* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Heart Failure with Preserved Ejection Fraction
Survey
Document related concepts
Saturated fat and cardiovascular disease wikipedia , lookup
Management of acute coronary syndrome wikipedia , lookup
Cardiovascular disease wikipedia , lookup
Remote ischemic conditioning wikipedia , lookup
Mitral insufficiency wikipedia , lookup
Coronary artery disease wikipedia , lookup
Hypertrophic cardiomyopathy wikipedia , lookup
Rheumatic fever wikipedia , lookup
Electrocardiography wikipedia , lookup
Antihypertensive drug wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Dextro-Transposition of the great arteries wikipedia , lookup
Quantium Medical Cardiac Output wikipedia , lookup
Transcript
Brutsaert.qxp 4/7/08 5:24 pm Page 31 Heart Failure Heart Failure with Preserved Ejection Fraction a report by G i l l e s W D e K e u l e n a e r and D i r k L B r u t s a e r t Department of Pharmacology, University of Antwerp Definitions and Historical Considerations – patients, measurements of LV ejection fraction do not allow for The Misleading Role of Ejection Fraction exclusion of any of these factors. Accordingly, rather than being two Chronic heart failure (CHF) is a heterogeneous syndrome with a separate identities, systolic and diastolic heart failure may be more complex pathophysiology. Although many different definitions for closely related than previously thought. In fact, it is preferable to heart failure exist, we prefer the following: “a clinical syndrome envisage CHF as a syndrome with a spectrum of diverse clinical characterised by symptoms and signs of increased tissue/organ water presentations, in which most if not all cases are hybrids of diastolic and decreased tissue/organ perfusion. Regardless of its aetiology, and systolic heart failure (see Figure 1). The misleading connotations symptoms and signs may be related either to impaired left ventricular of systolic and diastolic heart failure should be abandoned to avoid (LV) relaxation, suction and filling (predominantly diastolic pump biased clinical and scientific approaches. dysfunction/failure) or to impaired output of the cardiac compression pump (predominantly systolic pump dysfunction/failure) but almost Systolic Abnormalities in Heart Failure with Preserved always to a combination of both.”1 Ejection Fraction – The Heart as a Muscular Pump The recent unveiling of LV systolic dysfunction at normal LV ejection This definition of heart failure refrains from including any notion of LV fraction by tissue Doppler imaging, magnetic resonance imaging (MRI) ejection fraction. However, mostly driven by clinical trial design, heart and speckle tracking is surprising at first glance. Nevertheless, these failure has been dichotomised according to ejection fraction as observations are just a reminder that LV ejection fraction is an index of ‘preserved’ (heart failure with preserved ejection fraction [HFpEF]) or global haemodynamic pump performance, insensitive to disturbances ‘reduced’ (heart failure with reduced ejection fraction [HFredEF]). of ventricular muscle function1 (see Figure 2). A preserved ejection Recently, epidemiological surveys have revealed that the incidence of fraction often merely indicates that the radial (or circumferential) fibres of HFpEF has been steadily increasing over the past 25 years.2 Currently, the ventricle have compensated for dysfunction of the longitudinal fibres; the LV ejection fraction is found to be preserved in >50% of cases of it does not necessarily imply that the systolic function of the muscular heart failure. Patients with HFpEF appear to be older and are more pump is normal. These considerations may have important diagnostic likely to be female, have a history of hypertension and have less implications, since impaired longitudinal fibre function may be the single coronary artery disease. Once hospitalisation for ‘decompensation’ has or most marked sign of cardiac dysfunction in HFpEF. Systolic impairment occurred, the cardiovascular mortality and overall prognosis is as poor of longitudinal fibre shortening strongly correlates