at large and is universally applicable. What can an increased HR imply? It may imply low physical fitness, poor general health, or it may be a symptom of a specific disease (eg, thyrotoxicosis, etc), manifestation of increased sympathoadrenal tone, low parasympathetic tone, or their imbalance (dystonia). Epidemiological studies have documented a positive correlation between resting HR and blood pressure,1 a finding possibly reflecting increased sympathetic activity. Individuals with increased HR also show increased prevalence of other risk factors of atherosclerosis, eg, diabetes mellitus, dyslipidemia, smoking, and low physical activity.3 There is compelling evidence at several levels showing that slowing of resting HR should be beneficial in terms of reducing mortality and prolonging life expectancy. At the biological level, there is an inverse semilogarithmic correlation in mammals between resting HR and life expectancy. The total number of beats per life is remarkably constant across species, about 3 billion.4 The only exception and, hence, an anomaly among mammals, is humans. With a mean resting HR of 70 beats/min, humans seem to be equivalent to the tiger or giraffe whose life expectancy is about 20 years; however, the life expectancy in humans is about 80 years. It is estimated that slowing of mean resting HR from 70 Can we define an optimal heart rate for all patients? CO N T R O V E R S I A L beats/min to 60 beats/min (ie, by 10 beats/min) would prolong life expectancy in man from 80 to 93.3 years, ie, by more than 13 years! 4 It has also been calculated that reducing HR by 10 beats/min would result in energy saving equivalent to approximately 5 kg of ATP/day, which the myocardium has to generate and consume.5 At the pathophysiological level, reducing HR means reduced myocardial oxygen consumption and, also (via prolongation of diastole), an increase in coronary perfusion with increased oxygen supply. Experimental and preliminary clinical data suggest that reducing HR would selectively improve coronary endothelial function, stabilize atherosclerotic plaques, enhance collateral formation, have a preventive effect on atherosclerosis progression, and would increase the fibrillation threshold, thus reducing the incidence of sudden death.6 Evidence obtained from prospective cohort epidemiological studies regarding the relationship between increases in resting HR and mortality has been discussed above. Finally, there is evidence from drug interventional clinical trials showing that heart rate–reducing agents (eg, -blockers) significantly reduce mortality and morbidity in cardiovascular patients, eg, post–myocardial infarction patients or those with chronic heart failure. It seems that HR in the normal range should decrease the way normal (or target) blood pressure values or plasma lipid levels have been recently decreased, based on evidence that the decrease was associated with improved prognosis. I believe the normal resting HR range should be redefined to 60 to 80 beats/min. It is impossible to define an optimal HR for every individual, and particularly for those with a disease. In some disease settings (eg, hypotension, heart failure, anemia, etc), increased HR is often a useful compensatory mechanism. Still, one can try to define optimal HR for the majority of the population. The relationship between resting HR and mortality is almost linear. Virtually, all epidemiological studies have shown that the lowest rates of total, cardiovascular, coronary mortality, and sudden death can be found in individuals with resting HR ≤60 beats/min.2 For example, in the Framingham Heart Study, an increment of 10 beats/min in HR in both genders was associated with increases in total mortality by 20%, cardiovascular mortality by 14%, and coronary mortality by 16% and 12% in males and females, respectively.1 As a result, I believe the optimal resting HR for most individuals is 65 beats/min. ❒ REFERENCES 1. Gillman MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J. 1993;125: 1148-1154. 2. Singh BN. Morbidity and mortality in cardiovascular disorders: Impact of reduced heart rate. J Cardiovasc Pharmacol Ther. 2001;6:313-331. 3. Diaz A, Bourassa MG, Guertin MC, Tardiff JC. Long-term prognostic value of resting heart rate in patients with sus- pected or proven coronary artery disease. Eur Heart J. 2005; 26:967-974. 4. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol. 1997;30:1104-1106. 5. Boraso A. Why is reduced heart rate beneficial? Dialogues Cardiovasc Med. 2001;6:19-24. 6. Fox K. Future perspectives of If inhibition in various cardiac conditions. Eur Heart J. 2005;7(suppl H):H33-H36. 6 ◆ QU E S T I O N C.-B. Xu, China oronary artery disease (CAD) is one of the leading causes of mortality and morbidity in the world, especially in Western countries. In recent years, it has also become an important cause of death in East-Asian countries. There is abundant evidence indicating a strong link between elevated heart rate and mortality and morbidity. It has long been known that, in the animal kingdom, there is an inverse linear relationship between heart rate and life span: the higher the heart rate, the shorter the life span, the only exception being human beings.1 Very surprisingly, the total number of heart beats per lifetime is remarkably constant, about 3 billion, throughout mammalian species, despite a 40-fold difference in life span between animals with the shortest and longest life expectancy.2 Data from epidemiological studies and clinical trials with heart rate–lowering drugs 3 have yielded interesting findings on the relationship between elevated C Chengbin XU, MD Professor of Medicine The People’s Hospital Peking University No. 11 Xizhimen South Rd 100044 Beijing CHINA (e-mail: [email protected]) Can we define an optimal heart rate for all patients? heart rate and mortality and morbidity, in comparison with the general population. These studies, which involved a total of over 116 000 patients with cardiovascular disease, male and female, of various ethnic origins and from different parts of the world, aged between 18 to 80 years, and followed-up for 5 to 36 years, showed a close association between increased heart rate and increased risk of death from all causes, including cardiovascular disease. Based on these findings, an optimal heart rate for patients with CAD can be defined. The main findings reported were: (i) a 3-fold increase in death rate in subjects with a heart rate of 90 to 99 bpm compared with subjects with a heart rate less than 60 bpm 4; (ii) a consistent and significant relationship between increased heart rate and sudden death5; (iii) a 5- to 6-fold higher risk of sudden death in men and a 2-fold higher risk in women, for heart rates above 88 or 90 bpm, compared with subjects with heart rates MEDICOGRAPHIA, VOL 28, No. 3, 2006 263 CO N T R O V E R S I A L QU E S T I O N less than 65 or 60 bpm6,7; (iv) an overall increase in mortality associated with increased heart rate, with doubling of the risk for every 40-bpm increase in heart rate; 5,8,9 (v) after adjustment for known risk factors for coronary disease (race, gender, age, blood pressure, diabetes, body mass index), the heart rate remained a significant risk factor for excess number of deaths; (vi) excess mortality appears to be mainly due to CAD; and (vii) the relationship between heart rate and cardiovascular mortality is less compelling in women than in men, in some series of populations studies. Large clinical randomized controlled trials with heart rate–lowering agents such as metoprolol,10 bisoprolol,11 and carvedilol 12 in patients post myocardial infarction or with heart failure reported a marked reduction in cardiovascular mortality, total mortality, as well as sudden death, and all of these trials confirmed the epidemiological findings. The magnitude of the beneficial effect on ischemia, all-cause mortality, and sudden arrhythmic death was found to correlate closely with the degree of reduction in heart rate, though the exact mechanism of the beneficial effect of is not clear. Heart rate is known to be the major determinant of myocardial oxygen consumption (MVO2 ) in patients with coronary artery disease or ischemic myocardial syndromes, and, furthermore, the association between elevated heart rate and mortality is well established, as stated above. It is also recognized that heart rate lowering in CAD patients lower is beneficial, but the question is, how far can we go in the reduction of heart rate? Heart rate reduction is restricted by cardiac output (CO), (CO = heart rate stroke volume), as well as by the patient’s tolerance. In the event of relatively constant stroke volume, too low a heart rate will reduce cardiac output, and it should be pointed out that the optimal range of heart rate varies according to race, gender, age, hypertension, diabetes, cardiac function, body mass index, and other risk factors. In a male patient with stable coronary artery disease and without other risk factors, the optimal range of resting heart rate varies between a maximum of 80 bpm and a minimum of 55 bpm. In female patients the range is broader, with 85 bpm as the upper limit. Heart rate was also found to be the most powerful predictor of cardiovascular mortality in elderly patients from the CArdiovascular Study in The ELderly (CASTEL).12 Some authors have confirmed the independent contribution of elevated heart rate to allcause and cardiovascular mortality in patients with hypertension in 8 studies involving 129 588 normotensive subjects compared with 43 371 hypertensive patients. There was a 0.7 mm Hg diastolic pressure increase per each 10 bpm increment in heart rate.13 In a large study involving 1807 post–acute myocardial infarction patients, a decrease in the incidence of myocardial reinfarction was found in patients treated with -blockers, the extent of which was proportional to that of the decrease in heart rate.14 In CAD patients with additional risk factors or reduced cardiac function, the upper limit of heart rate should therefore be set lower. Thus, the mortality reduction observed with -blockers correlates significantly with their heart rate–lowering action, but their negative inotropic properties and other unwanted effects may limit their usefulness. In recent years, there has been a focus on the development of selective heart rate–reducing drugs acting specifically at sinus node level, and ivabradine appears to be promising in this respect.15,16 This agent differs from zatebradine by its selective inhibition of the I f current without any effect on other ion channels, and the reduction in heart rate does not lead to a relative increase in action potential duration (APD), thereby avoiding the occurrence of torsades de pointes. Ivabradine, therefore, should be of particular value in the treatment of coronary artery disease as well as in other cardiovascular disorders associated with high heart rate or in which the heart rate is not optimal. Further clinical trials are under way to confirm this point. ❒ REFERENCES 1. Levine HJ. Heart rate and life expectancy. J Am Coll Cardiol. 1997;30:1104. 2. White PD, Jenks JL, Benedict AB, et al. The electrocardiogram of the elephant. Am Heart J. 1988;16:744-750. 3. Habib GB. Is heart rate a risk in the general population? Dialogues Cardiovasc Med. 2001;6:25-31. 4. Wilhelmsensen L, Berglund G, Elmfeldt G, et al. The multifactor primary prevention trial in Göteborg, Sweden. Eur Heart J. 1986;7:279-288. 5. Kannel W, Kannel C, Paffenbarger R, et al. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113:1489-1494. 6. Shaper AG, Wannamethee G, Macfarlane PW, et al. Heart rate, ischemic heart disease, and sudden cardiac death in middle-aged British men. Br Heart J. 1993;70:49-55. 7. Singh BN. Morbidity and mortality in cardiovascular disorders: impact of reduced heart rate. J Cardiovasc Pharmacol Ther. 2001;6:313-331. 8. Mensink GB, Hoffmeister H. The relationship between resting heart rate and all-cause cardiovascular and cancer mortality. Eur Heart J. 1997;18:1404-1410. 9. Benetos A, Rucnichi A, Thomas F, et al. Influence of heart rate on mortality in a French population: role of age, gender and blood pressure. Hypertension. 1999;33:44-52. 10. MERIT-HF Study Group. Effect of metoprolol CX/XL in chronic heart failure (MERIT-HF). Lancet. 1999;353:2001-2007. 11. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. Lancet. 1999;353:9-13. 12. Palatini P, Casiglia E, Julius S, et al. High heart rate, a risk factor for cardiovascular death in elderly men. Arch Int Med. 1999;159:585-592. 13. Zhang J Kesteloot H. Anthropometric, lifestyle, and metabolic determinants of resting heart rate. A population study. Eur Heart J. 1999;20:103-110. 14. Hjalmarson A, Gilpin E, Kjekshus J, et al. Influence of heart rate on mortality after myocardial infarction. Am J Cardiol. 1990;65:547-553. 15. Indolfi C, Guth BD, Miura T, et al. Mechanism of improved regional myocardial dysfunction by bradycardia. Studies on UL-FS 49 in swine. Circulation. 1989;80:983-993. 16. Bois P, Bescond J, Renaudon B, et al. Mode of action of bradycardic agent, S 16257,on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol. 1996;118:1051-1057. 264 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Can we define an optimal heart rate for all patients? CO 7 ◆ N T R O V E R S I A L QU E S T I O N Y. Seino, Japan Heart rate optimization number of epidemiologic investigations including a recent Japanese general population cohort study1 have revealed a close correlation between elevated resting heart rate and both cardiovascular and all-cause mortalities. Various medical treatments have shown the benefit of reducing heart rate in the treatment of cardiovascular disease, namely, the use of -blockers for hypertension, angina pectoris, acute coronary syndrome (ST-segment elevation myocardial infarction, non–ST-segment elevation myocardial infarction/unstable angina), chronic heart failure, atrial tachyarrhythmias (including tachycardiainduced cardiomyopathy), as well as of the physiological decrease in elevated heart rate/blood pressure in response to physical exercise. However, there is no consensus yet about the optimal heart rate to be achieved, or about the influence of age, gender, medications for underlying diseases, or concomitant medical conditions. A Yoshihiko SEINO, MD, PhD Professor of Medicine Department of Cardiology Nippon Medical School Tokyo JAPAN (e-mail: [email protected]) Heart rate optimization and pacemaker therapy Another important aspect of heart-rate optimization is pacemaker therapy for bradyarrhythmiarelated symptoms associated with complete atrioventricular (AV) block or sick sinus syndrome. We have shown that AV synchrony, rate-responsiveness, interventricular and intraventricular synchrony, and neurohormonal circumstances are the four fundamental requirements for physiological pacing.2-4 Our studies have shown that the major contributor to the increase in cardiac output during exercise is rate-responsiveness, which increases approximately linearly as heart rate (rang 60 to 120 beats/min) increases and provides approximately 75% of the increment in cardiac output with exercise; while maintenance of AV synchrony and augmented contractility by sympathetic activation account for the remaining 25%. Several physiological parameters have been applied as input for regulating the rateresponsive function of the pacemaker, such as spontaneous atrial activation (P wave) for DDD, changes in QT interval, respiratory-rate or respiratory–volume, body temperature, etc, for the rate-responsive pacemakers. We have analyzed changes in plasma concentrations of A-type and B-type natriuretic peptides (ANP and BNP) and catecholamines during ergometer exercise. Plasma ANP levels are considered to reflect whether two conventional requirements of physiological REFERENCES 1. Okamura T, Hayakawa T, Kadowaki T, et al. Resting heart rate and cause-specific death in a 16.5-year cohort study of the Japanese general population. Am Heart J. 2004;147:1024-1032. 2. Seino Y, Shimai S, Nagae Y, et al. Cardiodynamic and neurohormonal importance of atrial contribution in rate-responsive pacing. Am J Cardiol. 1993;72:36-40. 3. Seino Y, Hayakawa H. Atrial versus ventricular pacing. (letter) Lancet. 1995;345:734. Can we define an optimal heart rate for all patients? pacing, namely, AV synchrony and rate-responsiveness, are fulfilled or not. Furthermore, measurement of BNP levels has led to the discovery of the third requirement for physiological pacing, synchronization of ventricular contraction, which highlights the importance of paced QRS narrowing. Thus we have proposed that pacemaker therapy should satisfy not only cardiodynamic requirements, but also neurohormonal conditions such as physiological optimal ranges of plasma ANP, BNP, and catecholamine levels associated with the optimal rate-responsiveness.2-4 Can we define an optimal heart rate for all patients? The pacemaker current (I f ) plays a central role in heart-rate control, and its inhibition results in pure heart rate reduction with no other effects on the heart. Ivabradine is a selective and specific I f current inhibitor and a novel therapeutic strategy for high-risk patients with elevated resting heart rate and/or concomitant cardiovascular diseases, such as angina pectoris, acute coronary syndrome, and chronic heart failure, which are described in detail in other articles in this issue. The question that remains to be discussed is whether there is—and what is—an optimal goal in terms of heart rate, and whether this goal needs to be adapted to different populations. We should be able to define an optimal heart rate based on physiological parameters; electrocardiographic changes during an exercise or pharmacological stress test for the assessment of the myocardial ischemia burden, a cardiopulmonary exercise test with expiratory-gas analysis (VE/VCO2 slope, AT, etc) for chronic heart failure, Holter’s ambulatory monitoring, echocardiographic assessment, and the metabolic parameters assessed by the application of radioisotope or PET investigations. Findings from the physical training programs for patients with post–myocardial infarction, post-CABG, or chronic heart failure accumulated over the past decades are important to take into consideration when defining an optimal heart rate. Analysis of neurohormonal biomarkers (ANP, BNP, NT-proBNP 5), etc, is also important. As for now, the prudent answer to the question of an optimal heart rate is that it should be “case-based,” taking into account age, gender, medications for underlying diseases, concomitant medical conditions, and physiological, metabolic, and neurohormonal conditions. ❒ 4. Wu X, Seino Y, Ogura H, et al. Plasma natriuretic peptide levels and daily physical activity in patients with pacemaker implantation. Jpn Heart J. 2001;42:471-482. 5. Seino Y, Ogawa A, Yamashita T, et al. Application of NTproBNP and BNP measurements in cardiac care: a more discerning marker for detection and evaluation of heart failure. Eur J Heart Fail. 2004;6:295-300. MEDICOGRAPHIA, VOL 28, No. 3, 2006 265 CO 8 N T R O V E R S I A L ◆ QU E S T I O N Y. N. Belenkov, Russia eart rate is now clearly established as an independent and reliable prognostic factor in patients with heart disease.1 Decreasing the heart rate may have significant benefit in terms of survival and mortality of patients with coronary heart disease (CHD), chronic heart failure, and possibly with other cardiovascular and endocrine disorders.2 Thus, we are aware that decreasing the heart rate is essential for cardiac patients, but what we still do not know is to which extent the heart rate can be decreased without jeopardizing safety. Obviously, the principle of “the lesser the better” cannot fully apply in this case. In fact, the concept of a “target heart rate” is no easier to define than that of a “target blood pressure.” In patients with CHD, heart rate should not be lowered to the point of eliciting bradycardia, with weakness and syncope (eg, 30 to 32 beats/min at rest). Hence, the lowest acceptable heart rate should be under 40 to 42 beats/min at rest or during sleep, and not above 60 beats/min. The lower value is considered as the most favorable prognostic factor in the majority of epidemiological and population-based studies of the influence of heart rate on survival and mortality.3,4 However, some studies report a value of 50 beats/min as the most favorable heart rate.5 Thus, 40 to 60 beats/min is the target heart rate most commonly given. However, closer inspection reveals that a heart rate 40 to 50 beats/min at rest is safer than the above target rate. However, in studies with -blockers seeking to establish a correlation between heart rate decrease and mortality reduction,6 a heart rate lower than 50 beats/min was achieved only in very few cases. Hence the ideal target heart rate in practice is 50 to 60 beats/min. Initial randomized studies of ivabradine in patients with stable angina pectoris showed that ivabradine 10 to 20 mg/day was the loading dosage that achieved the maximal delay of angina attack and 1-mm ST-segment depres- sion on the ECG, with a heart rate at rest of 54 to 56 beats/min. In my opinion, this is the interval that should be used as target level in phase 1 clinical studies of If -channel inhibitors. The same logic applies to patients with coronary heart disease with normal or slightly impaired left ventricular function. But can we extend the above reasoning to all patients with symptomatic heart failure? The Survival And Ventricular Enlargement (SAVE) study and some other studies showed that sinus tachycardia in decompensated patients predicted a higher mortality rate, and that a decrease in heart rate in patients with heart failure treated with -blockers or amiodarone was associated with improved survival. However, the Norwegian Timolol Multicenter Study showed that timolol treatment was related to a reduction in cardiac events at any given heart rate, suggesting that factors in addition to heart rate reduction were involved in the protective effects of timolol.7 The majority of studies with other -blockers did not show any reduction in mortality when the decrease in heart rate was less than 5 to 6 beats/min. Can we use the target heart rate of 50 to 60 beats/min in patients with symptomatic heart failure (functional class IIIIV)? Probably not. Firstly, because patients with baseline sinus tachycardia at rest need extremely high doses of medication to reach the target rate, and, secondly, because in patients with significantly depressed ejection fraction, bradycardia can lead to a further decrease in ejection fraction and worsening of heart failure. Therefore, for patients with severe left ventricular dysfunction it is recommended that the reduction in heart rate should not exceed 10 to 12 beats/min from the baseline resting value. In studies evaluating the correlation between bradycardic effect and improved survival, a reduction in heart rate of 10 to 17 beats/min was associated with the greatest mortality reduction. ❒ REFERENCES 1. Benetos A, Bean K, Prognostic significance of heart rate in general population. Medicographia. 2002;24:194-199. 2. Danchin N. Potential indications for exclusive heart rate reduction for the future. In: Fox K, Ferrari R, eds. Heart Rate Management in Stable Angina. New York, NY: Taylor & Francis; 2000:83-92. 3. Diaz A, Bourassa M, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26: 967-974. 4. Kannel W, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113:1489-1494. 5. Hialmarson A. Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol. 1998;21(suppl II):II3-II7. 6. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J Suppl. 1999;1(suppl H):H64-H69. 7. Gundersen T, Grottum P, Pedersen T, Kjekshus JK. Effect of timolol on mortality and reinfarction: prognostic importance of heart rate at rest. Am J Cardiol. 1986;58:20-24. H Yuri N. BELENKOV MD, PhD Member, Academy of Medical Sciences Director, A. L. Myasnikov Cardiology Institute Cardiology Research Complex 3rd Cherepkovskaya St 15A 121 552 Moscow RUSSIA (e-mail: [email protected]) ✦ 266 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Can we define an optimal heart rate for all patients? P R O C O R A L A N PROCORALAN: ANTIANGINAL EFFICACY THROUGH AN INNOVATIVE MODE OF ACTION by I. Elyubaeva, France table angina, a condition whose prevalence is increasing with the aging of the population, and which is associated with considerable morbidity and mortality, is a common and disabling disorder and a major cause of public health concern. In spite of a substantial therapeutic armamentarium, its management continues to pose a major challenge to contemporary cardiology. S Stable angina: magnitude of the problem and unmet medical needs Irina ELYUBAEVA, MD, PhD Servier International Neuilly-sur-Seine, FRANCE As the presenting symptom of coronary artery disease (CAD) in approximately 50% of patients,1 chronic stable angina remains a major burden on public health. In countries with high CAD rates, angina sufferers are estimated to number 30 000 to 40 000 per million of the total population.2-4 However, stable angina is important not just on account of its high prevalence, but also because it is associated with increased morbidity and mortality.5,6 Stable angina affects quality of life in all its aspects, relating not only to physical functioning, but also to emotional well-being, and it considerably restricts activities of daily living.2,7-10 Although nitrates, β-blockers, and calcium channel blockers are available for its control, almost two thirds of pa- tients continue to average two episodes per week, even despite concomitant use of several conventional antianginals.11 Due to considerable patient variation in prescribing restrictions, contraindications, and response to each class of drug, agents tend to be selected on an individual basis.2 Comorbidity is an additional key factor limiting drug selection and predisposing to intolerability. Almost all conventional antianginals have frequent and sometimes severe side effects, due mainly to their hemodynamic impact and wide range of cardiovascular and other repercussions. Even relativeSELECTED ABBREVIATIONS AND ACRONYMS BEAUTIFUL MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction CAD coronary artery disease CHF congestive heart failure HCN hyperpolarization-activated, cyclic nucleotide–gated channel HR heart rate INITIATIVE INternatIonal TrIal of the AnTianginal effects of IVabradinE compared to atenolol ✦ he management of stable angina continues to challenge contemporary cardiology. Since heart rate (HR) is the major determinant of myocardial oxygen consumption, it is unsurprising that an increase in HR should account for the majority of ischemic episodes in coronary artery disease. However, accelerated resting HR is also associated with increased all-cause and cardiovascular mortality. HR reduction is thus a central aim of therapeutic strategy in angina and other forms of heart disease. Conventional HR-reducing agents, primarily -blockers and nondihydropyridine calcium channel blockers, are nonspecific in this regard and often associated with use-limiting adverse effects. Procoralan (ivabradine) is the first selective and specific inhibitor of the If ionic current, a key regulator of sinoatrial pacemaker activity. As such, it provides pure HR reduction without impairing key cardiovascular or hemodynamic parameters such as myocardial contractility, ventricular repolarization, cardiac conduction, blood pressure, or coronary vascular resistance. The largest ever development program in stable angina has demonstrated noninferiority of anti-ischemic and antianginal efficacy of Proco- T Procoralan – Elyubaeva ralan compared with reference antianginals such as the -blocker atenolol and calcium channel blocker amlodipine, holding out the hope of well tolerated and effective therapy for the many patients who are either inadequately controlled on conventional treatments or have been considered poor candidates for such treatment because of contraindications, prescribing restrictions, or poor tolerability. To determine whether pure HR reduction carries benefits extending beyond the relief of angina, Procoralan is the subject of an ongoing 3-year study in 10 000 patients (MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction : the BEAUTIF UL trial). Medicographia. 