Download If Inhibition, Heart Rate, and Coronary Artery Disease

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
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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
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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.
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◆ 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
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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. ❒
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MEDICOGRAPHIA, VOL 28, No. 3, 2006 205
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If current inhibitor ivabradine in patients with chronic stable
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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
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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
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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
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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
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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
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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. ❒
✦
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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
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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
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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
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, H
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,
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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
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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
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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
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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. ❒
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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
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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. ❒
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22. Kaplan JR, Manuck SB. Antiatherogenic effects of beta-adrenergic blocking agents: theoretical, experimental, and epidemiologic considerations. Am Heart J. 1994;128(6 pt 2):1316-328.
23. Albaladejo P, Carusi A, Apartian A, et al. 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.
24. Skantze HB, Kaplan J, Pettersson K, et al. Psychosocial stress
causes endothelial injury in cynomolgus monkeys via beta1adrenoceptor activation. Atherosclerosis. 1998;136:153-161.
25. Kaplan JR, Manuck SB, Adams MR, et al. Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed
monkeys fed an atherogenic diet. Circulation.1987;76:1364-1372.
26. Strawn WB, Bondjers G, Kaplan JR, et al. Endothelial dysfunction in response to psychosocial stress in monkeys. Circ Res.
1991;68:1270-1279.
27. Perski A, Hamsten A, Lindvall K, et al. Heart rate correlates
with severity of coronary atherosclerosis in young postinfarction
patients. Am Heart J. 1988;116(5 pt 1):1369-1373.
28. Perski A, Olsson G, Landou C, et al. Minimum heart rate and
coronary atherosclerosis: independent relations to global severity and rate of progression of angiographic lesions in men with
myocardial infarction at a young age. Am Heart J.1992;123:609616.
29. Hedblad B, Wikstrand J, Janzon L, et al. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: main results from the Beta-Blocker CholesterolLowering Asymptomatic Plaque Study (BCAPS). Circulation.
2001;103:1721-1726.
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.
31. National Heart, Lung, and Blood Institute Coronary Artery
Surgery Study. A multicenter comparison of the effects of randomized medical and surgical treatment of mildly symptomatic
patients with coronary artery disease, and a registry of consecutive patients undergoing coronary angiography. Circulation.
1981;63(6 pt 2):I1-I81.
32. Menotti A, Mulder I, Nissinen A, Giampaoli S, Feskens EJ,
Kromhout D. Prevalence of morbidity and multimorbidity in elderly male populations and their impact on 10-year all-cause
mortality: the FINE study (Finland, Italy, Netherlands, Elderly).
J Clin Epidemiol. 2001;54:680-686.
33. Disegni E, Goldbourt U, Reicher-Reiss H, et al. The predictive
value of admission heart rate on mortality in patients with acute
myocardial infarction. J Clin Epidemiol. 1995;48:1197-1205.
34. Andrews TC, Fenton T, Glasser SP, et al. Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian
distribution and response to anti-ischemic medication. The Angina and Silent Ischemia Study Group (ASIS). Circulation.1993;88:
92-100.
35. Disegni E, Goldbourt U, Reicher-Reiss H, Kaplinsky E, Zion M,
Boyko V, Behar S. The predictive value of admission heart rate
on mortality in patients with acute myocardial infarction. J Clin
Epidemiol. 1995;48:1197-1205.
36. Kjekshus JK. Importance of heart rate in determining betablocker efficacy in acute and long-term acute myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F.
37. Kjekshus J. Heart rate reduction-a mechanism of benefit? Eur
Heart J. 1987;8(suppl L):115-122.
38. Braunwald E. Expanding indications for beta-blockers in
heart failure. N Engl J Med. 2001;344:1711-1712.
39. 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.
40. Heidland UE, Strauer BE. Left ventricular muscle mass and
elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104:1477-1482.
41. Sa Cunha R, Pannier B, Benetos A, et al. Association between
high heart rate and high arterial rigidity in normotensive and
222 MEDICOGRAPHIA, VOL 28, No. 3, 2006
Conclusion
Prognostic value of heart rate in cardiovascular disease – Tardif
IF I N
H I B I T I O N
hypertensive subjects. J Hypertens. 1997;15:1423-1430.
