Pathophysiology of Heart Failure - Neurohumoral Adaptations PDF

Pathophysiology of heart failure: Neurohumoral adaptations
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Author Wilson S Colucci, MD Section Editor Stephen S Gottlieb, MD Deputy Editor Susan B Yeon, MD, JD, FACC
Last literature review for version 16.1: January 31, 2008 | This topic last updated: January 25, 2008 INTRODUCTION The signs and symptoms of heart failure (HF) are due in part to compensatory mechanisms utilized by the body in an attempt to adjust for a primary deficit in cardiac output. Neurohumoral adaptations, such as activation of the renin-angiotensin-aldosterone and sympathetic nervous systems by the low output state, can contribute to maintenance of perfusion of vital organs in two ways [1,2] : Maintenance of systemic pressure by vasoconstriction, resulting in redistribution of blood flow to vital organs Restoration of cardiac output by increasing myocardial contractility and heart rate and by expansion of the extracellular fluid volume Volume expansion is often effective because the heart can respond to an increase in venous return with an elevation in enddiastolic volume that results in a rise in stroke volume (via the Frank-Starling mechanism). (See "Pathophysiology of heart failure: Left ventricular pressure-volume relationships" ). There are, however, a number of maladaptive consequences of neurohumoral activation ( show figure 1): The elevation in diastolic pressures is transmitted to the atria and to the pulmonary and systemic venous circulations; the ensuing elevation in capillary pressures promotes the development of pulmonary congestion and peripheral edema The increase in left ventricular afterload induced by the rise in peripheral resistance can both directly depress cardiac function and enhance the rate of deterioration of myocardial function (show figure 2) [1] Catecholamine-stimulated contractility and increased heart rate can worsen coronary ischemia Catecholamines and angiotensin II may promote the loss of myocytes by apoptosis, the induction of maladaptive fetal isoforms of proteins involved in contraction, and hypertrophy The relative importance of these beneficial and detrimental effects is not fully defined. However, the slowing of disease progression and improvement in survival observed with angiotensin converting enzyme (ACE) inhibitors and beta blockers in patients with heart failure due to systolic dysfunction suggest that there is, over time, a net negative effect of the neurohumoral adaptations on ventricular function. (See "Overview of the therapy of heart failure due to systolic dysfunction"). The major neurohumoral adaptations that occur in HF, including activation of the sympathetic and renin-angiotensin systems, and increased secretion of antidiuretic hormone, natriuretic peptides, and endothelin will be reviewed here. The effects of HF on other signaling systems (eg, nitric oxide and
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adrenomedullin) and on cytokines and chemokines are discussed separately. ( See "Nitric oxide, other hormones, cytokines, and chemokines in heart failure"). NEUROHUMORAL ADAPTATIONS The principal neurohumoral systems involved in the response to HF are the sympathetic nervous system, the reninangiotensinaldosterone system, and antidiuretic hormone (show figure 3) [1-3] . Other vasoactive substances are also affected, including the vasoconstrictor endothelin and the vasodilators atrial natriuretic peptide and nitric oxide. These hormonal changes are seen with both systolic and diastolic dysfunction. Sympathetic nervous system One of the first responses to a decrease in cardiac output (sensed as a fall in blood pressure) is activation of the sympathetic nervous system, resulting in both increased release and decreased uptake of norepinephrine (NE) at adrenergic nerve endings. Downregulation of peripheral alpha-2 receptor function, which normally inhibits NE release, may contribute to sympathetic activation in heart failure [4] . Early in heart failure, catecholamine-induced augmentation of ventricular contractility and heart rate help maintain cardiac output, particularly during exercise. However, with progressive worsening of ventricular function, these mechanisms are no longer sufficient. As an example, an increase in heart rate also enhances ventricular contractility due to the normal force-frequency relationship; this relationship is blunted in heart failure [5] . Increased sympathetic activity also leads to systemic and pulmonary vasoconstriction and enhanced venous tone, both of which initially contribute to the maintenance of blood pressure by increasing ventricular preload. Renal vasoconstriction (mediated by both NE and angiotensin II) occurs primarily at the efferent arteriole, producing an increase in filtration fraction that allows glomerular filtration to be relatively well maintained despite a fall in renal blood flow. Both NE and angiotensin II also stimulate proximal tubular sodium reabsorption, which contributes to the sodium retention characteristic of HF. Sympathetic activation results in an increase in the plasma NE concentration, which correlates directly with the severity of the cardiac dysfunction and inversely with survival ( show figure 4) [6] . An analysis