The Role of Mineralocorticoid Receptor Antagonists in Heart Failure with Reduced Ejection Fraction

Author(s): Vasilios Papademetriou*, Maria Toumpourleka, Konstantinos P. Imprialos, Sofia Alataki, Alexandros Manafis, Konstantinos Stavropoulos.

Journal Name: Current Pharmaceutical Design

Volume 24 , Issue 46 , 2018


Background: Heart failure (HF) is a worldwide modern epidemic, associated with significant morbidity and mortality. Several causes have been identified for the syndrome, most of which share common pathophysiologic pathways, including neurohormonal activation. Central to the latter lies activation of the reninangiotensin- aldosterone system, and its effects on cardiovascular disease progression.

Objectives: The aim of this review is to summarize the pathophysiology of aldosterone and the effects of its blockage in the failing heart, as well as to provide state-of-the-art evidence, and address future perspectives regarding the use of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction.

Method: Literature was reviewed for studies that assess the pathophysiology of aldosterone in HF with reduced ejection fraction (HFrEF), and the effects of mineralocorticoid receptor antagonists (MRAs) in this condition.

Results: Several major society guidelines have synthesized the available evidence on HFrEF management, and drugs that block the renin-angiotensin-aldosterone system at different levels continue to form the key component of standard of care for these patients. Mineralocorticoid receptor antagonists are an important part of HFrEF pharmacologic treatment, and their use is supported by a high level of evidence studies. This class of drugs demonstrated significant benefits for morbidity and mortality, across the spectrum oh HFrEF, including patients after acute myocardial infarction.

Conclusion: Current evidence supports the central role of aldosterone in HFrEF progression, and the significant benefits on outcomes with the use of MRAs.

Keywords: Heart failure, reduced ejection fraction, aldosterone, mineralocorticoid receptor antagonists, spironolactone, eplerenone.

