Pathophysiology of heart failure: Neurohumoral adaptations
- Wilson S Colucci, MD
Wilson S Colucci, MD
- Section Editor — Heart Failure
- Professor of Medicine
- Boston University School of Medicine
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.
In HF, these adaptations tend to overwhelm the vasodilatory and natriuretic effects of compensatory pathways including natriuretic peptides, nitric oxide, prostaglandins, and bradykinin [3-5]. 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). (See "Pathophysiology of heart failure: Left ventricular pressure-volume and other hemodynamic relationships".)
There are, however, a number of maladaptive consequences of neurohumoral activation (algorithm 1):
Subscribers log in hereLiterature review current through: Jul 2017. | This topic last updated: Aug 11, 2015.References
- Francis GS, Goldsmith SR, Levine TB, et al. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984; 101:370.
- Dzau VJ. Renal and circulatory mechanisms in congestive heart failure. Kidney Int 1987; 31:1402.
- Sarraf M, Masoumi A, Schrier RW. Cardiorenal syndrome in acute decompensated heart failure. Clin J Am Soc Nephrol 2009; 4:2013.
- Logeart D, Tabet JY, Hittinger L, et al. Transient worsening of renal function during hospitalization for acute heart failure alters outcome. Int J Cardiol 2008; 127:228.
- Cadnapaphornchai MA, Gurevich AK, Weinberger HD, Schrier RW. Pathophysiology of sodium and water retention in heart failure. Cardiology 2001; 96:122.
- Benedict CR, Johnstone DE, Weiner DH, et al. Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: a report from the Registry of Studies of Left Ventricular Dysfunction. SOLVD Investigators. J Am Coll Cardiol 1994; 23:1410.
- Aggarwal A, Esler MD, Socratous F, Kaye DM. Evidence for functional presynaptic alpha-2 adrenoceptors and their down-regulation in human heart failure. J Am Coll Cardiol 2001; 37:1246.
- Bhargava V, Shabetai R, Mathiäsen RA, et al. Loss of adrenergic control of the force-frequency relation in heart failure secondary to idiopathic or ischemic cardiomyopathy. Am J Cardiol 1998; 81:1130.
- Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311:819.
- Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003; 107:1278.
- Sigurdsson A, Amtorp O, Gundersen T, et al. Neurohormonal activation in patients with mild or moderately severe congestive heart failure and effects of ramipril. The Ramipril Trial Study Group. Br Heart J 1994; 72:422.
- SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293.
- Swedberg K, Bristow MR, Cohn JN, et al. Effects of sustained-release moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure. Circulation 2002; 105:1797.
- Cohn JN, Pfeffer MA, Rouleau J, et al. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003; 5:659.
- Kaye DM, Lambert GW, Lefkovits J, et al. Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure. J Am Coll Cardiol 1994; 23:570.
- Kaye DM, Lefkovits J, Jennings GL, et al. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 1995; 26:1257.
- Azevedo ER, Newton GE, Floras JS, Parker JD. Reducing cardiac filling pressure lowers norepinephrine spillover in patients with chronic heart failure. Circulation 2000; 101:2053.
- Kaye DM, Dart AM, Jennings GL, Esler MD. Antiadrenergic effect of chronic amiodarone therapy in human heart failure. J Am Coll Cardiol 1999; 33:1553.
- Nozawa T, Igawa A, Yoshida N, et al. Dual-tracer assessment of coupling between cardiac sympathetic neuronal function and downregulation of beta-receptors during development of hypertensive heart failure of rats. Circulation 1998; 97:2359.
- Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation 1998; 98:1329.
- Vatner DE, Asai K, Iwase M, et al. Beta-adrenergic receptor-G protein-adenylyl cyclase signal transduction in the failing heart. Am J Cardiol 1999; 83:80H.
- Nakayama H, Chen X, Baines CP, et al. Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest 2007; 117:2431.
- Newton GE, Azevedo ER, Parker JD. Inotropic and sympathetic responses to the intracoronary infusion of a beta2-receptor agonist: a human in vivo study. Circulation 1999; 99:2402.
- Bristow MR, Ginsburg R, Umans V, et al. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res 1986; 59:297.
- Altschuld RA, Starling RC, Hamlin RL, et al. Response of failing canine and human heart cells to beta 2-adrenergic stimulation. Circulation 1995; 92:1612.
- Turki J, Lorenz JN, Green SA, et al. Myocardial signaling defects and impaired cardiac function of a human beta 2-adrenergic receptor polymorphism expressed in transgenic mice. Proc Natl Acad Sci U S A 1996; 93:10483.
- Liggett SB, Wagoner LE, Craft LL, et al. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998; 102:1534.
- Brodde OE, Büscher R, Tellkamp R, et al. Blunted cardiac responses to receptor activation in subjects with Thr164Ile beta(2)-adrenoceptors. Circulation 2001; 103:1048.
- Communal C, Singh K, Sawyer DB, Colucci WS. Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte apoptosis : role of a pertussis toxin-sensitive G protein. Circulation 1999; 100:2210.
- Newton GE, Parker JD. Acute effects of beta 1-selective and nonselective beta-adrenergic receptor blockade on cardiac sympathetic activity in congestive heart failure. Circulation 1996; 94:353.
- Billman GE, Castillo LC, Hensley J, et al. Beta2-adrenergic receptor antagonists protect against ventricular fibrillation: in vivo and in vitro evidence for enhanced sensitivity to beta2-adrenergic stimulation in animals susceptible to sudden death. Circulation 1997; 96:1914.
- Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation 1981; 63:645.
- Schunkert H, Ingelfinger JR, Hirsch AT, et al. Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure. J Clin Invest 1992; 90:1523.
- Raman VK, Lee YA, Lindpaintner K. The cardiac renin-angiotensin-aldosterone system and hypertensive cardiac hypertrophy. Am J Cardiol 1995; 76:18D.
- Dostal DE, Baker KM. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ Res 1999; 85:643.
- Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 1993; 153:937.
- Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation 2001; 103:72.
- Silvestre JS, Heymes C, Oubénaïssa A, et al. Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation 1999; 99:2694.
- Danser AH, Schalekamp MA, Bax WA, et al. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 1995; 92:1387.
- Raynolds MV, Bristow MR, Bush EW, et al. Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet 1993; 342:1073.
- Andersson B, Sylvén C. The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure. J Am Coll Cardiol 1996; 28:162.
- McNamara DM, Holubkov R, Janosko K, et al. Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation 2001; 103:1644.
- Bedi MS, Postava LA, Murali S, et al. Interaction of implantable defibrillator therapy with angiotensin-converting enzyme deletion/insertion polymorphism. J Cardiovasc Electrophysiol 2004; 15:1162.