of more than 4000 patients from the Val-HeFT trial found that those with an initial plasma NE concentration in the highest quartile (572 pg/mL [3.38 nmol/L]) had a significantly higher mortality rate at two years than those with an initial plasma NE concentration in the lowest quartile (<274 pg/mL [1.62 nmol/L]) (24.2 versus 13.8 percent) (show figure 5) [7] . The degree of sympathetic activation can be reduced by effective treatment of HF, as with administration of an ACE inhibitor. In a study of 223 patients with mild or moderate heart failure, for example, ramipril therapy for 12 weeks significantly lowered the plasma NE concentration (compared with placebo) in patients with the most pronounced degree of neurohumoral activation [ 8] . In the SOLVD trial, patients who had more marked neurohormonal activation, as reflected by plasma NE or angiotensin II, had a larger survival benefit with ACE inhibition than patients with less activation [ 9] . In addition to systemic sympathetic activation, there is an increase in cardiac efferent sympathetic activity in patients with heart failure. This effect has been demonstrated by increased cardiac NE spillover (ie, elevated NE levels in cardiac veins) [ 10,11] . A reduction in ventricular filling pressures reduces cardiac NE spillover [12] . A similar effect is seen with amiodarone [13] . (See "Ventricular arrhythmias in heart failure and cardiomyopathy"). The chronic increase in sympathetic activity also leads to downregulation and reduction in density of the cardiac beta-adrenergic receptors and desensitization of the signaling cascade through which the receptors couple to physiologic events [14] ; this results in impaired inotropic and chronotropic responses. In addition, chronically increased stimulation of beta-adrenergic receptors may cause molecular and cellular abnormalities, which contribute to progression of myocardial dysfunction by the
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reexpression of fetal protein isoforms and the loss of cardiomyocytes due to apoptosis or necrosis [15] . Myocyte apoptosis in HF has been attributed to beta-adrenergic receptor coupling to stimulatory G protein (Gs)-dependent cAMP-mediated signaling [ 16] . Less evidence is available for a potential myocyte necrosis pathway mediated through a beta-1 adrenergic receptor modulated pathway involving calcium overload and mitochondria permeability transition [ 17] . On the other hand, beta-1 adrenergic receptors may also deliver an antiapoptotic signal through transactivation of epidermal growth factor receptors (EGFR) [18] . Role of beta adrenergic receptors There is evidence that ventricular myocardium contains beta-2 as well as beta-1 adrenergic receptors [19] and that, in HF, there is a selective reduction in the density of beta-1 but not beta-2 receptors [20,21] . As a result, the failing heart is more dependent upon beta-2 adrenergic receptors for inotropic support. There is evidence that myocardial beta-2 adrenergic receptors may mediate both beneficial and deleterious effects in heart failure. Genetic heterogeneity in the structure of the beta-2 receptor has been found and the most important polymorphic receptor results from a threonine (Thr) to isoleucine (Ile) switch at amino acid 164 [ 22] . This receptor displays a small decrease in binding affinity for catecholamines and certain beta receptor antagonists and a substantial decrease in basal and epinephrine-stimulated adenylyl cyclase activities. Transgenic mice expressing the Ile164 receptor display depressed resting and agonist-stimulated contractile function compared to mice with the Thr164 receptor [ 22] . In one series in humans, there was no difference in the frequency of these receptor genotypes in 259 patients with HF compared to 212 healthy controls [23] . However, patients with the Ile164 receptor had a reduced one year survival (42 versus 76 percent for those with the Thr164 receptor) and a relative risk of death or cardiac transplantation of 4.8 (p<0.001). A possible mechanism is blunted cardiac beta-2 receptor responsiveness [24] . In addition to helping to support the myocardial contractile response to sympathetic stimulation, beta-2 adrenergic receptors located on the cardiac myocyte exert an anti-apoptotic effect that opposes the pro-apoptotic action of beta-1 receptor stimulation [ 25] . On the other hand, stimulation of beta-2 receptors may also mediate adverse effects. In contrast to presynaptic alpha-2 adrenergic receptors, which inhibit sympathetic norepinephrine release, presynaptic beta-2 adrenergic receptors stimulate norepinephrine release [ 26] . Possibly related to this action, beta-2 receptor stimulation appears to increase the propensity for ventricular fibrillation. As an example, one study of animals with experimentally induced HF found that an isoproterenol infusion activated beta-2 receptors to a greater extent and resulted in a greater intracellular influx of calcium during ischemia compared to non-HF rats [27] . These actions were prevented by selective blockade of the beta-2 receptor, but not by blockade of the beta-1 receptor, and beta-2 receptor blockade prevented ischemia mediated ventricular fibrillation. These data suggest that activation of the beta-2 receptor on the cardiac myocyte, leading