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

Beta-blockade in CHF: pathophysiological considerations

Bernard Silke*

Division of Internal Medicine, St James' Hospital and Department of Therapeutics and Pharmacology, Trinity College Dublin, Trinity Centre for Health Sciences, St James' Hospital, James' Street, Dublin 8, Ireland

* Corresponding author. Tel: +353 1 6081563; fax: +353 1 4539033. E-mail address: silkeb{at}tcd.ie


   Abstract
Top
 Abstract
Introduction
 Pathophysiology of CHF
 Mode of action of...
 Conclusions
 References
 
Sympathetic activation leading to raised levels of catecholamines is one of the earliest responses to the fall in cardiac output that occurs in chronic heart failure (CHF). Raised catecholamine levels have numerous adverse effects that can be counteracted by beta-blockers. For example, the increased heart rate associated with sympathetic activation is associated with a poor prognosis in CHF. In the major beta-blocker trials in CHF, a reduction in mortality of about 35% was consistently demonstrated with beta-blockade, which was associated with a reduction in heart rate of 10–15 bpm. The resting heart rate predicts longevity in many mammalian species. A limited ability to increase heart rate during exercise (chronotropic incompetence) in left ventricular (LV) dysfunction and CHF also predicts mortality. Beta-blockers increase heart rate variability by rebalancing the sympatho-vagal axis. Beta-blockers also reduce remodelling in CHF, increase LV ejection fraction, reduce end-systolic volume, and improve ventricular filling time. They are also believed to have a direct anti-arrhythmic action that protects against sudden cardiac death and to have additional effects at the cellular level on myocyte hypertrophy and apoptosis.

Key Words: Chronic heart failure • Beta-blockers • Heart rate • Myocardium • Sudden cardiac death • Left ventricular dysfunction


   Introduction
Top
 Abstract
 Introduction
Pathophysiology of CHF
 Mode of action of...
 Conclusions
 References
 
Chronic heart failure (CHF) is an epidemic disease, the prevalence of which is increasing in most western countries in parallel with the ageing of the population. It is the most rapidly growing cardiovascular disorder worldwide, currently affecting nearly 6.5 million people in Europe.1 A rise of 70% in the prevalence of CHF caused by coronary heart disease has been calculated for the period 1985–2010.2 Because of improvements in treatment, patients are surviving longer after myocardial infarction (MI) and after developing CHF. Thus, the already heavy burden of CHF on healthcare systems will continue to increase in the foreseeable future.1

Population studies based on clinical criteria indicate prevalence rates of 0.3–2% in the general population,3–5 rising to more than 10% in those aged 65 years or older.1 The prevalence of echocardiographically determined left ventricular systolic dysfunction (LVSD) is similar to that of symptomatic CHF, but only about 50% of the patients with LVSD have symptomatic CHF. However, most patients with asymptomatic LVSD do have other cardiovascular disorders, such as previous MI or hypertension.6–9 Conversely, among patients diagnosed to have CHF on the basis of clinical criteria, only about half have LVSD on echocardiography; the rest have diastolic heart failure, an important but under-researched condition.10

CHF accounts for 5% of general medical and geriatric admissions and is the commonest cause of admission to a medical ward in patients older than 65 years.11 In our own hospital (St James' University Hospital, Dublin, Ireland), unpublished data show that CHF accounts for 7.5% of acute medical admissions. Our patients have a median age of 77 years, often have five or six different diagnoses, and may be receiving 15 or 16 different drugs. This suggests that the reality of treating CHF in everyday clinical practice is considerably more complicated than in the major CHF trials, where patients tended to be relatively young, predominantly male, and many comorbidities were excluded.

Mortality rates from CHF are comparable with those for malignant diseases,12 with ~60% of patients dying within five years of diagnosis.6 Mortality increases with clinical severity. Patients in NYHA class IV have an annual mortality of up to 50%, much higher than that encountered in landmark trials (most of which did not include true NYHA Class IV patients). Patients requiring hospitalization for CHF have a mortality rate of 11–20% in the month after a first admission, and 30–45% in the year after a first admission.13–15

These statistics mean that better prevention and treatment of CHF must continue to be a priority for healthcare systems in the industrialized countries. Major advances have been made in pharmacological treatment and device therapy in recent years, and there is recent evidence of a small improvement in prognosis that may be attributable to modern therapies.16–18 Although new treatments are being developed, we should also recognize that existing neurohormonal treatments, ACE-inhibitors and beta-blockers, are not yet being used to their full potential. We know that in randomized controlled trials, beta-blockers, added to standard therapy with ACE-inhibitors and diuretics, reduce mortality by approximately one-third and hospitalizations.19–21 Given the high mortality and morbidity in patients with CHF, such a substantial mortality reduction has major public health implications.