42. Patel S, Breall J, Diver D, et al. Bradycardia is associated with
development of coronary collateral vessels in humans. Coron
Artery Dis. 2000;11:467-471.
43. Palatini P, Julius S. Association of tachycardia with morbidity and mortality: pathophysiological considerations. J Hum Hypertens. 1997;11(suppl 1):S19-S27.
44. Stern MP, Morales PA, Haffner SM, et al. Hyperdynamic circulation and the insulin resistance syndrome (“syndrome X”).
Hypertension. 1992;20:802-808.
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45. Festa A, D'Agostino R Jr, Hales CN, et al. Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic
subjects. Diabetes Care. 2000;23:624-628.
46. Facchini FS, Stoohs RA, Reaven GM. Enhanced sympathetic nervous system activity. The linchpin between insulin resistance, hyperinsulinemia, and heart rate. Am J Hypertens.1996;9
(10 pt 1):1013-1017.
47. Grynberg A, Ziegler D, Rupp H. Sympathoadrenergic overactivity and lipid metabolism. Cardiovasc Drugs Ther. 1996;10(suppl 1):223-230.
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.
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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
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✪ 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
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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
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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
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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
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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
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2 weeks
AR
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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
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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
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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
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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
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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
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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
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9. Pino R, Cerbai E, Calamai G, et al. Effect of 5-HT4 receptor
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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.
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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.
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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
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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
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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
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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
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%
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
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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
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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
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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. ❒
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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-
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, H
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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
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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.
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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
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IF I N
H I B I T I O N
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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.
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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
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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
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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
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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
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IF I N
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INHIBITION IF :
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,
A N D
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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
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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
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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
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RAT
E
,
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DI
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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
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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
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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
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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
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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?
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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.
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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
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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,
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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.
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21. Thadani U. Treatment of stable angina. Curr Opin
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22. Heidenreich PA, MacDonald KM, Hastie T, et al.
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23. Kernis SJ, Harjai KJ, Stone GW, et al. Does betablocker therapy improve clinical outcomes of acute
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24. Turnbull F. Blood Pressure Lowering Treatment
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25. Münzel T, Sayegh H, Freeman BA, Tarpey MM,
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26. McGillion M, Watt-Watson J, Kim J, Yamada J. A
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trials for the management of chronic stable angina.
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27. Barlow JH, Shaw KL, Harrison K. Consulting the
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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
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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.
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33. Sullivan MD, LaCroix AZ, Russo JE, Walker EA.
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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.
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37. Dunn KM, Croft PR, Hackett GI. Sexual problems:
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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
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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
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46. Close CF, Ryder REJ. Impotence in diabetes mellitus. Diabet Metabol Rev. 1995;11:279-285.
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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
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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
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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
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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
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◆ 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
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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
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14. De Backer G, Ambrosioni E, Borch-Johnsen K,
et al. European guidelines on cardiovascular disease
prevention in clinical practice: third joint task force
of European and other societies on cardiovascular disease prevention in clinical practice (constituted by
representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil.2003;10:S1-S10.
15. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III
Guidelines. J Am Coll Cardiol. 2004;44:720-732.
16. No authors listed. MRC/BHF Heart Protection
Study of cholesterol lowering with simvastatin in
20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:7-22.
17. 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.
18. Sacks FM, Tonkin AM, Shepherd J, et al. Effect of
pravastatin on coronary disease events in subgroups
defined by coronary risk factors: the Prospective
Pravastatin Pooling Project. Circulation. 2000;102:
1893-1900.
19. Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of
cardiovascular events and death with pravastatin in
they are well tolerated and not contraindicated.2 In
such cases, other agents can be added as necessary.
A number of newer agents, such as the If inhibitors,
have recently been introduced to the armamentarium and should help to further combat anginal
symptoms. ❒
patients with coronary heart disease and a broad range
of initial cholesterol levels. N Engl J Med. 1998;339:
1349-1357.
20. LaRosa JC, Grundy SM, Waters DD, et al. Intensive
lipid lowering with atorvastatin in patients with stable
coronary disease. N Engl J Med. 2005;352:1425-1435.
21. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease
(PROSPER): a randomised controlled trial. Lancet.