with impairment of as for HFredEF. longitudinal fibre re-lengthening and with expression of brain natriuretic 2,3 peptide (BNP) messenger RNA (mRNA) in subendocardial LV layers.11 Erroneously, the pathophysiology of HFpEF and HFredEF were considered to be genuinely different. Whereas HFredEF was correlated with mere ‘systolic abnormalities’, these abnormalities were believed to be absent in HFpEF. Instead, when ejection fraction was preserved, heart failure was correlated with ‘diastolic abnormalities’, and was thought to occur without abnormalities in systole. Inevitably, the connotations ‘systolic’ and ‘diastolic’ heart failure were introduced as they were estimated to reflect distinct diseases. However, recent observations have neglected to refine this view.4,5 Most importantly, it Gilles W De Keulenaer is a cardiologist at Middelheim Hospital, where he serves as Director of the Centre for Heart Failure and Cardiac Rehabilitation. He also serves as a Professor of Physiology in the Department of Pharmacology at the University of Antwerp. His core research interests include physiological and molecular aspects of myocardial and ventricular function, with a specific focus on endothelial–cardiomyocyte cell communication. E: [email protected] is now generally recognised that in systolic heart failure LV diastolic abnormalities are profound, and predict a patient’s symptoms better than systolic (dys)function.6 In contrast, in diastolic heart failure there are marked, previously overlooked LV systolic abnormalities, as revealed by novel cardiac imaging techniques. 7 In fact, CHF, irrespective of ejection fraction (even when preserved), is emerging as a syndrome in which many pathophysiological processes interact. These processes include systolic dysfunction,7 diastolic dysfunction,6 circulatory volume overload,8 disturbed ventriculo-arterial coupling9 and activation of neurohormonal systems.10 Although the relative Dirk L Brutsaert is a Professor-Emeritus in the Department of Pharmacology at the University of Antwerp. Between 1966 and 2002 he served as a Professor of Physiology and Medicine in the Department of Medicine at the University of Antwerp; from 1981 to 2002 he was Co-Chairman of the Department of Cardiology at University Hospital Antwerp; and he was an Honorary Consultant in the Department of Cardiology at AZ Middelheim Hospital, University of Antwerp, until 2006. Professor Brutsaert is Past President of the Heart Failure Association of the European Society of Cardiology (ESC) and of the Royal Academy of Medicine of Belgium (both 2004–2006). contribution of each of these factors may vary among individual © TOUCH BRIEFINGS 2008 31 Brutsaert.qxp 4/7/08 5:24 pm Page 32 Heart Failure phenomenon, and it is influenced by many patient characteristics Figure 1: Phenotypic Diversity of Chronic Heart Failure acting as ‘disease modifiers’. LV remodelling, when quantified as cardiomyocyte diameter, covers a wide, continuous spectrum over the Cardiac insult whole range of LV ejection fraction.12 The ‘modifiers’ that influence LV LVEF preserved LVEF reduced Slight NYHA remodelling include haemodynamic load, coronary arterial function, Moderate Severe NYHA Disease modifiers I Indi II vidu a l pa III tien t tra ject IV ory gender, age, metabolic disturbances (obesity, diabetes), physical I fitness, cardiac endothelial function and genetic background, which II may either promote or decelerate remodelling. Future unravelling of III the cellular, molecular and biochemical puzzle of LV remodelling may IV reveal how these modifiers propel heart failure diversity over a wide spectrum of closely related disease phenotypes.4 ‘Diastolic’ heart failure ‘Systolic’ heart failure Spectrum of phenotypes Mechanisms of Left Ventricular Diastolic Dysfunction Community LVEF >50% CHARM – ‘preserved’ LVEF >40% MERIT-HF LVEF >40% 73 40 23 Female (%) Diastolic LV dysfunction is very common in, but not specific for, HFpEF. It often co-exists with – or is even caused by – other cardiovascular Hypertension (%) 78 64 44 abnormalities such as systolic LV dysfunction, arterial stiffening and Diabetes (%) 