Abstract
Aldosterone is an important mediator in the pathogenesis of heart failure, and increased plasma aldosterone levels are associated with a poor prognosis. Aldosterone-receptor blocking drugs can slow the progression of left ventricular remodeling and reduce the occurrence of sudden cardiac death. Two widely publicized clinical trials provide data demonstrating survival benefits with spironolactone and eplerenone in chronic and postinfarction heart failure. The publication of these trials has generated widespread enthusiasm for spironolactone and eplerenone, leading to the more frequent and sometimes unbridled use of these drugs in the medical community. We herein describe the likely mechanisms of action of aldosterone-receptor antagonists, discuss the existing clinical evidence supporting their use, and provide practical advice on their use in the management of patients with heart failure.
Key Points
-
Large clinical trials have shown aldosterone-receptor antagonists to be an effective treatment for patients with advanced symptomatic heart failure or postinfarction heart failure
-
Spironolactone and eplerenone have similar inhibitory effects on mineralocorticoid receptor activation, but cost and adverse effect profiles are different
-
Close monitoring of hyperkalemia and renal insufficiency are warranted to ensure the benefits of aldosterone-receptor antagonists outweigh the risks
-
Controversies still remain regarding the use of aldosterone-receptor antagonists in patients with mild symptoms or underlying diastolic heart failure, and the use of aldosterone-receptor antagonists in conjunction with angiotensin-converting-enzyme inhibitors, angiotensin-receptor antagonists and β-blockers
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rosamond W et al. (2006) Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115: e69
The CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316: 1429–1435
The SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325: 293–302
Packer M et al. (1996) The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group. N Engl J Med 334: 1349–1355
Swedberg K et al. (1990) Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 82: 1730–1736
Weber KT and Brilla CG (1991) Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 83: 1849–1865
Wilke A et al. (1996) Effect of the renin-angiotensin-aldosterone system on the cardiac interstitium in heart failure. Basic Res Cardiol 91 (Suppl 2): S79–S84
Rossi GP et al. (1996) Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension 27: 1039–1045
Milliez P et al. (2005) Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45: 1243–1248
Rocha R and Stier CT Jr (2001) Pathophysiological effects of aldosterone in cardiovascular tissues. Trends Endocrinol Metab 12: 308–314
Blacher J et al. (1997) Association between increased plasma levels of aldosterone and decreased systemic arterial compliance in subjects with essential hypertension. Am J Hypertens 10: 1326–1334
Duprez DA et al. (1998) Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J 19: 1371–1376
Rude MK et al. (2005) Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension 46: 555–561
Iglarz M et al. (2004) Involvement of oxidative stress in the profibrotic action of aldosterone: interaction with the renin-angiotension system. Am J Hypertens 17: 597–603
Sato A and Saruta T (2003) Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy. Am J Hypertens 16: 781–788
Sato A and Saruta T (2001) Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 29: 13–21
Cohn JN et al. (2003) Sustained reduction of aldosterone in response to the angiotensin receptor blocker valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial. Circulation 108: 1306–1309
McKelvie RS et al. (1999) Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 100: 1056–1064
Tang WH et al. (2002) Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure. J Am Coll Cardiol 39: 70–78
Staessen J et al. (1981) Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol 91: 457–465
Staessen J et al. (1981) Rise of plasma aldosterone during long-term captopril treatment. N Engl J Med 304: 1110
Pitt B (1995) “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 9: 145–149
Cicoira M et al. (2002) Relation of aldosterone “escape” despite angiotensin-converting enzyme inhibitor administration to impaired exercise capacity in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 89: 403–407
MacFadyen RJ et al. (1999) How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 82: 57–61
Pitt B et al. (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341: 709–717
Pitt B et al. (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348: 1309–1321
Pitt B et al. (2005) Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol 46: 425–431
Perrier E et al. (2004) Mineralocorticoid receptor antagonism prevents the electrical remodeling that precedes cellular hypertrophy after myocardial infarction. Circulation 110: 776–783
Hayashi M et al. (2003) Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 107: 2559–2565
Hohnloser SH et al. (2004) Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med 351: 2481–2488