to increased cytosolic calcium, may produce afterpotentials that can ultimately trigger ventricular fibrillation. These changes may explain the beneficial effects of beta blockers on both cardiac performance and survival in some patients with chronic HF. Acute studies suggest that cardiac sympathetic activity is reduced to a greater degree by nonselective than selective beta blockers [26] . (See "Use of beta blockers in heart failure due to systolic dysfunction" ). Reninangiotensin system Each of the factors that stimulate renal renin release is activated in HF: decreased stretch of the glomerular afferent arteriole, reduced delivery of chloride to the macula densa, and increased beta-1 adrenergic activity. (See "Chapter 2B: Renin-angiotensin system" for a review of the physiology of this system). There is also evidence that angiotensin II can be synthesized locally at a variety of tissue sites including the kidney, blood vessels, adrenal gland, and brain. For this reason, measurement of the plasma renin
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activity or angiotensin II concentration may underestimate tissue angiotensin II activity. As an example, the plasma renin activity is often normal in patients with stable, chronic HF, despite persistence of the low output state and renal sodium retention [ 28] . Studies in experimental models of heart failure suggest that there may be increased activity of the intrarenal renin-angiotensin system in this setting [26] . In comparison, plasma renin levels are usually markedly elevated in patients with recent onset or very symptomatic HF (show figure 3) [1,3,28] . In addition to activation of the systemic renin-angiotensin system in heart failure, there is evidence of local cardiac angiotensin II and angiotensin converting enzyme production is in proportion to the severity of heart failure [29-33] . This phenomenon could explain in part why angiotensin converting enzyme inhibitors are more beneficial in patients with HF than other vasodilators. ( See "Actions of angiotensin II on the heart" and see "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action"). Angiotensin II has similar actions to NE in HF, increasing sodium reabsorption (an effect mediated in part by enhanced release of aldosterone) and inducing systemic and renal vasoconstriction. Similar to NE, angiotensin II can act directly on myocytes and other cell types in the myocardium to promote pathologic remodeling via myocyte hypertrophy, reexpression of fetal protein isoforms, myocyte apoptosis, and alterations in the interstitial matrix. ( See "Cardiac remodeling: Basic aspects"). Aldosterone Secondary hyperaldosteronism in heart failure has been thought to reflect angiotensin II-mediated stimulation of the adrenal glands. However, there is also local production of aldosterone in the failing heart in proportion to the severity of heart failure [ 33] , an effect that is mediated by the induction of aldosterone synthase (CYP11B2) by angiotensin II in the failing ventricle [ 34] . Adverse effects of aldosterone-induced stimulation of cardiac mineralocorticoid receptors are thought to contribute to the survival benefit associated with the administration of mineralocorticoid receptor antagonists in selected patients with heart failure. ( See "Use of diuretics in heart failure", section on Improved survival with aldosterone antagonism). ACE gene polymorphism Plasma and tissue concentrations of ACE, and therefore of angiotensin II, are in part determined by the ACE gene. This gene may manifest insertion (I) or deletion (D) polymorphism and three genotypes (DD, ID, and II). Plasma and cardiac levels of ACE are 1.5 to 3-fold higher in patients with the DD compared to the II genotype; the values are intermediate in patients with ID genotype [35] . The DD genotype of the angiotensin converting enzyme gene has been associated with a number of adverse cardiovascular events. (See "Actions of angiotensin II on the heart", section on ACE gene polymorphism). There may be an association between the DD genotype and increased mortality and reduced transplant-free survival in patients with HF due to idiopathic dilated cardiomyopathy [ 36-39] . This difference may be abolished with beta blocker therapy as, in one study, transplant-free survival was equivalent in patients with the DD, ID, and II genotypes who were treated with a beta blocker [ 38] . The adverse effect of the DD genotype on survival in patients with HF may be related to progression of HF rather than to arrhythmic sudden cardiac death [39] . Antidiuretic hormone Activation of the carotid sinus and aortic arch baroreceptors by the low cardiac output in heart failure leads to enhanced release of ADH and stimulation of thirst. ( See "Chapter 6B: Antidiuretic hormone and water balance" ). Elevated levels of ADH may contribute to the increase in systemic vascular resistance in HF via stimulation of the V1A receptor, which is found on vascular smooth muscle cells, and also promote water retention via the V2 receptor by enhancing water reabsorption in the collecting tubules. The combination of decreased water excretion and increased water intake via thirst often leads to a fall in the plasma sodium concentration. The severity of these defects tends to parallel the severity of the heart failure. As a result, the degree of hyponatremia is an important predictor of