2006;28:267-274. (see French abstract on page 274) Keywords: stable angina; If current; heart rate reduction; sinus node; ivabradine (Procoralan) Address for correspondence: Dr Irina Elyubaeva, Servier International, 192 avenue Charles de Gaulle, 92578 Neuilly-sur-Seine Cedex, France (e-mail: [email protected]) MEDICOGRAPHIA, VOL 28, No. 3, 2006 267 O C O R A L A N Better balance Diastolic perfusion time supply O2 demand → → Oxygen consumption Diastolic duration/beat → → Number of contractions/min of unwanted other effects (Figure 2). They reduce myocardial contractility and depress atrioventricular conduction. In addition, β-blockers may indirectly modify vascular tone by unmasking α-adrenergic vasoconstriction in coronary arteries, while calcium channel blockers can induce hypotension and reduce coronary artery perfusion pressure.36-38 These effects may compound myocardial ischemia or constitute absolute or relative contraindications to the use of such drugs. An alternative class of agent is required with discriminant HR activity, not offset by adverse effects on force of contraction, peripheral circulation, bronchial tone, or glucose and triglyceride metabolism. → PR Subendocardial flow → Metabolic demand PREVENTION OF ANGINA ly mild side effects (eg, headaches with nitrates or ankle edema with calcium channel blockers) are common factors in noncompliance and dropout, reflecting a clear need for new therapeutic options that avoid such drawbacks. A novel concept of heart rate reduction: selective and specific I f inhibition Figure 1. Benefits of heart rate reduction in stable angina. Recent advances in the understanding of sinus node activity fostered the novel therapeutic concept of pure HR reduction. DiFrancesco in Milan laid the foundations by elucidating the basic mechanisms underlying the generation of spontaneous pacemaker activity, autonomic HR control, and the key role of the If current (first known as the outward potassium current IK2 , before being reinterpreted as a mixed Na+-K+ current and rebaptized the If , or “funny,” current).39-42 A direct correlation was de- Importance of heart rate reduction in stable angina 268 MEDICOGRAPHIA, VOL 28, No. 3, 2006 β-Blockers Blood pressure Inotropy Peripheral vasoconstriction Coronary resistance → Calcium channel blockers Blood pressure Peripheral vasoconstriction Limitations Bronchospasm Insulin responsiveness AV nodal blockade Lethargy/fatigue Nightmares/sleep disturbances Sexual dysfunction Claudication with peripheral vascular disease → HR reduction accounts, at least in part, for the antiischemic properties of β-blockers and nondihydropyridine calcium channel blockers. However, the effect is nonselective, and these drugs have a range Other CV effects → Pharmacological heart rate–reduction strategies Drugs → → Myocardial ischemia is characterized by imbalance between myocardial oxygen supply and demand. Since heart rate (HR) is the most important determinant of myocardial oxygen consumption, it is unsurprising that an increase in HR should be responsible for the majority of ischemic episodes in CAD patients.12-14 HR reduction is thus a primary aim in the treatment of stable angina. Physiologically, it prevents or relieves the mismatch between oxygen supply and demand by influencing both sides of the equation: not only does it decrease myocardial oxygen consumption, it also improves myocardial perfusion, prolonging diastolic time (Figure 1).15-19 High HR has associations that extend beyond the ischemia of CAD. There are strong associations with morbidity/mortality in general populations and patients with hypertension, diabetes, myocardial infarction, and congestive heart failure (CHF). HR remains an independent risk factor for all-cause and cardiovascular mortality after taking into account variables such as age, blood pressure, smoking, cholesterol level, diabetes, ejection fraction, exercise, and body weight.20-30 The extensive experimental evidence for potential mechanisms of improved CAD prognosis through chronic HR reduction includes limitation of atherosclerotic lesion progression and plaque rupture, promotion of coronary collaterals, and improved cardiac remodeling.31-35 In the last decade, such evidence has renewed interest in HR reduction as a therapeutic approach with benefits that comprise, but are not confined to, efficacy in ischemia. Hypotension Lower-extremity edema Constipation Figure 2. Pharmacological strategies of heart rate reduction. scribed between f-channels and pacemaker activity in which the If current determines HR by modifying the diastolic depolarization slope—effectively the basic method of HR regulation in everyday life. The If current thus became a natural target for pharmacological intervention aimed at HR control. Procoralan (ivabradine) is the first specific and selective If inhibitor to have completed clinical development in stable angina. It provides HR reduction without affecting left ventricular contractility or relaxation, atrioventricular or intraventricular cardiac conduction, or ventricular repolarization.43 Procoralan binds specifically to the f-channels on the intracellular side of the plasma membrane of the pacemaker cells in the sinoatrial node, thereby inhibiting the If current. The direct electrophysiological consequence is a reduction in the slope of Procoralan – Elyubaeva PR ◆ Effect on cardiac function and hemodynamics In contrast to conventional agents that slow HR, Procoralan reduces HR with no direct effect on other electrocardiographic or hemodynamic parameters, including blood pressure, myocardial contractility and relaxation, atrioventricular conduction, and ventricular repolarization.47-51 Experimental studies in conscious dogs showed that If inhibition with Procoralan has no intrinsic negative inotropic effect. Instead, it is associated with improved left ventricular loading. Stroke volume is increased at rest and during exercise, in contrast to β-blockers whose negative inotropic impact outweighs their positive effect on HR.49,50,52,53 The ability of Procoralan to preserve myocardial contractility is likely to be particularly important when the diastolic depolarization curve; this increases the interval between successive action potentials and thus decreases HR.42 The important features of Procoralan-induced If inhibition are selectivity and use dependency: ◆ Procoralan markedly decreases the rate of spontaneous action potential firing in sinoatrial node cells at concentrations that have no effect on other ionic currents involved in the sinus node action potential, in particular T- and L-type calcium currents and the delayed-rectifier potassium current.44 ◆ If current inhibition also appears use-dependent: because Procoralan binds and unbinds when the f-channel is in the open state, its ability to reduce HR is greater when spontaneous HR is higher, and lesser when spontaneous HR is lower.45 Advantages of pure heart rate reduction with Procoralan: preclinical studies The selectivity and specificity that account for the unique pharmacological properties of Procoralan deliver pure HR reduction without impairing other cardiac and hemodynamic parameters. Optimization of the balance between myocardial oxygen supply and demand translates into potent anti-ischemic activity. O C O R A L A N Control 40 Ivabradine 0.3 µM 20 mV 0 s 0.5 –20 – 40 ◆ Effect on heart rate reduction Direct correlation between If current and pacemaker activity makes HR reduction the main pharmacodynamic effect of Procoralan. Studies on sinoatrial preparations have shown that Procoralan significantly decreases the interval between two action potential firings (Figure 3), resulting in HR reduction. At all concentrations tested, only the slope of slow diastolic depolarization is reduced, while maximal diastolic potential and threshold activation potential remain unaffected.46,47 Experimental results in anesthetized or conscious animals have confirmed the concept that selective and specific inhibition of the cardiac pacemaker If current translates into pure HR reduction, with no direct effect on other electrocardiographic or hemodynamic parameters including atrioventricular conduction and ventricular repolarization.47-51 After single oral or intravenous administration, HR reduction with Procoralan is dose-dependent, at both rest and peak exercise.50-53 ◆ Effect on myocardial oxygen supply and demand Improved myocardial oxygen balance is a key target in the treatment of stable angina. The effects of Procoralan on myocardial oxygen supply and demand were assessed in dogs after single intravenous dosing (1 mg/kg). As a result of HR reduction, myocardial oxygen demand (MVO2) was significantly lower after Procoralan than after saline (6.7±0.6 mL/min vs 8.1±0.6 mL/min). Procoralan also increased diastolic perfusion time (233±11 ms vs 123±4 ms after saline),54 another major determinant of anti-ischemic activity. In addition, the oxygen delivery-consumption ratio was unaffected, indicating that Procoralan preserved coronary artery dilatation. Procoralan – Elyubaeva – 60 Figure 3. Spontaneous action potential in rabbit sino-atrial node in the absence or presence of ivabradine (Procoralan). Reproduced from reference 42: DiFrancesco D. Cardiac pacemaker If current and its inhibition by heart rate-reducing agents. Curr Med Res Opin. 2005; 21:1115-1122. Copyright © 2005, LibraPharm Ltd. treating myocardial ischemia with concomitant CHF, as often occurs in the natural history of CAD. In rats with CHF, Procoralan improves left ventricular function, increases stroke volume, and preserves cardiac output.55 In exercising animals (pigs, dogs), Procoralan limits exercise-induced tachycardia without dampening key physiological adaptive mechanisms such as myocardial contractility and relaxation, cardiac output, coronary blood flow and diameter, and total peripheral resistance. At similar degrees of HR reduction, β-blockers (propranolol and atenolol) demonstrate negative dromotropic, inotropic, and lusitropic effects that significantly impair hemodynamic responses to exercise.49 Coronary vasoconstriction can also be observed during exercise on β-blocker therapy47,49–52 — unsurprisingly, as it results from the unmasking of α-adrenergic vasoconstrictor tone persisting during atrial pacing. The cumulative preclinical evidence thus describes a pharmacological profile that is a genuine innovation in stable angina treatment. The anti-ischemic activity of Procoralan is devoid of negative impact on other cardiac and hemodynamic parameters. As such, its potential contribution to the treatment of chronic stable angina and a wide range of cardiovascular conditions promises to be both unique and substantial. MEDICOGRAPHIA, VOL 28, No. 3, 2006 269 PR O C O R A L A N Selective and specific I f inhibition with Procoralan in stable angina: clinical studies Heart rate (bpm) n=370 Heart rate reduction in the long term The Procoralan clinical development program involved over 5000 patients with chronic stable angina. Although this was the largest antianginal development effort yet recorded, it is currently being supplemented by a study being carried out in a population twice that size, recruited into the MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) trial, the design of which is presented at: http://www.Clinical Trials.gov. The primary objective is to demonstrate the superiority of ivabradine over placebo in the reduction in cardiovascular mortality, hospital admissions for acute myocardial infarction or for new onset or worsening heart failure (composite end point). The study results are expected in 2008. Additional studies in patients with CHF are also under way. Change in heart rate at rest (bpm) * * * * --20 * Placebo Change in heart rate at peak of exercise (bpm) B Ivabradine 2.5 mg bid Ivabradine 5 mg bid Ivabradine 10 mg bid At peak of drug activity At trough of drug activity 10 0 * --10 * * * --20 * * Placebo Ivabradine 2.5 mg bid Ivabradine 5 mg bid Ivabradine 10 mg bid Figure 4. Changes in heart rate at rest (A) and at peak exercise (B) in the different treatment groups during double-blinded doseranging of ivabradine (Procoralan). Error bars, standard error of the mean. *P<0.05 vs placebo in pairwise comparison. Reproduced from reference 56: Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blinded, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823. Copyright © 2003, Lippincott Williams & Wilkins. 270 MEDICOGRAPHIA, VOL 28, No. 3, 2006 7.5 mg 65 60 55 M0 M1 M3 M6 M9 M12 Based on data from reference 58: Lopez-Bescos L, Filipova S, Martos R, et al. Long-term safety and antianginal efficacy of the If current inhibitor ivabradine in patients with chronic stable angina. Eur Heart J. 2004;25. Abstract 876. Copyright © 2004, Oxford University Press. 0 * 5 mg Figure 5. Persistence of heart rate reduction on long-term treatment with ivabradine (Procoralan). 10 --10 Ivabradine 70 Months ◆ Efficacy in heart rate reduction A randomized, double-blind, multicenter, multinational placebo-controlled trial in 360 patients receiving twice-daily monotherapy with Procoralan 2.5 mg, 5 mg, or 10 mg demonstrated consistent HR reduction at rest and during exercise. Although A 75 the degree of reduction was similar to that expected with β-blockers at therapeutic doses and exceeded that usually seen with HR-slowing calcium channel blockers, the blood pressure reduction and other functional changes seen with these agents were absent. The effect was dose-related and observed across all doses (Figure 4); impact on the rate-pressure product, a recognized index of myocardial oxygen consumption, was clear and dose-dependent, both at rest and during exercise, and largely reflected the effect on HR.56 In the major clinical trials, Procoralan reduced HR by a mean 10 to 14 beats per minute. However, the linear relationship between baseline HR and Procoralan-induced HR reduction meant that HR reduction was greatest in patients with the highest initial HR and smallest in those with the lowest initial HR, thereby limiting the risk of excessive bradycardia. The decrease in HR was maximal after 2 to 4 weeks, with subsequent readings showing no evidence of pharmacological tolerance: a randomized double-blind multicenter study in stable angina patients showed that doses of 5 mg and 7.5 mg bid maintained optimal HR control over 1 year (Figure 5).57,58 ◆ Efficacy in angina symptoms and on improve- ment of exercise tolerance Four major efficacy studies of Procoralan were conducted in patients with chronic stable angina using standardized exercise tolerance testing (ETT). The initial randomized, double-blind, multicenter and multinational trial in 360 patients used ETT to compare Procoralan and placebo at trough drug levels over a 14-day treatment period.56 Time to 1mm ST-segment depression in the 5 mg and 10 mg groups increased compared with placebo (P<0.005), as did time to limiting angina (10 mg: P<0.05). Data from the subsequent open and run-out periods showed that both antianginal and anti-ischemic benefits persisted without the development of pharmacological tolerance. In addition, mean angina frequency decreased from 4/week at baseline to <1/week at the end of the open-label extension (P<0.001). Importantly, no rebound phenomena Procoralan – Elyubaeva PR were observed on treatment cessation. The INternatIonal TrIal of the AnTianginal effects of IVabradinE (INITIATIVE) compared Procoralan and a conventional antianginal, atenolol.59 Between inclusion and end of treatment (month 4), Procoralan 7.5 mg and 10 mg at trough drug activity produced increases in total exercise duration that were nominally larger (86.8±129.0 s and 91.7±18.8 s, respectively) than with atenolol 100 mg (78.8±133.4 s). n ◆ Ivabradine 5 mg bid vs. ate 50 mg od at M1 Atenolol better 1 min, respectively, while time to 1-mm ST-segment depression (anti-ischemic effect) increased significantly, by 0.7 min. In addition, mean weekly angina frequency and short-acting nitrate consumption decreased at study end by two thirds compared with baseline, again in all three groups. A multicenter, double-blind, randomized, parallel-arm study in 386 stable angina patients showed not only that the 5 mg and 7.5 mg doses of Procoralan were effective in angina, but that they remained so at 1-year follow-up (Figure 7).57,58 E [95% CI] P for noninf. Ivabradine better 595 286 6.7 [--7.4; 20.8] P<0.0001 7.5 mg bid 300 vs. ate 100 mg od 286 at M4 10.3 [--8.3; 28.8] P<0.0001 ◆ Ivabradine 10 mg bid vs. ate 100 mg od at M4 298 286 15.7 [--2.9; 34.3] P<0.0001 --35 s 0 Equivalence interval Mean differences (SE) compared with atenolol 100 mg were 10.3 (9.4) s and 15.7 (9.5) s in favor of Procoralan 7.5 mg and 10 mg (noninferiority: P<0.001) (Figure 6). Noninferiority in all end points was demonstrated versus atenolol at all doses. Both Procoralan and atenolol decreased angina frequency by two thirds. The study was a clear demonstration of equivalence of efficacy between Procoralan and a well-established reference drug in the treatment of stable angina. A 3-month randomized trial in 1195 stable angina patients similarly demonstrated the noninferiority of Procoralan at the same two doses (7.5 mg and 10 mg) with respect to amlodipine 10 mg daily (P<0.001).60,61 Efficacy was achieved within 1 month. In all three treatment groups, times to limiting angina and angina onset increased by 0.5 min and Angina attacks/week 4 +35 s Figure 6. Effects of ivabradine (Procoralan) on total exercise at trough of drug activity. Reproduced after reference 59: Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:25292536. Copyright © 2005, Oxford University Press. 30 5 mg 25 7.5 mg 3 2 1 0 M0 M1 M3 M6 ◆ Safety and tolerability Procoralan owes its excellent general acceptability profile to a mode of action that is highly specific and selective. The result is effective and safe HR reduction. Bradycardia was reported in only 2.2% of patients treated with Procoralan 7.5 mg bid vs in 4.4% of those receiving atenolol 100 mg daily.59 The explanation lies in the direct rate-related dynamics of the HR-lowering effect, which limit the risk of excessive bradycardia in patients with an initially low HR. Even when bradycardia does occur, its adverse effects are substantially lower than with other HRlowering drugs due to the preservation of myocardial contractility and hemodynamic parameters. Procoralan does not alter the electrophysiological profile. The only exception concerns the corrected sinus node recovery time, which statistically significantly increased from 87 to 120 ms after 30 min and from 118 to 123 ms after 60 min after a single intravenous dose of Procoralan (0.2 mg/kg). No any other significant or relevant effects other electrophysiological parameters (PR interval, QRS complex duration etc) were reported. Procoralan preserves the atrial refractory period, atrioventricular conduction time, and repolarization duration.62 QT intervals from all patients enrolled in the Procoralan development program were evaluated using a population-corrected formula (QTcP). Absence of change in the corrected QT interval throughout the follow-up period provides strong confirmation that Procoralan has no significant direct effect on the duration of ventricular repolarization (Figure 8).63 Ivabradine Change versus baseline (ms) ◆ Ivabradine M9 O C O R A L A N M12 Months QT 20 15 10 5 QTcP 0 --5 --10 0 1 Months 3 Figure 7. Persistence of antianginal efficacy on long-term treatment with ivabradine (Procoralan). Figure 8. Changes in QT and QTcP (n=995) with ivabradine (Procoralan). Based on data from reference 58: Lopez-Bescos L, Filipova S, Martos R, et al. Longterm safety and antianginal efficacy of the If current inhibitor ivabradine in patients with chronic stable angina. Eur Heart J. 2004;25. Abstract 876. Copyright © 2004, Oxford University Press. Modified from reference 63: Savelieva I, Camm AJ. Absence of direct effects of the If current blocker ivabradine on ventricular repolarization: analysis based on a population heart rate correction formula. J Am Coll Cardiol. 2005; (suppl) 1023-272-95A). Copyright © 2005, Elsevier Biomedical. Procoralan – Elyubaeva MEDICOGRAPHIA, VOL 28, No. 3, 2006 271 PR O C O R A L A N Visual symptoms have proved the most frequent adverse drug reaction. Most were phosphenes, which were transient, generally mild and well tolerated, and caused dropout in <1% of patients. Consisting of transiently increased brightness in limited areas of the visual field, usually triggered by abrupt changes in light intensity, phosphenes are associated with the action of Procoralan at the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels known to be present in the retina. All visual symptoms resolved spontaneously during therapy or after drug discontinuation. Thorough ophthalmic investigation found no clinically significant deleterious effects of Procoralan on retinal function or morphology.57 Building on the preclinical pharmacological data, the cumulative evidence from the clinical trials thus indicates that the pure HR reduction achieved by selective and specific If inhibition with Procoralan is an effective, well-tolerated strategy for preventing angina. Improvement in total exercise capacity and angina frequency has been documented in broad patient populations, together with noninferiority versus reference antianginals such as the β-blocker atenolol and calcium channel blocker amlodipine. More striking, perhaps, is the absence of direct effect on key cardiovascular parameters (left ventricular contractility and relaxation, cardiac conduction, whether atrioventricular or intraventricular, ventricular repolarization, coronary hemodynamics, blood pressure, and vascular resistance), setting Procoralan clearly apart from other antianginals. ◆ Place of Procoralan in stable angina management and future prospects The development of a novel pharmacological approach to angina prevention has important practical consequences. Given the positive results of the clinical trials, Procoralan has been approved for the symptomatic treatment of chronic stable angina in patients with normal sinus rhythm in whom βblockers are either contraindicated or not tolerated. Procoralan offers efficacy against angina and ischemia without the clinical problems sometimes associated with established drugs. It is thus suitable for most patients with stable angina, including those with contraindications to β-blockers (whether atrioventricular block, peripheral vascular disease, REFERENCES 1. Elveback LR, Connolly DC, Melton LJ. Coronary heart disease in residents of Rochester, Minnesota. Incidence 1950 through 1982. Mayo Clin Proc.1986;61: 896-900. 2. Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J. 1997;18:394-413. 3. Gibbons RJ, Chatterjee K, Daley J, et al. 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Nondihydropyridine calcium channel blockers, for their part, are relatively less effective at reducing HR; they are also contraindicated in left ventricular dysfunction, of have limited use in diabetes, and are subject to frequent tolerability problems. Being devoid of the side effects most often associated with conventional antianginals, and thus unfettered by their limitations and contraindications, Procoralan should prove easier to prescribe. The ability of Procoralan to decrease HR without negative inotropic effect could constitute a major advance, in both CAD and CHF. Pharmacological HR reduction, in particular when mediated by βblockade, has been associated with improved survival in clinical trials in CHF and post–myocardial infarction, with a correlation between amplitude of HR reduction and duration of survival.21,64-67 Procoralan could be particularly useful in such settings. There is substantial preclinical and clinical evidence for its good tolerability and efficacy in terms of left ventricular size and function in systolic CHF.55,68 The close relationship between elevated HR and all-cause, noncardiovascular and cardiovascular mortality in epidemiological and clinical studies is a convincing argument for prognostic benefit from HR reduction.20-30 The purpose of the ongoing BEAUTIFUL trial is precisely to test the survival effect of HR reduction with Procoralan in patients with CAD and moderate-to-severe left ventricular dysfunction. Pure HR reduction with Procoralan is thus not only an ingenious and clinically useful approach to the treatment of stable angina. It also promises exciting prospects in a number of common cardiac conditions. 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Perski A, Hamsten A, Lindvall K, Theorell T. Heart rate correlates with severity of coronary atherosclerosis in young postinfarction patients. Am Heart J. 1988;116:1369-1373. 33. Sutton-Tyrrell K, Alcorn HG, Wolfson SK, Kelsey SF, Kuller LH. Predictors of carotid stenosis in older adults with and without isolated systolic hypertension. Stroke. 1993;24:355-361. 34. Aronow WS, Ahn C, Mercando AD, Epstein S. Association of average heart rate on 24-hour ambulatory electrocardiograms with incidence of new coronary events at 48-month follow-up in 1,311 patients (mean age 81 years) with heart disease and sinus rhythm. Am J Cardiol. 1996;78:1175-1176. 35. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104:14771482. 36. Heyndrickx GR, Pannier JL, Muylaert P, Mabilde C, Leusen I. Alteration in myocardial oxygen balance during exercise after beta-adrenergic blockade in dogs. 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Press Release of European Medicines Agency: Committee for Medicinal Products for Human Use, 28 October 2005; http://www.emea.eu.int. Accessed February 16, 2006. 44. Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol. 1996;118:1051-1057. 45. Bucchi A, Baruscotti M, DiFrancesco D. Currentdependent block of rabbit sino-atrial node If channels by ivabradine. J Gen Physiol. 2002;120:1-13. 46. Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP. Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49. Br J Pharmacol. 1994;112:37-42. 47. Thollon C, Bidouard JP, Cambarrat C, et al. Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S 16257. Eur J Pharmacol. 1997; 339:43-51. 48. Gardiner SM, Kemp PA, March JE, Bennett T. 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European Medicines Agency: Committee for Medicinal Products for Human European Public Assessment Report (EPAR), Procoralan; http://www. emea.eu.int. Accessed February 16, 2006. 58. Lopez-Bescos L, Filipova S, Martos R, et al. Longterm safety and antianginal efficacy of the If current inhibitor ivabradine in patients with chronic stable angina. Eur Heart J. 2004;25. Abstract 876. 59. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536. 60. Borer J. Drug insight: If inhibitors as specific heartrate-reducing agents. Nature Clin Pract Cardiovasc Med. 2004;1:103-109. 61. Ruzyllo W, Ford I, Tendera M, et al. Antianginal and anti-ischemic effects of the If current inhibitor ivabradine compared to amlodipine as monotherapy in patients with chronic stable angina: a 3-month randomized, controlled, double-blind, multicenter trial. Eur Heart J. 2004;25:878. Abstract. 62. Camm AJ, Lau CP. Electrophysiological effects of a single intavenous administration of ivabradine (S 16257) in adult patients with normal electrophysiology. Drugs R&D. 2003;4:83-89. 63. Savelieva I, Camm AJ. Absence of direct effects of the If current blocker ivabradine on ventricular repolarization: analysis based on a population heart rate correction formula. J Am Coll Cardiol. 2005;(suppl) 1023-272-95A. 64. Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F. 65. Lechat P, Escolano S, Golmard JL, et al. Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency BIsoprolol Study (CIBIS). Circulation. 1997;96:21972205. 66. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J. 1999;1(suppl H):H64–H69. 67. Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation. 