Version May 2024
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 function. In HF, neurohumoral adaptations have beneficial as well as maladaptive effects.
The major neurohumoral adaptations that occur in HF, including activation of the sympathetic and renin-angiotensin-aldosterone systems; increased secretion of antidiuretic hormone, natriuretic peptides, and endothelin; and alterations in nitric oxide, will be reviewed here. Hemodynamic alterations in HF are discussed separately. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling".)
NEUROHUMORAL ADAPTATIONS — The principal neurohumoral systems involved in the response to HF are the sympathetic nervous system, the renin-angiotensin-aldosterone system, and antidiuretic hormone [1-3]. Other vasoactive substances are also affected, including the vasoconstrictor endothelin and the vasodilators atrial natriuretic peptide, brain natriuretic peptide (BNP), and nitric oxide. These hormonal changes are seen with both systolic and diastolic dysfunction.
Neurohumoral adaptations 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 end-diastolic volume that results in a rise in stroke volume (via the Frank-Starling mechanism).
In HF, these adaptations tend to overwhelm the vasodilatory and natriuretic effects of compensatory pathways including natriuretic peptides, nitric oxide, prostaglandins, and bradykinin [4-6].
There are a number of maladaptive consequences of persistent neurohumoral activation (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 (LV) afterload induced by the rise in peripheral resistance can both directly depress cardiac function due to the increase in LV afterload and, over time, enhance the rate of deterioration of myocardial function (figure 2) [1].
●The increases in contractility, heart rate, and LV afterload caused by neurohumoral adaptations can worsen or provoke coronary ischemia.
●Catecholamines, angiotensin II, and aldosterone contribute to cardiac dysfunction by promoting the loss of myocytes by apoptosis, inducing maladaptive fetal isoforms of proteins involved in contraction, and causing myocardial hypertrophy and fibrosis.
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 treatment with angiotensin converting enzyme inhibitors, angiotensin-receptor blockers, mineralocorticoid receptor antagonists, and beta blockers in patients with HF due to systolic dysfunction suggest that there is, over time, a net negative effect of the neurohumoral adaptations on ventricular function. The clinical benefits of inhibitors of these neurohormonal effects occur even in patients with mild or absent symptoms who may have only modest activation of these systems. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction", section on 'Approach to initial medical therapy' and "Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action".)
Sympathetic nervous system — The role of sympathetic nervous system activation in HF is complex, with both beneficial and adverse effects. Sympathetic nervous system activation is one of the first responses to a decrease in cardiac output, resulting in both increased release and decreased uptake of norepinephrine (NE) at adrenergic nerve endings. Downregulation or genetic loss-of-function variants of peripheral alpha-2 receptors, which normally inhibit NE release, may contribute to sympathetic activation in HF [7]. Early in HF, 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. In addition, intrinsic mechanisms that enhance ventricular contractility due to the normal force-frequency relationship are blunted in HF [8].
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 is reflected by an increase in the plasma NE concentration, which correlates directly with the severity of the cardiac dysfunction and inversely with survival (figure 3) [9,10].
In addition to systemic sympathetic activation, there is an increase in cardiac efferent sympathetic activity in patients with HF. This effect has been demonstrated by increased cardiac NE spillover (ie, elevated NE levels in cardiac veins) [11,12]. A reduction in ventricular filling pressures reduces cardiac NE spillover [13]. A similar effect is seen with amiodarone and may contribute to its clinical effects [14]. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".)
The chronic increase in sympathetic activity also leads to downregulation and reduction in the density of the cardiac beta-adrenergic receptors and desensitization of the signaling cascade through which the receptors couple to physiologic events [15]; this results in impaired inotropic and chronotropic responses. In addition, chronically increased stimulation of beta-adrenergic receptors may cause molecular and cellular abnormalities that contribute to the progression of myocardial dysfunction by the re-expression of fetal protein isoforms and the loss of cardiomyocytes due to apoptosis or necrosis [16].
The degree of sympathetic activation can be reduced by effective treatment of HF, as with administration of an angiotensin converting enzyme (ACE) inhibitor. In a study of 223 patients with mild or moderate HF, 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 [17]. In the SOLVD trial, patients who had more marked neurohumoral activation, as reflected by plasma NE or angiotensin II, had a larger survival benefit with ACE inhibition than patients with less activation [18].
These observations suggested that other methods of inhibiting sympathetic outflow might be of value in patients with HF, and led to the use of moxonidine, a drug that acts centrally to decrease sympathetic outflow. However, in the MOXCON trial, titration to a moxonidine target dose of 1.5 mg BID, which is associated with a decrease in plasma NE on the order of 50 percent [19], was associated with an increase in deaths and adverse events [20]. This experience showed that the role of sympathetic tone in HF is complex, and that generalized over-suppression of sympathetic tone can be harmful.