2002;360:1623-1630.
22. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma
concentration of C-reactive protein. The Cholesterol
and Recurrent Events (CARE) Investigators. Circulation. 1999;100:230-235.
23. Colhoun HM, Betteridge DJ, Durrington PN, et
al. Primary prevention of cardiovascular disease with
atorvastatin in type 2 diabetes in the Collaborative
Atorvastatin Diabetes Study (CARDS): multicentre
randomised placebo-controlled trial. Lancet. 2004;
364:685-696.
24. Shepherd J. Combined lipid lowering drug therapy for the effective treatment of hypercholesterolaemia. Eur Heart J. 2003;24:685-689.
25. Fox KM; 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.
26. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in
high-risk patients. The Heart Outcomes Prevention
Evaluation Study Investigators. N Engl J Med. 2000;
342:145-153.
27. Braunwald E, Domanski MJ, Fowler SE, et al.
Angiotensin-converting-enzyme inhibition in stable
coronary artery disease. N Engl J Med. 2004;351:20582068.
28. Faggiotto A, Paoletti R. State-of-the-Art lecture.
Statins and blockers of the renin-angiotensin system:
vascular protection beyond their primary mode of action. Hypertension. 1999;34:987-996.
29. Lonn EM, Yusuf S, Jha P, et al. Emerging role of
angiotensin-converting enzyme inhibitors in cardiac
and vascular protection. Circulation. 1994;90:20562069.
30. Standards of medical care for patients with diabetes
mellitus. Diabetes Care. 2003;26(suppl 1):S33-S50.
31. Yusuf S, Wittes J, Friedman L. Overview of results
of randomized clinical trials in heart disease. I. Treatments following myocardial infarction. JAMA. 1988;
260:2088-2093.
32. Freemantle N, Urdahl H, Eastaugh J, Hobbs FD.
What is the place of beta-blockade in patients who
have experienced a myocardial infarction with preserved left ventricular function? Evidence and (mis)interpretation. Prog Cardiovasc Dis. 2002;44:243-250.
33. Pepine CJ, Cohn PF, Deedwania PC, et al. Effects
of treatment on outcome in mildly symptomatic patients with ischemia during daily life. The Atenolol
Silent Ischemia Study (ASIST). Circulation.1994;90:
762-768.
34. Rehnqvist N, Hjemdahl P, Billing E, et al. Effects
of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J. 1996;17:76-81.
35. Dargie HJ, Ford I, Fox KM. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and
treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable
New European guidelines for the treatment of stable angina – Daly and Fox
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angina. The TIBET Study Group. Eur Heart J.1996;
17:104-112.
36. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention
of coronary heart disease in postmenopausal women.
Heart and Estrogen/progestin Replacement Study
(HERS) Research Group. JAMA. 1998;280:605-613.
37. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;
288:49-57.
38. Rossouw JE, Anderson GL, Prentice RL, et al.
Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results From the
Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
39. Manson JE, Hsia J, Johnson KC, et al. Estrogen
plus progestin and the risk of coronary heart disease.
N Engl J Med. 2003;349:523-534.
40. Mosca L, Appel LJ, Benjamin EJ, et al. Evidencebased guidelines for cardiovascular disease prevention
in women. Circulation. 2004;109:672-693.
41. Tolins M, Weir EK, Chesler E, Pierpont GL. “Maximal” drug therapy is not necessarily optimal in chronic angina pectoris. J Am Coll Cardiol. 1984;3:10511057.
42. Jackson G. Stable angina: maximal medical therapy is not the same as optimal medical therapy. Int
J Clin Pract. 2000;54:351.
43. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/
ACP-ASIM guidelines for the management of patients
with chronic stable angina: a report of the American
College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee on
Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 1999;33:2092-2197.
44. Savonitto S, Ardissino D. Selection of drug therapy in stable angina pectoris. Cardiovasc Drugs Ther.
1998;12:197-210.
45. Thadani U. Treatment of stable angina. Curr Opin
Cardiol. 1999;14:349-358.
46. Kerins DM, Robertson RM, Robertson D. Drugs
used for the treatment of myocardial ischemia. In:
Hardman JG, Limbird LE, Gilman AG, eds. Goodman
and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw Hill. 2001:
843-870.
47. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled
trial. JAMA. 2004;292:2217-2225.
48. Hjemdahl P, Wallen NH. Calcium antagonist treatment, sympathetic activity and platelet function. Eur
Heart J. 1997;18(suppl A):A36-A50.
49. Waters D. Proischemic complications of dihydropyridine calcium channel blockers. Circulation. 1991;
84:2598-2600.
50. Karlson BW, Emanuelsson H, Herlitz J, Nilsson
JE, Olsson G. Evaluation of the antianginal effect of
nifedipine: influence of formulation dependent pharmacokinetics. Eur J Clin Pharmacol.1991;40:501-506.
51. Packer M, O’Connor CM, Ghali JK, et al. Effect of
amlodipine on morbidity and mortality in severe
chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J
Med. 1996;335:1107-1114.
52. Ardissino D, Savonitto S, Egstrup K, et al. Selection of medical treatment in stable angina pectoris:
results of the International Multicenter Angina Exercise (IMAGE) Study. J Am Coll Cardiol.1995;25:15161521.
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53. Forslund L, Hjemdahl P, Held C, et al. Prognostic
implications of results from exercise testing in patients with chronic stable angina pectoris treated with
metoprolol or verapamil. A report from the Angina
Prognosis Study In Stockholm (APSIS). Eur Heart J.
2000;21:901-910.
54. von Arnim T. Medical treatment to reduce total ischemic burden: total ischemic burden bisoprolol study
(TIBBS), a multicenter trial comparing bisoprolol and
nifedipine. The TIBBS Investigators. J Am Coll Cardiol. 1995;25:231-238.
55. Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ.
The Total Ischaemic Burden European Trial (TIBET).
Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET
Study Group. Eur Heart J. 1996;17:96-103.
56. Heidenreich PA, McDonald KM, Hastie T, et al.
Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA.
1999;281:1927-1936.
NOUVELLES
57. Kanamasa K, Hayashi T, Takenaka T, Kimura A,
Ikeda A, Ishikawa K. Continuous long-term dosing
with oral slow-release isosorbide dinitrate does not
reduce incidence of cardiac events in patients with
healed myocardial infarction. Clin Cardiol. 2001;24:
608-614.
58. Markham A, Plosker GL, Goa KL. Nicorandil. An
updated review of its use in ischaemic heart disease
with emphasis on its cardioprotective effects. Drugs.
2000;60:955-974.
59. Borer JS, Fox K, Jaillon P, Lerebours G. 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.
60. 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;26:2529-2536.
61. Marzilli M, Klein WW. Efficacy and tolerability of
trimetazidine in stable angina: a meta-analysis of ran-
domized, double-blind, controlled trials. Coron Artery
Dis. 2003;14:171-179.
62. Chazov EI, Lepakchin VK, Zharova EA, et al.
Trimetazidine in Angina Combination Therapy—the
TACT study: trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. Am
J Ther. 2005;12:35-42.
63. Chaitman BR, Skettino SL, Parker JO, et al. Antiischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375-1382.
64. Chaitman BR, Pepine CJ, Parker JO, et al. Effects
of ranolazine with atenolol, amlodipine, or diltiazem
on exercise tolerance and angina frequency in patients
with severe chronic angina: a randomized controlled
trial. JAMA. 2004;291:309-316.
65. Messin R, Opolski G, Fenyvesi T et al. 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
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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
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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
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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
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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
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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
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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.
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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
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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
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T
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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
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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.
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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
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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
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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
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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.
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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.
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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.
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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.
✦
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(including spaces) double-spaced, 2.5-cm margins = a total of
about 320 words per page.
N All texts should be submitted in English.
N Provide 1 color photograph of main author.
N On the title page, provide: a title (concise and informative); full
names of authors (first name, middle name initial, and last name);
highest academic degrees (in country-of-origin language); affiliations (names of department[s] and institution[s] at the time the work
was done); a short running title (no more than 50 letters and spaces),
keywords (5-10); corresponding author’s complete mailing address
and telephone No., fax No., and e-mail address; acknowledgments
(on title page, or at end of main text).