2001;103:1428-1433. 68. Manz M, Reuter M, Lauck G, Omran H, Jung W. A single intravenous dose of ivabradine, a novel If inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology. 2003;100:149-155. MEDICOGRAPHIA, VOL 28, No. 3, 2006 273 PR O C O R A L A N PROCORALAN : EFFICACITÉ ANTIANGOREUSE GRÂCE À UN MODE D’ACTION INNOVANT a prise en charge de l’angor stable demeure encore aujourd’hui un défi pour la cardiologie. La fréquence cardiaque (FC) étant le déterminant majeur de la consommation en oxygène du myocarde, il n’est pas surprenant que son accélération participe à la majorité des épisodes ischémiques de la maladie coronaire. Une FC de repos accélérée est en outre également associée à une augmentation de la mortalité globale et cardiovasculaire. La réduction de la FC représente donc un objectif central dans la stratégie thérapeutique tant de l’angor que d’autres formes de cardiopathies. Toutefois, du fait de leur absence de spécificité d’action sur la FC, les thérapeutiques classiques de réduction de la FC, principalement les -bloquants et les inhibiteurs calciques non dihydropyridiniques, sont souvent responsables d’effets indésirables qui en limitent l’utilisation. Procoralan (ivabradine) est le premier inhibiteur sélectif et spécifique du courant ionique If , un régulateur clé de l’activité sinusale « pacemaker ». En tant que tel, il permet une réduction de la FC pure, sans altération des paramètres hémodynamiques et cardio-vasculaires clés tels que la contractilité myocardique, la repolarisation ventriculaire, la conduction cardiaque, la pression artérielle ou la résistance vasculaire coronaire. Un programme de développement le plus important jamais effectué dans le cadre de l’angor stable a démontré la non-infériorité de l’efficacité anti-ischémique et antiangoreuse de Procoralan comparé à des antiangoreux de référence comme l’aténolol (-bloquant) et l’amlodipine (inhibiteur calcique), ouvrant la perspective d’un traitement efficace et bien toléré pour les nombreux patients mal contrôlés par les traitements conventionnels, ou ne relevant pas de tels traitements à cause de contre-indications, de restrictions d’utilisation ou d’intolérance. Une étude sur Procoralan, l’étude BEAUTIF UL (MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) d’une durée de 3 ans et menée chez 10 000 patients a été mise en place pour déterminer si la réduction de la FC pure apporte des bénéfices s’étendant au-delà de la sédation de l’angor. L ✦ 274 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Procoralan – Elyubaeva I N T E R V I E W WHAT CAN If INHIBITION CONTRIBUTE TO THE TREATMENT OF LEFT VENTRICULAR DYSFUNCTION? I n t e r v i e w w i t h M . Te n d e r a , P o l a n d Michal Tendera, MD Department of Cardiology Silesian School of Medicine, Katowice POLAND Is left ventricular dysfunction very common among coronary patients? n most patients heart failure is due to left ventricular systolic dysfunction. It has been estimated that more than 20 million people worldwide have heart failure, including about 5 million in Europe. Two to four times as many people are estimated to have asymptomatic left ventricular dysfunction. Coronary artery disease (CAD) and hypertension alone or in combination account for more that 90% of cases of heart failure. In the Studies Of Left Ventricular Dysfunction (SOLVD) registry, for example, CAD was the underlying cause in 70% of patients.1 In addition, the proportion of patients I with ischemic left ventricular dysfunction still tends to increase. This is true for at least two reasons. First, the population is aging, and age is a powerful predictor for the presence of left ventricular systolic dysfunction and heart failure. Data from the Framingham Heart Study indicate that the prevalence of heart failure may rise even tenfold in people aged 80 as compared with those aged 50 to 59.2 Another reason for an increasing prevalence of left ventricular systolic dysfunction is the better treatment of CAD, and in particular myocardial infarction. Better survival post myocardial infarction means that increasing numbers of people survive with impaired myocardial function, some of whom will develop heart failure with time. What is the prognosis in this population? he prognosis depends on the severity of left ventricular damage, as expressed by the ejection fraction, and on the patient’s functional status. In T patients with heart failure the prognosis is still severe. European data indicate that, with the exception of lung cancer, mortality in heart failure is as high as in many common types of cancer, and is associated with a comparable number of expected life-years lost.3 The median survival after diagnosis of heart failure was only 1.7 years for men and 3.2 years for women, according to Framingham data for the years 1948 to 1988.4 Implementation of proper preventive and therapeutic measures has improved this situation to some degree, with a decrease in mortality by about 12% per decade. However, a recent study of patients newly hospitalized with heart failure indicated that overall 1-year and 5-year survival rates were still no better than 57% and 27%, respectively.5 Overall 5-year mortality in patients with heart failure is around 50%. Even in patients with no symptoms of heart failure, annual mortality is in the range of 6% to 8%. In patients with CAD, presence of ischemia adds to the burden of the disease. ✦ L eft ventricular systolic dysfunction is common in patients with coronary artery disease, especially in those who have suffered myocardial infarction. Treatment of these patients must address ventricular dysfunction, myocardial ischemia, and prevention of recurrent coronary events. Angiotensin-converting enzyme inhibitors and -blockers are the two main therapeutic groups used to reduce mortality in patients with impaired left ventricular function. -Blockers are also used to alleviate ischemia. Heart rate control is an important mechanism by which -blockers exert their favorable action. Pharmacologic- and lifestyle-oriented secondary prevention also need to be employed. Despite increasing effectiveness of drug treatment, prognosis in patients with systolic dysfunction remains severe. It is expected that ivabradine, a specific If current inhibitor that lowers heart rate without any effect on the inotropic properties of the heart, may improve prognosis in these patients. In order to test this, BEAUTIF UL (MorBidity-mortality EvAlUaTion of the If inhibitor What can If inhibition contribute to the treatment of LV dysfunction? – Tendera ivabradine in patients with coronary disease and left ventricULar dysfunction), a large, randomized, study of ivabradine versus placebo in optimally treated patients with left ventricular dysfunction due to coronary artery disease, has been initiated. The primary end point is the composite of cardiovascular mortality and hospital admission for acute myocardial infarction or worsening of heart failure. BEAUTIF UL is the first major outcome trial of a specific heart rate–reducing agent. Medicographia. 2006;28:275-277. (see French abstract on page 277) Keywords: left ventricular dysfunction; coronary artery disease; myocardial infarction; heart rate; f-channel; treatment; heart rate reduction; ivabradine; clinical trial Address for correspondence: Prof Michal Tendera, MD, Department of Cardiology, Silesian School of Medicine, Ziolowa Street 47, 40-635 Katowice, Poland (e-mail: [email protected]) MEDICOGRAPHIA, VOL 28, No. 3, 2006 275 IN T E RV I E W What are the main objectives in the treatment of this population? onsidering that this population is at high risk of dying, mortality reduction is the most important therapeutic goal. This is true for both symptomatic and asymptomatic patients with left ventricular systolic dysfunction due to coronary artery disease. Another important goal is to reduce the need for hospitalization. This may be achieved by prevention of disease progression, reduction of acute ischemic events, and prevention of ventricular remodeling. In symptomatic patients, improvement in exercise tolerance, alleviation of exercise-induced ischemia, and better healthrelated quality of life are also extremely important. C What are the main treatments for this population and how do they act? schemia, underlying coronary atherosclerosis, and left ventricular dysfunction with or without heart failure, all need to be addressed in the treatment of this population.6 Let’s first talk about ventricular dysfunction. Angiotensin-converting enzyme (ACE) inhibitors are recommended as first-line therapy in all patients with decreased ejection fraction, regardless of etiology and symptoms of heart failure. In asymptomatic patients, ACE inhibitors tend to delay or prevent development of heart failure. They also reduce the probability of myocardial infarction and sudden cardiac death. In patients with symptomatic heart failure, this class of drugs has been shown to improve survival, symptoms, and functional capacity, as well as reducing hospitalizations. Adrenergic β-receptor blockers, administered on top of ACE inhibitors, further improve survival in asymptomatic patients with impaired left ventricular systolic function after myocardial infarction, and offer a significant survival benefit to patients with heart failure, regardless of their functional class. At least some β-blockers can also improve health-related quality of life. In addition, β-blockers are a mainstay of treatment for ischemia and angina. In patients with advanced heart failure, addition of an aldosterone antagonist and of an angiotensin receptor blocker may further improve prognosis. Diuretics are indicated in patents with fluid retention in order to alleviate symptoms.6 β-Blockers are also useful in controlling myocardial ischemia. Additional measures, both pharmacological and lifestyle-relat- I 276 MEDICOGRAPHIA, VOL 28, No. 3, 2006 ed, need to be employed to prevent recurrent ischemic events. As stated before, despite this extensive armamentarium, patients with ischemic heart failure still have a severe prognosis. What is the importance of heart rate control in the treatment of left ventricular dysfunction? ccelerated heart rate in patients with angina is a major determinant of oxygen consumption, and precipitates most episodes of ischemia, both symptomatic and silent. Tachycardia was also found to be an independent risk factor for mortality, not only in patients with ischemic heart disease, but also in the general population.7 There are several mechanisms that can explain the negative impact of elevated heart rate on prognosis. Tachycardia may contribute to the development of atherosclerosis. It can also promote plaque destabilization, resulting in acute events, such as unstable angina, myocardial infarction, or sudden cardiac death. The atherogenic role of the accelerated heart rate may involve both mechanical and metabolic factors. Increased vascular wall stress may result in endothelial injury, with greater permeability of the endothelium and easier penetration of the lipids into the vessel wall. Increased heart rate can also reflect the presence of sympathetic overactivity, which is detrimental per se. In patients with acute myocardial infarction, elevated heart rate is generally considered to be a marker of depressed left ventricular systolic function, reflecting the severity of myocardial damage. In addition, there is accumulating evidence that tachycardia is an independent predictor of in-hospital and late mortality in acute myocardial infarction, particularly in patients with no heart failure or in those with mild/ moderate left ventricular dysfunction. In general, heart rate provides important clinical information in patients with different subsets of coronary heart disease. Most of coronary blood flow takes place in diastole. When the threshold of vasodilatory reserve is reached, coronary flow mostly depends on the duration of diastole. This indicates that heart rate reduction alone could potentially prevent most ischemic episodes present in daily life. In addition, slowing of heart rate can favorably modify myocardial energetics. It is estimated that slowing of heart rate by 10 beats per minute may save as much as 5 kg of ATP per day.8 This energy-saving effect is especially important in patients with left ventricular dysfunction. A Why do you think that If inhibition is useful in the treatment of left ventricular dysfunction? eneficial effects of heart rate lowering in this group of patients have already been discussed. For a long time β-adrenergic blockers have been the only class of drug with a consistent bradycardic action. Their favorable clinical effect is believed to be, at least in part, due to their heart rate–lowering properties. β-Blockers, however, cannot be used in all patients, because of contraindications or side effects. It is, therefore, worth exploring whether drugs that lower heart rate by acting on the sinus node and are devoid of adrenergic receptor–blocking effects, may be equally beneficial.9 B What is the BEAUTIF UL study? EAUTIFUL (MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), is the first clinical outcome study comparing ivabradine with placebo in patients with CAD and left ventricular systolic dysfunction. It provides the first opportunity to investigate the benefits of a heart rate–lowering agent that acts specifically on the sinus node in terms of reducing major cardiovascular events. Furthermore, it is the first study that will provide a prospective evidence-based data on heart rate as an independent risk factor. BEAUTIFUL is a multicenter, randomized, double-blind, placebo-controlled trial evaluating the superiority of ivabradine over placebo in reducing cardiovascular events in patients with CAD and left ventricular systolic dysfunction, more precisely with ejection fraction ≥39%. The primary end point is a composite of cardiovascular mortality and hospital admission for acute myocardial infarction or new onset or worsening of heart failure. The study will randomize almost 10 000 patients, and will continue until 950 primary end points have occurred. In approximately 660 centers worldwide, patients aged ≥55 if nondiabetic and ≥18 years if diabetic will be randomized to placebo or oral ivabradine. Follow-up is expected to last between 18 and 36 months. All patients will receive optimal background cardiovascular treatment, which may include a β-blocker, statin, ACE inhibitor, angiotensin receptor blocker, aspirin, and/or another antiplatelet drug. The starting dose of ivabradine will B What can If inhibition contribute to the treatment of LV dysfunction? – Tendera IN T E RV I E W be 5 mg twice daily in all patients, or matching placebo. Patients receiving 5 mg twice daily, or matching placebo, 2 weeks after the inclusion visit with a resting heart rate of 60 beats per minute and more will receive the target dose 7.5 mg twice daily. With resting heart rate between 50 and 59 beats per minute, the dose will be maintained. If the resting heart rate is below 50 beats per minute and no symptoms are present, or if the patient experiences signs or symptoms likely to be due to bradycardia, the study treatment will be discontinued. The administration of heart rate–lowering agents (for example, β-blockers) after randomization will be neither encouraged nor prohibited, but will have to be clinically he primary end point of the study is a composite of cardiovascular death and hospitalization for acute myocardial infarction or new onset or worsening heart failure. Secondary end points include a combination of hospitalization for acute coronary syndrome, hospitalization for new onset or worsening heart failure, or coronary revascular- ization, the individual components of the primary and secondary end point, mortality due to coronary artery disease, allcause mortality, and both fatal and nonfatal myocardial infarction. In addition, development of new-onset diabetes and the metabolic syndrome, and changes in left ventricular systolic function will be investigated. An End Point Validation Committee, blinded to the allocation of randomized study medication, will review all events. It is expected that the BEAUTIFUL study will show clinical benefit in patients with CAD and impaired left ventricular systolic function receiving ivabradine, as compared with placebo given on top of optimal medical therapy, as available today. ❒ REFERENCES 1. Bourassa MG, Gurne O, Bangdiwala SI, et al. Natural history and patterns of current practice in heart failure. The Studies of Left Ventricular Dysfunction (SOLVD) investigators. J Am Coll Cardiol. 1993;22: 14A-19A. 2. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol. 1993;22:6A-13A. 3. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJV. More “malignant” than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail. 2001;3:315-322. 4. Kannel WB. Vital epidemiologic clues in heart failure. J Clin Epidemiol. 2000;53:229-235. 5. Blackledge HM, Tomlinson J, Squire IB. Prognosis for patients newly admitted to hospital with heart failure: survival trends in 12,220 admissions in Leicestershire 1993-2001. Heart. 2003;89:615-620. 6. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J. 2005;26:1115-1140. 7. Dyer AR, Persky V, Stamler J. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol. 1980;112:736-749. 8. Ferrari R, Nesta F, Boraso A. Increased heart rate is detrimental: the myocardial metabolic theory. Eur Heart J Suppl. 1999;1:H24-H28. 9. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757-1765. DANS indicated. Patients will be fully informed and written consent for participation in the study will be obtained. The first patient was randomized in January 2005, and study results are expected in 2008. What results are expected from this study? T QUELLE MESURE L’INHIBITION IF PEUT-ELLE CONTRIBUER AU TRAITEMENT DE LA DYSFONCTION VENTRICULAIRE GAUCHE ? a dysfonction systolique ventriculaire gauche est courante chez les patients ayant une maladie coronaire, surtout chez ceux ayant présenté un infarctus du myocarde. Le traitement de ces patients doit cibler la dysfonction ventriculaire, l’ischémie myocardique et la prévention d’événements coronaires récidivants. Les deux principaux types de traitement utilisés pour réduire la mortalité des patients ayant une altération de la fonction ventriculaire gauche sont les inhibiteurs de l’enzyme de conversion de l’angiotensine et les -bloquants, ces derniers étant également utilisés pour soulager l’ischémie. Le contrôle de la fréquence cardiaque est un mécanisme important de l’action favorable des -bloquants. Une prévention secondaire tant pharmacologique que visant l’amélioration du mode de vie est également nécessaire. Le pronostic des patients ayant une dysfonction systolique reste sévère malgré la l’efficacité thérapeutique croissante des thérapeutiques utilisées. L’ivabradine, un inhibiteur spécifique du courant If qui diminue la fréquence cardiaque sans aucun effet sur les propriétés inotropes du cœur, semble pouvoir améliorer le pronostic de ces patients. C’est pour confirmer ce point qu’a été débutée l’étude BEAUTIF UL (MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventriULar dysfunction), une grande étude randomisée ivabradine versus placebo chez des patients traités de façon optimale ayant une dysfonction ventriculaire gauche secondaire à une maladie coronaire. Le critère primaire est composé de la mortalité cardio-vasculaire et de l’hospitalisation pour infarctus du myocarde aigu ou une aggravation de l’insuffisance cardiaque. BEAUTIF UL est la première et la plus grande étude portant sur les résultats d’un médicament réduisant de façon spécifique la fréquence cardiaque. L ✦ What can If inhibition contribute to the treatment of LV dysfunction? – Tendera MEDICOGRAPHIA, VOL 28, No. 3, 2006 277 F O C U S TREATMENT STRATEGIES FOR THE STABLE ANGINA PATIENT: MORE THAN JUST THE HEART b y T. M e i n e r t z , G e r m a n y oronary artery disease (CAD) remains a major global public health problem. Although there has been a recent decline in age-standardized cardiovascular mortality, the prevalence of CAD remains high because of the aging of the population. Chronic stable angina is the initial manifestation of CAD in approximately half of all presenting patients.1,2 Angina is more than twice as common in middle-aged men than in middle-aged women (Table I).3 The prevalence increases sharply with age. It amounts to 2% to 5% in men aged 45 to 54 years and increases to 11% to 20% in men aged 65 to 74 years. The prevalence of 0.5% to 1.1% in women aged 45 to 54 years increases to 10% to 14% in women aged 65 to 74 years. There are marked differences in the incidence and prevalence of angina between different countries (Table II).3 The annual incidence in men is quite low in Japan (0.1%), and highest in Finland (0.6% to 1.1%). In the Framingham Study cohort, the incidence of angina was followed for 20 years. The annual incidence was in a similar range to that of the 10-year follow up in the Seven Country Study cohort (ie, 0.2% to 0.8%). In the Health Survey for England and the British Regional Heart (BRH) study, data on the prevalence of angina are given for men and women. The prevalence of angina in men aged 55 to 64 was 9% vs 14% in men aged 65 to 74. The prevalence of angina in the respective female age groups was 5% in the lower- and 8% in the higher-age group. Chronic stable angina is important not only because of its high C Prof Dr med Thomas MEINERTZ Universitäres Herzzentrum, GERMANY prevalence, but also because of its associated morbidity and mortality. The annual rate of myocardial infarction in patients with symptoms of angina is 3% to 3.5%, but approximately half of this group die before reaching the hospital (American College of Cardiology/American Heart Association [ACC/ AHA] 2002 Guideline Update for the Management of Patients with chronic stable angina).4 Many more patients with angina were hospitalized for an acute coronary syndrome or the evaluation and/or treatment of stable chest pain syndromes. Patients with chronic stable angina have an annual mortality of SELECTED CABG CAD CAPRIE CURE EUROPA HOPE HPS PEACE PTCA ABBREVIATIONS AND ACRONYMS coronary artery bypass grafting coronary artery disease Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events Clopidogrel in Unstable angina to prevent Recurrent Events EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease Heart Outcomes Prevention Evaluation Heart Protection Study Prevention of Events with Angiotensin Converting Enzyme inhibition percutaneous transluminal coronary angioplasty ✦ hronic stable angina is the initial manifestation of coronary artery disease in approximately half of all presenting patients. It is more common in men than in women and its prevalence increases sharply with age. The annual rate of myocardial infarction is 3% to 3.5% and the annual mortality 2% to 3%. Treatment strategies include risk factor modification, pharmacological and interventional (percutaneous transluminal coronary angioplasty/coronary artery bypass grafting) management, and treatment of concomitant diseases (hypertension, diabetes, renal impairment), as well as patient education, possibly with psychoeducational intervention, and treatment of depression and sexual dysfunction. During recent years, persistent or refractory angina—ie, angina that is unresponsive to both maximal drug treatment and revascularization techniques—has be- C 278 MEDICOGRAPHIA, VOL 28, No. 3, 2006 come increasingly more relevant and poses a problem of great magnitude. This article discusses treatment strategies that can be used to improve prognosis and quality of life in patients with stable angina: treatment of concomitant disorders, vasculoprotective therapy, psychoeducational intervention, treatment of depressive symptoms and sexual dysfunction, and treatment of refractory angina. Medicographia. 2006;28:278-284. (see French abstract on page 284) Keywords: chronic stable angina; treatment strategy; concomitant disease; depression; sexual dysfunction; refractory angina Address for correspondence: Prof Dr med Thomas Meinertz, Universitäres Herzzentrum, Martinistraße 52, 20251 Hamburg, Germany (e-mail: [email protected]) Treating the stable angina patient: more than just the heart – Meinertz FO EPIDEMIOLOGY OF ANGINA WORLDWIDE EPIDEMIOLOGY OF ANGINA WORLDWIDE ◆ In countries with high CAD rates, angina is ◆ Seven Countries Studies cohorts, 10-year follow-up – Annual incidence in men aged 40-59 was 0.1% in Japan, Greece, and Croatia; 0.2% to 0.4% in Italy, Serbia, Netherlands, and USA; 0.6% to 1.1% in Finland prevalent in 30 000 to 40 000 per one million population ◆ Angina is more than twice as common in mid- dle-aged men than in middle-aged women ◆ Framingham Study cohorts, 20-year follow-up – Annual incidence in men aged 45-54 was 0.3%; in men aged 55-64, 0.8%; in men aged 65-74, 0.6% – Annual incidence in women aged 45-54 was 0.2%; in women aged 55-64, 0.6%; in women aged 65-74, 0.6% ◆ The prevalence of angina increases sharply with age – Prevalence of 2%-5% in men aged 45-54 years increases to 11%-20% in men aged 65-74 years – Prevalence of 0.5%-1% in women aged 45-54 years increases to 10%-14% in women aged 65-74 years ◆ ASSIST trial: Health Survey for England; British Regional Heart Study – Prevalence of angina in men aged 55-64 was 9%, and 14% in men aged 65-74 – Prevalence of angina in women aged 55-64 was 5%, and 8% in women aged 65-74 Table I. Epidemiology of angina: prevalence in the general population, and according to sex and age. CAD, coronary artery disease. Table II. Epidemiology of angina: prevalence according to countries. Modified from reference 3: Task Force of the European Society of Cardiology. Management of stable angina. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J. 1997;18:394-413. Copyright © 1997, Oxford University Press. Modified from reference 3: Task Force of the European Society of Cardiology. Management of stable angina. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J. 1997; 18:394-413. Copyright © 1997, Oxford University Press. 