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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

What does the future hold for the management of chronic heart failure?

Emilio Vanoli^1,2,3,* and Philip B. Adamson³

¹ Department of Cardiology, University of Pavia and Policlinico S. Matteo IRCCS, Pavia, Italy
² Policlinico di Monza, Monza, Italy
³ University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

^* Corresponding author. Tel: +39 2382 503 934; fax: +39 2545 76 66. E-mail address: evanoli{at}compuserve.com

	Abstract

Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 
Sudden cardiac death (SCD) represents a major challenge in managing chronic heart failure (CHF). There is extensive evidence of the antifibrillatory action of beta-blockers and their ability to prevent SCD in patients with CHF and left ventricular (LV) dysfunction following myocardial infarction (MI). In contrast, angiotensin-converting enzyme-inhibitors have minimal effects on SCD risk, reducing mortality primarily by preventing or delaying pump failure. The mechanisms by which beta-blockers reduce lethal arrhythmias and thereby prevent SCD mostly reflect blockade of the beta₁-subtype. Dog models have been used to investigate ventricular remodelling and arrhythmogenesis after MI; dogs with chronic ischaemic LV dysfunction susceptible to SCD have depressed vagal and elevated sympathetic control of heart rate coupled with abnormal repolarization. Furthermore, susceptibility to SCD appears to be associated with non-uniform catecholamine release within the left ventricle. Cardiac nerve sprouting and sympathetic hyperinnervation consequent to ischaemic neural damage are important co-factors causing ventricular electrical dyshomogeneity and, thus, malignant tachyarrhythmias and SCD. Regulating nerve growth factor and growth-associated protein 43 expression after MI might provide a means of controlling arrhythmias and preventing SCD. An intriguing possibility might be the prevention of cardiac norepinephrine spillover by means of gene therapy to increase expression of the norepinephrine transporter molecule uptake-1. At this stage, the evidence from clinical trials, and especially that from Cardiac Insufficiency Bisoprolol Study III, strongly supports the use of selective beta-adrenergic blockade as a primary intervention in the management of patients with CHF.

Key Words: Heart failure • Sudden death • Autonomic nervous system • Adrenergic blockade

	Introduction

Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 
Prevention of sudden cardiac death (SCD) remains one of the greatest challenges in managing chronic heart failure (CHF). SCD is usually defined as death due to cardiac causes, with loss of consciousness within 1 h of the onset of acute symptoms. It accounts for half of all cardiac deaths in the industrialized countries,¹ with up to 400 000 deaths annually in the USA alone.² Most cases of SCD are of arrhythmic origin, caused by the degeneration of ventricular tachycardia (VT) into ventricular fibrillation (VF). Most instances of sudden cardiac arrest occur out of hospital, and few of these individuals are resuscitated. For example, the Maastricht study showed that nearly 80% of sudden cardiac arrests occurred at home, with a witness present in 60% of cases.³ Although cardiac resuscitation was attempted in about half of all cases, survival rates for witnessed sudden cardiac arrest were 8% at home and 18% outside the home. These data underscore the need of adequate preventive strategies to attack SCD, a major challenge in cardiology.⁴

The risk of SCD is elevated six- to nine-fold in patients with CHF, compared with the general population.⁵ At present, 1–2% of the population has CHF and numbers continue to increase.⁶ The prevalence of SCD is therefore also likely to increase in the coming decades. Prevention of SCD, particularly in CHF patients, is therefore a critical public health issue. This review discusses the current status of SCD prevention in CHF, particularly with regard to beta-blockade, and highlights some promising areas of research that could lead to future treatment approaches.

	Prevalence of SCD in CHF

Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 
SCD accounts for more than half of all deaths in NYHA classes II and III, and in patients with left ventricular ejection fraction (LVEF) >21%, whereas progressive heart failure is more important in NYHA class IV^7,8 (Figure 1). An aspect of sudden death that is critical to understand is that, by definition, it is not preceded by warning events, even in patients with symptomatic CHF. A post hoc analysis of the Cardiac Insufficiency Bisoprolol Study (CIBIS) II trial demonstrated that only 20% of the patients who died suddenly during follow-up had worsening heart failure symptoms or warning hospitalization prior to the lethal event.⁹ In contrast, worsening heart failure symptoms and hospitalization preceded death in almost 90% of the patients who died of pump failure.¹⁰ Therefore, because warning symptoms are not present to identify patients at risk for impending sudden cardiovascular collapse, primary prevention of SCD must rely on identifying high-risk patients before their fatal event.

