SCIENCE & PRACTICE
Pathophysiology of chronic heart failure
Traditionally, heart failure has been regarded as a disorder in which the ventricles fail to pump adequate quantities of blood to meet the needs of peripheral organs. Therefore, for the past half-century, the physiological abnormalities of the disease have largely been described in haemodynamic terms. According to this model, heart failure follows an injury to the heart, which impairs its ability to eject blood; renal blood flow is reduced and subsequent sodium retention leads to pulmonary and peripheral oedema. This focus on haemodynamics led to the widespread use of digitalis and diuretics in the treatment of the condition. However, heart failure is now thought of as a disorder of the circulation, not merely a disease of the heart. Many patients have structural cardiac damage that adversely affects systolic or diastolic function, but they do not have heart failure because compensatory mechanisms maintain cardiac output and peripheral perfusion. Since the response of the circulation to stress is governed by neurohormonal mechanisms, in addition to haemodynamic factors, these compensatory processes cannot be understood in mechanical terms alone. Heart failure develops not when the heart is injured but when compensatory haemodynamic and neurohormonal mechanisms are overwhelmed or exhausted. The disorder progresses when these endogenous mechanisms exert adverse effects. Although heart failure may be caused by disorders of the pericardium or endocardium, together with hypertrophic or restrictive diseases of the myocardium, I will focus on the pathophysiology of chronic heart failure due to systolic dysfunction of the left ventricle.
among addition, the
The key event leading to heart failure is loss of a critical quantity of functioning myocardial cells after an injury to the heart. This injury may be an acute myocardial infarction, toxins (alcohol or cytotoxic drugs), infection by viruses or parasites (viral myocarditis or Chagas’ disease), or prolonged cardiovascular stress (hypertension or valvular disease). In many cases, the cause of the injury is unknown. To compensate for myocardial cell loss, both are
activated to enhance the contractile force of the non-injured myocardium, and so preserve cardiac function. First, a decrease in the ability to empty the ventricle during systole increases the tension on the non-injured parts of the heart during diastole; the ventricle responds to this increase in dias-olic tension (preload) by enhancing its contraction (the
increased number of
myofibrillar proteins synthesised during haemodynamic stress have the biochemical characteristics of fetal myocardium and are bioenergetically more efficient than their adult isoforms.3 Hence, both quantitatively and qualitatively, cardiac hypertrophy reduces the energy expenditure of the overloaded heart. Second, an increase in diastolic wall
haemodynamic and neurohormonal mechanisms
Frank-Starling principle). Second, a decrease in the ability to eject blood into the aorta activates the nervous sympathetic system; the resulting stimulation of P-adrenergic receptors in the non-injured myocardium increases both the force and frequency of contraction. These two compensatory mechanisms involve different, but complementary, intracellular calcium-dependent inotropic pathways. Whereas sympathetic activation increases the delivery of calcium to myofilaments, ventricular dilatation enhances sensitivity of the myofilaments to calcium.1 and neurohormonal haemodynamic Although for the mechanisms provide inotropic support injured heart, they can introduce an important risk. Both ventricular dilatation and sympathetic activation (by constriction of peripheral arteries and veins) strikingly increase the internal stress on the heart wall during diastole, which can dramatically distort its architecture and accelerate its energy expenditure.2 To prevent such adverse structural and functional effects, the circulation closely regulates the magnitude of ventricular dilatation and sympathetic activation. First, an increase in diastolic wall stress in ventricles leads to the induction of specific proto-oncogenes (c-fos and c-myc) that trigger synthesis of myofibrillar proteins.3 The subsequent increase in wall thickness reduces ventricular strain and dilatation by distributing the excess
of the ventricle
in the atria suppresses the actions of the sympathetic nervous system. Atrial stretch stimulates atrial baroreceptors that inhibit sympathetic outflow from the vasomotor centre in the central nervous system 4 Atrial stretch leads to the secretion of atrial natriuretic peptide, which inhibits the release of noradrenaline and the actions of this neurotransmitter on peripheral blood vessels.5,6 The peptide also exerts direct vasodilator and natriuretic effects that reduce the haemodynamic load on the heart. Together, these stress-reducing mechanisms (whether triggered by atrial or ventricular stimuli) have a central role in limiting the adverse consequences of ventricular dilatation and sympathetic activation. ADDRESS:
Division of Circulatory Physiology, Columbia University, College of Physicians and Surgeons, New York, NY 10032 USA (Dr M. Packer, MD).