2% to 3%, only twice that of aged-matched controls. This relatively benign prognosis is of importance when considering needs of revascularization treatment. Some patients with stable angina, however, are at much higher risk. Predictors of that risk include pure exercise capacity with easily inducible ischemia or a pure hemodynamic response to exercise, angina of recent onset, previous myocardial infarction, impaired left ventricular function, and the number of coronary vessels with significant stenoses, especially when the disease involves the left main or the proximal left anterior descending artery. Based on current guidelines, the management of stable angina has progressively broadened to include risk factor modification, patient education, pharmacological and interventional (percutaneous transluminal coronary angioplasty/coronary artery bypass grafting [PTCA/CABG]) management. Tailoring therapy to individual needs has become progressively more challenging because of the marked changes in the clinical profile of patients with CAD. Compared with the past, today’s patients are older, have undergone revascularization procedures, and frequently have concomitant diseases including hypertension, diabetes, and renal impairment. In recent years, substantial progress has been made in understanding the mechanism of acute coronary events. Treatment strategies for acute coronary syndrome have been designed to take into consideration both the risk profile of the patients and the resources available in the receiving institution. As the result of these efforts, reduction in mortality and morbidity for acute coronary syndrome during recent years has been clearly demonstrated. Less attention has been paid to stable angina pectoris or to chronic ischemic syndromes, possibly because these conditions are not considered by the majority of cardiologists as major clinical problems. A reason why the therapeutic challenge of chronic stable angina is somehow underestimated by cardiologists C U S Treating the stable angina patient: more than just the heart – Meinertz is that those patients are believed to have only minor angina symptoms. However, although the majority of these patients take more than one cardiovascular drug, effort angina is present in more than 1 % of these patients.5 This article discusses treatment strategies that can be used to improve prognosis and quality of live of patients with stable angina pectoris. Lifestyle management Although the mainstay of treatment of angina is pharmacological, the importance of lifestyle adjustments must not be underestimated. Of these, smoking cessation, dietary control, and increased exercise are the most important. ◆ Weight loss, exercise, and diet The incidence of angina is directly associated with increasing body mass.6 Patients with a body mass index of more than 25 should be encouraged to lose weight by diet control and increased exercise.7 Reduction in weight will also help control of hypertension. The incidence of CAD is higher in patients with sedentary lifestyle.8 All patients should be encouraged to increase their levels of aerobic exercise by walking, cycling, or swimming (see, for example, reference 9). All newly diagnosed patients with angina should be given dietary advice and, where possible, with the help of a dietician. Their overall intake of fat should be reduced, especially saturated fats found mostly in meat and dairy products. Consumption of oily fish 2 or 3 times a week may help to reduce the level of triglycerides due to the high omega-3-content. Patients should be encouraged to eat a diet with a high proportion of fruit and vegetables. ◆ Smoking cessation The causal link between smoking and CAD is universally accepted. Smoking cessation is probably the single most important intervention for primary and secondary prevention of CAD. The physician must highlight the importance of smoking cessation to all smoking patients while accepting that smoking is a chronic problem requiring long-term multidis- MEDICOGRAPHIA, VOL 28, No. 3, 2006 279 FO C U S among patients with coronary disease,14,17 although the recent Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial did not confirm these findings,18 possibly due to the relatively low risk among patients in this trial as compared with those in the Heart Outcomes Prevention Evaluation (HOPE) trial14 and the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA).17 The use of ACE inhibitors in patients with vascular disease who do not have the traditional indication for ACE inhibition increased following HOPE, in which 9541 normotensive patients were randomized to ramipril or placebo over a 6-year period. ciplinary management. Advice should be given to assist smokers to stop and pharmacological assistance should be considered with either nicotinic replacement therapy or bupropion.10 Treatment of concomitant diseases Vasculoprotective therapy There is considerable evidence that lifestyle changes and pharmacologic therapy may reduce the progression of atherosclerosis, stabilize plaque, or both, in chronic stable angina.13-16 ACE inhibitors have been reported to reduce morbidity and mortality 280 MEDICOGRAPHIA, VOL 28, No. 3, 2006 70 Prevalence of angina with comorbidities (% of patients) Hypertension, metabolic syndrome, diabetes, and hyperlipidemia are associated with an accelerated development of atherosclerosis. In patients with chronic stable angina appropriate treatment of these diseases is indicated (Figure1).11 Hypertension causes arterial wall stress, endothelial damage, left ventricular hypertrophy, and ultimately hypertensive heart disease. Effective treatment of hypertension reduces the relative risk of myocardial infarction by 20% and stroke by 40%.12 Current guidelines for the management of hypertension should be followed. In brief, the drugs of choice for patients with chronic stable angina and hypertension are: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type 1 (AT1) receptor blockers, β-receptor blockers, calcium channel antagonists with a long duration of action, and lastly, low-dose diuretics. Patients with hyperlipidemia should be given appropriate advice regarding diet, weight loss, and regular aerobic exercise. In the majority of patients, hyperlipidemia requires the additional use of lipidlowering drugs. Several trials have demonstrated that patients with cardiovascular disease and hyperlipidemia benefit from therapy with lipid-lowering drugs. The majority of those studies show a reduction in total and cardiovascular mortality. More recently, the Heart Protection Study (HPS) Group demonstrated that those patients at increased risk of CAD with normal cholesterol levels also had a marked reduction in myocardial infarction, stroke, or need of revascularization. In any case, patients with clinically overt CAD and hyperlipidemia (low-density lipoprotein [LDL] cholesterol above 100 mg/dL) are in need of additional therapy with statins. The addition of ezetimibe may allow the use of statins at a lower dose. Patients with metabolic syndrome or diabetes develop ischemic heart disease earlier than nondiabetic patients due to accelerated atherosclerosis. Inadequate blood glucose control is associated with early atheroma formation and increased plaque burden. In patients with metabolic syndrome, weight loss, diet, and aerobic exercise may improve the situation markedly. In patients with manifest diabetes, routine management of this disease should take into account the other risk factors of atherosclerosis such as smoking, hypertension, and hyperlipidemia. 60 59% 50 40 28% 30 26% 17% 20 13% 12% COPD LVEF<35% 10 0 HTN PVD DM CVD Figure 1. Prevalence of comorbidities in patients with coronary artery disease. Abbreviations: COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; DM, diabetes mellitus; HTN, hypertension; LVEF; left ventricular ejection fraction; PVD, peripheral vascular disease. Modified from reference 11: Rumsfeld JS, MaWhinney S, McCarthy M Jr, et al. Health-related quality of life as a predictor of mortality following coronary artery bypass graft surgery. Participants of the Department of Veterans Affairs Cooperative Study Group on Processes, Structures, and Outcomes of Care in Cardiac Surgery. JAMA. 1999;281:1298-1303. Copyright © 1999, The American Medical Association. HOPE demonstrated significant reduction in mortality in patients at high risk for cardiovascular events due to a history of previous ischemic heart disease, stroke, peripheral artery disease, or in individuals with diabetes.14 The beneficial clinical effects in these disease states are assumed to be at least in part due to reversal of endothelial dysfunction. Therefore, ACE inhibitors should be prescribed in patients with chronic stable angina who have a history of myocardial infarction, hypertension, left ventricular systolic dysfunction, or diabetes, as well as in patients with renal dysfunction who do not have contraindications to the use of these agents. It remains to be discussed whether ACE inhibitors should also be prescribed to patients with chronic stable angina who do not fulfill these criteria. AT1 receptor blockers can be given instead of ACE inhibitors to patients who do not tolerate these drugs. Antithrombotic therapy The beneficial effects of aspirin have been proved over a dose range of 75 to 325 mg. Given the potential for increased gastrointestinal side effects at higher doses, it is recommended that patients should be treated with an initial dose of 75 mg to 100 mg once daily for an indefinite period. In the CAPRIE trial (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events), the thienopyri- Treating the stable angina patient: more than just the heart – Meinertz FO dine derivative clopidogrel was found to be slightly more effective than aspirin in reducing ischemic complications (ischemic stroke, myocardial infarction, vascular death) in patients with atherosclerotic vascular disease.19 Therefore, clopidogrel is indicated in patients with aspirin intolerance. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial randomized more than 12 000 patients with non–ST-segment elevation acute coronary syndromes to clopidogrel or placebo for 3 to 12 months. The trial found that addition of clopidogrel to conventional treatment with aspirin resulted in a 23% reduction in myocardial infarction at 9 months. There was no significant reduction in death or stroke.20 The combination of aspirin and clopidogrel has not been investigated in stable angina. Anti-ischemic therapy All antianginal drugs—β-adrenergic blockers, calcium-channel blockers, and nitrates — have been shown to prolong the duration of exercise before the onset of angina and ST-segment depression as well as decreasing the frequency of anginal attacks.15 Treadmill performance typically increases by 30 to 60 seconds with anginal drugs as compared with performances on placebo. However, none of these agents have been shown to prevent myocardial infarction or death in patients being treated specifically for chronic stable angina. Head-to-head-comparative trials have not demonstrated that any single class of drugs has greater antianginal efficacy than the others.15,21,22 Although β-blockers have not been shown to reduce the rate of coronary events of mortality specifically in patients with chronic stable angina, they are approved as first-line drugs for the management of stable angina.15 This classification is based on older trials showing that these agents prolong survival after myocardial infarction and on recent data showing that they have similar benefits after primary angioplasty for acute non–ST-segment elevation myocardial infarction.23 There are no large trials assessing the effects of β-blockers on survival or rates of coronary events in patients with chronic stable angina. Such studies would require very large patient numbers due to the relatively benign prognosis of this condition, and are unlikely to be scheduled during the upcoming years. The results of a recent meta-analysis by the Blood Pressure–Lowering Treatment Trial Collaboration indicate that the use of long-acting calcium antagonists for hypertension does not increase morbidity or mortality.24 Therefore, at least in patients with chronic stable angina and hypertension refractory to ACE inhibitors or AT1 blockers, long-acting calcium antagonists can be used without increasing morbidity and mortality. Whereas long-acting nitrates decrease angina and prolong exercise performance, experimental data and data from catheterization laboratories suggest that nitrates increase vascular oxidative stress and may induce paradoxical coronary arterial vasoconstriction.25 Therefore, nitrates should be used prophylactically only in patients with frequent attacks Treating the stable angina patient: more than just the heart – Meinertz C U S of angina who do not sufficiently respond to other anginal therapy. In addition, in these patients, prophylactic use of sublingual or spray nitroglycerin or short-acting nitrates before activity can be helpful. Combination therapy The majority of the patients with chronic stable angina require treatment with two or three antianginal agents.15,21 Some drug combinations are recommended, while others should be avoided. Recommended combination therapies include a nitrate with a β-blocker and a dihydropyridine calcium channel blocker with a β-blocker. The combination of dihydropyridine calcium channel blocker with a nitrate or the combination of a heart rate–slowing calcium channel blocker with a β-blocker is not recommended. Data from randomized clinical trials support the efficacy of combination therapy with two drugs, but provide less support for the use of three agents together. Psychoeducational intervention More than one third of patients with CAD suffer from chronic stable angina. This has a major negative impact on health-related quality of life, including general health status, angina symptoms, angina symptom-related distress, and physical functioning.26 Recent attention has been given to psychoeducational interventions as a means to mitigate the impact of angina in this patient population. Psychoeducational interventions are educational treatment programs featuring multimodal self-help treatment packages. They employ both information-based material and cognitive-behavioral strategies.27 These multimodal interventions, usually delivered in small groups, result in chronic disease-related learning effecting changes in knowledge and behavior for disease self-management.27 Recent randomized controlled trials have tested the effectiveness of multimodal psychoeducational interventions for the self-management of chronic stable angina symptoms. Recently, a systematic review of randomized controlled trials testing the effect of psychoeducational interventions on angina symptoms has been published.26 Although the trials analyzed showed some positive effects for chronic stable angina patients with respect to angina symptoms, angina symptom– related distress, and physical functioning, methodological problems related to sampling, allocation concealment, experimental controls, interventions, and measurements precluded generalization. Individual effect sizes and a pooled common effect for psychoeducation on outcomes reviewed could not be estimated because of heterogeneity of outcomes examined, measures used, timing of measures, and divergent approaches to analysis. Therefore, future psychoeducational intervention trials will require greater methodological rigor to reduce biases and random error. Adequate power and well-standardized intervention approaches would help to preserve external and internal validity. In addition, clinical utility would be increased by the use of theMEDICOGRAPHIA, VOL 28, No. 3, 2006 281 FO C U S oretically or conceptually justified interventions, and outcome measures that have been conceptually justified as well as having well-established reliability and validity. Other therapeutic goals in stable angina? Another goal of therapy for chronic stable angina patients is to improve their health status, such as symptoms, functional status, and quality of life. Cardiovascular interventions are known to improve health status, but the extent to which such benefits result from changes in cardiac versus noncardiac factors is unclear. Most studies have found a limited association between cardiac function and health status measures.28 This suggests that other factors may be as important as cardiac function in determining the health status of patients with heart disease. Quality of life in this patient population is specifically affected by depressive symptoms and sexual problems. ◆ Depression Depressive symptoms are known to be associated with worse health status in stable angina patients.29-33 However, their relative contribution to disease severity is unknown.34 In a recently published study,28 the relative influence of depressive symptoms and cardiac function on health status was analyzed by measuring depressive symptoms using a specific questionnaire, and cardiac function was evaluated by measuring left ventricular ejection fraction, exercise capacity on treadmill testing, and ischemia on stress echocardiography. Health status outcomes were measured by symptom burden, physical limitation, and quality of life. Of the 1024 adults with stable angina, 20% had depressive symptoms. In multivariate analyses adjusted for measures of cardiac function and other patient characteristics, depressive symptoms were strongly associated with greater symptom burden, greater physical limitation, worse quality of life, and worse overall health. A dose-response relationship between depression score and all four measures of health status was found. The authors concluded “that depressive symptoms were strongly associated with health status outcomes, including symptom burden, physical limitation, quality of life, and overall health status.” In contrast, two physiological measures of disease severity — left ventricular ejection fraction and ischemia— were not related to health status outcome. Exercise capacity by treadmill testing was also predictive of health status outcome, but depressive symptoms remained associated with health status in all strata of exercise capacity. Although causal pathways between depressive symptoms and health status outcomes could not be determined by this crosssectional study and are almost certainly bidirectional, the results suggest “that depressive symptoms are an important factor in the perceived health status of patients with coronary artery disease.” The authors also found “that depressive symptoms were associated with overall and disease-specific health status, independent of cardiac function. Depressive 282 MEDICOGRAPHIA, VOL 28, No. 3, 2006 symptoms were as strongly associated with diseasespecific health status as was exercise capacity.”28 The findings of Ruo and coworkers discussed above suggest that efforts to improve the health status of cardiac patients should include assessment and treatment of depressive symptoms. Treatment of depression leads to improvement in health status, and improved health status is associated with better health outcomes (for a review of the literature, see reference 28). Some antidepressant therapies, such as selective serotonin reuptake inhibitors, may even improve cardiovascular outcomes among patients with coronary artery disease.35,36 In summary, the findings of Ruo and coworkers demonstrate that depressive symptoms are at least as important as cardiac function in the health-related quality of life of patients with coronary artery disease. ◆ Sexual function disorders Sexual function is an issue of growing interest, commonly defined by sexual problems and dysfunction, with reported rates of sexual dysfunction in published studies over recent years of around 30% among men and around 40% among women.37-39 There is clinical evidence that sexual problems have a mixed etiology, with physical, social, and psychological components.39,40 The impact of certain disorders, such as depression and diabetes, is well-known.41,42 In a study from Sweden,43 sexual functioning was assessed by making cross-sexual surveys of patients aged 45 to 84 years with chronic disorders (diabetes, glaucoma, chronic stable angina). Sexual functioning was assessed on a scale from the Swedish HealthRelated Quality of Life Survey adapted from the medical outcomes study. Both sexual functioning in general and specific sexual items were studied. The most important results of this study were that a loss of male erectile function was as common in diabetes (30%) as in angina pectoris (29%) and significantly higher than in a control standard population sample (20%). Besides age, significant factors for erectile dysfunction in angina were the presence of diabetes and peripheral artery disease.43 Traditionally, diabetes has been regarded as one of the most important factors contributing to impotence, accounting for at least 33% of all cases of impotence in the US.44 The prevalence of erectile dysfunction among men of all ages suffering from long-term diabetes has been estimated to be in the range between 25% to 60%.45-47 Wändell and Brorsson (2001)43 found the rate of loss of erectile function to be as high in cases of angina pectoris as in those of diabetes. They claimed that the presence of diabetes and of peripheral vascular disease are significantly contributing factors. They further discussed the possible role of drugs on male sexual dysfunction. Antihypertensive drugs are said to be associated with sexual dysfunction, but in most studies during recent years no such association could be demonstrated except for thiazide diuretics. Wändell and Brorsson concluded that sexual dysfunction is common in the general population and especially high among subjects with diabetes and angina. Treating the stable angina patient: more than just the heart – Meinertz FO C U S Treatment of refractory angina ◆ Incomplete revascularization Increasing numbers of patients with CAD have angina that is unresponsive to both maximal drug treatment and revascularization techniques. Many will have already undergone multiple percutaneous interventions or bypass surgery procedures, or have diffuse and distal coronary artery disease.48 Direct data of the prevalence of persistent or refractory angina are not available. The follow-up data from large intervention trials in CAD suggest the prevalence of refractory angina to be high and clinical relevance of this problems to be of great magnitude (Figure 2).49 In fact, considering that the Table III. Pathogenetic mechanisms of refractory angina after revascularization procedures. Abbreviations: CABG, coronary artery bypass grafting; PTCA, percutaneous transluminal coronary angioplasty. Prevalence of refractory angina (% of patients) Continued angina and antianginal medication use 12 months after optimal revascularization of angina (n=1205) 100 20 62% 59% 60 40 81% 79% 80 21% 20% 0 Continued angina Stenting group Continued antianginal medication Continued angina and/or antianginal medication Surgery group Figure 2. Prevalence of refractory angina and antianginal medication use. Modified from reference 49: Serruys PW, Unger F, Sousa JE, et al; Arterial Revascularization Therapies Study Group. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl Med J. 2001;344: 1117-1124. Copyright © 2001, The Massachusetts Medical Society. early symptomatic benefit achieved with coronary revascularization tends to attenuate with time and that, eventually, all patients become symptomatic again, regardless of treatment received, the estimates of refractory angina can get close to the estimates of chronic angina. REFERENCES 1. Elveback LR., Connolly DC, Melton LJ III. Coronary heart disease in residents of Rochester, Minnesota VII. Incidence, 1950 through 1982. Mayo Clin Proc.1986; 61:896-900. 2. Kannel WB, Feinleib M. Natural history of angina pectoris in the Framingham Study: prognosis and survival. Am J Cardiol. 1972;29:154-163. 3. Task Force of the European Society of Cardiology. Management of stable angina. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J. 1997;18:394-413. 4. American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). ACC/AHA 2002 guidelines update for the management of patients with chronic stable angina— summary article. J Am Coll Cardiol. 2003;41:159-168. 5. Pepine CL, Abrams J, Marks RG, Morris JJ, Scheidt SS, Handberg E. Characteristics of a contemporary population with angina pectoris. TIDES Investigators. J Am Coll Cardiol. 1994;74:226-231. 6. Schuler G, Hambrecht R, Schlierff G, et al. Regular physical exercise and low-fat diet: effects on progression of coronary artery disease. Circulation.1992; 86:11. 7. Haskell WL, Alderman EL, Fair JM, et al. Effects of intensive multiple risk factor reduction on coronary ◆ CABG/PTCA failure ◆ Disease progression in native coronary arteries ◆ Inadequate treatment of concomitant diseases (eg, hypertension) ◆ Microvascular dysfunction Several mechanisms may be considered to explain the persistence of angina/ischemia after revascularization procedures (Table III). Incomplete revascularization may be a planned choice in patients with acute coronary syndromes and multivessel CAD. Under these circumstances, many operators limit treatment to the culprit lesion. Incomplete revascularization may also be inevitable in patients with obstructions not amenable to dilatation, such as lesions in small vessels or in the very distal portion of larger coronary arteries. Refractory angina may also be the consequence of graft or PTCA failure early after intervention. This is today a rare occurrence and may offer some therapeutic options. Disease progression in native CAD can offer another explanation for refractory angina. However, reported rates of disease progression are to low to explain the prevalence of persistent angina in the majority of patients. In summary, it remains difficult to explain why so many patients suffer from persistent angina after removal of significant coronary obstructions. This unexpected prevalence of angina suggests that additional mechanisms unrelated to the atherosclerotic plaque or stenoses in major coronary artery branches may contribute to the pathogenesis of pain and/or ischemia.50 Microvascular dysfunction was assumed to play a prominent role in this context.51,52 If this is true, how does one deal therapeutically with persistent angina? Which are the drugs of choice to treat angina refractory to conventional therapy? ❒ atherosclerosis and clinical cardiac events in men and women with coronary artery disease: the Stanford Coronary Risk Intervention Project (SCRIP). Circulation. 1994;89:975-990. 8. Pinsky JL, Jette AM, Branch LG, et al. The Framingham Disability Study: the relationship of various coronary heart disease manifestations to disability in older persons living in the community. Am J Public Health. 1990;80:1363-1367. 9. Ades PA. Cardiac rehabilitation and secondary prevention of coronary heart disease. N Engl J Med. 2001; 345:892-902. 10. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med. 1999;340:685-691. 11. Rumsfeld JS, MaWhinney S, McCarthy M Jr, et al. Health-related quality of life as a predictor of mortality following coronary artery bypass graft surgery. Participants of the Department of Veterans Affairs Cooperative Study Group on Processes, Structures, and Outcomes of Care in Cardiac Surgery. JAMA. 1999; 281:1298-1303. 12. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke and coronary heart disease. 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution Treating the stable angina patient: more than just the heart – Meinertz bias. Lancet. 1990;335:765-774. 13. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:10711080. 14. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an Angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med.2000;342:145-153. 15. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/ AHA 2002 guidelines update for the management of patients with chronic stable angina- summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic stable Angina). J Am Coll Cardiol. 2003;41: 159-168. 16. Heart Project Study Collaborative Group. MRC/ BHF Heart Protection Study of cholesterol lowering with Simvastatin in 20.536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002; 360:7-22. 17. Fox KM; The EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with MEDICOGRAPHIA, VOL 28, No. 3, 2006 283 FO C U S stable coronary artery disease: randomized, doubleblind, placebo-controlled, multicentre trial (the EUROPA Study). Lancet. 2003;362:782-788. 18. The PEACE-trial Investigation. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-2068. 19. CAPRIE Steering Committee. A randomized, blinded, trial of Clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet.1996;348: 1329-1339. 20. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of Clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-elevation. N Engl J Med. 2001;345:494-502. 21. Thadani U. Treatment of stable angina. Curr Opin Cardiol. 1999;14:349-358. 22. Heidenreich PA, MacDonald KM, Hastie T, et al. Meta-analysis of trials comparing β-blockers, calcium antagonists, and nitrates for stable angina. JAMA.1999: 281:1927-1936. 23. Kernis SJ, Harjai KJ, Stone GW, et al. Does betablocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty? J Am Coll Cardiol. 2004;43:1773-1779. 24. Turnbull F. Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure-lowering regimes on major cardiovascular events: results of prospectively-designed overviews of randomized trials. Lancet. 2003;362:1527-1535. 25. Münzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG. Evidence for enhanced vascular superoxide anion production in nitrate tolerance and crosstolerance. J Clin Invest. 1995;95:187-194. 26. McGillion M, Watt-Watson J, Kim J, Yamada J. A systematic review of psychoeducational intervention trials for the management of chronic stable angina. J Nurs Manage. 2004;12:174-182. 27. Barlow JH, Shaw KL, Harrison K. Consulting the experts: children and parents’ perceptions of psychoeducational interventions in the context of juvenile arthritis. Health Educ Res. 1999;14:597-610. 