Role of myocardial adrenergic receptors — The effects of the sympathetic nervous system on the myocardium are mediated by both beta- and alpha-adrenergic receptors in the myocardium. Stimulation of beta-1, and to a lesser extent, beta-2 adrenergic receptors on the cardiac myocyte increases contractility of the heart. These same receptors also mediate the adverse effects of pathologically increased catecholamines on myocyte viability. Myocyte apoptosis in HF has been attributed primarily to beta-1 adrenergic receptors that couple to stimulatory G protein (Gs)-dependent cAMP-mediated signaling [21]. Excessive stimulation of beta-1 receptors may also lead to myocyte necrosis that is modulated by calcium overload and mitochondria permeability transition [22].
In HF, there is a selective reduction in the density of beta-1 but not beta-2 receptors on the cardiac myocyte [23,24]. As a result, the failing heart may be more dependent upon beta-2 adrenergic receptors for inotropic support. In addition, a polymorphism of the beta-2 receptor has been found in which a threonine (Thr) is replaced by isoleucine (Ile) at amino acid 164 [25], resulting in a substantial decrease in the activity of the receptor. Transgenic mice expressing the Ile164 switch display depressed resting and agonist-stimulated contractile function compared with mice with the Thr164 receptor [25]. In one series in humans, there was no difference in the frequency of these receptor genotypes in 259 patients with HF compared with 212 healthy controls [26]. 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 [27]. 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 [28].
On the other hand, stimulation of pre-synaptic beta-2 receptors in the myocardium may mediate adverse effects. In contrast to presynaptic alpha-2 adrenergic receptors, which inhibit sympathetic NE release, presynaptic beta-2 adrenergic receptors stimulate NE release [29]. Beta-blockers may act in part by reducing beta-2 receptor-mediated NE release in the heart, an effect that appears to be greater with nonselective versus selective beta blockers [29]. (See "Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action", section on 'Beta blockers' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)
Renin-angiotensin 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 (figure 4). Typically, plasma renin levels are elevated in patients with symptomatic HF (figure 5) [1,3,30].
In addition, angiotensin II can be synthesized locally at a variety of tissue sites including the heart, kidney, blood vessels, adrenal gland, and brain. For this reason, measurement of the plasma renin 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 [30]. Studies in experimental models of HF suggest that there may be increased activity of the intrarenal renin-angiotensin system in this setting [29].
Likewise, local cardiac angiotensin II and angiotensin converting enzyme production is increased in proportion to the severity of HF [31-35].
Angiotensin II has many 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, re-expression of fetal protein isoforms, myocyte apoptosis, and alterations in the interstitial matrix. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Neurohormonal activation'.)
Aldosterone — Secondary hyperaldosteronism in HF 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 HF [35], an effect that is mediated by the induction of aldosterone synthase (CYP11B2) by angiotensin II in the failing ventricle [36].
Blockade of the adverse effects of aldosterone-induced stimulation of cardiac mineralocorticoid receptors is thought to contribute to the survival benefit associated with the administration of mineralocorticoid receptor antagonists in selected patients with HF. The effects of mineralocorticoid receptor antagonists on remodeling are discussed separately. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling", section on 'Neurohormonal activation' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.)
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 with the II genotype; the values are intermediate in patients with ID genotype [37]. The DD genotype of the ACE gene has been associated with a variety of adverse cardiovascular events, including conflicting data on impact on risk of coronary disease [38-53].
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 [44,45,54,55]. 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 [45]. 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 [55].
Antidiuretic hormone — Activation of the carotid sinus and aortic arch baroreceptors by the low cardiac output in HF leads to enhanced release of antidiuretic hormone (ADH) and stimulation of thirst (see "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Role of ADH in volume regulation'). 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 HF. As a result, the degree of hyponatremia is an important predictor of survival in these patients (figure 6). (See "Hyponatremia in patients with heart failure".)
Endothelin — Endothelins are potent vasoconstrictor peptides produced by the vascular endothelium and cardiac myocytes which 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 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 [56,57]. This has led to the evaluation of endothelin inhibition as a therapy for HF. However, clinical trials of endothelin receptor blockade in patients with HFrEF have demonstrated no benefit and some evidence of harm [58-60].
Natriuretic peptides — Volume expansion and/or increased intra-cardiac pressures leads to increased atrial and ventricular strain which triggers the release of atrial natriuretic peptide (ANP), primarily from the atria, and BNP, primarily from the ventricles. Thus, plasma levels of these natriuretic peptides are elevated in patients with HF. The diagnostic and prognostic value of measuring levels of these hormones and related peptides is discussed separately. (See "Natriuretic peptide measurement in heart failure".)