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survival in these patients (show figure 6). (See "Hyponatremia in heart failure"). Atrial and brain natriuretic peptides Atrial natriuretic peptide (ANP) is primarily released from the atria in response to volume expansion, which is sensed as an increase in atrial stretch. ANP release is increased in heart failure. Plasma ANP levels rise early in the course of the disease and have been used as a marker for the diagnosis of asymptomatic left ventricular dysfunction. With chronic and more advanced heart failure, ventricular cells can also be recruited to secrete both ANP and brain natriuretic peptide (BNP), an analogous peptide, in response to the high ventricular filling pressures. These relationships have allowed the plasma concentration of these peptides, particularly BNP, to be used to detect heart failure and to predict the outcome and perhaps guide therapy in patients with established disease. These issues are discussed elsewhere. (See "Brain natriuretic peptide measurement in left ventricular dysfunction and other cardiac diseases" ). Endothelin Endothelin, another substance produced by the vascular endothelium, may contribute to the regulation of myocardial function, vascular tone, and peripheral resistance in HF. Plasma endothelin concentrations are increased in patients with HF; experimental studies suggest that endothelin is released in part from cardiac myocytes and coronary vascular endothelium, and that angiotensin II may contribute to the high circulating levels in HF. Over the long-term, high levels of endothelin (as with angiotensin II) may be deleterious to the heart due, for example, to pathologic remodeling. This has led to the evaluation of endothelin inhibition as a therapy for heart failure. ( See "Role of endothelin in heart failure"). SUMMARY In the short term, neurohumoral activation is beneficial in patients with HF since the elevations in cardiac contractility and vascular resistance and renal sodium retention tend to restore the cardiac output and tissue perfusion toward normal. However, the deleterious effects may predominate over the long-term, leading to pulmonary and peripheral edema, increased afterload, pathologic myocardial remodeling, and more rapid progression of myocardial dysfunction. The ability of ACE inhibitors and beta blockers to improve survival and slow the progression of the heart failure is compatible with this hypothesis. ( See "Overview of the therapy of heart failure due to systolic dysfunction" and see "Cardiac remodeling: Clinical assessment and therapy" ).
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REFERENCES
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35. 36. 37. 38.
39.
GRAPHICS
Functional and structural modifications following neurohormonal stimulation in heart failure
Neurohumoral activation in CHF
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Depressed ventricular contractility, induced by the underlying cardiac disease, leads to neurohumoral activation (moving clockwise) that is initially adaptive in that it maintains blood pressure and tissue perfusion. Over the long-term, however, the increase in outflow resistance (afterload) hastens the rate of myocardial deterioration and worsens ventricular performance. This leads to a vicious cycle of increasing release of norepinephrine, angiotensin II, and ADH that further increases afterload.
Hormone levels in CHF
Plasma levels of norepinephrine, renin activity, and antidiuretic hormone are increased two to eight fold (when compared to normal subjects) in patients with stable congestive heart failure treated with digitalis, but not diuretics or vasodilators. Data from Francis, GS, Goldsmith, SR, Levine, TB, et al, Ann Intern Med
1984; 101:370.
Plasma norepinephrine and survival in CHF
Percent probability of survival in patients with advanced congestive heart failure according to the plasma norepinephrine concentration. Survival was inversely related to the degree of norepinephrine activation, a
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presumed reflection of worsening cardiac function. The time to 50 percent survival was approximately 30 months in patients with normal norepinephrine levels (200 pg/mL), but only about 10 months in those with marked hypersecretion (1200 pg/mL). Data from Cohn, JN, Levine,
TB, Olivaro, MT, et al, N Engl J Med 1984; 311:819.
Plasma NE concentration predicts survival in patients with HF
In an analysis from the Val-HeFT trial, patients with NYHA class II to III heart failure (HF) were stratified according to quartiles of plasma concentration of norepinephrine (NE). The mortality rates at two years after randomization were significantly higher in higher quartiles of plasma NE. Data from: Anand, IS, Fisher, LD, Chiang, YT, et al.
Circulation 2003; 107:1278.
Hyponatremia associated with reduced survival in CHF
Survival over time in patients with severe heart failure and a normal plasma sodium concentration (solid line) or hyponatremia (dashed line). Survival was significantly reduced in patients with hyponatremia. Data from Lee, WH,
Packer, M, Circulation 1986; 73:257.
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