View larger version (11K): [in this window] [in a new window]   Figure 1 Prevalence of SCD in patients with varying severity of heart failure or LV dysfunction. SCD accounts for more than half of all deaths in NYHA classes II and III and in patients with mild to moderate LV impairment. Data from MERIT-HF Study Group7 and Cleland et al.8

 
Although SCD is often presumed to be due mainly to arrhythmias, myocardial infarction (MI) is also an important cause. Autopsies of patients who died suddenly in the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial showed that, among patients with coronary artery disease who died suddenly, about half had no specific pathology (i.e. these deaths were probably mainly arrhythmic in origin).¹¹ However, 42% had evidence of MI. A further 5% died of other cardiovascular causes (aortic dissection, cerebrovascular causes, or ruptured aortic aneurysm) and the remaining 2% of non-cardiovascular causes.

	Effect of beta-blockers on SCD in CHF

Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 
There is extensive experimental and clinical evidence documenting the protection offered by beta-blockade against SCD.

Studies in high-risk patients
Beta-blocker use was analysed retrospectively using data from the Antiarrhythmics Versus Implantable Defibrillator (AVID) trial, from a subgroup of 412 eligible, non-randomized patients who were not treated with specific antiarrhythmic therapy [amiodarone or an implantable cardioverter defibrillator (ICD)].¹² All of these patients were at high risk of SCD, with a history of VF or symptomatic VT. The risk of death was reduced by 53% in patients who received beta-blockers (P=0.018), compared with those who did not. In a study by Levine et al.¹³ ICD-implanted patients who received a beta-blocker were less likely to experience ICD discharge within the next 5 years than patients who did not receive beta-blockers.

Post-MI studies
Various post-MI studies have shown that beta-blockers reduce the risk of sudden death by 28–47% when compared with 3–26% for angiotensin-converting enzyme (ACE)-inhibitors. A meta-analysis of 31 secondary prevention trials of beta-blockade found that beta-blockers reduced the risk of re-infarction (a potential cause of SCD) by 28%.¹⁴

CHF and LV dysfunction trials
Several trials have demonstrated that beta-blocker therapy substantially decreases SCD risk in patients already receiving treatment with an ACE-inhibitor. When compared with the standard treatment, the addition of a beta-blocker reduced sudden death by 44% in the CIBIS II¹⁵ and by 41% in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF).⁷ A post hoc analysis of the Studies on Left Ventricular Dysfunction (SOLVD) Prevention trial in patients with LV dysfunction found that the combination of a beta-blocker and enalapril was associated with a synergistic reduction in the overall risk of death.¹⁶

In contrast, CHF and post-MI trials show that ACE-inhibitors reduce mortality primarily by inhibiting the progressive architectural changes leading to inefficient LV function and thus prevent or delay pump failure. No significant reduction in SCD with ACE-inhibitors was recorded in the Cooperative North Scandinavian Enalapril Survival Study,¹⁷ the SOLVD treatment trial,¹⁸ or the Survival and Ventricular Enlargement (SAVE) trial.¹⁹ There is, however, some evidence of a possible beneficial effect of ACE-inhibitors on SCD in post-MI patients from the Trandolapril Cardiac Evaluation (TRACE)²⁰ and Acute Infarction Ramipril Efficacy (AIRE)²¹ studies.

Given the importance of preventing SCD in the early stages of CHF, the results of CIBIS III^22,23 are particularly interesting. A post hoc analysis of data from the first year of CIBIS III showed that patients in whom the beta-blocker bisoprolol was initiated before the ACE-inhibitor enalapril were 31% less likely to die than patients in whom enalapril was initiated first (42 vs. 60 deaths; HR 0.69, 95% CI 0.46–1.02, between-group difference P=0.065). This trend might be explained by a reduction in SCD, although the results of the SCD analysis of CIBIS III have not yet been published. If the apparent benefit of a bisoprolol-first strategy on early mortality is attributable to a reduction in SCD, it might be argued that patients judged to be at high risk of SCD should receive a beta-blocker first.