N Include an Abstract of 200-230 words for all texts except Editorials and replies to the Controversial Question.
N Figures and Tables. Figures should be of good quality or professionally prepared, numbered according to their order, with proper
orientation indicated (eg, "top," or "left"). Figures may be provided
as pdf files (printing resolution = 300 dpi scans, on CDrom, or via
e-mail; screen resolution = 72 dpi scans acceptable only if largesized format [A4]). Provide fully explicit legends, not repetitive of
text. All abbreviations used should be explained in the legends. As
figures and graphs may need to be reduced or enlarged, all absolute
values and statistics should be provided. Illustrations will be reproduced in full color only when clearly necessary, eg, images from nuclear medicine or histology. Provide each table on a separate sheet,
with title above and description below. All figures and tables should
be cited in the text, with distinct numbering for figures and tables.
N Note that Editorials and Abstracts will be published in English
and French. Translations into French will be provided by the Publisher’s Editorial Department.
N Include Headings using a consistent style for the various levels
of headings, to highlight key points and facilitate comprehension of
the text. The Editorial Department reserves the right to add or delete
headings when necessary.
N Abbreviations should be used sparingly and expanded at first
mention. A list of selected abbreviations and acronyms should be
provided (or will be prepared by the Editorial Department) where
necessary.
N Use Système International (SI) units.
N Use generic names of drugs.
N All references should be cited in the text and numbered consecutively using superscript arabic numerals. Presentation of the
references should be based on the Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Ann Intern Med. 1997;
126:36-47 (“Vancouver style”). The author-date system of citation
is NOT acceptable. In press references are to be avoided. In the
bibliography, titles of journals should be abbreviated according to
the Index Medicus. All authors should be listed up to six; if there
are more, only the first three should be listed, followed by “et al.”
Where necessary, references will be styled by the Editorial Department to Medicographia copyediting requirements. Authors bear
total responsibility for the accuracy and completeness of all references and for correct text citation. Example of style for references:
1. Ouriel K, Geary K, Green RM, Geary JE, DeWeese JA. Factors
determining survival after ruptured abdominal aneurysm. J Vasc Surg.
1990;11:493-496.
2. Darling RC, Brewster DC, Ottinger LW. Autopsy study of unoperated abdominal aortic aneurysms: the case for early resection.
Circulation. 1977;56(suppl II):II161-II164.
3. Schulman JL. Immunology of influenza. In: Kilbourne ED, Alfade
RT, eds. The Influenza Viruses and Influenza. Orlando, Fla: Academic
Press Inc; 1975:373-393.
Specific formats
N Editorial: 1500 words. No abstract or illustrations should be includ-
ed. A French translation of the Editorial will be provided by the Editorial Department and submitted to the author.
N Theme - Focus - Update - Therapeutic outlook article - Touch
of France: Abstract: 200-230 words. Main text: 2800-3200 words.
References: their number should not exceed 50. Illustrations (figures and tables): their number should not exceed 5 unless clearly
necessary.
N Interview: Abstract: 200-230 words. Main text: 2000-2500 words.
Headings are the questions posed at the interview. References, if
cited, should in no case exceed 10. No illustrations.
N Replies to the Controversial Question: 400-600 words. No abstract or illustrations should be included. References, if cited, should
in no case exceed 6.
Editorial processing
N Editorial style: All contributions to Medicographia will be styled
by the Editorial Department according to the specifications of the current edition of the American Medical Association Manual of Style,
Williams & Wilkins.
N Page proofs and editorial queries will be sent to the corresponding author for approval. Corrections should be returned within 48
hours by e-mail, and fax or express mail. If this deadline is not met,
changes made by the Editorial Department will be assumed to be
accepted by the author. Authors are responsible for all statements
made in their work, including changes made by the Editorial Department and authorized by the author. Articles and abstracts will be edited to required length or returned to the author if specific requirements
are not complied with.
Copyright
N Copyright of articles will be transferred to the Publisher of Medicographia. The Copyright Transfer Agreement must be signed by the
main author and all coauthors and returned to the Publisher.
N For reproduction of copyrighted work, it is the author’s responsibility to obtain authorizations from the author(s) (including self) and
the publisher(s) and provide copies of these authorizations with the
manuscript.