46 28 25 volume overload. More specifically, diastolic LV dysfunction is a Chronic heart failure (CHF) is a syndrome progressing along different time trajectories, and is unique to each patient. During progression, disease severity and symptoms increase with variable changes on left ventricular (LV) remodelling and, hence, on LV ejection fraction. The heart failure disease trajectory is influenced by numerous patient characteristics that function as ‘disease modifiers’. These modifiers include diabetes, arterial hypertension and female gender, which promote disease progression without eccentric LV remodelling and, hence, a preserved ejection fraction. This phenomenon leads to increasing incidences of these modifiers in clinical trials and heart failure surveys when LV ejection fraction in the inclusion criteria becomes higher (lower part of figure). consequence of impaired LV suction due to impaired LV systolic relaxation and reduced LV diastolic compliance.13 Causes of impaired relaxation are related to factors intrinsic and extrinsic to cardiomyocytes. The intrinsic factors include impaired inactivation processes (disturbed intracellular calcium homeostasis, myofilament function and cell energetics), whereas the extrinsic factors include Figure 2: Subdivision of the Cardiac Cycle Taking Ventricular Haemodynamic Pump and Ventricular Muscular Pump Approaches pressure volume overload, ventricular dyssynchrony and abnormal activity of soluble cardio-active factors (angiotensin, endothelin, nitric oxide). Decreased compliance of the LV is due to extracellular matrix or Haemodynamic compression pump Muscular pump Diastole Aorta Systole cytoskeletal abnormalities. Interestingly, none of the above mechanisms of diastolic dysfunction seems to be specific for HFpEF or HFredEF, V P F Superficial longitudinal fibres Inner longitudinal fibres Inner horizontally looping fibres Papillary muscle Vortex cordis although there is emerging evidence that passive forces and resting tension of cardiomyocytes from patients with HFpEF are higher than those from patients with non-ischaemic HFredEF.12 Clinical Aspects of Heart Failure with Preserved Ejection Fraction Wiggers (1883–1963) P Brutsaert et al. (1964–) Pump f Muscle Diagnosis 1 The clinical symptoms and signs of patients with HFpEF are the same Pump P V Systole t 4 1 2 3 Diastole HFpEF = diastolic failure P V as for those with HFredEF. During diagnosis, the finding of a normal t 4 3 Systole Diastole HFpEF = systolo-diastolic failure P 1 ejection fraction obviously should not be used to doubt the clinical diagnosis of heart failure. Recently, the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has proposed novel diagnostic guidelines for heart failure when LV ejection fraction is preserved14 (see Figure 3). Within these guidelines, blood flow Doppler, tissue Doppler, serum BNP or N-terminal proBNP (NT-pro-BNP) concentrations and atrial diameters play a central role. 2 3 4 V 3 4 V The predictive values of BNP and NT-pro-BNP are still too vague to use as the gold standard for diagnosis in individuals, but certainly reflect Left: Wiggers’ traditional subdivision of the cardiac cycle with systole ending slightly before aortic valve closure. Right: novel insight since the early 1960s into the intracellular physiological and pathophysiological mechanisms of the heart as a muscular pump, which were obviously unknown in the Wiggers era, have logically led to reconsidering the traditional Wiggers subdivision of the cardiac cycle. The figure compares the time traces (t) of an the severity of disease when used in cohorts of HFpEF patients. In the absence of atrial fibrillation, left atrial size provides morphological and physiological evidence of chronic elevation in LV filling pressures. afterloaded twitch in cardiac muscle (f = force; l = length) with the synchronised time traces of pressure (P) and volume (V) of a ventricular haemodynamic pump. The similarity between the corresponding time traces has led to the inclusion of isovolumic relaxation into systole of a ventricular muscular pump. Accordingly, the definition of heart failure with