While plasma natriuretic peptide levels are useful biomarkers of disease severity, there is also evidence that natriuretic peptides, and in particular BNP, play an important beneficial role in the pathophysiology of HF. The natriuretic peptides exert a wide array of cellular and systemic effects which, by and large, oppose those of the adverse effects of the sympathetic nervous system and renin-angiotensin-aldosterone system. For example, they oppose vasoconstriction, promote salt and water excretion, and protect target organs from the adverse effects of NE and angiotensin. (See "Natriuretic peptide measurement in heart failure", section on 'Physiologic role in HF'.)
The combination drug sacubitril-valsartan exerts outcome effects superior to ACE inhibition in patients with HFrEF. A major action of sacubitril is inhibition of the degradation of natriuretic peptides. Whether sacubitril's effectiveness relates to enhanced natriuretic peptide levels or to vasodilation from other peptides remains uncertain. (See "Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action", section on 'Angiotensin receptor-neprilysin inhibitor (ARNI)'.)
Nitric oxide — Nitric oxide (NO) is enzymatically formed from L-arginine by three isoforms of NO synthetase (NOS): neuronal-type (nNOS, NOS1), cytokine-inducible NOS (iNOS, NOS2), and the endothelial-type (eNOS, NOS3) [61]. These enzymes differ markedly in their localization and function. Many cell types, most notably endothelial cells, constitutively express eNOS, generating relatively low levels of NO that are under tight control by regulatory factors. By contrast, iNOS is normally not expressed, but when induced by inflammatory cytokines can generate large amounts of NO far in excess of those made by eNOS. There may be alterations in all three isoforms of NOS in HF.
In endothelium — In endothelium - Chronic HF is associated with arterial endothelial dysfunction and impaired endothelium-dependent, flow-mediated dilation; the mechanism is probably a reduction in NO synthesis via eNOS [62] as well as a decrease in endothelial release of and response to NO [63,64]. By contrast, venous endothelial function and tone and basal and stimulated NO release from the venous capacitance bed are preserved [65]. (See "Coronary endothelial dysfunction: Clinical aspects".)
There is evidence of increased free radical formation in HF, and it is possible that these species inactivate NO. Support for this hypothesis comes from one study in which vitamin C improved endothelial function in patients with HF in association with an increased availability of NO [66].
In myocardium and skeletal muscle — The level of NOS activity in the failing human myocardium is variable, likely reflecting the multiple types of NOS and the heterogeneity of myocardial failure. Increased levels of activity of eNOS [67] and nNOS [68], and increased NO production, have been observed within myocytes from patients with HF due to either an ischemic or nonischemic dilated cardiomyopathy [67-70]. The expression of iNOS, in particular, appears to correlate with the level of tumor necrosis factor alpha (TNFa) [71].
NO may exert detrimental as well as beneficial effects in the myocardium:
●NO production lowered myocyte energy production by directly affecting mitochondrial function in an animal model [72]. While this effect may limit energy availability, it may also reduce the generation of reactive oxygen radicals in the mitochondria.
●In an animal model of myocardial infarction, eNOs limited LV remodeling and dysfunction [73].
●NO can also affect basal myocardial function and can impair the inotropic response to beta-adrenergic receptor stimulation [70,74-77].
●The induction of iNOS by inflammatory cytokines can generate high levels of NO that combine with superoxide to produce peroxynitrite, a reactive oxygen species that exerts harmful effects on the myocardium [78].
Inducible NO synthase gene expression and local NO production may also be increased within skeletal muscle of patients with HF [79]. This response could contribute to a reduction in contractile performance and muscle wasting [79].
SUMMARY
●The principal neurohumoral systems involved in the response to heart failure (HF) are the sympathetic nervous system, the renin-angiotensin-aldosterone system, and antidiuretic hormone. Other vasoactive substances are also affected, including the vasoconstrictor endothelin and the vasodilators atrial natriuretic peptide, brain natriuretic peptide, and nitric oxide (NO). (See 'Neurohumoral adaptations' above.)
●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, 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 angiotensin converting enzyme inhibitors and beta blockers to improve survival and slow the progression of the HF is compatible with this hypothesis. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)
●NO is enzymatically formed from L-arginine by three isoforms of NO synthetase (NOS): neuronal-type (nNOS, NOS1), cytokine-inducible NOS (iNOS, NOS2), and the endothelial-type (eNOS, NOS3). There may be alterations in all three isoforms of NOS in HF. (See 'Nitric oxide' above.)
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