28. Ruo B, Rumsfeld JS, Hlatky MA, Liu H, Browner STRATÉGIES WS, Whooley MA. Depressive symptoms and healthrelated quality of life. JAMA. 2003;290:215-221. 29. Spertus JA, McDonell M, Woodman CL, Fihn SD. Association between depression and worse diseasespecific functional status in outpatients with coronary artery disease. Am Heart J. 2000;140:105-110. 30. Sullivan MD, LaCroix AZ, Spertus JA, Hecht J. Five-year prospective study of the effects of anxiety and depression inpatients with coronary artery disease. Am J Cardiol. 2000;86:1135-1138. 31. Spitzer RL, Korenke K, Linzer M, et al. Health related quality of life in primary care patients with mental disorders: results from the PRIME-MA 1000 Study. JAMA. 1995;274:1511-1517. 32. Wilson IB, Clearly PD. Linking clinical variables with health-related quality of life: a conceptual model of patient outcomes. JAMA. 1995;273:59-65. 33. Sullivan MD, LaCroix AZ, Russo JE, Walker EA. Depression and self-reported physical health in patients with coronary disease: mediating and moderating factors. Psychosom Med. 2001:63:248-256. 34. Sullivan MD, LaCroix AZ, Baum C, Grothaus LC, Katon WJ. Functional status in coronary artery disease: a one-year-prospective study of the role of anxiety and depression. Am J Med. 1997:103:348-356. 35. Sauer WH, Berlin JA, Kimmel SE. Selective serotonin reuptake inhibition and myocardial infarction. Circulation. 2001;104:1894-1898. 36. Glassman AH, O´Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA.2002;288:701-709. 37. Dunn KM, Croft PR, Hackett GI. Sexual problems: a study of the prevalence and need for health care in the general population. Fam Pract.1998;15:519-524. 38. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States. Prevalence and predictors. JAMA. 1999;281:537-544. 39. Dunn KM, Croft PR, Hackett GI. Association of sexual problems with social, psychological, and physical problems in men and women: a cross sectional population survey. J Epidemiol Commun Health.1999; 53:144-148. 40. Stewart AL, Ware JE. Measuring Functioning and THÉRAPEUTIQUES DANS L’ANGOR STABLE a première manifestation de coronaropathie chez environ la moitié des patients atteints est l’angor stable chronique. Il est plus fréquent chez les hommes que chez les femmes et sa prévalence augmente de façon abrupte avec l’âge. Le taux annuel d’infarctus du myocarde est entre 3 et 3,5 % et la mortalité annuelle est entre 2 et 3 %. Les stratégies thérapeutiques comprennent la modification des facteurs de risque, la prise en charge pharmacologique et interventionnelle (angioplastie coronaire transluminale percutanée/pontage aorto-coronaire) et le traitement des maladies concomitantes (hypertension, diabète, insuffisance rénale), et aussi l’éducation du patient (intervention psy- : Well-Being. Durham, NC: Duke University Press; 1992. 41. Souetre E, Achard F. Impact des thérapeutiques sur la sphère sexuelle. Interêt des mesures de la qualité de vie [Drug-induced sexual dysfunction: the approach of quality of life studies]. In French with English summary. Therapie. 1993;48:461-464. 42. Schiel R, Muller UA. Prevalence of sexual disorders in a selection-free diabetic population (JEVIN). Diabet Res Clin Pract. 1999;44:115-121. 43. Wändell PE, Brorsson B. Assessing sexual functioning in patients with chronic disorders by using a generic health-related quality of life questionnaire. Qual Life Res. 2001;9:1081-1092. 44. Montague DK, James RE, DeWolfe VG, Martin LM. Diagnostic evaluation, classification, and treatment of men with sexual dysfunction. Urology. 1979;14:545549. 45. Benet AE, Melman A. The epidemiology of erectile dysfunction. Urol Clin North Am. 1995;22:699-709. 46. Close CF, Ryder REJ. Impotence in diabetes mellitus. Diabet Metabol Rev. 1995;11:279-285. 47. Podolsky S. Diagnosis and treatment of sexual dysfunction in the male diabetic. Med Clin North Am. 1982;66:1389-1396. 48. O’Toole L, Grech ED. Chronic stable angina: treatment options. BMJ. 2005;326:1185-1188. 49. Serruys PW, Unger F, Sousa JE, et al. Arterial Revascularization Therapies Study Group. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl Med J. 2001;344:1117-1124. 50. Marzilli M. Recurrent and resistant angina: is the metabolic approach an appropriate answer? Coron Artery Dis. 2004;15:S23-S27. 51. Sambuceti G, Marzilli M, Fedele S, Marini C, L’Abbate A. Paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease. Circulation. 2001;103:2352-2360. 52. Marzilli M, Sambuceti G, Testra R, Fedele S. Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina. J Am Coll Cardiol. 2002;40:2102-2109. AU-DELÀ DU CŒUR choéducative éventuelle) et le traitement d’une dépression et d’une dysfonction sexuelle. Ces dernières années, l’angor persistant ou réfractaire – par exemple, l’angor non répondeur à la fois aux techniques de revascularisation et aux traitements prescrits aux posologies maximales – est de plus en plus à l’ordre du jour et pose un problème de grande ampleur. Cet article traite des stratégies thérapeutiques qui peuvent améliorer le pronostic et la qualité de vie des patients ayant un angor stable : le traitement des troubles concomitants, le traitement vasculoprotecteur, l’intervention psychoéducative, le traitement des symptômes dépressifs et d’une dysfonction sexuelle, et le traitement d’un angor réfractaire. L ✦ 284 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Treating the stable angina patient: more than just the heart – Meinertz U P D A T E NEW EUROPEAN GUIDELINES FOR THE TREATMENT OF STABLE ANGINA by C. Daly and K. Fox, United Kingdom table angina can be defined as a clinical syndrome that can usually be attributed to myocardial ischemia. This ischemia is usually due to obstructive atheromatous coronary artery disease (CAD), which causes an imbalance between myocardial perfusion and the oxygen demands of the myocardium. Progress in the investigation and management of stable angina in the last 10 years has led to changes in clinical practice and has considerably improved the prognosis of patients. The first European Society of Cardiology (ESC) guidelines for the management of stable angina were published in 1997,1 and 2006 has seen the publication of a new set of guidelines updated with particular attention to new therapeutic strategies.2 A broad array of strategies is currently available for the management of stable angina, including pharmacological therapy and revascularization. Percutaneous and surgical revascularization procedures have revolutionized the management of patients with ischemic heart disease, offering effective relief of symptoms and, in severe cases, improving prognosis. New pharmacological options are available and secondary prevention is becoming more effective. Whatever the management strategy chosen, individual care is paramount and there is still an important place for clinical judgment, experience, and common sense. S Caroline DALY, MB Cardiology Fellow Kim FOX, MD, FESC Professor of Cardiology Royal Brompton Hospital London, UNITED KINGDOM Despite this positive outlook, there remain a number of unmet needs in stable angina.3-5 Revascularization is not always possible, and many revascularized patients continue to present with anginal symptoms.6 Indeed, however successful the revascularization, it in no way obviates the need for pharmacological treatment to prevent subsequent events and treat residual or recurrent ischemia. Moreover, many of the current pharmacological SELECTED ABBREVIATIONS AND ACRONYMS APSIS ASIST CAD CCB ESC EUROPA Angina Prognosis Study In Stockholm Atenolol Silent Ischemia STudy coronary artery disease calcium channel blocker European Society of Cardiology EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease Heart Outcomes Prevention Evaluation Heart Protection Study hormone replacement therapy myocardial infarction nonsteroidal anti-inflammatory drug Prevention of Events with AngiotensinConverting Enzyme inhibition Total Ischemic Burden European Trial HOPE HPS HRT MI NSAID PEACE TIBET ✦ he investigation and treatment of coronary artery disease (CAD) is the subject of a vast and rapidly expanding medical literature. Practicing physicians are expected to keep track of the wealth of information available, and to assimilate and interpret its clinical value. This is essential if they are to translate progress at an investigational level into improved clinical care and prognosis for all patients, rather than just a select few. To this end, the European Society of Cardiology (ESC) produces clinical practice guidelines on the management of individual conditions, or the use of particular treatment modalities. The year 2006 has seen the appearance of a new set of ESC guidelines for the management of stable angina pectoris, which updates the previous document, published in 1997. In this article, we review the current options in the pharmacological management of stable angina, according to the new European guidelines, which most notably include the recent advances in secondary prevention via T New European guidelines for the treatment of stable angina – Daly and Fox angiotensin-converting enzyme (ACE) inhibition and agents with novel modes of action, such as If inhibition. Appropriate risk stratification should guide the decision for further investigations and the choice between revascularization and pharmacological therapy. Despite the recent advances in revascularization techniques, all revascularized patients can expect to receive drug treatment to improve their long-term prognosis. Medicographia. 2006;28:285-292. (see French abstract on page 292) Keywords: stable angina; coronary artery disease; prognosis; therapy; ACE inhibitor; -blocker; calcium channel blocker; I f inhibitor; revascularization; risk stratification; clinical practice guidelines Address for correspondence: Dr Caroline Daly, MB, Cardiology Fellow, Royal Brompton Hospital, London SW3 6NP, UK (e-mail: [email protected]) MEDICOGRAPHIA, VOL 28, No. 3, 2006 285 UP D AT E strategies are far from ideal, due to side effects, inefficacy, or intolerance. The changing environment of the management of stable angina makes the new 2006 ESC guidelines particularly timely.2 Pharmacological therapy remains the recommended firstline strategy to control symptoms and improve long-term prognosis. In this article, we summarize and review the current options in the pharmacological treatment of stable angina, as they appear in the new 2006 ESC guidelines. Our aim is to simplify the information contained therein. For more details, the reader should refer to the original document.2 Diagnosis and risk stratification Age, sex, total cholesterol, smoking, pattern of pain, the presence of diabetes mellitus, hypertension, and noncoronary vascular disease are predictors of prognosis in stable angina. Clinical evaluation is the most important step in evaluating these risks, and risk stratification is crucial to the management of any patient presenting with chest pain.3 After clinical evaluation, including history, electrocardiography (ECG), and laboratory tests, specific investigations can identify the presence of ischemia due to CAD. These include an exercise ECG or pharmacological or exercise stress testing. Coronary angiography is often necessary in medium- to highrisk cases and to resolve equivocal test results, especially since false-positive and false-negative results can occur in up to 30% of cases. Additional useful prognostic information includes exercise tolerance, the presence and extent of inducible left ventricular (LV) dysfunction, blood pressure and heart rate response to exercise, and the degree of myocardial ischemia. These can be determined noninvasively. Aims of treatment The treatments for stable angina can be divided into two categories: (i) treatments that improve prognosis; and (ii) treatments that improve symptoms.2 Lifestyle changes and pharmacological treatment can alter the atherosclerotic disease process, slowing its progression and reducing platelet activation and the fibrinolytic and inflammatory abnormalities that predispose to acute plaque rupture and thrombotic occlusion. Agents that reduce myocardial oxygen demand and/or increase blood flow to the ischemic area can reduce the symptoms of angina pectoris and the signs of ischemia (even silent ischemia). An algorithm summarizing the strategies described in this article is presented in Figure 1.2 Lifestyle modification There are a number of lifestyle changes that can be implemented to improve the prognosis of stable angina.1,2 These include smoking cessation, change to a “Mediterranean” diet, reduction of body weight in overweight patients, and increased physical activity according to the severity of the symptoms. 286 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Psychological risk factors should also be addressed, such as excessive anxiety or depression. Concomitant disorders, such as diabetes and hypertension, should be managed aggressively. Improving prognosis with pharmacological treatment ◆ Antithrombotic therapy Aspirin irreversibly inhibits platelet cyclooxygenase (COX-1) and, as a consequence, reduces the synthesis of thromboxane. At low doses (75 to 150 mg/day), chronic therapy with aspirin remains the best pharmacological option for the prevention of arterial thrombosis.7 Outside this dose range, the advantage conferred by treatment with aspirin is lower.8 Low-dose aspirin is therefore to be recommended in all patients, provided they do not present specific contraindications.2 Higher doses of aspirin increase the risk of gastrointestinal (GI) side effects,7 and so the dosage should be carefully adjusted to find the lowest effective dose and balance the equilibrium between therapeutic advantage and GI side effects. While aspirin does increase the relative risk of intracranial bleeding,9 such complications are rarely observed at recommended therapeutic dosages.7,10 The presence of specific contraindications to aspirin means that alternative antithrombotic strategies should be sought.2 The antiplatelet agents clopidogrel and ticlopidine are more expensive than aspirin, but have a similar overall safety profile and may be good options in cases of aspirin intolerance, eg, patients with bronchospasm. They have comparable antithrombotic effects to aspirin.7 These thienopyridines are noncompetitive adenosine diphosphate (ADP) receptor antagonists and inhibit platelet aggregation. The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic events (CAPRIE) trial11 included three large groups of patients with recent myocardial infarction (MI), recent ischemic stroke, or symptomatic peripheral arterial disease (>6300 patients in each clinical subgroup). CAPRIE demonstrated the benefits of long-term treatment with clopidogrel as an antiplatelet agent by reducing the combined risk of ischemic stroke, MI, or vascular death. Alternatives for patients with GI intolerance to aspirin2 include inhibition of gastric acid secretion in cases of mucosal erosion due to aspirin or nonsteroidal anti-inflammatory drug (NSAID) therapy. Another option is to test for infection with Helicobacter pylori and treat for it if the infection is found. This strategy has been reported to decrease the rate of GI bleeding due to aspirin.12 It has also been noted that adding esomeprazole to aspirin is more effective in preventing recurrent bleeding in patients with ulcers and vascular disease than replacing aspirin with clopidogrel.13 Moreover, the combination of aspirin and clopidogrel is not currently warranted in stable angina pectoris, though it may be useful for acute treatment following an acute coronary syndrome or coronary stenting. The antithrombotic effects of dipyridamole are limited,8 and this agent may even increase the fre- New European guidelines for the treatment of stable angina – Daly and Fox UP Immediate short-term relief D AT E MEDICAL MANAGEMENT OF STABLE ANGINA Short-acting nitrate Aspirin 75 to 150 mg/day Improving prognosis Intolerant or contraindicated Clopidogrel 75 mg/day Intolerant or contraindicated Switch statin, or add ezetimibe with lower-dose statin, or replace with alternative lipid-lowering agent Statin (titrate to target cholesterol level) ACE inhibitor in proven CVD β-Blocker (post-MI) β-Blocker (no prior MI) Intolerant or contraindicated Symptoms not controlled after optimization of dose CCB, or long-acting nitrate, or potassium channel opener, or I f inhibitor Add CCB or long-acting nitrate Intolerant Symptoms not controlled after optimization of dose Either substitute alternative CCB subclass, or long-acting nitrate Add long-acting nitrate, CCB, or potassium channel opener Improving symptoms Symptoms not controlled after optimization of dose Consider suitability for revascularization quency of anginal symptoms. For these reasons, dipyridamole is not recommended as an antithrombotic in stable angina. High-risk patients (eg, those with previous MI) may benefit from combinations of aspirin with anticoagulant agents such as thrombin inhibitors or warfarin. However, unless there is a specific separate indication, anticoagulants should be avoided in stable angina. ◆ Lipid-lowering drugs There is a strong association between increased low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular disease.14 Cholesterol-lowering reduces the risk of atherosclerosis,15 and the currently recommended treatment goals for patients with established coronary heart disease and those considered to be at high risk (10-year risk for cardiovascular mortality >5%) are total cholesterol <4.5 mmol/L (175 mg/dL) and LDL cholesterol <2.5 mmol/L (96 mg/dL).14 While lipid-lowering therapy has not been tested in a stable angina population per se, post-MI trials16 and subgroup analysis of the large lipid-lowering trials, such as the Heart Protection Study (HPS),17 provided information on the advantages of such treatment in this New European guidelines for the treatment of stable angina – Daly and Fox Symptoms not controlled on two-drug therapy after optimization of dose Figure 1. Algorithm for medical management of stable angina.2 High-risk candidates for revascularization on prognostic grounds alone should be identified and referred appropriately. ACE, angiotensin-converting enzyme; CVD, cardiovascular disease; MI, myocardial infarction; CCB, calcium channel blocker. Modified after reference 2: Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J. 2006;27:13411381. Copyright © 2006, Oxford University Press. population. HPS clearly demonstrated that lipidlowering treatment was beneficial in patients with a history of CAD, and such therapy should be an integral part of the management of all CAD patients.2 The statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) lower lipids by reducing hepatic cholesterol synthesis, and have been reported to decrease cardiovascular complications by up to 30%,16,18-20 even in the elderly (>70 years) and patients with diabetes.17,21 Statins also appear to have nonlipid effects, such as a reduction in fibrinogen and an inhibition of the inflammatory response associated with atherogenesis.22 The relative contributions of the lipid and nonlipid effects of statins to the overall reduction in cardiovascular risk continue to be debated. It is known that the deleterious effects of serum cholesterol begin at low-normal levels,15 and pretreatment cholesterol level does not determine the benefits of long-term statin therapy, therefore treatment may be useful in patients with normal cholesterol levels, but high cardiovascular risk.16,23 This explains why it is currently recommended to treat patients at high cardiovascular risk with a statin, even if they have normal or near-normal LDL cholesterol levels.2 MEDICOGRAPHIA, VOL 28, No. 3, 2006 287 UP D AT E By targeting the cholesterol goals detailed above,14 the benefits of treatment with higher doses of statins may not be exploited. While the usual starting dose of 10 mg/day atorvastatin prevents clinical events, one study showed that cardiovascular risk can be dramatically decreased in CAD patients by increasing the dose to 80 mg/day.20 However, in the same study, the higher dose of statin was associated with a greater incidence of elevated liver enzymes.20 The current recommendation is to treat only high-risk patients with proven CAD with highdose atorvastatin therapy in the absence of refractory hyperlipidemia.2 Combinations of statins with other hypolipidemic agents is possible in cases of severe dyslipidemia, particularly when high-density lipoprotein (HDL) cholesterol levels are low and triglyceride levels high. However, target levels of HDL cholesterol or triglycerides have not yet been determined for the CAD population. Other lipid-lowering agents include fibrates, long-acting nicotinic acid, and ezetimibe. The primary action of fibrates is to reduce triglycerides, and their combination with statins may be a recommended option in patients with severe dyslipidemia who do not respond to conventional treatment, and in patients with diabetes or the metabolic syndrome.2 In patients who are intolerant to statins, ezetimibe may be combined with lower doses of statins to lower LDL.24 This cholesterol absorption inhibitor acts via blockade of the passage of cholesterol across the intestinal wall. ◆ ACE inhibition Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of hypertension and heart failure. Trials in patients with heart failure and post-MI reported reduced cardiac mortality and MI with ACE inhibition,25-27 which ultimately led to the investigation of the role of these agents in secondary prevention for CAD patients without heart failure. In the EUropean trial of Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA), there was a 20% relative risk reduction in the composite primary end point of cardiovascular death, MI, or resuscitated cardiac arrest in the perindopril treatment group.25 Results in favor of ACE inhibition also came from the Heart Outcomes Prevention Evaluation (HOPE) study with ramipril, in which there was a 22% reduction in the composite primary end point of cardiovascular death, MI, and stroke,26 while the Prevention of Events with Angiotensin-Converting Enzyme inhibition (PEACE) study found no significant risk reduction for ACE inhibition with trandolapril in a composite primary end point of cardiovascular death, MI, and coronary revascularization.27 Why is there such a variation among the results of these three trials on agents from the same class? First, we should note that analysis of the differences is speculative because the baseline populations and end points used were not the same. Furthermore, the variation could be linked to differences between the action of the three ACE inhibitors, the dosages used in the studies, and non-study–related therapy. 288 MEDICOGRAPHIA, VOL 28, No. 3, 2006 The absolute risk of cardiovascular events in the population at the start of the trial in PEACE was low, while the HOPE population was at high risk of cardiovascular events; and EUROPA included patients at more moderate cardiovascular risk. The level of risk may have had a significant impact on cardiovascular outcome. In support of this hypothesis, the relative effects of ramipril and perindopril were similar in high- and intermediate-risk populations, respectively. The conclusion drawn from these studies is that ACE inhibition with perindopril or ramipril could have additional cardiovascular effects via mechanisms other than reduction of blood pressure.28-30 Secondary prevention with ACE inhibition is therefore recommended for patients with stable angina and proven CAD, if they have had a previous MI, or have diabetes, or concomitant hypertension, heart failure or asymptomatic LV dysfunction.2 In the absence of these coincident indications, the physician should carefully evaluate the potential benefits of secondary prevention with an ACE inhibitor on an individual patient basis. Only ACE inhibitors proven to be effective for this indication should be used, and they should be titrated toward the appropriate dose. ◆ -Blockers β-Blocker therapy can reduce the risk for cardiovascular death or MI by about 30% in post-MI populations.31 Mortality benefits with β-blockade post MI appear to be associated with longer-term use of these drugs.32 β-Blockers are currently recommended in such patients, and in patients with heart failure. Extrapolated from the proven benefit of βblockade in reducing mortality in these populations, β-blockade remains a first-line therapy for patients with anginal symptoms in the expectation of improved prognosis.2 Analysis of post MI populations has found that β-blockers with intrinsic sympathomimetic activity afforded less protection, and highlighted the absence of documentation regarding post-MI mortality for the most frequently prescribed agent, atenolol.32 Evidence from trials in patients with previous MI also suggests benefits in patients with stable CAD. β-Blocker therapy has been compared with placebo in mildly symptomatic angina in the Atenolol Silent Ischemia STudy (ASIST), which reported a longer event-free survival in patients receiving atenolol versus placebo.33 ASIST demonstrated that β-blocker treatment is beneficial in patients with stable angina, but did not provide any information on whether it has an influence on their long-term prognosis. The effects of treatment with β-blocker or calcium channel blocker (CCB) on outcomes in stable angina have been compared in two moderately sized long-term studies. The Angina Prognosis Study In Stockholm (APSIS) compared metoprolol and verapamil,34 while the Total Ischemic Burden European Trial (TIBET) compared atenolol and slow-release nifedipine.35 Neither trial managed to show a significant difference in outcome between the two classes of drugs. New European guidelines for the treatment of stable angina – Daly and Fox UP ◆ Hormone replacement therapy Recent placebo-controlled trials have demonstrated that hormone replacement therapy (HRT) with a combination of oral estrogen and progestin is not effective in the secondary prevention of cardiovascular disease.36,37 In primary prevention, HRT was associated with increased cardiovascular and breast cancer risk.38 Similarly, unopposed estrogen therapy does not confer cardiac protection in hysterectomized women.39 HRT is not recommended for the prevention of cardiovascular disease.2,40 Improving symptoms with pharmacological treatment Agents for the treatment of anginal symptoms include β-blockers, CCBs, organic nitrates, potassium channel openers, nitric oxide donors, and If inhibitors, which may be prescribed in monotherapy or combination. A number of different combinations of antianginal agents have been tested in clinical trials, and found to have additive effects. However, individual anginal patients respond in different ways, which is why they should be followed up carefully and their treatment modified according to their response. In cases of unsatisfactory control of anginal symptoms, combinations of two or three agents can be considered. Increasingly intense antianginal treatment is problematic, and any change in regimen should be made cautiously. It is essential to optimize the dosage of one agent or combination of agents before adding another,2 particularly considering reports that triple therapy is less effective than two-drug therapy in reducing symptoms.41,42 Indeed, triple therapy should only be prescribed in cases where optimized two-drug therapy has failed and, even then, the effects of additional drugs should be evaluated carefully. The role of poor compliance should also be assessed. Patients who require such intensive treatment should be considered for revascularization, if this is technically feasible.2 ◆ -Blockers β-Blockers decrease the oxygen demand of the heart by reducing blood pressure and heart rate, and by attenuating myocardial contractility. The ischemic zones are better perfused, as β-blockade lengthens diastolic filling time and increases vascular resistance in nonischemic zones. β-Blockers act on the heart rate at rest and during exercise, though some agents with partial agonist activity only affect exercising heart rate. They are