	Relevance beta-receptor subclass

Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 
The effect of beta-blockers on SCD is probably related to beta₁-blockade. Beta₁-receptors account for about 77% of the adrenergic receptors in the non-failing human heart.²⁴ However, there is a relative redistribution of adrenergic receptors in the failing heart (Figure 2). Increased catecholamine stimulation results in selective down-regulation of the beta₁-receptor. In contrast, the number of beta₂-receptors on cardiomyocytes remains unaltered, and there is a small increase in alpha₁-receptors.²⁵

View larger version (10K): [in this window] [in a new window]   Figure 2 Changes in myocardial receptors in heart failure. Beta1-receptor down-regulation is the most dramatic change that occurs in the failing left ventricle. Data from Bristow.25

 
The neurotransmitter norepinephrine, the primary signalling molecule of neural cardiac adrenergic activity, is a powerful mediator of cardiac hypertrophy and myocardial damage in CHF. Norepinephrine has higher affinity for beta₁- than for beta₂-receptors or alpha₁-receptors; the relative potency of norepinephrine for beta₁:beta₂:alpha₁-receptors is 20:1:2. Thus, despite the receptorial remodelling occurring with HF, 88–90% of the total adrenergic receptor occupancy is of the beta₁-subtype, even at the high norepinephrine concentrations occurring in CHF (Table 1).²⁶

View this table: [in this window] [in a new window]   Table 1 Calculated receptor occupancy of adrenergic receptors by norepinephrine in the failing human heart

 
Transgenic animal studies show that beta₁-pathways have much greater cardiomyopathic potential than beta₂- and alpha₁-pathways. It requires approximately 10-fold greater expression of beta₂-receptors to achieve the same degree of cardiomyopathy when compared with beta₁-receptor expression.²⁶ Moreover, in the intact failing human heart, reversal of remodelling/dysfunction associated with deinduction of the foetal gene programme is mediated by beta₁-receptor blockade, with no obvious contribution by either the beta₂- or alpha₁-receptor pathways.²⁶ Such findings may explain why the mortality reductions obtained in placebo-controlled clinical trials with the beta₁-selective blockers bisoprolol and metoprolol succinate are virtually identical to those obtained with carvedilol, which is a beta₁/beta₂/alpha₁-blocker.²⁶

Additionally, although a potential pro-fibrillatory action of beta₂-adrenergic receptors has been suggested, the consequence of a block on pre-synaptic beta₂-receptors may have negatively affected the outcome of the Beta-blocker Evaluation of Survival Trial (BEST).²⁷ In this trial, bucindolol was associated with a 19% reduction in systemic norepinephrine at 3 months, a change similar to the 23% reduction in systemic norepinephrine observed in the Moxonidine for Congestive Heart Failure (MOXCON) trial.²⁸ In MOXCON, moxonidine increased mortality by >50%, leading to the trial being stopped early. The BEST authors suggest that, in contrast to the beneficial effects of cardiac beta₁-receptor blockade, reduction in plasma norepinephrine may have produced an irreversible loss of adrenergic support to the failing heart and to peripheral resistance, which could have been deleterious in patients with advanced CHF. This effect could have offset the beneficial effects of cardiac beta₁-receptor blockade in BEST.

	Catecholamines and SCD: evidence from animal models of SCD

Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 
The relationship between circulating catecholamines, functional class, and total mortality in CHF^10,29 is well established. However, the perception of sympathetic activation as the mere reflection of the haemodynamic impairment might be misleading. In the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI), patients with similar LV impairment (LVEF<35%) had different autonomic derangements resulting in either preserved or depressed cardiac vagal control.³⁰ The latter was associated with a marked increase in risk for arrhythmic death. This evidence suggests two important considerations. The first is that autonomic derangement is not the mere consequence of haemodynamic dysfunction but rather reflects individual aspects of autonomic function. The second is that whenever such a loss of cardiac vagal activity occurs, as revealed by a depressed baroreflex sensitivity, this results in an increased arrhythmic risk.³¹ Experimental evidence in conscious dogs has demonstrated the powerful effect of vagal activation in preventing VF.^32,33