Through a combination of ventricular dilatation hypertrophy, and the activation of vasoconstrictor vasodilator forces, a delicate haemodynamic
and and and neurohormonal balance is achieved, which restores cardiac function towards that found before injury at minimum
energetic cost (fig 1). Loss of compensatory mechanisms
Long-term activation of endogenous positive inotropic and stress-reducing mechanisms leads to a diminution of their favourable physiological effects. Loss of stress-reducing mechanisms ventricular distension leads to thinning, and fibrosis of the ventricular wall,7,8 which necrosis, the compromises hypertrophic response and restricts the heart’s capacity to normalise wall stress. Prolonged atrial distension leads to structural and functional changes in atrial receptor endings, which reduce the ability of these baroreceptors to inhibit sympathetic outflow from the vasomotor centre 4Abnormalities of baroreceptor function have been described in both experimental and clinical heart failure.4,9 Prolonged atrial distension also leads to depletion of natriuretic peptides, such that their release after an increase in atrial pressure is blunted To compensate for this loss, natriuretic peptides are synthesised by the ventricles as well as the atria, but as with hypertrophy, the magnitude of this response is inadequate. These events represent a critical loss in the ability of the circulation to limit ventricular wall stress and the release of vasoconstrictor hormones. Ventricular dilatation progresses, the nervous becomes system persistently activated, sympathetic and heart failure begins.
Loss of positive-inotropic mechanisms When wall stress increases after the loss of load-reducing mechanisms, the heart becomes more dependent on endogenous inotropic processes to maintain cardiac function. Again, however, the long-term activation of these inotropic mechanisms leads to loss of their effects on myocardial contractility. First, the failing heart loses its ability to enhance its inotropic state in response to increases in ventricular volume. When sarcomeres are stretched to their limits because of progressive ventricular dilatation, increases in preload do not enhance systolic ejection, so the Frank-Starling curve becomes both depressed and flattened. Second, the failing heart loses its ability to respond to the positive inotropic effects of endogenous and exogenous catecholamines. This attenuation results from changes in the cardiac 0-adrenergic pathway, which include down-regulation of (3-receptors (mainly (31) and uncoupling of (3-receptors from their effector enzyme, adenylate cyclase.ll Such uncoupling seems to be related to an alteration in the guanine nucleotide binding proteins that stimulate (G) or inhibit (G) the interaction of the receptor and the enzyme. Both a decrease in G and an increase in Gi1 have been reported in patients with heart failure.12,13 Furthermore, prolonged ventricular dilatation and sympathetic activation not only leads to a loss of their beneficial effects on cardiac contractility, but accentuates their adverse actions on ventricular wall stress. Concomitant with loss of the Frank-Starling mechanism, the failing ventricle loses its capacity to augment its function so as to overcome increases in resistance (afterload). Thus, whereas
Fig 1-Compensatory mechanisms activated after myocardial injury.
ventricular dilatation enhances systolic ejection (because the normal ventricle is sensitive to increases in preload but resistant to increases in afterload), an enlargement in chamber size depresses cardiac function in heart failure (because the failing heart is resistant to increases in preload but highly susceptible to increases in afterload). This situation is strikingly exacerbated by a similar shift in the benefit-to-risk relation for sympathetic activation. Not only is heart failure accompanied by a loss of responsiveness to P-adrenergic stimuli in the heart, but it is also characterised by an enhanced responsiveness to oc-adrenergic stimuli in peripheral vessels.14 The resulting constriction of systemic arteries and veins strikingly increases the pressure and volume in the heart and exacerbates the load on the ventricle. Hence, the same endogenous mechanisms that exerted favourable effects in the normal heart (by increasing its inotropic state) produce detrimental effects in the failing heart (by increasing its wall stress). The heart has less capacity to contract, and it must use this limited capacity to overcome stress rather than eject blood. Systolic function cannot be sustained, and cardiac output falls.