the standard choice for the symptomatic treatment of stable angina and ischemia, provided the agent is initiated carefully and titrated progressively to full dose.2,43-46 Relative contraindications to β-blockers include asthma and peripheral vascular disease, and β blockers cannot be used in severe bradycardia, high-degree atrioventricular (AV) block, or severe decompensated LV failure. The most common adverse effects of treatment are fatigue, a reduction in exercise capacity, lethargy, insomnia, nightmares, and worsening claudication. β-Blockers can be combined with agents from other classes in the case of New European guidelines for the treatment of stable angina – Daly and Fox D AT E poor response to monotherapy; patients who are intolerant to β-blockers should be switched to another class (Figure 1).2 ◆ Calcium channel blockers Selective inhibition of the L-type calcium channels by a CCB leads to dilation of the coronary and other arteries, which decreases cardiac work and counteracts vasospasm.43,46 CCBs constitute an effective symptomatic treatment of angina in patients who cannot receive β-blockers due to intolerance or contraindications,44,45,47 but there is no evidence supporting their use to improve prognosis in stable angina. The CCB class can be divided chemically into the nondihydropyridine CCBs (eg, verapamil and diltiazem) and dihydropyridine CCBs (eg, nifedipine, amlodipine, and felodipine). The nonselective nondihydropyridine CCBs reduce heart rate, myocardial contractility, and AV nodal conduction.43,46 Heart rate may actually increase with the vasoselective dihydropyridine CCBs due to tachycardia led by rapid reflex adrenergic activation in response to cardiodepression. The heart rate may return to basal levels with long-term treatment with vasoselective CCBs, though sympathetic activation often remains elevated.48 CCBs are recommended for the treatment of Prinzmetal’s angina,43 but short-acting dihydropyridine preparations may, in some patients, increase the risk of ischemia.49 Variations in plasma concentrations and cardiac effects can be optimized by prescribing long-acting CCBs (eg, amlodipine) or short-acting agents in sustained-release formulations (eg, nifedipine, felodipine, verapamil, and diltiazem).50 A CCB plus β-blocker combination is recommended for patients with insufficient response to monotherapy with β-blocker.2 Vasoselective dihydropyridine CCBs are recommended for combination with β-blockers, which oppose reflex adrenergic activation; nonselective (ie, heart rate– lowering) CCBs should be avoided due to the risk of conduction disturbances with β-blocker. The use of CCBs in heart failure requires caution, though amlodipine does appear to be safe in this setting.51 Anginal patients who remain symptomatic with optimized CCB treatment (monotherapy or combination) may be prescribed a long-acting nitrate or potassium channel opener in the place of or in addition to the CCB. ◆ Comparison of -blocker and CCB While β-blockade is the routine choice for the symptomatic treatment of stable angina, a CCB may often be prescribed in its place due to patient intolerance or contraindications, or concomitant diseases or treatments. β-Blockers and CCBs are comparable in terms of increasing exercise tolerance and decreasing ischemia,35,52-55 though β-blockers are better at decreasing the number of anginal attacks.56 β-Blockers remain the treatment of choice in patients with prior MI. ◆ Nitrates Nitrates alleviate pain and ischemia by supplying an exogenous source of the vasodilator nitric ox- MEDICOGRAPHIA, VOL 28, No. 3, 2006 289 UP D AT E ide. All anginal patients should receive short-acting nitroglycerin for immediate symptom relief.2 Patients should receive detailed instructions on how to use nitrates, particularly for the prevention of symptoms during daily activities. Long-acting nitrates reduce the frequency and severity of anginal attacks, and may also increase exercise tolerance. These agents do not appear to have any effect on the prognosis of post-MI patients.57 The major drawback to the use of nitrates is the development of tolerance, which can attenuate response to short- and long-acting nitrates, and measures should be taken to avoid this situation. The buildup of nitrate tolerance can be avoided by prescribing a daily regimen including 8 to 12 hours without nitrates.2 In this context, nitroglycerin patches should not be used continuously. strated in clinical trials versus placebo or conventional antianginal agents. The mechanism of action of the metabolic agents is to favor glucose metabolism over fatty acid metabolism, thereby protecting against ischemia. They do not modify heart rate or blood pressure. The effects of the metabolic agents on the improvement of prognosis in stable angina have not been investigated. These agents can be used in monotherapy when β-blockers or CCBs are not tolerated or are contraindicated, or as an add-on therapy with hemodynamic agents.2 Trimetazidine is widely available in Europe and Asia, while ranolazine has not yet been licensed for use by the EMEA. The nitric oxide donor molsidomine acts a vasodilator and can be prescribed for the symptomatic treatment of angina.2 Molsidomine is available in a limited number of countries. ◆ Comparison of nitrates with -blockers or CCBs There does not appear to be any compelling reason to prescribe a long-acting nitrate first line, other than to a patient who cannot receive a β-blocker or CCB.2 Moreover, there are no reports on the effects of nitrates on prognosis in stable angina. The few comparative trials in patients with stable angina have indicated less nitrate use in patients receiving a β-blocker and a reduction in the number of anginal attacks in those receiving a CCB, compared with long-acting nitrates in monotherapy, though these results never reached significance.56 ◆ Potassium channel openers Nicorandil is a combined potassium channel opener and nitrate, which gives it additional nitrate-like effects.58 Nicorandil may have a cardioprotective effect in high-risk patients with angina. Tolerance can occur in long-term treatment, but there have been no reports of it inducing tolerance to nitrates. Nicorandil is available in a number of countries.2 ◆ Other agents Specific If current inhibitors, such as ivabradine, have heart rate–reducing properties both at rest and during exercise, and can be considered as a first-line therapy in cases where β-blocker therapy is contraindicated or not tolerated.2 A randomized, placebo-controlled trial lasting 4 months in 360 patients with a history of chronic stable angina demonstrated that ivabradine produces a dose-dependent improvement in exercise tolerance and time to 1-mm ST-segment depression.59 In a recent double-blind, 4-month trial in 939 patients with stable angina, ivabradine was shown to be as effective as the β-blocker atenolol in improving total exercise duration and reducing the number of anginal attacks.60 Ivabradine is the first agent in the If inhibitor class to have completed its clinical development and has recently been licensed for use by the European Agency for the Evaluation of Medicinal Products (EMEA). These pure heart rate–reducing agents may prove to have an important role in the future, particularly as an alternative in patients who do not tolerate β-blockers.59,60 The antianginal efficacy of the metabolic agents trimetazidine61,62 and ranolazine63,64 has been demon- 290 MEDICOGRAPHIA, VOL 28, No. 3, 2006 Revascularization Revascularization includes either percutaneous transluminal coronary angioplasty, usually with stent implantation, or coronary artery bypass graft. Revascularization should be considered in cases where optimized pharmacological therapy is insufficient to relieve symptoms.2 In some circumstances, for example in patients with severe lesions in coronary arteries that supply a large area of the myocardium, revascularization can improve prognosis by increasing the effectiveness of the existing perfusion or providing alternative routes of perfusion. Whatever the decision—to revascularize or not— the patient should be advised that secondary preventative pharmacological therapy will continue to be necessary, even after the intervention. The risks and benefits of surgery or PCI should also be carefully discussed with the patient. Conclusion The new guidelines prepared by the Task Force of the ESC reflect an expert consensus on the appropriate management of stable angina pectoris,2 with recommendations that encompass all the latest advances in the field. Angina is common and disabling, but in the current era symptoms can be reduced or abolished in the majority of cases and the risk of future events reduced with an appropriate management strategy. Optimal management clearly demands aggressive secondary prevention. The best opportunities for this come from drug treatment and lifestyle modifications. We now have evidence that ACE inhibition and statins are beneficial in broader populations, and this should be taken into account in any pharmacological intervention that is designed to improve prognosis.2 Drug treatment may also be used to alleviate symptoms of angina as well as improve prognosis. Further significant advances in operative techniques and the continuing evolution of percutaneous intervention can be expected in the future. Such techniques will undoubtedly improve symp- New European guidelines for the treatment of stable angina – Daly and Fox UP toms and the quality of life of patients. However, all revascularized patients should receive appropriate long-term secondary prevention, in order to improve their long-term prognosis. From a symptomatic point of view, β-blockers will remain the mainstay of first-line therapy, provided REFERENCES 1. Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. 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Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris. Int J Cardiol. 2005;98: 79-89. RECOMMANDATIONS EUROPÉENNES POUR LE TRAITEMENT DE L’ANGOR STABLE exploration et le traitement de la maladie coronaire (MC) font l’objet d’une vaste littérature médicale en développement rapide. Les médecins libéraux doivent garder la trace de la richesse de l’information disponible, assimiler et interpréter sa valeur clinique. Ceci est essentiel afin de leur permettre d’étendre les avancées résultant des investigations en termes d’améliorations cliniques, thérapeutiques et pronostiques à tous les patients, plutôt qu’à quelques-uns seulement. La Société Européenne de Cardiologie (ESC) a dans ce but émis des recommandations de pratique clinique sur la prise en charge des pathologies individuelles ou sur l’utilisation de modalités thérapeutiques particulières. L’année 2006 a vu naître de nouvelles recommandations de l’ESC pour la prise en charge de l’angor stable, mettant à jour le précédent document publié en 1997. Dans cet article, nous analysons les positions actuelles sur la prise en charge pharmacologique de l’angor selon les recommandations européennes qui incluent plus particulièrement les progrès récents de la prévention secondaire grâce aux IEC (inhibiteurs de l’enzyme de conversion) et aux médicaments ayant un nouveau mode d’action, tels que les inhibiteurs If . Une stratification appropriée du risque devrait guider la décision d’investigations ultérieures et le choix entre traitement par revascularisation ou médicament. Malgré les progrès récents de la revascularisation, le traitement médicamenteux demeure la règle chez tous les patients revascularisés, pour améliorer leur pronostic à long terme. L’ ✦ 292 MEDICOGRAPHIA, VOL 28, No. 3, 2006 New European guidelines for the treatment of stable angina – Daly and Fox A T O U C H O F F R A N C E Jean DUCRUET, SJ Emeritus Rector Saint-Joseph University Beirut, LEBANON (e-mail: [email protected]) France and medical education under the Ottoman Empire by J. Ducruet, Lebanon F rench physicians practicing in the Ottoman Empire in the first half of the 19th century were few and far between (exceptions include, in the Lebanon, Dr Blois, a surgeon from Nice, who practiced in Tripoli from 1807 onwards, and Dr Suquet, known for having treated Ernest Renan).1 Qualified physicians were a rare breed at the time as medicine was only taught at the army medical school in Constantinople. It was thanks to Bonaparte’s expedition to Egypt and later initiatives by the viceroy of Egypt, Mohamed Ali (Mehemet Ali), that French physicians increased their presence in this part of the world and, in particular, became active in medical education. Like its counterpart in Constantinople, Kasr El-Aini medical school was an army institution. It was army schools that brought Western medicine to the Ottoman Empire in the first half of the 19th century. The second half of the century unfolded under a quite different banner. The Hatti Sharif of Gulhane (Noble Edict of the Rose Chamber), promulgated by the Sultan on November 3, 1839 and the Hatti Humayun (Imperial Edict) of February 18, 1856 were the Ottoman equivalents of a declaration of the rights of man and the citizen. They opened up the Middle East to a whole range of new initiatives, with particular respect to education and health. It was during this period that virtually all the main French hospital institutions,2 as well as the schools that taught in French were founded (as reported by the French Foreign Minister at the November 26th, 1904, sitting of the Chamber of Deputies, the Ministry of Foreign Affairs reckoned that there were 600 schools in the Ottoman Empire teaching French to 100 000 pupils).3 It was in this setting that the French Faculty of Medicine was founded in Beirut in 1883 and that an application for a firman (imperial decree) authorizing the construction of the Hôtel-Dieu de France, or Saint-Joseph University Hospital, was submitted in Constantinople in 1912. ✦ I t was Bonaparte’s expedition to Egypt that first propelled French physicians, under the aegis of Drs Desgenettes and Larrey, into a region in which they were few and far between in the early 19th century. The next advance came 25 years later under the aegis of Dr Clot, appointed senior medical officer to the Egyptian army, and later chairman of the Egyptian Health Council, by Mohamed Ali (Mehemet Ali), viceroy of Egypt. The most lasting achievement of the émigré French physicians was the advancement of medical education, beginning with the foundation of Abu-Zabal medical school, which transferred in 1837 to Kasr El-Aini, also just outside Cairo, where the first class of Lebanese physicians was to graduate. In the Lebanon itself, medical education was provided in English by the Syrian Protestant College and in French by Saint-Joseph University. Following an agreement between the French government and the Jesuits, Saint-Joseph University opened the French Faculty of Medicine on November 30, 1883. Teaching the official French syllabus, with staff and examining board despatched from France, it was empowered to award the French doctor of medicine degree. Between October 1887 and November 1913, it produced 451 doctors, half of whom practiced in the Lebanon, a quarter in Egypt and a quarter elsewhere in the Ottoman Empire. Students received their clinical training in a variety of hospitals before the Faculty founded its own Hôtel-Dieu de France or Saint-Joseph University Hospital. Medicographia. 2006;28:293-300. France and medical education under the Ottoman Empire – Ducruet (see French abstract on page 300) MEDICOGRAPHIA, VOL 28, No. 3, 2006 293 A T O U C H O F FR A N C E Jean Ducruet, SJ: Jesuit, born in Bourg-en-Bresse, France, in 1922, dual Franco-Lebanese citizenship. PhD in Economics. Dean of the Faculties of Law, Economics and Management, Saint-Joseph University, Beirut, 1963-1975. Rector of Saint-Joseph University, 1975-1995. Chairman, Board of Directors, Hôtel-Dieu de France (Saint-Joseph University Hospital), Beirut, 1981-2001. Currently Vice-Chairman, Lebanese National Ethics Committee. Commander of the Legion of Honor. Commander of the Order of the Cedar. Mohamed Ali (Mehemet Ali) (1769-1849) Viceroy of Egypt. Oil on canvas, by Louis Charles Auguste Couder (1790-1873). Château de Versailles, France. © The Bridgeman Art Library. Army medical schools in Egypt In 1798, after the Battle of the Pyramids, Bonaparte ordered four army hospitals to be set up in Giza, Cairo, and Old Cairo. In the wake of senior medical officer René-Nicolas Desgenettes (who famously inoculated himself publicly with pus from a suppurating bubo to reassure the troops that this would afford protection against bubonic plague), senior surgical officer Dominique Larrey (who introduced field hospitals and his renowned “flying” ambulances, which first came into use in 1797 during the campaign of Italy), and health corps practitioners, French physicians made their entry into the region. Initially, their patients were soldiers, but it was not long before they turned their attention to the local population. Their official mission was to characterize the most common diseases in Egypt and determine their treatment. After Bonaparte considered setting up a civilian hospital, Dr Desgenettes began by refurbishing the dilapidated 13th century Moristan Hospital, but also drew up plans for a three to four hundred-bed hospital with a medical school attached. However, the resources necessary for carrying out such a project were lacking, especially after Bonaparte returned to France in October 1799.4 Dr Desgenettes’ plans were revived 25 years later. Mohamed Ali set consular agent Florent-Tourneau the task of recruiting French instructors for the Egyptian army, but also doctors. Landing in Marseille in 1824, Florent-Tourneau met up with a friend, Dr Cauvière, a physician at the local HôtelDieu, who recommended one of his former students, Dr Antoine-Barthélemy Clot, originally from Grenoble, and a graduate in medicine and surgery from the Faculty of Montpellier. Dr Clot was eventually won over and on December 22, 1824 signed a 5-year contract as senior medical officer to the 150 000-strong Egyptian army, which did not have 50 physicians, health officers, or pharmacists to its name. Over the following 3 years, Dr Clot achieved the two targets closest to his heart: mandatory smallpox vaccination throughout Egypt, and the construction of a hospital plus medical school at Abu-Zabal, near Heliopolis. In 1832, he managed to send 12 of his graduates to continue their studies at the Faculty of Medicine in Paris so that they could return as teachers to Egypt and gradually replace the staff seconded from France, such as Drs Duvigneau, Bernard, and Gaetan. Mohamed Ali honored Dr Clot with the title of Bey, appointed him chairman of the Health Council, and provided him with the necessary resources for upgrading his hospital and medical school and moving it in 1837 close to the seat of Sheikh Aini, where it took the name Kasr (castle or palace) El-Aini.5 In the same year, 1837, Emir Bechir II asked Clot-Bey, during a visit to Beirut, to take back to Kasr El-Aini a group of young Lebanese who were keen to study medicine, and whose expenses he would pay. Notable names in this first group of Lebanese physicians trained by Clot-Bey in the French system were Youssef Jalkh (1821-1869) and Ibrahim Najjar (1822-1864) from Deir-El-Kamar. Dr Jalkh practiced for a year at Damietta (modern Dumyat, 200 km to the north east of Cairo), before setting up first in Beirut, where he became family doctor to the Chehabs, one of the country’s patrician families, and later in Baabda, the mountain town overlooking Beirut.6 Dr Najjar wanted to return to the Lebanon after graduating, but was 294 MEDICOGRAPHIA, VOL 28, No. 3, 2006 France and medical education under the Ottoman Empire – Ducruet A T O U C H O F FR A N C E told he would first have to serve the Egyptian army, since Kasr El-Aini was an army school. While visiting Constantinople during a 3-month leave, he was invited to continue his studies at the city’s army medical school. He stayed 4 years, receiving his diploma in the presence of Sultan AbdulMajid. He turned down the offer of a post in Constantinople and was appointed senior medical officer to the Ottoman army in Beirut in 1846. In particular, he was in charge of the Beirut army hospital built in 1849 at Bab Idriss.7 The Kasr El-Aini graduation class also included Dr Ghaleb ElKhoury (1818-1896), who returned to the Lebanon in 1845 to attend the Maronite patriarch Youssef Hobeiche in the final year of his life and later the Druze leader Said Bey Jumblatt.8 Extent of the Ottoman Empire between 1798 and 1923. Perry-Castañeda Library Map Collection. Courtesy of the University of Texas Libraries, The University of Texas at Austin. The French Faculty of Medicine in Beirut under the Ottoman Empire The Jesuits had been wanting to establish a Faculty of Medicine in Beirut as early as 1872, but the credit for actually doing so belongs to Father Rémi Normand. On August 8, 1880 he submitted his Report to the French government on the necessity of establishing a French Catholic medical school in Beirut.9 His idea was well-received by the Consul General in Beirut, the French Ambassador in Constantinople, the French Minister of Foreign Affairs, and even Jules Ferry, who headed the French government. There were powerful motives to play on when it came to rallying support: the hunger of a new generation for professional careers, the promotion of French-speaking culture and achievement, the opportunity of giving Catholicism an edge over its Protestant rival, and of course the advancement of public health, as emphasized by Professor Jules Rouvier, one of the School’s founder members: The key idea motivating the founding of the French Faculty of Medicine in Beirut and informing every detail of its organization was that of producing a corps of physicians who would practice in the towns and countryside of Syria and its surrounding provinces. Charlatanism in these provinces was rife. There was acute awareness of the lack of practicing physicians. In 1883, as today, the Ottoman Empire had only one official Faculty, the Faculty in Constantinople, whose mission was to meet the needs of the civil and military administrations. It was too remote from our region. As a result most Syrians headed first to the Cairo school, and when that collapsed, they came back to the medical school that the American Protestant mission had opened a few years earlier in Beirut.10 Dr Antoine-Barthélemy Clot-Bey (1793-1868), founder of the Egyptian School of Medicine of Kasr El-Aini. © BIUM, France. France and medical education under the Ottoman Empire – Ducruet After agreement was reached on May 7, 1883, between the Jesuits and the French Government, the French Medical School opened on November 30 the same year in an annex to Saint-Joseph University, from which it moved on October 15, 1912 to its current location on Damascus Street. It opened despite the failure to settle a number of problems that would subsequently be resolved in stages. The School’s status required clarification from both the Ottoman and French governments. Ibrahim Pacha, Governor of Beirut, made it plain that the School could not open without authorization. The Consul General replied that the science courses on offer were merely an extension to the syllabus already authorized at Saint-Joseph University and covered by the firmans of 1665 and 1695.11 Not until 1901 would the Sublime Porte fully confirm the existence in law of educational instituMEDICOGRAPHIA, VOL 28, No. 3, 2006 295 A T O U C H O F FR A N C E Franco-Ottoman examining board of the French Faculty of Medicine of Beirut on 11 November 1907. The graduates are behind, in the third row, holding their diplomas. tions operated under French Embassy auspices.12 As for the French Ministry of Higher Education, it authorized the Beirut Medical School to prepare students for the degree of doctor of medicine on October 6, 1888. The School thus became a Faculty, with a status equivalent to that of a free faculty. The Minister spelled out the position a few years later: My office combined the best of both worlds, with a very loose interpretation of the laws of July 12, 1875, and March 18, 1880, on freedom in higher education. On the one hand we considered the Beirut Faculty as a free faculty on foreign soil, while at the same time recognizing that its students had the same rights in law as free faculty students in France, including the right to graduate with a French doctor of medicine degree. They also enjoyed preferential treatment in that instead of coming to France to take their examinations, one of our faculties would dispatch its board of examiners to Beirut every year.13 The examinations held at the Beirut Faculty between October 1887 and November 1913 produced 451 physicians with full-fledged doctor of medicine degrees from the French State. After a further examination or mere formality, depending on their graduation class, 405 of these physicians duplicated their French qualification with a degree from the Constantinople Faculty of Medicine enabling them to practise legally throughout the Ottoman Empire.14 The examining boards from France played a very important role in the early days of the Faculty’s history by supervising not only its results, as measured by examination, but also its syllabus and teaching methods. Later the chairmen of these boards went to make up a Faculty upper council sitting in Paris whose function was to rule on teaching appointments and the general scientific and technical direction taken by the Beirut Faculty. The 28 examination sessions held from 1887 to 1913 drew 66 missions of French professors from the faculties of medicine in Lyon (30), Paris (19), Bordeaux (5), Nancy (4), Toulouse (3), Montpellier (3), and Lille (2).15 Only in October 1898 were Faculty graduates finally authorized to practice in the Ottoman Empire without having to sit a further examination: “One Dr Hippolyte de Brun, Professor at the French Faculty of Medicine of Beirut or two delegates from the Imperial Medical School in Constantinople will be (chair of clinical medicine) from 1885 co-opted with full voting rights to the examining board from France and will to 1914 and 1919 to 1926. directly authorize successful candidates to practice in the Ottoman Empire.”16 Henceforth, new graduates were effectively awarded two doctor of medicine degrees: the French State degree and the Constantinople Faculty of Medicine degree. Graduates from earlier years were assisted in normalizing their status as necessary. The Beirut syllabus was aligned to 3 years of study as in France, following the decree of June 20, 1878. The decree of July 31, 1893, extended this to 4 years. Extension to 5 years, provided for in the decrees of November 29, 1911, and July 29, 1912, was not applied in Beirut until after the World War I, starting in January 1919. 