Cardiovascular Drugs and Therapy

, Volume 24, Issue 4, pp 345–350 | Cite as

Aldosterone Inhibition and Cardiovascular Protection: More Important Than it Once Appeared

Article

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.

Key words

Aldosterone Aldosterone antagonists Cardiovascular protection Heart failure 

References

  1. 1.
    Lombes M, Ferman N, Bonvalot J, Zennaro M. Identification and role of aldosterone receptors in the cardiovascular system. Ann Endocrinol. 2000;61:41–61.Google Scholar
  2. 2.
    Pfeffer M. New treasures from old drugs. EPHESUS. Cardiovasc Drugs Ther. 2001;15:11–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Mano A, Tatsumi T, Shiraishi J, et al. Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways. Circulation. 2004;110:317–23.CrossRefPubMedGoogle Scholar
  4. 4.
    Rajagopalan S, Duquaine D, King S, Pitt B, Patel P. Mineralcorticoid receptor antagonism in experimental atherosclerosis. Circulation. 2002;105:2212–6.CrossRefPubMedGoogle Scholar
  5. 5.
    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.PubMedGoogle Scholar
  6. 6.
    Ramires FJA, Salemi VMC, Ianni BM, et al. Aldosterone antagonism in an inflammatory state: evidence for myocardial protection. J RAAS. 2006;7:162–7.Google Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    Xiao F, Puddefoot JR. Vinson GP.Aldosterone mediates angiotensin II- stimulated rat vascular smooth muscle cell proliferation. J Endocrinol. 2000;165:533–6.CrossRefPubMedGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    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.PubMedGoogle Scholar
  15. 15.
    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.Google Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    Fallo F. Hyperaldosteronism, hypertension and metabolic syndrome. Endocr Metab. 2006;91:454–61.CrossRefGoogle Scholar
  20. 20.
    Ferrari P, Krozowski Z. Role of the 11-hydroxysteroid dehydrogenase type 2 in blood pressure regulation. Kidney Int 2000: 1374–1381Google Scholar
  21. 21.
    Min E. Signalling pathways for mitogenic interaction between aldosterone and angiotensin. Circ Res. 2005;97:434–42.CrossRefPubMedGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedGoogle Scholar
  24. 24.
    Vasan RS, Evans JC, Larson MG. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004;351:33–41.CrossRefPubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedGoogle Scholar
  26. 26.
    Struthers A, Krum H, Williams GH. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol 2008; 153–158Google Scholar
  27. 27.
    Krum H, Nolly H, Workman D, et al. Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension. 2002;40:117–23.CrossRefPubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedGoogle Scholar
  31. 31.
    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.CrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    ACC/AHA. Guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol. 2004;44:671–719.CrossRefGoogle Scholar
  34. 34.
    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.CrossRefPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    Goodfriend TL, Calhoun DA. Resistant hypertension, obesity, sleep apnea and aldosterone: theory and therapy. Hypertension. 2004;43:518–23.CrossRefPubMedGoogle Scholar
  37. 37.
    Sligl W, McAlistar FA, Ezekowitz J, Armstrong PW. Usefulness of spironolactone in a specialized heart failure clinic. Am J Cardiol. 2004;94:443–7.CrossRefPubMedGoogle Scholar
  38. 38.
    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.Google Scholar
  39. 39.
    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.CrossRefPubMedGoogle Scholar
  40. 40.
    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.CrossRefGoogle Scholar
  41. 41.
    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.PubMedGoogle Scholar
  42. 42.
    www.clinicaltrials.gov TOPCAT NCT00094302
  43. 43.
    www.clinicaltrials.gov EMPHASIS-HF NCT 00232180
  44. 44.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.DAMIC- Rusculleda FoundationNational University of CórdobaCórdobaArgentina

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