preserved ejection fraction (HFpEF) as a systolo-diastolic disease, instead of a disease of isolated diastolic function, depends on the acceptance of the function of the heart as a ventricular muscular pump. Treatment of Heart Failure with Preserved Ejection Fraction Randomised multicentre trials in patients with HFpEF are scarce. Therefore, The diversity of CHF does not reside in the presence or absence of the recommendations for the management of HFpEF are based on small systolic or diastolic dysfunction, but rather in the degree and type of clinical studies lacking a pathophysiological concept and validated diagnostic LV remodelling, developed along the pathophysiological progression guidelines. Treatment of HFpEF should have two essential goals: reducing of the disease. However, LV remodelling is not an all or nothing symptoms and improving prognosis by targeting the mechanisms of disease. 32 EUROPEAN CARDIOLOGY Brutsaert.qxp 30/7/08 3:47 pm Page 33 Heart Failure with Preserved Ejection Fraction Symptom-targeted Treatment Reducing the symptoms of individual patients with HFpEF can be Figure 3: Diagnostic Flow Chart for Heart Failure with Preserved Ejection Fraction challenging as they may be multifactorial. For example, exertional How to diagnose HFpEF? dyspnoea, the most common symptom of HFpEF, can be caused by increased LV diastolic pressures or reduced cardiac (chronotropic) reserve, Symptoms or signs of heart failure 1 but also by peripheral deconditioning. Optimising therapy in HFpEF is often a matter of trial and error, and can be frustrating when arterial blood pressure is normal. Diastolic LV pressure can be reduced by 2 Preserved haemodynamic pump performance: LVEF >50%, LVEDVI >97ml/m2 decreasing circulatory or LV volume (with diuretics, venodilators or neurohormonal inhibitors), reducing heart rate to normal, reducing blood pressure and maintaining synchronous atrial contraction. As treatment 3 Dysfunction of muscular pump performance resulting in impaired relaxation, suction and filling with diuretics can vary substantially, it may be appropriate to start at a relatively low dosage, since a small change in diastolic volume may cause a large change in pressure and cardiac output, and may lead to hypotension. Blood pressure lability is often noted in HFpEF, not only due to passive ventricular stiffening, but also due to arterial stiffening. Invasive haemodynamic measurements: mPCW >12mmHG or LVEDP >16mmHg or t >48ms or b >0.27 TD: E/E’ >15 15>E/E’>8 Biomarkers: NT-proBNP >220pg/ml or BNP >200pg/ml TD E/E’ >8 Reducing heart rate in HFpEF acts as a double-edged sword. On the one hand, it may have a beneficial impact on ischaemia-related diastolic dysfunction, and may avoid the problem of incomplete relaxation seen at high heart rates. On the other hand, blunting exercise-induced increases Biomarkers: NT-proBNP >220pg/ml or BNP >200pg/ml in heart rate may also inappropriately impair an important mechanism of Echo – bloodflow Doppler E/A >50yr <0.5 and DT >50yr >280ms or Ard-Ad >30ms or LAVI >40ml/m2 or LVMI >122 g/m2 ( ): > 149g/m2 ( ) or atrial fibrillation the (hypertrophic) heart to increase cardiac output, especially as some of these hearts manifest a small recruitable inotropic and preload reserve, and thus rely on chronotropy for adaptations of cardiac output to HFpEF peripheral demands.15 Consistent with the conceptual physiological considerations explained in Figure 2 and throughout the article, Mechanism-targeted Treatment the diagnostic criteria of heart failure with preserved ejection fraction (HFpEF) include the clinical demonstration Randomised clinical trials on mechanism-targeted treatment in HpEF have of a normal haemodynamic pump performance and a dysfunctional muscular pump performance. The latter can be realised by invasive haemodynamic measurements, cardiac imaging techniques or using serum biomarkers. been slow to develop. Thus far, none of the trials specifically targeting HFpEF has shown a significant effect of either digoxin, Perindopril for Elderly Persons with CHF (PEP-CHF) trial, a study in elderly angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor people with rather milder degrees of HFpEF (mean LV ejection fraction inhibitors on overall mortality. In the Digitalis Investigation Group (DIG), in 65%), perindopril did not reduce overall mortality, perhaps because of low those with ejection fraction >45% and ancillary sinus rhythm digoxin event rates (4% per year), but significantly reduced hospitalisations for heart induced a significant reduction in heart failure hospitalisations, but also a failure.17 Of note, in some recent heart failure trials, inclusion criteria no trend towards more hospitalisations for non-heart failures. In the longer include limitations for ejection fraction, thereby studying heart failure Candesartan in Heart Failure Assessment of Reduction in Mortality and over the whole spectrum of ejection fraction. In one of such trials, the of the Morbidity (CHARM)-preserved trial (heart failure with LV ejection fraction Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in higher than 40%, but patient characteristics strongly diverging from HFpEF Seniors With Heart Failure (SENIORS) trial, nebivolol reduced the composite patients in the community), candesartan had a moderate but significant end-point of death or cardiovascular hospitalisation, but the modest trend impact on preventing hospital admissions for heart failure.16 Similarly, in the towards improved mortality did not reach statistical significance.18 ■ 1. 2. 3. 4. 5. 6. 7. Brutsaert DL, Cardiac dysfunction in heart failure: the cardiologist’s love affair with time, Prog Cardiovasc Dis, 2006;49:157–81. Owan TE, Hodge DO, Herges RM, et al., Trends in prevalence and outcome of heart failure with preserved ejection fraction, N Engl J Med, 2006;355:251–9. Fonarow GC, Stough WG, Abraham WT, et al., OPTIMIZE-HF Investigators and Hospitals. Characteristics, treatments and outcomes of patients with preserved systolic function hospitalized for heart failure, J Am Coll Cardiol, 2007;50: 768–77. De Keulenaer GW, Brutsaert DL, Systolic and diastolic heart failure: different phenotypes of the same disease, Eur J Heart Fail, 2007;9:352–6. Brutsaert DL, De Keulenaer GW, Diastolic heart failure: a myth, Curr Opin Cardiol, 2006;21:240–48. Skaluba SJ, Litwin SE, Mechanisms of exercise intolerance: insights from tissue Doppler imaging, Circulation, 2004;109: 972–7. Sanderson JE, Heart failure with a normal ejection fraction, Heart, 2007;93:155–8. EUROPEAN CARDIOLOGY 8. 9. 10. 11. 12. 13. Maurer MS, Burkhoff D, Fried LP, et al., The cardiovascular health study: Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction, J Am Coll Cardiol, 2007;49:972–81. Kawaguchi M, Hay I, Fetics B, Kass DA, Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations, Circulation, 2003;107:714–20. Kitzman DW, Little WC, Brubaker PH, et al., Pathophysiological characterization of isolated diastolic heart failure in comparison of systolic heart failure, JAMA, 2002;288:2144–50. Prestle J, Dieterich S, Preuss M, et al., Heterogeneous transmural gene expression of calcium-handling proteins and natriuretic peptides in the failing human heart, Cardiovasc Res, 1999;43:323–31. van Heerebeek L, Borbély A, Niessen HW, et al., Myocardial structure and function differ in systolic and diastolic heart failure, Circulation, 2006;113:1966–73. De Keulenaer GW, Brutsaert DL, Molecular Mechanisms of Diastolic Dysfunction. In: Smiseth O, Tendera M (eds), Diastolic Heart Failure, Springer, 2008;3–21. 14. Paulus WJ, Tschöpe C, Sanderson JE, et al., How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology, Eur Heart J, 2007;28:2539–50. 15. Borlaug BA, Melenovsky V, Russell SD, et al., Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction, Circulation, 2006:114:2138–47. 16. Yusuf S, Pfeffer MA, Swedberg K, et al., Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial, Lancet, 2003;362:777–81. 17. Cleland JG, Tendera M, Adamus J, et al., PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study, Eur Heart J, 2006;27:2338–45. 18. Flather MD, Shibata MC, Coats AJ, et al., SENIORS Investigators, 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;26:215–25. 33