296 MEDICOGRAPHIA, VOL 28, No. 3, 2006 France and medical education under the Ottoman Empire – Ducruet A T Dr Henri Nègre, Professor at the French Faculty of Medicine of Beirut (chair of anatomy) from 1885 to 1914 and 1919 to 1932. O U C H O F FR A N C E Following the French faculty tradition, teaching was divided between professorial chairs, numbering four at the School’s foundation, and 11 in 1914. Jesuits already present in Beirut were assigned the chairs of chemistry, biology, microbiology, and physics. Professors from France were appointed to the other chairs. From November 1883 to November 1914, the incumbents of the chair of internal pathology and clinical medicine were Professors Jules Rouvier and Hippolyte de Brun, in that order. Their counterparts for the chair of external pathology and clinical surgery were Professors Elisée Sénès, Maurice Hache and Eugène Cottart. Professors Etienne Flavard, Frédéric Baldy, and Pierre-Paul Guigues were the successive incumbents of the chair of pharmacology from November 1884 to November 1914. Professor Henri Nègre held the chair of anatomy from November 1885 to November 1914, and Professor Jules Rouvier, followed by Professor Albert Chapotain, that of obstetrics and gynecology. The successive incumbents of the chair of therapeutics and hygiene from October 1889 to November 1914 were Professors Benoit Boyer, Jérôme La Bonnardière, and Justin Calmette, while Professor d’Auber de Peyrelongue held the chair of physiology from September 1912 to November 1914.17 First-year medical students totaled 124 in the decade from 1883 to 1892 (78 from the Lebanon, nine from Syria, 16 from Egypt, five from Turkey, and 16 from other countries), climbing to 313 for the decade from 1893 to 1902 (148 from the Lebanon, 37 from Syria, 46 from Egypt, 36 from Turkey, and 46 from other countries), and to 516 for the decade from 1903 to 1912 (202 from the Lebanon, 34 from Syria, 64 from Egypt, 120 from Turkey, 17 from Iran, 14 from Palestine, 6 from Iraq, and 59 from other countries). Of these 516 students, 252 were Catholic, 164 Orthodox or Protestant, 54 Moslem and 46 Jewish. Annual medical student numbers climbed from 10 in 1883-1884 to 90 in 1896-1897, 158 in 1902-1903, and 271 in 1912-1913.18 World War I introduced a hiatus into the Faculty’s development. Despite Germany’s declaration of war against France on August 4, 1914, the academic year started as normal on October 12. However, on November 2 came the news that diplomatic relations had been suspended between France and the Ottoman Empire. On November 11, the wali, or Turkish Governor of Beirut, closed down the Faculty. In the following weeks, all members of religious orders who were enemy nationals were expelled to Egypt, together with the lay teaching staff and their families. In the spring of 1915, the Faculty buildings were taken over by a telegraphy school, succeeded on April 1, 1916, by an Ottoman medical school, which operated for 2 1/2 years. After its defeat, Turkey sued for an armistice, which was signed on October 30, 1918, in the harbor town of Mudros, on the Aegean island of Lemnos. The French Faculty of Medicine was back in business 3 months later on January 17, 1919.19 The Faculty Chancellor described the extent of his graduates’ influence beyond the confines of the Lebanon and Syria: We can boast many graduates in neighboring countries… In Egypt, we have 156 in Cairo, Alexandria, Damanhur, Tanta, Beni-Suef, Tahta, Helwan, Sohag, Port Said, Ismailia, Suez, Heliopolis, Mansoura, Qina, Fayoum, Port Tewfik, Al Minya, Assiut, etc. Over 100 are spread over the Turkish provinces, in Asia Minor, Cilicia, Constantinople, Smyrna, the Dardanelles, Bursa, Orfa, Ankara, Adana, Eskisehir, Izmit, Samsun, Zonguldak, etc. Mesopotamia boasts 12, including one who has become Minister of Hygiene in Iraq. There are no less than 31 in Palestine… One has just been put in charge of a hospital in Amman, in Transjordan. To round off these statistics, let me add that as well as some 50 other graduates who have either settled in Europe or are taking specialist degrees in France, the Faculty has 23 graduates in the Egyptian army in Sudan, 8 in America, 7 in Persia, 4 in Greece, 4 on the island of Cyprus, 2 in Bulgaria, 1 each in Chania (Crete), Rhodes, Tunis, Serbia, and Senegal, and even 1 in Hangzhou, China.20 Reverend Father Lucien Cattin, Chancellor of the French Faculty of Medicine of Beirut from 1895 to 1913 and 1921 to 1923. The Hôtel-Dieu de France The problem common to all faculties of medicine, that of integrating the teaching of clinical and hospital skills into the course, was particularly thorny in the first decades of the Beirut Faculty. The Daughters of Charity hospital and later St George’s Hospital provided temporary solutions until the Faculty was able to found its own hospital. This required funds. Reverend Father Lucien Cattin, the Faculty Chancellor, journeyed to France to whip up interest among parliamentarians, bankers, major corporations, and numerous private individuals. He received active support from the French Asia Committee, which was instrumental, along with a newspaper, Le Temps, in the launch of a national subscription in May 1911, in particular by the Paris press association, the Syndicat de la Presse Parisienne. France and medical education under the Ottoman Empire – Ducruet MEDICOGRAPHIA, VOL 28, No. 3, 2006 297 A T O U C H O F FR A N C E Laying of the foundation stone of the Hôtel-Dieu de France hospital on May 2, 1922 by General Goureaud, High Commissioner, flanked by Mgr Giannini, Apostolic Delegate, and Reverend Father Chanteur, Rector of the University. Graduation ceremony at the French Faculty of Medicine of Beirut on July 7, 1923, attended by the High Commissioner General Weygand (white uniform, front row, middle), Reverend Father Lucien Cattin, Chancellor of the Faculty, on his left, and Professor Dubreuil, President of the Examining Board, on his right), further, military doctors and professors of the Faculty. Inauguration of the Hôtel-Dieu de France on May 26, 1923, by General Weygand (second storey, 1st arch on the right after the flags, with the Bishop). Two adjoining properties totaling nearly 4 hectares (40 000 m2) came up for sale not far from the Faculty of Medicine. While awaiting authorization from the Sublime Porte for registration of this land in the name of the French State, purchase by the solicitor Emile Eddé “on behalf of, and with the funds of, the French government” proceeded on July 11, 1912. Authorization proved slow in coming. On January 29, 1914, the French Consul General in Beirut went ahead regardless and instructed the project architect, Father Joseph Mattern, to build the boundary wall and assemble his construction materials. After the Ottoman Empire entered the war and closed the Faculty of Medicine on November 11, 1914, the future hospital site was looted. The building stone was filched for the Beirut garrison barracks (Grand Sérail) and principal administrative building (Petit Sérail). The project was not revived until hostilities ceased. On December 1, 1921, an application was accordingly submitted to General Gouraud, High Commissioner of Syria and the Lebanon, who granted his approval. An association, the Hôtel-Dieu de France Charity, governed by the French law of August 3, 1909, was set up to supervise construction of the hospital based on the prewar design, its subsequent management, and the organization of clinical teaching for the Faculty of Medicine. Its governing board had five members: a chairman (the High Commissioner), an executive director (the Jesuit Faculty Chancellor), and three other members from among the Faculty professors. General Gouraud laid the foundation stone of the Hôtel-Dieu de France on May 2, 1922. Land ownership was transferred to the French State and the Charity was gifted 2 800 000 francs by the French government. General Gouraud’s successor, General Weygand, opened the hospital on May 27, 1923. Within a year, the Hôtel-Dieu de France had catered for 1018 patients, 929 of whom were non–fee-paying because looked after by the welfare services (Assistance Publique); these were of particular value for the Faculty of Medicine because they were the only patients to whom students had access at that time. The departments of medicine and surgery opened on January 2, 1924, under Professors Justin Calmette and Eugène Cottard, respectively. The Hospital recruited externs and interns from the senior student body into its departments by competitive examination, as well as junior staff physicians from among the new graduates. Even twinned with its own hospital, the French Faculty of Medicine was hardly equipped to provide the Lebanon and surrounding region with a health service on its own. Other institutions that were founded by it or alongside it came some way to- 298 MEDICOGRAPHIA, VOL 28, No. 3, 2006 France and medical education under the Ottoman Empire – Ducruet A T Wideangle view of today’s Hôtel-Dieu de France complex in Beirut. O U C H O F FR A N C E ward achieving this aim. In first place were the Schools of Pharmacy and Dentistry. In 1883, the French Medical School was properly known as the Joint School of Medicine and Pharmacy. Pharmacy gradually achieved its due independent status, largely thanks to Professors Etienne Flavard, Frédéric Baldy, and Pierre-Paul Guigues, producing 94 French-qualified pharmacists between 1887 and 1914. The idea of a Dental School alongside the French Faculty of Medicine dated from 1912, but came to fruition only in 1920 under the leadership of André Fernagut, catering for 10 students in its first year (7 from Egypt, 2 from Greece, and 1 from the Lebanon). It was followed The buildings of the Faculty of Medicine of SaintJoseph University in 1940. by the Faculty of Medicine Midwifery School, which although planned in 1896 did not open until November 3, 1922, becoming the School of Midwifery and Nursing in 1929. It became fully operational in 1939, when the French Maternity Hospital was built opposite the Faculty of Medicine. Lastly, we must mention the Institutes. In 1913, the entire Middle East could boast only two anti-rabies institutes, in Cairo and Constantinople. The French Faculty of Medicine opened its Anti-Rabies Institute on May 1, 1913, and managed to treat 143 patients before being closed, along with the Faculty, on November 14, 1914. It then reopened on May 1, 1919, operating without interruption until 1958, when it reverted to the Ministry of Health. The Institute of Bacteriology also reverted to same Ministry at the same time, having been founded on March 1, 1919, after which it played a key role in the fight against cholera, smallpox, tetanus, and diphtheria. The Institutes drove the creation of laboratory technician schools. Thus any reference to France THE HÔTEL-DIEU DE FRANCE TODAY and medical education under the Ottoman Empire cannot fail to evoke the multiple institu◆ 170 hospital physicians ◆ 20 000 patients every year tions that have helped to make the health ser◆ 300 registered nurses ◆ 11 operating rooms vices in this part of the world into what they have ◆ More than 100 residents ◆ 2 cardiovascular surgery become today. ❒ (in speciality training) operating rooms ◆ 60 interns ◆ 430 hospital beds ◆ Central 15-bed postanesthetic recovery facility REFERENCES 1. Khouri R. La Médecine au Liban de la Phénicie à nos Jours [Medicine in the Lebanon from Phoenicia to the Present]. Beirut, Lebanon; undated, p. 79. 2. Verney N, Dambmann G. Puissances Étrangères dans le Levant [Foreign powers in the Levant]. Paris, France; Guillaumin, 1900: 81-83. 3. Journal Officiel. France, November 27, 1904. 4. Charles-Roux F. Bonaparte, Gouverneur d’Égypte [Bonaparte, Governor of Egypt]. Paris, France; Plon; 1935:102-106, and 212-223. 5. Peretz H. Clot Bey et son Œuvre en Egypte [Clot Bey and his Achievement in Egypt]. Cairo, Egypt; Institut Français d’Archéologie Orientale; 1928. 6. Haddad FS. Le Dr Youçif Bichara Jalkh et la Médecine du Liban à son Époque [Dr Youçif Bichara Jalkh and medicine in the Lebanon of his time]. J Med Libanais. 1963;16:102-115. 7. Haddad FS. Le Dr Ibrahim Najjar, premier médecin diplômé du Liban [Dr Ibrahim Najjar, Lebanon’s first medical graduate]. J Med Libanais. 1968;21:299-314. 8. Khouri R. La Médecine au Liban de la Phénicie à nos Jours [Medicine in the Lebanon from Phoenicia to the Present]. Beirut, Lebanon; undated, p. 85. 9. Julien M. La Nouvelle Mission de la Compagnie de Jésus en Syrie 1831-1895 [The New Jesuit Mission to Syria, 1831-1895], vol. 2. Tours, France; 1898:75. 10. Report to the Higher Education Conference, March 13, 1900 vol. 1, p. 913). 11. Recueil des Documents Diplomatiques et Consulaires Rela- France and medical education under the Ottoman Empire – Ducruet Unless otherwise specified, illustrations are provided by the Author, courtesy of Université Saint-Joseph de Beyrouth. tifs à l’Histoire du Liban [Compendium of Diplomatic and Consular Documents Relating to Lebanese History]. vol 15. Beirut, Lebanon; Adel Ismaïl, 1979:p. 72. 12. Ministry of Foreign Affairs. Documents Diplomatiques. Turquie 1900-1901 [Diplomatic documents. Turkey 1900-1901]. Paris, France; 1902:49-67. 13. Mr Liart. Letter of January 18 1899 to Dean Vergely, Chairman, Beirut Examining Board. Faculty of Medicine Archives. File 5; Document 3. 14. Visitors’ Book. Faculty of Medical Sciences, Saint-Joseph University, Beirut, Lebanon, 1902:150. 15. Visitors’ Book. Faculty of Medical Sciences, Saint-Joseph University, Beirut, Lebanon, 1902:25-29. 16. Foreign Affairs Archives. Post Office Archives. Turkish Embassy. Box 173; File 707; Section 3. 17. Ducruet J. Un Siècle de Coopération Franco-Libanaise au Service des Professions de la Santé [A Century of Franco-Lebanese Cooperation in the Service of the Health Professions]. Beirut, Lebanon; 1992. (Faculty syllabuses: pp 98-114; Departmental chairs: pp 273-282.) 18. Ducruet J. Un Siècle de Coopération Franco-Libanaise au Service des Professions de la Santé [A Century of Franco-Lebanese Cooperation in the Service of the Health Professions]. Beirut, Lebanon; 1992. (Student numbers: pp. 331-354.) 19. History and Various Documents of the Faculty. Undated; vol 3:605-635. 20. Cattin L. Speech to the general reunion of former faculty graduates, May 23, 1921. Bull Annu Faculte Med. 1921-1922;71. MEDICOGRAPHIA, VOL 28, No. 3, 2006 299 A T O U C H O F FR A N C E LA FRANCE ET L’ENSEIGNEMENT DE LA MÉDECINE SOUS L’EMPIRE OTTOMAN L ors de l’expédition de Bonaparte en Égypte, sous l’égide des Drs Desgenettes et Larrey, et, vingtcinq ans plus tard, grâce à Mohammed Ali (Méhémet Ali), vice-roi d’Égypte, sous l’égide du Dr Clot, nommé médecin-chirurgien en chef de l’armée égyptienne, puis Président du Conseil égyptien de la santé, les médecins français firent leur entrée officielle dans une région où ils étaient clairsemés au début du XIXe siècle. La promotion de l’enseignement de la médecine fut leur œuvre la plus marquante avec la fondation de l’école de médecine d’Abou-Zabal transférée à Kasr El-Aïni en 1837. Une première promotion de médecins libanais fut formée à Kasr El-Aïni. Au Liban, le Syrian Protestant College, en langue anglaise, et l’Université Saint-Joseph, en langue française, assurèrent à leur tour cet enseignement de la médecine. Suite à un accord entre le Gouvernement français et les Jésuites, la Faculté française de médecine fut ouverte à l’Université Saint-Joseph le 30 novembre 1883. Appliquant les programmes d’enseignement officiels en France, ses enseignants et les membres des jurys d’examens venant alors de France, elle fut habilitée à délivrer le diplôme d’État français de docteur en médecine; elle décerna ce diplôme d’octobre 1887 à novembre 1913 à 451 médecins dont environ la moitié exercèrent au Liban, un quart en Egypte et un quart dans les autres régions de l’Empire ottoman. Elle assura son enseignement hospitalier dans divers hôpitaux avant la fondation de l’Hôtel-Dieu de France. ✦ 300 MEDICOGRAPHIA, VOL 28, No. 3, 2006 France and medical education under the Ottoman Empire – Ducruet A T O U C H O F F R A N C E Lucile ALLORGE, DSc Département de Botanique et Systématique Muséum National d’Histoire Naturelle 16 rue Buffon 75005 Paris, FRANCE E-mail: [email protected] French naturalists in the Levant during the Ottoman Empire by L. Allorge, France E ven though agriculture and language first blossomed in the famous Fertile Crescent that wraps around Mesopotamia and stretches from Palestine and Syria to Persia, nevertheless it was not until the end of the Middle Ages that Europeans began to compile botanical inventories covering Asia Minor. And yet, a large proportion of our nutritional plants stem from that region. For instance, three cereal grasses — wheat, barley, and sorghum — and legumes, such as peas, chickpeas, broad beans, lentils, fenugreek, saffron, garlic, onions—as well as the Damascus nigella, better known as black cumin (Nigella sativa), whose seeds are added to bread to improve its flavor— not to mention the vine, olive, peach, and fig tree—all originated there (see box, next page). Then there are the ornamental plants such as the highly toxic oleander, which contains cardenolides (Apocynaceae), and trees like the cedar of Lebanon, which the Egyptians used for constructing their small boats, and is now the symbol of Lebanon. And finally the Judas tree, Cercis siliquastrum, the Aleppo pine, and the magnificent Parrotia persica C. A. Mey, which is decked in splendid colors in the autumn and can be admired in the Jardin des Plantes, in Paris. The Fertile Crescent is also the birthplace of goats and sheep. The Jardin des Plantes seen from the Cabinet of Natural History. Colored engraving, 19th century, French School. © Bridgeman Art Library. The first herbariums of Middle-Eastern plants After the Crusades numerous ambassadors were sent to the Middle East during the Byzantine Empire from the 7th to 13th centuries. Whether or not they returned with plants, they did not leave any written trace or dried plant specimens. It was not until Luca Ghini (1490-1556) established the first herbarium in about 1530 in Bologna that European botanists began to adopt this technique. The oldest herbarium in the Na- ✦ I f you stroll around Paris, you are sure to come across the Rue Tournefort in the fifth arrondissement, near the Jardin du Roi, which became the Jardin des Plantes at the time of the French Revolution. The street was named in honor of a pioneer of the flora of the countries of the Levant (stretching from Greece to Egypt). Others before and after him had returned with plants that enriched not only botany, but furthered knowledge in all the fields of science. This article retraces the lives of the most important among them, and will lead you through these countries in company with Pierre Belon, André Thévet, Jean Thévenot, La Billardière, Michaux, and Bruguière and his friend, Olivier. They were knowledgeable in all fields of science and were passionate explorers of the unknown. Medicographia. 2006;28:301-309. (see French abstract on page 309) French naturalists in the Levant during the Ottoman Empire – Allorge MEDICOGRAPHIA, VOL 28, No. 3, 2006 301 A T O U C H O F FR A N C E Lucile Allorge: Doctor of Science (botany), Poitiers. Engineer at the CNRS (National Center of Scientific Research), attached to the Museum of Natural History, Paris. Specialist in the medical plants of Madagascar. Numerous field trips to Madagascar, French Guiana, and Asia. Numerous publications on medical plants, the Apocynaceae and Crassulaceae families, and others. Her father, Pierre Boiteau, a botanist, founded the botanical and zoological gardens of Tsimbazaza at Tananarive, Madagascar, where Lucile Allorge was born. In 2003, published La Fabuleuse Odyssée des Plantes: Les Botanistes Voyageurs, les Jardins des Plantes, les Herbiers [The Fabulous Odyssey of Plants: Voyager Botanists, Plant Gardens, Herbariums]. Paris, France: JC Lattès (730 pages). tional Museum of Natural History (Jardin des Plantes) dates from 1558, two years after the death of Luca Ghini. It is the second oldest herbarium in the world after that in the Vatican. In 1535, Suleiman I signed one of the treaties known as the Capitulations with Francis I, king of France. Under its terms, the sultan permitted Europeans to live and work in the Ottoman Empire according to their own laws and under their own consuls. Thanks to this the Sultan avoided the burden of administrating justice to foreign merchants. The treaty opened the trade of the Levant to the kingdom of France and paved the way for expeditions of French naturalists, particularly of botanists, who, throughout the long duration of the Ottoman Empire, were to discover, draw, and classify hundreds of plants, many of which still have a major economic impact today. However, along the growing fascination of the France with the Orient, which was to culminate in a veritable “turcomania” under Louis XIV and Louis XV, influencing fashion and the arts (Molière, Montesquieu, etc), the Turcs themselves were intrigued by France, and after an earlier failed attempt in 1669, in 1721, Sultan Ahmed III sent an ambassador to France, who, among many other places, was highly impressed by his visit to the Jardin du Roi (see box, right page). SOME REMARKABLE PLANTS TRACEABLE TO THE MIDDLE EAST The origin of plants is difficult to establish if records or a herbarium do not exist. For example, the so-called Indian chestnut tree originated in the Balkans, and was introduced in Pisa around 1550. Charles de Écluse is known to have introduced it to Vienna in 1576. Bachelier brought the tree to France after returning from the Levant in 1615. Thus the chestnut tree probably passed through the Lebanon. In France it is considered to have originated in India. In 1733, a chestnut tree was planted in the Tuileries Gardens and survived for 178 years until 1911. The fenugreek is not Greek but originates from Mesopotamia. The tamarind tree, named Tamarindus indica by Linné, does not originate from India but from Madagascar, from whence it was exported to India by the Arabs. The “poule d’Inde” does no come from India but from Turkey. Cape peas (lima beans) originated in Central America, and were introduced into South Africa by the Portuguese at the Cape of Good Hope. Apart from the plants already mentioned, many others originate from the Middle East, including cyclamen, castor oil plant, chickpea, lentils, peas, and broad beans. Then thee is the salep, an old world orchid that gives a starchy extract that is supposed to be aphrodisiac, the liquidambar oriental, which is endemic in Turkey and gives storax, an oleoresin used in perfumery and known since antiquity. There is also the mandragora (mandrake) whose fruits are toxic since they contain scopolamine, but are also known for their nocturnal brilliance like the fireflies. Which probably accounts for the superstitions surrounding the mandrake. In addition the bay tree, the almond tree, the Arabian jasmine, and the Oriental ash all originate form the Middle East. The Arabs also disseminated many oriental plants, as did the Chinese, and the origin of sugarcane, for example, is still under discussion, as are the origins of a number of plants. The great merit of the research achieved by the adventurous French naturalists was to discover many wild plants that have given birth to cultivated descendents. This work is being continued at the grass roots and indirectly by the study of DNA. Fenugreek (Trigonella foenum-graecum L.), literally “Greek hay,” an aromatic leguminous annual Eurasian herb, cultivated for forage and the medicinal use (cataplasms) of its mucilaginous seeds. Illustration by Turpin. Reproduced from: Chaumeton FP. Flore Médicale Illustrée par E. Panckouke et P. J. F. Turpin. Paris, France: Éd. Panckouke ; 1816. Courtesy of L. Allorge. 302 MEDICOGRAPHIA, VOL 28, No. 3, 2006 French naturalists in the Levant during the Ottoman Empire – Allorge A T O U C H O F FR A N C E Pierre Belon: tulips and murder Pierre Belon, 1517-1564, born in Le Mans, doctor, surgeon, and zoologist, served as French ambassador to the Orient in 1536. From 1545 to 1550, he traveled to Greece, Crete, Constantinople, Mount Athos, Thrace, and Asia Minor. He then went by boat to Alexandria and explored Lower Egypt, then returned via the Sinai to Judea. Pierre Belon was above all interested in coniferous trees and their natural products. He noted the tolerance of the Turks who practiced the freedom of religion, albeit in exchange for paying a tax. He also did major research on the ancient history of the countries he had visited. He brought back the Oriental plane tree and the tulip to Europe. In around 1635, the tulip sparked an extravagant enthu- 1721: AN OTTOMAN AMBASSADOR VISITS PARIS In the early years of the 18th century, the Ottoman Sultan in the morning and take his meals, in stark contrast to the Ahmed III (1673-1736) sent an ambassador to the French court. Turkish sultan who rarely appeared in public and whose elabHis envoy was Mehmet Effendi, a highly intelligent and insaorate ceremonial effectively removed him from contact with tiably curious mind. His mission was a first, since Ottoman his people and even visiting dignitaries. Mehmet also visited rulers, to whom European nations had, for their part, repeatVersailles, informing his sultan that it was the most splendid edly sent ambassadors in the past, had always considered it palace in Europe. He marveled at the Trianon, the gardens, beneath their dignity to do the same, and and admired Mansart’s royal stables with merely sent low-level representatives to their stone vaults and arcades. As a result deal with pressing issues. The visit started of the visit, Paris and the court were won most inauspiciously, as upon disembarkover, and “turcomania” reigned supreme. ing in Toulon after 45 days at sea, Mehmet During the 8 or some months he stayed in was escorted by the French authorities to France, Mehmet acted the perfect tourist, the small island of Maguelone, near Sète, and although he spoke no French took evwhere he and his party of 80(!) were placed erything in and never appeared at a culin quarantine, because the plague was ravtural disadvantage, even when witnessing aging the region. Mehmet then set off by things as alien to Turkish traditions as theboat on the canal du Midi, the technology atrical performances. of which fascinated him, and which he deHaving returned to Constantinople, scribed in detail in his account of his voyMehmet set upon writing an account of his age. Arriving in Bordeaux, the party then embassy, producing an abridged version proceeded toward Paris in horse-drawn for the court, and a fuller one for the sulcarriages. Along the way, Mehmet imbibed tan. This account, which to this day can everything he saw, thoroughly fascinated still be found in a pocketbook edition in by the differences between France and his French bookstores under the title Le PaTurkish homeland. On March 8, 1721, he radis des Infidèles [The Paradise of the reached the gates of Paris, and Parisians Infidels], is a vibrant record of Mehmet’s poured into the streets to watch the statejourney, which sometimes goes into intriAhmed III (1673-1736),the first Ottoman ly passage of the envoy and his colorful encate scientific detail as when he describes Sultan to have established diplomatic relations with France by sending his tourage. Among many other sites, Mehmet the lock system of the Canal du Midi or ambassador Mehmet Effendi in 1721. toured the Jardin du Roi (Jardin des Reproduced from: Holevoet J. The Ottoman Empire. the instruments in the Paris Observatory, Chicago Ill: St Francis University; 2002. Plantes), then one of the principal botanbut whose contemporary interest resides All rights reserved. ical gardens in Europe. He was much imin the fascinating face-to-face of two culpressed with the garden of medicinal plants, and wrote: “They tures, French and Turkish, Christian and Muslim. Ironically, have applied themselves so assiduously to collecting simples the very same year the Turkish embassy arrived in France, mentioned in medical books, that they have even collected Montesquieu published (anonymously) a work that made histhose that grow in Persia and transplanted them to France.” He tory, the Lettres Persanes [Persian Letters], in which under the also visited the Royal Library, the Observatory, were, much impretense of recounting the astonishment of two Persian visitors pressed, he took a peek through the telescope at the moon and to France at the customs they observe, he analyzes and criticizes several planets. Mehmet was received by 11-year-old Louis XV the extant political system and offers his own ideas, which were at the Tuileries palace, where the crowd was so great that he to exert a profound influence during the French Revolution. had trouble making his way through it. Tiers of benches had For extensive details on the embassy of Mehmet Effendi to France, been erected on either side for the ladies of the court “whose and its repercussions, read: A Turk in Versailles, by Paul Lunde, published in Saudi Aramco World, November-December 1993;44(6); dresses sparkled with precious stones.” He was shocked by the and Mehmed Efendi; Galland JC (transl); Veinstein G (comments). total absence of “privacy” at the French court, were anyone was Le Paradis des Infidèles. Paris, France: La Découverte; 2004 (in French). free to wander in the palace to