At present, the potential benefits of beta-blockade are not currently being realized in clinical practice, fewer than 40% of eligible CHF patients currently receive beta-blockers.22,23 An understanding of the complex pathophysiological processes underlying CHF may encourage the practitioner to use therapy in a tailored approach, related to the underlying clinical condition, with the objective of achieving maximal benefit. This review examines the pathophysiology of CHF and discusses the key points at which beta-blockers can intervene to retard progression, reverse remodelling, prevent sudden cardiac death (SCD) and thereby reduce morbidity and mortality.


   Pathophysiology of CHF
Top
 Abstract
 Introduction
 Pathophysiology of CHF
Mode of action of...
 Conclusions
 References
 
CHF is essentially a clinical diagnosis, in which the contractile reserve of the myocardium is impaired, rendering the heart unable to match short-term demand by increasing power output. Underlying this simple description is a complex web of pathophysiological changes (Figure 1) involving the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS). The RAAS is the target for ACE-inhibitors, aldosterone antagonists, and angiotensin receptor blockers, whereas the SNS is the target for beta-blockers. The SNS is the main target for beta-blockers, but they also target the RAAS by inhibiting renin release by blocking beta1-receptors at the juxtaglomerular apparatus in the kidneys (discussed subsequently).


Figure 0091
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  		Figure 1 Neuroendocrine consequences of CHF.

 
The processes leading to CHF are believed to be initiated by various forms of myocardial injury, for example, by MI, prolonged cardiovascular overload (e.g. hypertension, valvular disease), toxins (alcohol, cytotoxic drugs), or infection (e.g. viral myocarditis). In many instances, the cause, notwithstanding continuing advances, is surrounded by some uncertainty (idiopathic dilated cardiomyopathy).24,25 Regardless of the nature of the initiating event, heart failure ultimately results from the loss of a critical number of functioning myocardial cells, leading to progressive cardiac dysfunction. To preserve cardiac output and maintain blood flow to major organs, a series of compensatory haemodynamic and neurohormonal mechanisms are activated in early CHF. Initially, the increase in diastolic tension (preload) due to a decrease in the ability to empty the ventricle during systole results in enhanced contraction of the ventricle (the Frank–Starling effect). However, despite this, the heart gradually becomes unable to increase power output to match short-term demand. Patients' total energy requirements must be reduced to match cardiac performance, with the consequence that, for example, in NYHA class IV CHF, activity is reduced to minimal levels. In addition, CHF often leads to a catabolic state, an emerging area of research.26

The SNS is activated early in CHF. In fact, plasma norepinephrine levels predict the development of symptomatic CHF, as well as all-cause and cardiovascular mortalities.27–30 Activation of the SNS is followed by that of other neurohormonal systems including the RAAS and by increased release of cytokines. Activation of the SNS and the RAAS initially maintains systemic blood pressure (by vasoconstriction) and cardiac output (by fluid retention and the Frank–Starling effect). However, the reduction in cardiac output results in a greater volume remaining at the end of diastole (end-diastolic volume), which stretches the myocardium and restores myocardial contraction at the cost of an increased pressure. The decrease in cardiac output results in further sympathetic activation and vasoconstriction to maintain blood pressure.31 However, this increase in afterload further decreases cardiac output, increases the end-diastolic pressure, and causes hypertrophy and then further dilatation of the right ventricle.

During initial dilatation, various mechanisms are employed by the heart muscle to normalize wall stress, but these are lost with continuing dilatation, and contractile function is progressively reduced, a process known as ventricular remodelling. Remodelling is a fundamental mechanism of myocardial dysfunction in CHF. It involves hypertrophy and apoptosis of myocytes, regression to a molecular phenotype that expresses foetal genes and proteins, and changes in the nature of the extracellular matrix.32 Activation of the SNS plays an important role in remodelling, leading to impaired beta-adrenergic receptor function, myocyte necrosis and fibrosis, and extracellular matrix fibrosis. Cardiac fibrosis not only leads to the development of myocardial stiffness and consequent diastolic dysfunction, but also results in electrical abnormalities in the myocardium, leading to the development of lethal arrhythmias and an increased risk of SCD.