Some important aspects of autonomic derangements after MI and their consequences on LV electrical stability remain unknown. This is also attributable to the lack of studies in chronic conscious animal models suitable for autonomic investigations. In the past, sustained rapid pacing has been used to produce severe biventricular systolic dysfunction in large animals.³⁴ However, pacing-induced mechanical dysfunction resolves rapidly after pacing is terminated, limiting the suitability of such models for chronic evaluation. Moreover, models created by rapid pacing are likely to represent non-ischaemic dilated cardiomyopathy more closely than CHF of ischaemic origin. The clinical characteristics of arrhythmias in ischaemic heart disease differ from those of non-ischaemic origin. Ischaemic CHF results in regional abnormalities of mechanical and electrical function adjacent to normal or hypertrophied myocardium. Such a heterogeneous substrate is not found in non-ischaemic cardiomyopathy, in which global homogeneous dysfunction occurs. With these considerations in mind, a model of chronic ischaemic heart disease and LV dysfunction has been developed in dogs and used to investigate ventricular remodelling and arrhythmogenesis.^35–38

Building on this work, Adamson and Vanoli³⁹ have developed a dog model of ischaemic LV dysfunction in which dogs at high risk for spontaneous SCD can be reliably identified, enabling the investigation of life-threatening arrhythmias and SCD in chronic LV dysfunction. This study investigated 15 dogs with a healed anterior MI, in which SCD risk was assessed during submaximal exercise and brief acute circumflex ischaemia.³⁹ Six dogs were categorized as susceptible to SCD and nine as resistant. LV dysfunction was then induced by repetitive circumflex micro-embolization until LVEF was 35%. After LV dysfunction was induced, all ‘susceptible’ dogs developed spontaneous sustained VT culminating in SCD, whereas only one resistant dog died suddenly. When compared with resistant dogs, susceptible dogs had lower baroreflex sensitivity and longer post-MI QT intervals (which further increased as LV dysfunction progressed). They also had a greater increase in heart rate during transient ischaemia and with progressive LV dysfunction. Thus, dogs susceptible to SCD after MI are characterized by depressed vagal and elevated sympathetic control of heart rate coupled with abnormal repolarization.

Serum catecholamine data were available for four susceptible and four resistant dogs. Total catecholamine levels were nearly twice as high in dogs susceptible to SCD, compared with resistant animals (1017 vs. 661 ng/dL, P<0.05). This difference was accounted for by increased norepinephrine in susceptible dogs (715 vs. 463 ng/dL, P<0.05). Epinephrine and dopamine did not differ between the groups. Very recent (unpublished results) investigation in this model indicates that dyshomogeneity in interstitial norepinephrine levels, rather than plasma levels, is a critical factor involved in arrhythmogenesis in the ischaemic myocardium.

These findings support the hypothesis that cardiocardiac reflexes originating from the damaged ventricle initiate adverse sympathetic activation coupled with vagal withdrawal, independent of haemodynamic effects. There is a clear association in this model between abnormal cardiac autonomic control in susceptible subjects and a rapid progression of electrophysiological alterations.⁴⁰ Thus, abnormal autonomic control of the heart appears to be linked to electrophysiological derangements leading to SCD in ischaemic LV dysfunction.

Recently, it has been discovered that heterogeneous cardiac nerve sprouting and sympathetic hyperinnervation play important roles in causing arrhythmias and SCD in both humans with CHF and animal models of MI. For example, there is an association between a history of spontaneous ventricular arrhythmia and an increased density of sympathetic nerves in patients with severe CHF. These findings suggest that abnormally increased post-injury sympathetic nerve density may contribute to dyshomogeneity in sympathetic neural discharge to the ventricles and, thus, to ventricular arrhythmias and SCD in CHF.⁴¹

Studies in dogs show that MI results in atrial sympathetic hyperinnervation.⁴² This can be augmented by nerve growth factor (NGF) infusion to the left stellate ganglion in dogs with chronic MI and AV block, creating a high-yield model of spontaneous VT, VF, and SCD.⁴³ Further research in dogs suggests that, after MI, there is a rapid and persistent up-regulation of NGF and growth-associated protein 43 (GAP43) expression at the site of the infarct, leading to cardiac nerve sprouting.⁴⁴ The amount of sympathetic nerve sprouting could be an important determinant of risk for SCD. In theory, regulating NGF and GAP43 expression after MI might provide a means of controlling arrhythmias and preventing SCD.