watch the king get out of bed French naturalists in the Levant during the Ottoman Empire – Allorge MEDICOGRAPHIA, VOL 28, No. 3, 2006 303 A T O U C H O F FR A N C E Tulip (Tulipa gesneriana L.), originally published between 1802 and 1816, by P. J. Redouté, in Les Liliacées, in 8 volumes containing 486 plates. Reproduced from: Mathew B, Stearn WT, Watson WP. Lilies and Related Flowers. London, UK: Michael Joseph London; 1981. Copyright © 1981, Michael Joseph London, Ltd. siasm known as “tulipomania,” when the price of bulbs reached the equivalent of an average salary for a whole year. He published several works including: “Observations on various Singularities and Memorable Items Found in Greece, Asia, Judea, Egypt, Arabia, and other Foreign Countries” (three volumes), published by Corrozet and Cavellat, Paris, in 1553. Belon was murdered in Rome by a band of brigands, and a statue was erected in the village where he was born, the hamlet of Souletière at Ceran in the Maine-et-Loire. André Thévet: tobacco and dog-killing plants André Thévet (1502-1590) was born in Angoulême and journeyed to Jerusalem as a Franciscan monk. He then traveled throughout the Near East, returning to France via Italy. He published his Cosmography of the Levant in 1554. As a result he was invited to depart with Villegaignon for Brazil, accompanied by numerous Calvinists who were fleeing from France to found a France-Antarctic colony on an island in the Bay of Rio de Janeiro. They left on the 15th of August 1555. Two years later, Thévet returned home with tobacco, which he planted in his garden at Angoulême in 1556, well before the diplomat Nicot imported the weed. The plant rapidly became known as angoumoise, but its scientific name was dedicated to Nicot by the naturalist Linné nearly 200 years later— Nicotiana tabacum L., Thévet’s name was given by Linné to the Thevetia family whose seeds are highly toxic due to their content of cardenolides, like many of the family of Apocynaceae, as indicated by the name: apo (that kills) cynum (dogs). André Thévet (1502-1590), the first discoverer of the tobacco plant, to whom Linné dedicated the Thevetia genus (Apocynaceae). Tobacco (Nicotianum tabaccum L.). Illustration by Turpin. Reproduced from: Chaumeton FP. Flore Médicale Illustrée par E. Panckouke et P. J. F. Turpin. Paris, France: Éd. Panckouke ; 1816. Courtesy of L. Allorge. Reproduced from: Vve Kerver, Chaudiere G. Les Vrais Pourtraits et Vies des Hommes Illustres. Paris, France: 1583. Courtesy of L. Allorge. Jean de Thévenot: the polyglot and coffee lover Around 1650, Europeans began to learn the languages necessary for communicating directly with the Muslims without translators. This enabled merchants to trade further from home and commerce between Asia and Europe was facilitated. Asia Minor is at the crossroads of the grand routes, such as the silk and spice routes. Merchants could only travel to the Orient by the sea and this was controlled by the Consulates. The Ottoman Empire became weakened after its defeat before Vienna in 1640. Jean de Thévenot (1633-1667), born in Paris, was a surgeon and a botanist. Eager to understand the Muslim world that was fascinating Europeans, he learned several “dead” languages before departing in 1655 for Sicily, Malta, and Turkey. Setting out from Marseilles, he had to wait five months on Malta, from where he explored the Greek islands, then settled in Alexandria. He next attempted to go to Jerusalem via the Sinai, but was taken prisoner and had to return to Cairo twice. Six months later, in April 1659, he arrived in Marseilles, whence he had departed six years earlier, bringing with him hundreds of sacks of mocha coffee. After selling these, he returned to Paris, where he published an account of his journeys, and with his uncle spent four years studying the Arab, Persian, and Turkish languages. In November 1664, he left for Alexandria, Damascus, Aleppo, Mesopotamia, and Mosul (in Iraq). He then traveled through Persia to Basra, departed for India where he spent thirteen months, voyaged to Shiraz, arrived in Ispahan, and died in Miana, on November 28, 1667 at the age of thirty-four. He had sent his 304 MEDICOGRAPHIA, VOL 28, No. 3, 2006 French naturalists in the Levant during the Ottoman Empire – Allorge A T O U C H O F FR A N C E Coffee (Coffea arabica L.). Illustration by Turpin. Reproduced from: Chaumeton FP. Flore Médicale Illustrée par E. Panckouke et P. J. F. Turpin. Paris, France: Éd. Panckouke ; 1816. Courtesy of L. Allorge. travel journals back to France, and the first, Report on a Journey to the Levant, was published in Paris in 1664, the second, Continuation of the Journey to the Levant, covering Persia, was published after his death in 1674, and the last, Journey to Hindustan, the New Moguls, and the Regions of India, was published in 1684. His collection of dried plants consisted of five volumes, but only one found its way back to France, in 1796. Thus his travels did not greatly increase knowledge of the vegetation he had encountered, even though he had made a list of the herbs he had gathered, and this was published by Edmond Bonnet in 1906. However, the loss would be made up for by his successor, Tournefort, in his famous voyage to the Levant. Joseph Pitton de Tournefort: the Jesuit and the fig Joseph Pitton de Tournefort (1656-1708) a member of the order of Jesuits, relinquished his imposed religious vocation with alacrity as soon as his father died. After studying medicine and botany at Montpellier he investigated the flora in the region of Aix-en-Provence, and climbed the mountains of Provence, Languedoc, those around Grenoble, as well as the Alps and the Pyrenees. He made astronomical observations, and in 1694 published The Elements of Botany or How to Understand Plants. His History of Plants in the Vicinity of Paris was published after his death. His influence was considerable since he was the first Joseph Pitton de Tournefort (1656-1708). Reproduced from: Pitton de Tournefort J. Relation d’un Voyage du Levant, Fait par Ordre du Roy, Contenant l’Histoire Ancienne et Moderne de Plusieurs Îles de l’Archipel, de Constantinople, de Côtes de la Mer Nopire, de l’Arménie, de la Géorgie, des Frontiières de Perse et de l’Asie Mineure. 3 vol., Lyon, France: Anisson & Posuel; 1717. Courtesy of D. Lamy, Cryptogamie, MNHN, ic 268. Fig (Ficus carica L.). Illustration by E. Pancoucke. Reproduced from: Chaumeton FP. Flore Médicale Illustrée par E. Panckouke et P. J. F. Turpin. Paris, France: Éd. Panckouke ; 1816. Courtesy of L. Allorge. to use a systematic method to determine the characteristics of plants and especially flowers. In 1683 he was appointed Botanist of the King’s Garden. Tournefort was sent by Louis XIV to the Levant in march 1700, with the aim of rediscovering the plants that were known in ancient times. He also made observations on the natural history of the country as well as noting its geographic features and antiquities. He was accompanied by an artist, Claude Aubriet (1665-1762), whose drawings were so precise that Lamarck used some of them 80 years later in his Methodical Encyclopedia of 1781 and 1789. Tournefort was also accompanied by one of his German students who later became a famous doctor, André von Gubdelcheimer (1668-1715). On the way they stopped in Greece, Istanbul, and Iráklion (Crete), followed the coastline of the Black Sea as far as Sinop, then went on to Armenia and Georgia. They botanized on Mont Ararat, visited the ruins of Ephesus, and re-embarked at Smyrna for France. Tournefort collected about 3200 botanical samples. He was also the first to observe the caprification of cultivated figs (the fastening of wild male flowers in the trees to assist pollination by wasps). Aubriet made numerous black and white drawings of plants, ancient monuments, musical instruments, local dress, and the layout of villages. But above all he created sixty very fine plates that are now in the vellum collection of the museum, and which were inspired by the new plants that had been brought back in good condition to Paris. On his return, Tournefort wrote the draft of the first part of their long voyage. He was appointed professor of medicine at the Collège de France and director of the Jardin du Roi. But in the nearby road, now called Lacépède, he was struck violently in the chest by a cartwheel, and died six months French naturalists in the Levant during the Ottoman Empire – Allorge MEDICOGRAPHIA, VOL 28, No. 3, 2006 305 A T O U C H O F FR A N C E later at the age of fifty-two. The second account of his voyage appeared after his death, and Desfontaines published the vellums and added descriptions based on the dried plants brought back by Tournefort. Lebanese carnation (pink) (Dianthus libanotis Labill.). Illustration by P. J. Redouté. Reproduced from: La Billardière. Icones Plantarum Syriae Rariorum. 5 volumes. Paris, France: Prévost; 1791. Courtesy of L. Allorge. La Billardière, the compulsive plant collector Jacques-Julien Houtou de La Billardière (1755-1834) was born on October 28, 1755, in Alençon. He studied medicine in Montpellier from 1772 to 1780 and received his doctorate in Paris. He traveled to England to learn the language and stayed for six months. There he met Banks, a botanist who had accompanied Cook on his first great voyage of exploration. Then in 1787, Billardière departed for the Levant. Before La Billardière went to Palestine, only three other botanists had ever been there, Leonard Rauwolf (1540-1596) whose herbarium is in Leiden, Tournefort (1656-1708) whose herbarium is in Paris, and Frederik Hasselquist (1722-1752) pupil of Linné, whose herbarium is in Uppsala. Jacques Julien de La Billardière (1755-1834). Embarking at Marseilles, he made a stop in Cyprus where Reproduced from: Jacques Julien de la Billardière. Courtesy of D. Lamy, Cryptogamie, MNHN, ic 242. he learned that the plague was ravaging Syria. He then decided to continue via Antioch thus avoiding Aleppo. On arrival in Damascus he explored the surrounding regions as well as those of Beirut, Tripoli, and Mount Lebanon, where the cedars then numbered about one hundred. He spent nearly two years in Syria and Lebanon, which was then known as Ottoman Syria. On returning to France he stopped again in Cyprus, Corsica, and Sardinia. He arrived back in 1789, in the middle of the Revolution, with close to a thousand dried plants, as well as living plants which he entrusted to the head gardener of the King’s Garden, André Thouin. His dried plants were purchased by the King’s doctor, Le Monnier, who had helped arrange the voyage. La Billardière had his findings published in 1791 under the title Icones Plantarum Syriae Rariorum (Rare Syrian Plant Images) by Prévost, Paris, in 5 volumes. The first, Decas Primas, consisted of 22 pages with 10 plates by the famous painter of roses, Pierre-Joseph Redouté; the second, Decas Second, consisted of 18 pages with 10 plates also by Redouté. These included around one hundred new species unknown to the scientists of that time: Astragalus gummifer Labill., known since early Greece for its colloidal, medicinal, and cosmetic properties, Prunus prostrata Labill., Phlomis rigida Labill., and Juniperus drugacea Labill. After Le Monnier died, the herbarium was purchased by a rich Geneva Banker, Delessert (17731847), and the collection is now in the Geneva Herbarium. There, Alphonse de Candolle, whose botanical abbreviation is DC, continued to study them and described more new species including: Astragalus echinus DC., 1802, Oriental type Labill.; Astragalus macropus DC., 1802, Oriental type Labill. On September 28, 1791 La Billardière boarded the ship La Recherche that was setting out from Brest under the command of Rear Admiral Bruni d’Entrecasteaux (1740-1793). It’s mission was to search for La Boussole and L’Astrolabe, two ships that had disappeared three years earlier under the command of the Comte de La Pérouse (1741-1788). La Billardière did not return to France until March 12, 1796, after many incidents, and with the news that La Pérouse had died at sea. During the earlier part of the voyage La Billardière collected numerous plants in Australia and Tasmania. Among them was the famous blue gum tree, Eucalyptus globulus Labill., whose leaves when distilled give eucalyptus oil. And above all several plants of the famous breadfruit tree, an object of envy between England and France, since the two countries were planning to feed breadfruit to the slaves on their sugar plantations in the West Indies. Unfortunately, d’Entrecasteaux died, and La Billardière was denounced by one of the ship’s officers for his revolutionary ideas. However, he managed to entrust his precious plants to the ship’s chief gardener, La Haye, before he was arrested. La Haye took enormous care of his charges, and later succeeding in returning them in good condition to Paris. On another expedition, La Billardière nearly lost his collections again when they were confiscated in Indonesia and sent to England. 306 MEDICOGRAPHIA, VOL 28, No. 3, 2006 French naturalists in the Levant during the Ottoman Empire – Allorge A T O U C H O F FR A N C E There, fortunately, it was the botanist Banks who received them, and returned them in their entirety to their owner. A letter written by Dupuis, an official on the island of Mauritius, to the French botanist Jussieu, in 29 Brumaire, year 4 of the French Republic, was entrusted to La Billardière. It stated: I am giving this letter to citizen La Billardière, one of the savants on the d’Entrecasteaux expedition, who returns to France with the poor remains of a collection that would have been precious if it had not been almost entirely pillaged by men who were less interested than him in science and their country. La Billardière’s collections numbered nearly four thousand plants, three quarters of which were not previously known. He then devoted himself to writing The Story of the Voyage to Locate La Pérouse, which was published in 1800. He did not continue classifying his Syrian collections until after he had been elected to the French Academy on November 26, 1800, division of science, botanical section. The third part of his Icones Plantarum Syriae Rariorum, Decas Tertia, consisting of 16 pages and 10 plates, was published in 1805, again in Paris by Prévost; then Decas Quatra, in 1812, with 16 pages and 10 plates; and finaly Decas Quinta et Ultima in 1812, with 16 pages and 10 plates. The plates were prepared once again by Pierre-Joseph Redouté, aided by Pierre Poiteau and Pierre Turpin, both of whom had returned from the West Indies, and who later jointly illustrated the works of Humboldt, Bonpland, and Chaumeton. André Michaux: cuneiform writing and bellflowers André Michaux (1746-1802) was born near Versailles on the farm of a Monsieur Satory. Le Monnier, doctor to Louis XV and XVI, noticed him, took him under his wing, and organized his vocational training, which led to final studies in the King’s Garden. During a stay in England Michaux met other botanists, and in 1780, Lamarck, who had just published his Flore de France, invited friends to investigate the flora of central France. Among them were Thouin (the King’s Gardener), Desfontaines, Boissanjeu, de Laussat, and Michaux. For him the experience was a revelation, and his one ambition was henceforth to be a plant hunter. He left for the Pyrenees and searched for flora on the French and Spanish slopes. He became a member of the Linné Society created by Broussonet in memory of the famous Swedish botanist. Then, thanks again to Le Monnier, Michaux had the chance to ex“Stone of Michaux” with cuneiplore the Orient. He accompanied the nephew of Jean-Jacques Rous- The form writing, discovered in 1785 seau, Jean-François Rousseau, who had been appointed ambassador in Iraq. to Persia. Jean-François had been born in Ispahan (now Esfahan), and Reproduced from: Deleuze J. Memoirs of the Life and Botanical Travels of André Michaux. had served as consul in Baghdad and Bassora. He arrived in Versailles Michaux’s Bicentennial, 2002. Charlotte, NC: wearing oriental robes for his official enrollment as ambassador. The Fourbears Press; 2002. Copyright © 2002, Fourbears Press. two men left from Marseilles on February 28, 1782. Michaux began studying Arab and Persian with the idea of traveling through Mesopotamia, Syria, and Persia. He arrived in Aleppo on April 14, 1782 and spent six months collecting plants (see box, next page). He made numerous archeological discoveries and copied down ancient inscriptions. Later in Iraq in 1785 he discovered a stone engraved with cuneiform writing now known as the “Stone of Michaux.” He and Rousseau then left for Baghdad, in the middle of Mesopotamia, which he reached after a forty-day march across the desert. They found a vast town at the convergence of the main commercial routes. This was Rousseau’s destination (1782-1785), and Michaux departed by himself for Bassora (Iraq), where he stayed for three months. On the way he was stopped by Arabs who were at war with Persia and was relieved of his measuring instruments and money. However, they were not interested in his books. He was saved by the English consul in Bassora who gave him funds so he could continue. From there he went to Schiraz and Ispahan, then for two years explored Persia from the Arabian to the Caspian sea, encountering on the way both mountains and deserts. During his travels he managed to send back plants, animals, and minerals to Paris, nonetheless he arrived home with bursting trunks. He discovered new species among them a new member of the Campanulacea (bellflower) family, which was named Michauxia in his honor. The French government sent him to America where he crossed through very inhospitable regions. His exploits have been recounted by Régis Pluchet, a distant nephew. Finally, in 1800 he sailed with Nicolas Baudin’s expedition to Australia, but left him on arrival at Mauritius and headed west to Madagascar. There he died of malaria on October 11, 1802 on the banks of the Ivondro river, twelve kilometers south of Tamatave. It was there that I was able to find his tomb on a promontory from which there was a 360° view of the land where he had planted the trees he had brought with him form Mauritius. French naturalists in the Levant during the Ottoman Empire – Allorge MEDICOGRAPHIA, VOL 28, No. 3, 2006 307 A T O U C H O F FR A N C E Jean-Guillaume Bruguière: umbellifers and seashells Jean-Guillaume Bruguière (1750-1798), a naturalist aged 23 years, departed from Brest on March 24, 1773 with Yves-Joseph de Kerguelen on a quest to find the elusive southern continent. Their voyage took them to Mauritius, October 16, 1773, and the islands later named after Kerguelen, then they returned via Madagascar on September 7, 1774. Bruguière set off again in 1792, with his friend Guillaume-Antoine Olivier (1756-1814), entomologist, and they headed for the Ottoman empire. Leaving Toulon they arrived at Constantinople and the Dardanelles Strait, where they had to wait six months for a laissez-passer. They then visited different Greek islands, Tenedos, Lemnos, Lesbos, Skyros, and continued via Crete (Iráklion), and Alexandria. In 1794 they went up the Nile, then visited the islands of Thera and Rhodes. After stopping in Tripoli and Aleppo, they rested for three months and then set out for Mesopotamia. They took thirty days to arrive at Mosul, then went on to Baghdad (Iraq), and continued to Tehran, where they explored Mount Elburz and the ancient city of Ispahan. They then headed for home, but Bruguière never saw France again. LETTER FROM MICHAUX TO THOUIN COPIED BY J. P. F. DELEUZE AND TRANSLATED BY C. D. E. KÖNIG AND JOHN SIMS FOR THE ANNALS OF BOTANY IN 1805 Rough-leaved Michauxia (Michauxia campanuloides L’Hér.), named after André Michaux. Reproduced from: Pluchet R. In: Hommes et Plantes. 2005(No. 52):9. Copyright © 2005, Conservatoire Français des Collections Végétales Spécialisées (CCUS). Courtesy of L. Allorge. Allepo, July 30, 1782. My Dear Sir, I landed at Alexandretta on the 30th of March. I cannot express to you the delight with which I crossed the country here. In examining the multitude of plants with which the fields abound, I was often transported beyond myself, and compelled to pause and tranquillize my mind for some moments. At night I could not sleep, but watched the dawn of day with impatience. What happiness! To find myself in Asia, and at my pleasure to traverse the mountains and valleys covered with liliaceous plants, orchids, daphnes, laurus, vitex, myrtles, and rachmes, styrax, palms, and other vegetable productions different from those of Europe. The seashore abounded with shellfish, varied in form and color: land and sea birds came every morning to feed upon them. The flamingos came in flocks of three and four hundred each. The marshes abounded with reptiles. Unfortunately, the greater part of the plants were not yet in flower; and the mountains were infested by the Bayas, who the preceding year had pillaged the caravan of Alexandretta, and a few days before our arrival had put to flight the troops sent to guard the town and had burnt several of the houses. Since my arrival at Aleppo, I have made two tours among the mountains. The town is situated on the side of a valley in which are gardens abounding with trees, none of which are grafted. The rest of the country is dry, stony, and uncultivated. For six leagues round, not a single tree or shrub is to be seen. Beyond are vast plains, whose fertility, if cultivated, would be prodigious. 308 MEDICOGRAPHIA, VOL 28, No. 3, 2006 On these were formerly villages, which have been successively destroyed. The predecessor of the present pasha destroyed more than eighty, on the pretext that the inhabitants had formerly revolted. His soldiers committed unheard of things. They ransacked the houses, and cut off the heads of women and children, to make themselves masters of the pieces of gold which ornamented their headdresses. It is by such vexations that the pashas indemnify themselves for tributes they pay to the grand seigneur. These ruined villages are at present the haunts of robbers. Excursions are equally painful and dangerous throughout the whole of this part of Asia, which extends from Syria to the frontiers of India. The traveler carries his provisions and sleeps on the ground, avoiding the caravanserais on account of their filthiness and the insects with which they abound. He must, however, follow the caravans; otherwise he would be plundered by the Arabs on the plains, and the Kurds who infest the mountains. The caravans are often attacked: last March the robbers took from those of Alexandretta 380 camels; and the one which is now ready to depart has been compelled to wait ten days beyond their time, expecting troops which the pasha of Aleppo and Antioch has detached for their escort. Every traveler must take with him an Armenian, whom he must watch attentively; for the conductors of the caravans are for the most part knaves, who watch an opportunity secretly to rob the traveler. While I am waiting for our departure from Baghdad, which will not take place in less than a month, I propose to make a botanical excursion over 150 leagues. I shall pass by Laodicea, Antioch, and Seleucia: I hope to find medals in the last city. At my return I shall send you and Mr de Malesherbes some specimens of seed. The consuls and merchants can tell you that no one labors with more ardor to make his fortune, than I do in the interests of botany. French naturalists in the Levant during the Ottoman Empire – Allorge A T O U C H O F FR A N C E He died of exhaustion in the Italian port of Ancona having spent six years abroad. His friend Olivier returned to Paris with their collections. Like La Billardière, Olivier was elected to the French Academy of Science in 1800. He published the account of their travels under the title: Voyage to the Ottoman Empire, Egypt, and Persia (three volumes, 1801 to 1807) and the plates were once again signed by Pierre-Joseph Redouté. A genus of umbellifers brought back from Syria and Iraq was named Oliviera in honor of Olivier. Bruguière, who had identified a new species in Madagascar was honored posthumously by Lamarck who named the species Bruguiera gymnorhiza Lam., (Rhizophoraceae). Brugière’s vast collection of rare shells was sold to a museum for 6000 francs in 1799. Guillaume Antoine Olivier (1756-1814). Reproduced from: Guillaume Antoine Olivier. Courtesy of D. Lamy, Cryptogamie, MNHN, ic 258. Enlightened naturalists return with treasures from the Orient These naturalist voyagers were to have a great influence on their time. While quite young men they left for countries that were dangerous, not only because of diseases like the plague, but also because conditions were totally different from those of today: traveling on foot in close contact with the population and living like them, not to mention the incessant wars. Nevertheless they managed to give an impulse to fundamental research to which they dedicated their lives with passion. The museums encouraged them to travel, as did the Academy of Science. Their publications still remain a very precious tool for understanding the origins and history of plants. They returned not only with new plants for Europe, but with nutritional and medical plants, as well as trees and shrubs to enliven our gardens. Moreover, they had very profound knowledge in many other domains, geology, archeology, and languages, among others. They were indeed men of the Enlightenment. ❒ Ispahan, in Persia. 19th century engraving. Courtesy of L. Allorge. REFERENCES – Allorge L. La Fabuleuse Odyssée des Plantes: Les Botanistes Voyageurs, les Jardins des Plantes, les Herbiers [The Fabulous Odyssey of Plants, the Voyager Botanists, the Jardin des Plantes, the Herbariums]. Paris, France: JC Lattès; 2003. – Bonnet E. Le Voyageur Jean de Thévenot (1633-1667). Son Herbier de l’Hindoustan [The Voyager Jean de Thévenot (1633-1667). His Hindustan Herbarium]. Reports of the French Association for the Promotion of Science, 1-10; 1906. – Deleuze J. Memoirs of the Life and Botanical Travels of André Michaux. Michaux’s Bicentennial, 2002. Charlotte, NC: Fourbears Press; 2002. LES – Pluchet R. André Michaux le Laboureur Explorateur [André Michaux, Ploughman Turned Explorer]. In Hommes et Plantes, n°52: 4-12; 2005. – Pitton de Tournefort J. Relation d’un Voyage du Levant, Fait par Ordre du Roy, Contenant l’Histoire Ancienne et Moderne de Plusieurs Îles de l’Archipel, de Constantinople, de Côtes de la Mer Noire, de l’Arménie, de la Géorgie, des Frontières de Perse et de l’Asie Mineure [Report of a Journey to the Levant by Order of the King, Describing the Ancient and Modern Histories of Several Islands of the Archipelago, of Constantinople, the Coasts of the Black Sea, Armenia, Georgia, the Frontiers of Persia, and Asia Minor]. 3 vol., Lyon, Anisson & Posuel; 1717. VOYAGEURS-NATURALISTES FRANÇAIS AU LEVANT PENDANT L’EMPIRE OTTOMAN S i vous parcourez Paris, vous trouverez la rue Tournefort dans le cinquième arrondissement, près du Jardin du Roi, devenu Jardin des plantes à la révolution française. Ce nom fut donné en hommage rendu à ce pionnier de la flore des pays du Levant. D'autres avant lui et après lui rapporteront des plantes et vont enrichir la botanique et la connaissance dans tous les domaines des sciences. Nous retraçons la vie des plus importants d'entre eux, et vous emmenons dans ces contrées avec Pierre Belon, André Thévet, Jean Thévenot, La Billardière, Michaux et Bruguière et son ami, Olivier. Ils avaient une formation universelle et étaient portés par une passion de découverte dans tous les domaines. ✦ French naturalists in the Levant during the Ottoman Empire – Allorge MEDICOGRAPHIA, VOL 28, No. 3, 2006 309 Medicographia A Ser vier publication I nstructions for authors General instructions N Manuscripts should be provided by e-mail ([email protected]. com) or by CD double-spaced, with 2.5-cm margins. Pages must be numbered. Standard typed page = 25 lines of 90 characters (including spaces) double-spaced, 2.5-cm margins = a total of about 320 words per page. 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