Consequences of sustained neurohormonal activation When cardiac output falls, systemic perfusion is maintained vasoconstriction
characteristic findings in patients with established heart failure, and both are produced by the interplay of haemodynamic and neurohormonal factors (fig 2).
Peripheral vasoconstriction Many neurohormonal systems that are activated in patients with heart failure exert potent constrictor effects on peripheral blood vessels. The sympathetic nervous system is activated early in the disease process (when ventricular dilatation takes place), whereas the renin-angiotensin system is usually triggered once symptoms develop (after diuretics are given), and vasopressin is released mainly in the terminal phases of the disease (when systemic perfusion is threatened). Studies with selective hormonal antagonists have provided compelling evidence that each hormonal system has a role in the vasoconstriction of some patients with heart failure. 15 In addition to these circulating factors, heart failure is accompanied by an increased release of locally active vasoconstrictors produced by vascular endothelium (eg, endothelin); endothelin concentrations are increased in heart failure in proportion to the severity of the disease. 16 In patients without heart failure, the actions of these endogenous vasoconstrictor factors are counterbalanced by endogenous vasodilators. Atrial natriuretic peptide normally inhibits release of noradrenaline, renin, and vasopressin as well as their actions on peripheral blood vessels.6 The release of endothelium-derived relaxing factor normally offsets the actions of endothelin. However, in heart failure, the actions of these circulating and locally active vasodilators are attenuated. Not only is the release of atrial natriuretic peptide blunted after long-term atrial distension, but also the peptide (once released) loses its ability to suppress the release of renin or dilate peripheral blood vessels. 17,111 Similarly, the release of endothelium-derived relaxing factor is strikingly diminished in patients with heart failure.19 As a result of the loss of these vasodilator factors, the actions of vasoconstrictors are left unopposed. The resulting vasoconstriction is enhanced by a process of mutual neurohormonal amplification--eg, activation of the sympathetic nervous system increases release of renin, and angiotensin enhances the release of both noradrenaline and
vasopressin.4 In addition to neurohormonal activation, mechanical factors may contribute to increased peripheral resistance. Sodium retention may impair the vasodilator capacity of peripheral blood vessels, either because of an increase in the sodium content of peripheral vessels or because oedema enhances the compressive forces of perivascular tissues.2o Long-term decreases in regional blood flow may also produce structural changes in the vessel walls, which may limit their ability to accomodate sudden increases in flow.21
Sodium retention In addition to peripheral vasoconstriction, activation of neurohormonal systems leads to salt and water retention in patients with heart failure .2223 This alteration in fluid balance results from the direct and indirect effects of the renin-angiotensin system on glomerular and tubular function. Angiotensin exerts constrictor effects on the efferent arteriole; the resulting increase in filtration fraction alters the peritubular balance of hydraulic and oncotic forces, such that proximal tubular sodium reabsorption is enhanced. In addition, angiotensin augments sodium
reabsorption directly release of aldosterone.
indirectly by stimulating the Angiotensin causes water retention
Fig 2-Haemodynamic and neurohormonal factors in the development of heart failure.