Degre S et al. (1998) Effects of spironolactone-altizide on left ventricular hypertrophy. Acta Cardiol 53: 261–267
Sato A et al. (1999) Effects of spironolactone and angiotensin-converting enzyme inhibitor on left ventricular hypertrophy in patients with essential hypertension. Hypertens Res 22: 17–22
Pitt B et al. (2003) Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 108: 1831–1838
Fraccarollo D et al. (2005) Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction. Cardiovasc Res 67: 97–105
Barr CS et al. (1995) Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 76: 1259–1265
Yee KM et al. (2001) Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J Am Coll Cardiol 37: 1800–1807
MacFadyen RJ et al. (1997) Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 35: 30–34
Ramires FJ et al. (2000) Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol 85: 1207–1211
Schulman M and Narins RG (1990) Hypokalemia and cardiovascular disease. Am J Cardiol 65: 4E–9E
Schersten B et al. (1980) Clinical and biochemical effects of spironolactone administered once daily in primary hypertension. Multicenter Sweden study. Hypertension 2: 672–679
Burgess ED et al. (2003) Long-term safety and efficacy of the selective aldosterone blocker eplerenone in patients with essential hypertension. Clin Ther 25: 2388–2404
Bauersachs J et al. (2000) Striking increase of natriuresis by low-dose spironolactone in congestive heart failure only in combination with ACE inhibition: mechanistic evidence to support RALES. Circulation 102: 2325–2328
Farquharson CA and Struthers AD (2000) Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 101: 594–597
Rajagopalan S et al. (2002) Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation 105: 2212–2216
Bauersachs J et al. (2002) Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction: role of vascular superoxide anion formation and endothelial nitric oxide synthase expression. J Am Coll Cardiol 39: 351–358
Ahokas RA et al. (2003) Aldosteronism and peripheral blood mononuclear cell activation: a neuroendocrine-immune interface. Circ Res 93: e124–e135
Bozkurt B et al. (2003) Complications of inappropriate use of spironolactone in heart failure: when an old medicine spirals out of new guidelines. J Am Coll Cardiol 41: 211–214
Masoudi FA et al. (2005) Adoption of spironolactone therapy for older patients with heart failure and left ventricular systolic dysfunction in the United States, 1998-2001. Circulation 112: 39–47
Juurlink DN et al. (2004) Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 351: 543–551
Shah KB et al. (2005) The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol 46: 845–849
Hunt SA et al. (2005) ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 112: e154–e235
Berry C and McMurray JJ (2001) Serious adverse events experienced by patients with chronic heart failure taking spironolactone. Heart 85: E8
Daniels IR and Layer GT (2001) Gynaecomastia. Eur J Surg 167: 885–892
Weintraub WS et al. (2005) Cost-effectiveness of eplerenone compared with placebo in patients with myocardial infarction complicated by left ventricular dysfunction and heart failure. Circulation 111: 1106–1113
Cohn JN and Tognoni G (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 345: 1667–1675
McMurray JJ et al. (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 362: 767–771
Mottram PM et al. (2004) Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 110: 558–565
Klappacher G et al. (1995) Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol 75: 913–918
Host NB et al. (1995) The aminoterminal propeptide of type III procollagen provides new information on prognosis after acute myocardial infarction. Am J Cardiol 76: 869–873
Zannad F et al. (2001) Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension 38: 1227–1232
Krum H et al. (2002) Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension 40: 117–123
Francis GS and Tang WH (2005) Should we consider aldosterone as the primary screening target for preventing cardiovascular events? J Am Coll Cardiol 45: 1249–1250
Acknowledgements
Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
WHW Tang serves as a consultant for AstraZeneca Pharmaceuticals. He receives research support from the American Heart Association and GlaxoSmithKline Pharmaceuticals.
Gary S Francis serves on Scientific Advisory Boards for Pfizer. He receives research grant support from Pfizer for conducting a mechanistic study using eplerenone. He also serves as a consultant to Novartis Pharmaceuticals.
Rights and permissions
About this article
Cite this article
Kalidindi, S., Tang, W. & Francis, G. Drug Insight: aldosterone-receptor antagonists in heart failure—the journey continues. Nat Rev Cardiol 4, 368–378 (2007). https://doi.org/10.1038/ncpcardio0914
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpcardio0914
This article is cited by
-
Besonderheiten der Pharmakotherapie beim älteren Hypertoniker
Der Internist (2009)
-
The failing diabetic heart: Focus on diastolic left ventricular dysfunction
Current Diabetes Reports (2009)