Another important piece of the puzzle comes from the analysis of norepinephrine turnover. Normally, most of the norepinephrine released by sympathetic nerves is taken back up by the nerves where it is metabolized. Cardiac norepinephrine spillover results from a combination of excessive release from nerve terminals and reduced re-uptake. In human heart failure, there is a reduced activity of the norepinephrine transporter molecule uptake-1,⁴⁵ which is presumed to lead to an increased synaptic concentration of norepinephrine. As humans age, levels of myocardial uptake-1 decrease.⁴⁶ A recent study⁴⁷ investigated the effects of myocardial overexpression of uptake-1 in failing and non-failing rabbit hearts. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium and resulted in marked structural and functional improvement of heart failure. Not only does this study underline the importance of uptake-1 in clearing norepinephrine from the cardiac synaptic cleft, it may also suggest a future role for gene therapy in the treatment of CHF.

Taken together, the evidence points to the major role of norepinephrine release from sympathetic endings in arrhythmogenesis in the failing ventricle. Thus, specific and early inhibition of this signalling via beta₁-receptor inhibition is a rational pharmacological approach to SCD prevention.

	Prevention of SCD by ICDs

Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 
Recently, attention has also focused on the role of the ICD in preventing SCD, a strategy complementary to that of neurohormonal intervention. Recent ESC guidelines⁴⁸ recommend ICD implantation in two categories of patient: as secondary prevention in those who have already survived cardiac arrest or sustained VT (poorly tolerated or associated with reduced systolic LV function) and as primary prevention in selected symptomatic patients with LVEF <30–35%, not within 40 days of MI, who are already on optimal pharmacological therapy. The guidelines are based on evidence from randomized controlled trials, principally the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II)⁴⁹ and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)⁵⁰ and from meta-analyses.^51–53 However, the guidelines also state that ICD implantation in patients in NYHA class IV is not well established, unless associated with cardiac resynchronization therapy (CRT) in the context of dyssynchrony. They note that the age of the patient and their co-morbidities should be taken into account when selecting patients for ICD implantation.

The European guidelines also recommend CRT plus an ICD (CRT-D) in patients in NYHA class III–IV with LVEF 35% and QRS width >120 ms. CRT-D should be reserved for patients considered at very high risk of SCD, despite medical treatment and CRT alone. This recommendation is based on the COMPANION trial,⁵⁴ which showed a significant reduction in the primary endpoint (death and hospitalization) for both CRT and CRT-D. The reduction in the secondary endpoint of mortality was significant for CRT-D but not for CRT.

ICD implantation rates are increasing in many European countries.⁵⁵ However, largely for economic reasons, the rate of implantation in Europe is likely to lag behind that in the United States. Identifying those patients at highest risk of SCD remains an impediment to effective and economic ICD implantation. The criteria used in the guidelines are based on the entry criteria used in the major clinical trials, but more studies are needed to identify more specifically who can benefit, so that a relatively expensive intervention can be focused on those at highest risk. In the meantime, it is important to establish optimal pharmacological therapy in all patients with CHF.

	Conclusions

Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 
Progress has been made in the prevention of SCD in CHF patients in recent years, but much more is needed. It is becoming increasingly clear that beta-blockers have a critical role to play in preventing SCD. Furthermore, the high mortality due to SCD in patients with established CHF or LV dysfunction following MI is only part of a continuum of progressive cardiovascular disease, in which SCD can occur at any point. In fact, about half the people who suffer SCD have no recognized cardiac disease before the event. The Maastricht study showed that in 44% of men and 53% of women SCD was the first manifestation of heart disease.³ Primary prevention of the sympathetic activation that heads to lethal arrhythmias is therefore an important goal for patients at high risk of cardiovascular disease. Our first priority is, however, a better understanding of the autonomic and electrophysiological mechanisms of arrhythmias in CHF, leading to better risk assessment and better targeting of treatment. At this time, based on the CIBIS III data, it seems rational to provide selective beta₁-adrenergic inhibition as a primary intervention in all patients at risk of developing an ischaemic heart evolving to LV dysfunction, with the aim of reducing SCD risk at any stage of the disease.

Conflict of interest: E.V. has received honoraria for consultant activities from Merck KGaA.

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Top Abstract Introduction Prevalence of SCD in... Effect of beta-blockers on... Relevance beta-receptor subclass Catecholamines and SCD: evidence... Prevention of SCD by... Conclusions References

 

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				B. Olshansky, H. N. Sabbah, P. J. Hauptman, and W. S. Colucci Parasympathetic Nervous System and Heart Failure: Pathophysiology and Potential Implications for Therapy Circulation, August 19, 2008; 118(8): 863 - 871. [Full Text] [PDF]

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