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37(27): 2129-200.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341(10): 709-17.
Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348(14): 1309-21.
Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1): 11-21.
Roger VL. Epidemiology of heart failure. Circ Res 2013; 113(6): 646-59.
Zarrinkoub R, Wettermark B, Wändell P, et al. The epidemiology of heart failure, based on data for 2.1 million inhabitants in Sweden. Eur J Heart Fail 2013; 15(9): 995-1002.
Bleumink GS, Knetsch AM, Sturkenboom MCJM, et al. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. Eur Heart J 2004; 25(18): 1614-9.
Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007; 93(9): 1137-46.
van Riet EES, Hoes AW, Wagenaar KP, Limburg A, Landman MA, Rutten FH. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail 2016; 18(3): 242-52.
Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis of heart failure: A population based study. Heart 2000; 83(5): 505-10.
The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: An individual patient data meta-analysis. Eur Heart J 2012; 33(14): 1750-7.
Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis 2008; 51(3): 213-28.
Maggioni AP, Dahlström U, Filippatos G, et al. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2013; 15(7): 808-17.
Gerber Y, Weston SA, Redfield MM, et al. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med 2015; 175(6): 996-1004.
Blecker S, Paul M, Taksler G, Ogedegbe G, Katz S. Heart failure–associated hospitalizations in the United States. J Am Coll Cardiol 2013; 61(12): 1259-67.
Lesman-Leegte I, Jaarsma T, Coyne JC, Hillege HL, Van Veldhuisen DJ, Sanderman R. Quality of life and depressive symptoms in the elderly: A comparison between patients with heart failure and age- and gender-matched community controls. J Card Fail 2009; 15(1): 17-23.
Kraai IH, Vermeulen KM, Luttik MLA, Hoekstra T, Jaarsma T, Hillege HL. Preferences of heart failure patients in daily clinical practice: quality of life or longevity? Eur J Heart Fail 2013; 15(10): 1113-21.
Greene SJ, O’Brien EC, Mentz RJ, et al. Home-Time after discharge among patients hospitalized with heart failure. J Am Coll Cardiol 2018; 71(23): 2643-52.
Cook C, Cole G, Asaria P, Jabbour R, Francis DP. The annual global economic burden of heart failure. Int J Cardiol 2014; 171(3): 368-76.
Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc Pathol 2012; 21(5): 365-71.
Floras JS, Ponikowski P. The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur Heart J 2015; 36(30): 1974-82b.
Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P. Inflammatory cytokines in heart failure: mediators and markers. Cardiology 2012; 122(1): 23-35.
Del Ry S, Cabiati M, Clerico A. Natriuretic peptide system and the heart. Front Horm Res 2014; 43: 134-43.
Yang O, Li J, Kong J. The endothelium as a target for the treatment of heart failure. Cell Biochem Biophys 2015; 72(3): 751-6.
Neubauer S. The failing heart--an engine out of fuel. N Engl J Med 2007; 356(11): 1140-51.
Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet 2011; 378(9792): 704-12.
Shibata H, Ogishima T, Mitani F, et al. Regulation of aldosterone synthase cytochrome P-450 in rat adrenals by angiotensin II and potassium. Endocrinology 1991; 128(5): 2534-9.
Hurwitz S, Cohen RJ, Williams GH. Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed rest. J Appl Physiol 2004; 96(4): 1406-14.
McKay LI, Cidlowski JA. Pharmacokinetics of Corticosteroids.In:Kufe DW, Pollock RE, Weichselbaum RR, et al edsHolland-Frei Cancer Medicine. Hamilton, ON: BC Decker 2003.
Funder JW. Non-genomic actions of aldosterone: role in hypertension. Curr Opin Nephrol Hypertens 2001; 10(2): 227-30.
Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation 1990; 82(5): 1730-6.
Vantrimpont P, Rouleau JL, Ciampi A, et al. Two-year time course and significance of neurohumoral activation in the Survival and Ventricular Enlargement (SAVE) Study. Eur Heart J 1998; 19(10): 1552-63.
MacFadyen RJ, Lee AF, Morton JJ, Pringle SD, Struthers AD. How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 1999; 82(1): 57-61.
McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. Circulation 1999; 100(10): 1056-64.
Struthers AD. The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail 2004; 6(5): 539-45.
Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension 2005; 46(6): 1227-35.
Chun T-Y, Bloem LJ, Pratt JH. Aldosterone inhibits inducible nitric oxide synthase in neonatal rat cardiomyocytes. Endocrinology 2003; 144(5): 1712-7.
Farquharson CAJ, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond) 2002; 103(4): 425-31.
Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 2000; 101(6): 594-7.
Yee KM, Struthers AD. Aldosterone blunts the baroreflex response in man. Clin Sci (Lond) 1998; 95(6): 687-92.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128(16): e240-327.
Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation 2001; 103(1): 72-7.
Garthwaite SM, McMahon EG. The evolution of aldosterone antagonists. Mol Cell Endocrinol 2004; 217(1-2): 27-31.
Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol Cell Endocrinol 2012; 350(2): 310-7.
Roush GC, Ernst ME, Kostis JB, Yeasmin S, Sica DA. Dose doubling, relative potency, and dose equivalence of potassium-sparing diuretics affecting blood pressure and serum potassium: systematic review and meta-analyses. J Hypertens 2016; 34(1): 11-9.
Kolkhof P, Jaisser F, Kim S-Y, Filippatos G, Nowack C, Pitt B. Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside. Handb Exp Pharmacol 2017; 243: 271-305.
Landau RL, Bergenstal DM, Lugibihl K, Kascht ME. The metabolic effects of progesterone in man. J Clin Endocrinol Metab 1955; 15(10): 1194-215.
Kagawa CM, Cella JA, Van Arman CG. Action of new steroids in blocking effects of aldosterone and desoxycorticosterone on salt. Science 1957; 126(3281): 1015-6.
de Gasparo M, Joss U, Ramjoué HP, et al. Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther 1987; 240(2): 650-6.
Lombès M, Oblin ME, Gasc JM, Baulieu EE, Farman N, Bonvalet JP. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ Res 1992; 71(3): 503-10.
Muñoz-Durango N, Vecchiola A, Gonzalez-Gomez LM, et al. Modulation of Immunity and Inflammation by the Mineralocorticoid Receptor and Aldosterone. BioMed Res Int 2015; 2015: 652738.
Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 1993; 25(5): 563-75.
Stein M, Boulaksil M, Jansen JA, et al. Reduction of fibrosis-related arrhythmias by chronic renin-angiotensin-aldosterone system inhibitors in an aged mouse model. Am J Physiol Heart Circ Physiol 2010; 299(2): H310-21.
Ouvrard-Pascaud A, Sainte-Marie Y, Bénitah J-P, et al. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation 2005; 111(23): 3025-33.
Gekle M, Grossmann C. Actions of aldosterone in the cardiovascular system: the good, the bad, and the ugly? Pflugers Arch 2009; 458(2): 231-46.
Kuster GM, Kotlyar E, Rude MK, et al. Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload. Circulation 2005; 111(4): 420-7.
Fraccarollo D, Galuppo P, Schmidt I, Ertl G, Bauersachs J. Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction. Cardiovasc Res 2005; 67(1): 97-105.
Fraccarollo D, Berger S, Galuppo P, et al. Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. Circulation 2011; 123(4): 400-8.
Lother A, Berger S, Gilsbach R, et al. Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function. Hypertension 2011; 57(4): 746-54.
Favre J, Gao J, Zhang AD, et al. Coronary endothelial dysfunction after cardiomyocyte-specific mineralocorticoid receptor overexpression. Am J Physiol Heart Circ Physiol 2011; 300(6): H2035-43.
Zhao W, Ahokas RA, Weber KT, Sun Y. ANG II-induced cardiac molecular and cellular events: role of aldosterone. Am J Physiol Heart Circ Physiol 2006; 291(1): H336-43.
Milliez P, Deangelis N, Rucker-Martin C, et al. Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction. Eur Heart J 2005; 26(20): 2193-9.
Shroff SC, Ryu K, Martovitz NL, Hoit BD, Stambler BS. Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure. J Cardiovasc Electrophysiol 2006; 17(5): 534-41.
MacFadyen RJ, Barr CS, Struthers AD. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 1997; 35(1): 30-4.
Khan MI. Treatment of refractory congestive heart failure and normokalemic hypochloremic alkalosis with acetazolamide and spironolactone. Can Med Assoc J 1980; 123(9): 883-7.
Dahlström U, Karlsson E. Captopril and spironolactone therapy for refractory congestive heart failure. Am J Cardiol 1993; 71(3): 29A-33A.
Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 1995; 9(1): 145-9.
Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Circulation 2000; 102(22): 2700-6.
Rousseau MF, Gurné O, Duprez D, et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy. J Am Coll Cardiol 2002; 40(9): 1596-601.
Pitt B, White H, Nicolau J, et al. 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 2005; 46(3): 425-31.
Adamopoulos C, Ahmed A, Fay R, et al. Timing of eplerenone initiation and outcomes in patients with heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction: insights from the EPHESUS trial. Eur J Heart Fail 2009; 11(11): 1099-105.
Pitt B, Gheorghiade M, Zannad F, et al. Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction <or=30%. Eur J Heart Fail 2006; 8(3): 295-301.
Carillo S, Zhang Y, Fay R, et al. Heart failure with systolic dysfunction complicating acute myocardial infarction - differential outcomes but similar eplerenone efficacy by ST-segment or non-ST-segment elevation: A post hoc substudy of the EPHESUS trial. Arch Cardiovasc Dis 2014; 107(3): 149-57.
Iqbal J, Fay R, Adlam D, et al. Effect of eplerenone in percutaneous coronary intervention-treated post-myocardial infarction patients with left ventricular systolic dysfunction: A subanalysis of the EPHESUS trial. Eur J Heart Fail 2014; 16(6): 685-91.
O’Keefe JH, Abuissa H, Pitt B. Eplerenone improves prognosis in postmyocardial infarction diabetic patients with heart failure: results from EPHESUS. Diabetes Obes Metab 2008; 10(6): 492-7.
Gheorghiade M, Khan S, Blair JEA, et al. The effects of eplerenone on length of stay and total days of heart failure hospitalization after myocardial infarction in patients with left ventricular systolic dysfunction. Am Heart J 2009; 158(3): 437-43.
Rossignol P, Cleland JGF, Bhandari S, et al. Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study. Circulation 2012; 125(2): 271-9.
Iraqi W, Rossignol P, Angioi M, et al. Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study. Circulation 2009; 119(18): 2471-9.
Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1): 11-21.
Swedberg K, Zannad F, McMurray JJV, et al. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. J Am Coll Cardiol 2012; 59(18): 1598-603.
Eschalier R, McMurray JJV, Swedberg K, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: Analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol 2013; 62(17): 1585-93.
Lee D, Wilson K, Akehurst R, et al. Cost-effectiveness of eplerenone in patients with systolic heart failure and mild symptoms. Heart 2014; 100(21): 1681-7.
Ezekowitz JA, McAlister FA. Aldosterone blockade and left ventricular dysfunction: A systematic review of randomized clinical trials. Eur Heart J 2009; 30(4): 469-77.
Li X, Qi Y, Li Y, et al. Impact of mineralocorticoid receptor antagonists on changes in cardiac structure and function of left ventricular dysfunction: A meta-analysis of randomized controlled trials. Circ Heart Fail 2013; 6(2): 156-65.
Japp D, Shah A, Fisken S, Denvir M, Shenkin S, Japp A. Mineralocorticoid receptor antagonists in elderly patients with heart failure: A systematic review and meta-analysis. Age Ageing 2017; 46(1): 18-25.
Komajda M, Böhm M, Borer JS, et al. Incremental benefit of drug therapies for chronic heart failure with reduced ejection fraction: A network meta-analysis. Eur J Heart Fail 2018; 20(9): 1315-22.
Le H-H, El-Khatib C, Mombled M, et al. Impact of aldosterone antagonists on sudden cardiac death prevention in heart failure and post-myocardial infarction patients: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2016; 11(2): e0145958.
Bapoje SR, Bahia A, Hokanson JE, et al. Effects of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with left ventricular systolic dysfunction: A meta-analysis of randomized controlled trials. Circ Heart Fail 2013; 6(2): 166-73.
Wei J, Ni J, Huang D, Chen M, Yan S, Peng Y. The effect of aldosterone antagonists for ventricular arrhythmia: A meta-analysis. Clin Cardiol 2010; 33(9): 572-7.
Faselis C, Boutari C, Doumas M, Imprialos K, Stavropoulos K, Kokkinos P. Novel drugs for hypertension and heart failure: struggling for a place under the sun. Curr Pharm Des 2017; 23(10): 1540-50.
Stavropoulos K, Imprialos KP, Doumas M. Sacubitril/valsartan instead of renin-angiotensin system inhibition alone: A step forward in resistant hypertension. J Clin Hypertens (Greenwich) 2018; 20: 65-8.

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Year: 2018
Page: [5517 - 5524]
Pages: 8
DOI: 10.2174/1381612825666190219141326
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