Heart failure disrupts the geometry of cardiac contraction and mechanical function. The cardiac pump can be considered as a three-component sandwich, consisting of an epicardial, mid-zone, and endocardial sections. The orientation of the epicardial and endocardial fibres is longitudinal with linkage through the vortex cordis. However, the mid-zone, comprising ~75% of the myocardial bulk, is orientated circumferentially. The epiendocardial unit and the circumferential pumps appear to operate with temporal phase asynchronism. The latter delivers the main power output by reducing symmetrically the chamber dimensions, whereas the former shortens the heart in the longitudinal axis and imparts an appreciable twist to the chamber in systole. The energetics of cardiac relaxation and the rapid early diastolic filling is derived to a large extent by a suction effect. The spring or twist energetics depends on the dynamic interaction between the cardiac muscle layers, that is, to a large extent impaired by chamber dilation or wall hypertrophy. It is debatable as to whether any of the major therapeutic modalities restore these relationships.


   Mode of action of beta-blockers in CHF
Top
 Abstract
 Introduction
 Pathophysiology of CHF
 Mode of action of...
Conclusions
 References
 
The mode of action of beta-blockers in CHF is still incompletely understood, despite 30 years of research. Beta-blockers may act by multiple mechanisms (Table 1),33 the most important of which are discussed earlier.


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  		Table 1 Possible beneficial actions of beta-blockers in CHF

 
Effects on heart rate
Among mammals, there is an inverse semi-logarithmic relation between heart rate and life expectancy (Figure 2).34 The product of heart beats and lifetime remains remarkably constant over species despite a 35-fold difference in life span (Figure 3). The implication of this observation is unclear. However, it might be that the heart rate is an epiphenomenon (i.e. that lifespan is determined by the basic energetics of cells or a fixed number of cell cycles and that the underlying relationship between lifespan and heart rate may be indirect).


Figure 0092
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  		Figure 2 Semi-logarithmic relationship between resting heart rate and life expectancy in mammals. Reproduced with permission from The American College of Cardiology Foundation.34

 

Figure 0093
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  		Figure 3 Relationship between life expectancy and total heart beats/lifetime in mammals. Reproduced with permission from The American College of Cardiology Foundation.34

 
Nevertheless, it is known that the increased heart rate associated with SNS activation is associated with a poor prognosis in CHF and after MI.35 For example, an analysis of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-2 and GISSI-3 post-MI databases showed that heart rate independently predicted mortality both in hospital and at 6-month follow-up.36 In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), patients with baseline heart rates of >85 bpm, particularly those in the placebo group, had the worst prognosis.37 In a substudy of the Survival and Ventricular Enlargement trial in CHF patients, in patients with left ventricular (LV) dysfunction and LV ejection fraction (LVEF) <40%, raised heart rate predicted LV dilatation and cardiovascular mortality.38 Moreover, an analysis of data from the Italian Network on Congestive Heart Failure registry found that the higher the heart rate the greater the likelihood of short-term destabilization of CHF.39

Increased heart rate may increase mortality in a number of ways (though it could also be a marker for other pathophysiological mechanisms leading to death).35 A high heart rate is known to be associated with both LV dysfunction and remodelling. Animal and human studies show that a high heart rate due to atrial fibrillation leads to cardiomyopathy, which is reversible with rate lowering.40 However, in the GISSI trial, increased heart rate was associated with increased mortality whether or not LV dysfunction was present.36 Other mechanisms, including increased myocardial oxygen consumption leading to ischaemia, may also be relevant.41 Slowing of the heart rate by beta-blockade can reduce myocardial oxygen demand, and prolonged diastole increases coronary perfusion time.42

The reduction in mortality in beta-blocker post-MI intervention trials is proportional to the reduction in heart rate (Figure 4).43,44 In the major beta-blocker trials in CHF, a reduction in mortality of about 35% was consistently demonstrated with beta-blockade, which was associated with a marked decrease in heart rate of 10–15 bpm.19–21


Figure 0094
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  		Figure 4 Relationship between the heart-rate-lowering effects of beta-blockers and their effects on mortality in post-MI trials. Reproduced with permission from Excerpta Medica Inc.43