by increasing water intake (by stimulating the cerebral thirst centre) and decreasing water excretion (by enhancing the release of vasopressin from the pituitary). All of these salt and water retaining effects are potentiated by the stimulation of renal sympathetic nerves (in patients with early heart failure) and by a fall in renal blood flow (in patients with late heart failure). The actions of these endogenous salt-retaining systems are normally offset by the actions of endogenous saltexcreting systems (atrial natriuretic peptide and prostaglandins). In patients without heart failure, atrial natriuretic peptide increases sodium and water excretion by a direct effect on glomerular and tubular function, as well as by an inhibitory effect on the release and actions of renin and vasopressin. However, these counterbalancing effects of atrial natriuretic peptide are lost in patients with heart failure who show little change in renin release or sodium excretion following infusion of the peptide. 18 This attenuated natriuretic response seems to be directly attributable to decreased renal blood flow, which alters intrarenal haemodynamics and triggers intrarenal release of vasoconstrictors.24,25 Renal hypoperfusion also leads to the intrarenal release of prostaglandins that exert some natriuretic and diuretic effects.26 However, these actions are limited by the inhibitory effect that renal hypoperfusion on sodium and water excretion. The development of peripheral vasoconstriction and sodium retention in heart failure represents an important shift in circulatory priorities, with the cardiovascular system moving from a state of compensation to a state of decompensation. Whereas before the onset of heart failure, endogenous mechanisms are directed to the support of cardiac function, after the onset of heart failure, the circulation’s main object is to support systemic perfusion pressures. However, peripheral vasoconstriction and
sodium retention cannot be explained only by the excessive activation of endogenous vasoconstrictor systems; their development requires loss of counter-regulatory vasodilator influences, both in blood vessels and in the kidneys. The loss of these compensatory peripheral mechanisms adds dramatically to the haemodynamic burden of the failing heart, whose function is already compromised by loss of compensatory myocardial mechanisms.
Progression of disease Haemodynamic stress and neurohormonal activation- if sustained over the long-term-not only depress cardiac function but also cause necrosis of myocardial cells in previously non-injured segments of the heart. Ventricular function progressively deteriorates, leading to terminal heart failure.
However, the precise way in which haemodynamic and neurohormonal factors interact to cause progression remains undefined. Both mechanisms increase heart wall stress, and this can cause irreversible structural remodelling of the heart because of slippage and elongation of myocardial fibres. In addition, progressive ventricular dilatation may undermine support for the mitral valve, with subsequent mitral regurgitation. Increases in cardiac pressure and volume may also cause myocardial ischaemia by augmenting energy expenditure while decreasing subendocardial perfusion, especially in patients with underlying coronary artery disease. The hypertrophic response to stress may further increase energy demands (by increasing the number of energy-consuming myofibrils) while reducing energy supply (since wall thickening may impair oxygen
diffusion). Furthermore, prolonged activation of the sympathetic nervous and renin-angiotensin system may exert adverse effects on the heart independent of their haemodynamic actions. High concentrations of noradrenaline and angiotensin exert direct toxic effects on myocardial cells ’27 ’28 and interference with the actions of these hormones can prevent cell injury, replacement fibrosis, and disease progression in experimental models of cardiac dysfunction.28-30 How neurohormonal exposure leads to cell toxicity remains uncertain. Although some investigators have suggested that noradrenaline and angiotensin cause a state of calcium overload in the failing heart, recent evidence suggests that the main mechanism of neurohormonally mediated tissue damage may involve oxygen free radicals. Free radical production is increased in patients with chronic heart failure.31 In addition, increased activity of the sympathetic nervous system and renin-angiotensin system (by altering intracellular cyclic AMP and potassium, respectively) may exert adverse electrophysiological effects and thereby provoke lethal arrhythmias. Finally, circulating concentrations of potentially cardiotoxic cytokines (eg, tumour necrosis factor) are increased in heart failure, notably in patients with neurohormonal activation.32 Cytokines may contribute to the development of the anorexia and cachexia, may enhance production of free radicals, and may explain the attenuated myocardial response to catecholamines and the diminished peripheral vascular response to endothelium-mediated vasodilators.33.34 All of these physiological abnormalities are corrected after cardiac transplantation, when circulating levels of tumour necrosis factor decline.35 The role that cytokines may have in the progression of heart failure is an exciting area of future research.
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26. Packer M. Interaction of prostaglandins and angiotensin II in the modulation of renal function in congestive heart failure. Circulation 1988; 77 (suppl I): 64-73. 27. Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992; 85: 790-804. 28. Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991; 69: 1185-95. 29. Ver Donck L, Wouters L, Olbrich HG, Mutschler E, Borgers M. Nebivolol increases survival in cardiomyopathic hamsters with congestive heart failure. J Cardiovasc Pharmacol 1991; 18: 1-3. 30. Pfeffer JM, Pfeffer MA, Mirsky I, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation 1985; 72: 406-12.
