Abstract
Aldosterone is present and active all along the cardiovascular continuum. Excessive tissue production occurs in cardiovascular diseases including myocardial infarction (MI) and heart failure, resulting in a multitude of adverse effects in the cardiovascular system necessitating pharmacologic blockade of this neurohormone. Both human and animal studies have consistently proven the beneficial effects of antialdosteronics in the improvement of: 1) endothelial function, 2) modulation of inflammatory mechanisms between blood and the vascular wall and 3) reduction of tissue proliferation and cardiovascular remodeling leading to different severities of cardiovascular damage. These basic mechanisms of anti-aldosterone therapy strongly support the promising data observed in major clinical trials with aldosterone blockers in cardiovascular diseases, specially in heart failure patients. Whereas aldosterone receptor blockers were initially viewed as potassium-sparing diuretics there has been a clear change of concept in the past 10 years, mainly following the positive results of RALES with spironolactone in chronic heart failure, followed by EPHESUS using eplerenone in patients with systolic dysfunction post MI. The significant positive results in both studies were a clear support for the inclusion of this pharmacologic intervention as first line treatment in most international guidelines for the management of heart failure. More recent and ongoing studies are exploring the usefulness of this type of intervention in preventing vascular and myocardial hypertrophy and remodeling in refractory hypertensive and some hyperfibrotic syndromes. There are also provocative studies investigating in the possibility of inhibiting atherosclerosis. More recently, some studies are suggesting the benefit of aldosterone blockade in sleep apnea. In addition, two large multicentric trials, TOPCAT and EMPHASIS are analyzing the potential use of antialdosteronics in patients with cardiac insufficiency and preserved systolic function and the possibility of extending their indication in systolic heart failure to Phase II respectively. New compounds, blocking the synthesis of aldosterone instead of blocking its receptor are being developed, and initial Phase 2 studies are positive. All of the above results are very interesting, show an optimistic future and are consolidating and enlarging the spectrum of aldosterone blockade in cardiovascular disorders every day.
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References
Lombes M, Ferman N, Bonvalot J, Zennaro M. Identification and role of aldosterone receptors in the cardiovascular system. Ann Endocrinol. 2000;61:41–61.
Pfeffer M. New treasures from old drugs. EPHESUS. Cardiovasc Drugs Ther. 2001;15:11–3.
Mano A, Tatsumi T, Shiraishi J, et al. Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways. Circulation. 2004;110:317–23.
Rajagopalan S, Duquaine D, King S, Pitt B, Patel P. Mineralcorticoid receptor antagonism in experimental atherosclerosis. Circulation. 2002;105:2212–6.
Warnholtz A, Nichening G, Schuiz L, et al. Increased NADH- oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation. 1999;99:2027–33.
Ramires FJA, Salemi VMC, Ianni BM, et al. Aldosterone antagonism in an inflammatory state: evidence for myocardial protection. J RAAS. 2006;7:162–7.
Nishioka T, Suzuki M, Onishi K, et al. Eplerenone attenuates myocardial fibrosis in the angiotensin II-induced hypertensive mouse: involvement of tenascin-C induced by aldosterone-mediated inflammation. J Cardiovasc Pharmacol. 2007;49:261–8.
Fraccarollo D, Galuppo P, Schraut S, et al. Immediate mineralcorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response. Hypertension. 2008;51:905–14.
Irita J, Okura T, Manabe S, Kurata M. Plasma osteopontin levels are higher in patients with primary aldosteronism than in patients with essential hypertension. Am J Hypertens. 2006;19:293–7.
Zhou G, Kandala JC, Tyagi SC, et al. Effects of angiotensin II and aldosterone on collagen gene expression and protein turnover in cardiac fibroblasts. Mol Cell Biochem. 1996;154:171–8.
Walker BR, Yau JL, Brett TP, et al. 11 beta- hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids. Endocrinol. 1991;129:3305–12.
Xiao F, Puddefoot JR. Vinson GP.Aldosterone mediates angiotensin II- stimulated rat vascular smooth muscle cell proliferation. J Endocrinol. 2000;165:533–6.
Brilla CG, Matsubara LS, Weber KT. Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension. Am J Cardiol. 1993;71:12A–6A.
Zannad F, Alla E, Dousset B, et al. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: Insights from Randomized Aldactone Evaluation Study (RALES). Circulation. 2000;102:2700–6.
Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT. Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res. 1990;67:1335–64.
Duprez D, Bauwens FR, Debuyzere M, et al. Influence of arterial blood pressure and aldosterone on left ventricular hypertrophy in moderate essential hypertension. Am J Cardiol. 1993;71:17A–20A.
Duprez D, Debuyzere M, Rietzschel E, et al. Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J. 1998;19:1371–6.
Blacher J, Amah G, Girerd X, et al. Association between increased plasma levels of aldosterone and decreased systemic arterial compliance in subjects with essential hypertension. Am J Hypertens. 1997;10:1326–34.
Fallo F. Hyperaldosteronism, hypertension and metabolic syndrome. Endocr Metab. 2006;91:454–61.
Ferrari P, Krozowski Z. Role of the 11-hydroxysteroid dehydrogenase type 2 in blood pressure regulation. Kidney Int 2000: 1374–1381
Min E. Signalling pathways for mitogenic interaction between aldosterone and angiotensin. Circ Res. 2005;97:434–42.
Szmitko P, Wang C, Weisel R, Jeffries G, Anderson T, Verma S. Biomarkers of vascular disease linking inflammation to endothelial activation: part II. Circulation. 2003;108:2041–8.
Kobayashi N, Yoshida K, Nakano S, et al. Cardioprotective mechanisms of eplerenone on cardiac performance and remodeling in failing rat hearts. Hypertension. 2006;47:671–9.
Vasan RS, Evans JC, Larson MG. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004;351:33–41.
Pitt B, Zannad F, Remme WJ, et al. For the randomized aldactone evalution study investigators. The effect of spironolactone on morbidity and mortalily in patients with severe heart failure. N Engl J Med. 1999;341:709–17.
Struthers A, Krum H, Williams GH. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol 2008; 153–158
Krum H, Nolly H, Workman D, et al. Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension. 2002;40:117–23.
Pitt B, Reichek N, Willenbrock R, et al. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy. Circulation. 2003;108:1831–8.
White W, Carr A, Krause S, Jordan R, Roniker B, Oigman W. Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension. Am J Cardiol. 2003;92:38–42.
Pitt B, Williams G, Remme W, et al. The EPHESUS Trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Cardiovasc Drugs Ther. 2001;15:79–87.
Pitt B, Remme WJ, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.
Pitt B, White H, Nicolau J, et al. For the EPHESUS investigators: 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;46:425–31.
ACC/AHA. Guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol. 2004;44:671–719.
McMurray J, Cohen-Solal A, Dietz R, et al. Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice. Eur J Heart Fail. 2005;7:710–21.
Pratt-Ubunama, Nishizaka MK, Boedefeld RL, Cofield SS, Harding SM, Calhoun DA. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest. 2007;131:453–9.
Goodfriend TL, Calhoun DA. Resistant hypertension, obesity, sleep apnea and aldosterone: theory and therapy. Hypertension. 2004;43:518–23.
Sligl W, McAlistar FA, Ezekowitz J, Armstrong PW. Usefulness of spironolactone in a specialized heart failure clinic. Am J Cardiol. 2004;94:443–7.
Martinez F, Thierer J. Todos los pacientes con insuficiencia cardíaca y función sistólica conservada o levemente deprimida deben recibir antagonistas de la aldosterona. Rev Argent Cardiol. 2006;74:389–95.
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351:543–51.
Rastogni S, Mishra S, Zaca V, et al. Effect of long-term monotherapy with the aldosterone receptor blocker eplerenone on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure. Cardiovasc Drugs Ther. 2007;21:415–22.
Farquharson CAJ, 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;101:594–7.
www.clinicaltrials.gov TOPCAT NCT00094302
www.clinicaltrials.gov EMPHASIS-HF NCT 00232180
Huang BS, White RA, Ahmad M, Tan J, Jeng AY, Leenen FH. Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodelling in rats after myocardial infarction. Cardiovasc Res. 2009;81:574–81.
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Martinez, F.A. Aldosterone Inhibition and Cardiovascular Protection: More Important Than it Once Appeared. Cardiovasc Drugs Ther 24, 345–350 (2010). https://doi.org/10.1007/s10557-010-6256-6
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DOI: https://doi.org/10.1007/s10557-010-6256-6