 
Effects on heart rate variability
A limited ability to increase heart rate during exercise (chronotropic incompetence) in LV dysfunction and CHF also predicts mortality.45 This reduction in chronotropic incompetence is attributable to an autonomic imbalance in which there is increased sympathetic and decreased vagal activity.41 There is evidence to suggest that beta-blockers may improve this autonomic imbalance.41 A subgroup analysis of patients in the first Cardiac Insufficiency Bisoprolol Study showed that bisoprolol increased heart rate variability, but only in patients with the largest RR interval.46 This suggests that the heart rate-lowering effect of beta-blockers in CHF can correct autonomic imbalance and that increased vagal tone may contribute to their beneficial effects.41

Other haemodynamic effects
In addition to the effect of beta-blockers on heart rate and heart rate variability, they also have other beneficial effects including increased LVEF, reduced end-systolic volume, and improved ventricular filling time.41 In a meta-analysis of 18 double-blind, placebo-controlled trials in CHF involving 3023 patients, mean LVEF was 23±4% in the placebo group and 31±4% in the beta-blocker group, indicating a highly significant increase of 29% in patients receiving beta-blockers.47 This increase is three to five times greater than that achieved by ACE-inhibitors and suggests a strong effect on cardiac remodelling (discussed susequently).

Effects on ventricular fibrillation
Chronic sympathetic activation appears to increase the risk of SCD in CHF by lowering the threshold for ventricular fibrillation.48 Several mechanisms may be involved, including enhanced automaticity of myocytes, hypokalaemia (resulting from a shift of potassium into cells), and provocation of ischaemia. A direct anti-arrhythmic action of beta-blockade may be inferred from the protective effect of beta-blockers against SCD, and this is discussed further in the proceedings by Vanoli et al.49

Counteraction of stimulation of the RAAS
Chronic sympathetic activation potentiates the activity of the RAAS leading to salt and water retention, arterial and venous constriction, and increased ventricular preload and afterload.50 By blocking beta1-receptors, beta-blockers inhibit the activation of both the SNS and the RAAS.

Reverse remodelling
The reduction in mortality achieved with beta-blockers in CHF may relate to modification of the remodelling process. ACE-inhibitors seem to prevent progressive LV dilatation, whereas beta-blockers may actually reverse the remodelling process by reducing LV volumes and improving systolic function.51 This has been demonstrated recently by the Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation trial study,52 in which carvedilol monotherapy or carvedilol plus enalapril reversed LV remodelling, but enalapril monotherapy did not. Reverse remodelling (as measured by change in LV end systolic volume) has also been reported in the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study with carvedilol plus an ACE-inhibitor, but not with placebo plus an ACE-inhibitor.53

Reverse remodelling has also been demonstrated with metoprolol54 and bisoprolol.55 For example, in a study in 201 patients with stable CHF, after 3 months of treatment with bisoprolol, mean LVEF had increased from 31 to 41% (P<0.0001). There was a significant decrease in end-diastolic and end-systolic left ventricle diameters and volumes, indicating reverse remodelling.

The mechanism by which beta-blockers reverse remodelling is unclear, but may relate to effects at the cellular level. There is evidence that activation of myocardial beta-receptors promotes dysfunction and death of cardiomyocytes.56 These effects might be mediated by elevation of cAMP, leading to an increase in intracellular calcium, which if prolonged could lead to calcium overload and cell necrosis.57 Catecholamines can also act directly as growth factors on cardiomyocytes,58 and myocyte hypertrophy in the context of oxidative stress triggers programmed cell death (apoptosis).59 Beta-blockade might protect against such effects.


   Conclusions
Top
 Abstract
 Introduction
 Pathophysiology of CHF
 Mode of action of...
 Conclusions
References
 
The past few years have seen a revolution in attitudes towards beta-blockers in CHF. Only a decade ago, many considered these agents to be contraindicated. However, we now know beta-blockers are potentially life-saving therapies that should be given to the majority of patients with CHF. This paradigm shift has come about as a result of major mortality trials demonstrating that beta-blockade can cut mortality in CHF by one-third,19–21 a benefit additional to that obtained with ACE-inhibitors and diuretics. Recent years have also seen a growing recognition of the fact that activation of the SNS is central to the pathophysiology of CHF and that beta-blockers probably act by multiple mechanisms to reduce mortality. Much remains to be learnt about the mode of action of this fascinating group of compounds. In the meantime, the practical challenge is to ensure that they are prescribed early in the course of CHF to as many eligible patients as possible, so that their potential to reduce mortality and morbidity can be fulfilled in everyday clinical practice.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Pathophysiology of CHF
 Mode of action of...
 Conclusions
 References
 

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