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Treatment of chronic heart failure
Since heart failure has been thought of as a mechanical treatment has necessarily been focused on achieving haemodynamic goals. This approach may seem logical because heart failure develops after an injury to the heart and can be alleviated with replacement of the heart (eg, by transplantation). However, as I described in my preceding article, the development and progression of heart failure result from a complex interplay of haemodynamic and neurohormonal factors, rather than simply changes in cardiac function. Therefore, the treatment of patients with heart failure should be directed, not to improving systolic performance, but to correcting the primary pathophysiological abnormalities of the circulation, and thus, to improving symptoms and prolonging life. In patients with left ventricular systolic dysfunction, the main pathophysiological features of heart failure are increased cardiac wall stress and increased neurohormonal activity. Both haemodynamic and neurohormonal forces contribute to symptoms and to progression of the underlying disorder. Therapeutic interventions designed to limit the adverse effects of these factors have met with variable success.
Drugs to reduce ventricular wall stress Several therapeutic agents produce haemodynamic benefits in heart failure by antagonising the three pathophysiological factors that contribute to an increase in ventricular wall stress: sodium retention (diuretics), peripheral vasoconstriction (direct-acting vasodilators), and reduced cardiac contractility (positive inotropic agents).
Diuretics Diuretics alleviate the sodium retention of heart failure by
inhibiting sodium and chloride reabsorption at specific sites in the renal tubules. Two classes of diuretic agents have been developed. Drugs that act on the distal tubules (thiazides and potassium-sparing diuretics) increase the fractional excretion of sodium only modestly (up to 5-10% of the filtered load), and they lose their effectiveness when renal function is impaired (when the glomerular filtration rate [GFR] decreases to below 30 ml/min). Agents that act on the loop of Henle (frusemide, ethacrynic acid, bumetanide, and piretanide) increase the fractional excretion of sodium (up to 25% of the filtered load), and they retain their effectiveness until GFR falls below 5 ml/min. Loop diuretics are preferred because of their greater efficacy. However, they may be combined with thiazides (especially
and potassium-sparing diuretics when additional sodium excretion or potassium conservation, respectively, is desired. Diuretics produce consistent haemodynamic and symptomatic benefits in patients with pulmonary or peripheral congestion. These drugs rapidly relieve dyspnoea and oedema, and their natriuretic action may enhance the responsiveness of peripheral blood vessels to direct-acting vasodilators and converting-enzyme inhibitors. Thus, diuretics had long been regarded as the cornerstone of treatment for heart failure. However, controlled clinical trials show diuretics alone cannot maintain the clinical stability of patients with chronic heart failure. Many patients whose symptoms are well controlled deteriorate clinically during long-term follow-up when treated with diuretics alone.2 Furthermore, diuretic use is associated with a high risk of electrolyte depletion (potassium and magnesium) that may predispose to the development of lethal ventricular
arrhythmias. Both the limited efficacy and potential toxicity of diuretic monotherapy seem to be related to drug-induced activation of the renin-angiotensin system. Diuretics are an important cause of increased plasma renin activity in heart failure,3 and angiotensin attenuates the haemodynamic effects and potentiates the potassium-losing effects of these agents. Both the risk of clinical deterioration and the adverse metabolic effects of diuretic therapy can be reduced by simultaneous treatment with a converting-enzyme inhibitor.2 These observations suggest that the efficacy and safety of treatment may be limited if it improves one of the central physiological abnormalities of heart failure (wall stress) but worsens the other (neurohormonal activation). This view has led to attempts to develop diuretic drugs with favourable neurohormonal effects-eg, the atriopeptidase inhibitors.’ By inhibiting the enzyme responsible for degradation of atrial natriuretic peptide, these experimental drugs increase the circulating and renal tubular concentrations of the peptide-the body’s own diuretic. These agents produce natriuretic effects that are accompanied by suppression (rather than augmentation) of plasma renin activity. Studies of the long-term efficacy of these drugs in heart failure are now under way. Division of Circulatory Physiology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA (Dr M Packer, MD). ADDRESS: