Skip to main content
SpringerLink
Log in

Aldosterone in Heart Disease

  • Hypertension: Kidney, Sodium, and Renin-Angiotensin System (R Carey and A Mimran, Section Editors)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Numerous studies have now shown that sustained elevation of aldosterone levels induces cardiovascular damage independent from its effects on regulation of renal sodium and blood pressure. Increased aldosterone and cortisol levels in patients with heart failure independently predict the risk of mortality. Over the past decade, there has been increased interest in identifying the role of the receptor for aldosterone, the mineralocorticoid receptor (MR), following the results from the large clinical heart failure trials that showed low doses of MR antagonists reduced morbidity and mortality in heart failure and myocardial infarction, even though plasma levels of aldosterone were in the physiologic range. The mechanism for this cardioprotective action remains to be defined, although changes in the redox state have been shown to play a key role in MR-mediated cardiac damage. This review will highlight some of these studies and provide an update on the action of aldosterone in heart disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Simpson SA, Tait JF, Wettstein A, et al. Isolierung eines neuen kristallisierten Hormons aus Nebennerien mit besonders hoher Wirksamkeit auf den Mineralsoffwechsel. Experientia. 1953;9:333–5.

    Article  PubMed  CAS  Google Scholar 

  2. Beygui F, Collet J-P, Benoliel J-J, et al. High plasma aldosterone levels on admission are associated with death in patients presenting with acute ST-elevation myocardial infarction. Circulation. 2006;114:2604–10.

    Article  PubMed  CAS  Google Scholar 

  3. Beygui F, Montalescot G, Vicaut E, et al. Aldosterone and long-term outcome after myocardial infarction: A substudy of the French nationwide Observatoire sur la Prise en charge hospitalière, l’Evolution à un an et les caRactéristiques de patients présentant un infArctus du myocarde avec ou sans onde Q (OPERA) study. Am Heart J. 2009;157(4):680–7.

    Article  PubMed  CAS  Google Scholar 

  4. Weir RAP, Tsorlalis IK, Steedman T, et al. Aldosterone and cortisol predict medium-term left ventricular remodelling following myocardial infarction. Eur J Heart Failure. 2011;13:1305–13.

    Article  CAS  Google Scholar 

  5. Weinberger MH, Roniker B, Krause SL, Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens. 2002;15:709–16.

    Article  PubMed  CAS  Google Scholar 

  6. Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens. 2003;16:925–30.

    Article  PubMed  CAS  Google Scholar 

  7. Chapman N, Dobson J, Wilson S, et al. Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007;49:839–45.

    Article  PubMed  CAS  Google Scholar 

  8. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure: Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.

    Article  PubMed  CAS  Google Scholar 

  9. Pitt B, Remme W, Zannad F, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.

    Article  PubMed  CAS  Google Scholar 

  10. •• Zannad F, McMurray JJ, Krum H, et al.; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21. This study shows that mineralocorticoid receptor (MR) antagonists may delay the progression of heart failure in patients with mild heart failure symptoms (NYHA II) and has affirmed the important role of MR blockade across both severe and mild systolic heart failure.

    Article  PubMed  CAS  Google Scholar 

  11. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation. 1990;82:1730–6.

    Article  PubMed  CAS  Google Scholar 

  12. 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;19:1552–63.

    Article  PubMed  CAS  Google Scholar 

  13. Güder G, Bauersachs J, Frantz S, et al. Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure. Circulation. 2007;115:1754–61.

    Article  PubMed  Google Scholar 

  14. 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.

    Article  PubMed  CAS  Google Scholar 

  15. Young M, Fullerton M, Dilley R, Funder J. Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest. 1994;93:2578–80.

    Article  PubMed  CAS  Google Scholar 

  16. Wang Q, Clement S, Gabbiani G. Chronic hyperaldosteronism in a transgenic mouse model fails to induce cardiac remodeling and fibrosis under a normal-salt diet. Am J Physiol Renal Physiol. 2004;286:F1178–84.

    Article  PubMed  CAS  Google Scholar 

  17. •• Pimenta E, Gordon RD, Ahmed AH, et al. Cardiac dimensions are largely determined by dietary salt in patients with primary aldosteronism: results of a case control study. J Clin Endocrinol Metab. 2011;96:2813–2820. This important clinical study extends the results from the experimental animal models to humans and confirms an interaction between aldosterone and salt status as a strong determinant of cardiac damage.

    Article  PubMed  CAS  Google Scholar 

  18. Rocha R, Rudolph AE, Frierdich GE. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol. 2002;283:H1802–10.

    PubMed  CAS  Google Scholar 

  19. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:3266–81.

    Article  PubMed  CAS  Google Scholar 

  20. •• Shibata S, Mu S, Kawarazaki H, Muraoka K., et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121:3233–3243. This important study provides the mechanism for the synergistic action between high salt and aldosterone in renal damage & hypertension.

    Article  PubMed  CAS  Google Scholar 

  21. Shibata S, Nagase M, Yoshida S, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med. 2008;14:1370–6.

    Article  PubMed  CAS  Google Scholar 

  22. • Nagase M, Ayuzawa N, Kawarazaki W, et al. Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension 2012 Jan 9 (Epub ahead of print). This paper provides preliminary evidence for reactive oxygen species–mediated MR activation and cardiac damage.

  23. Noble D. Ionic mechanisms determining the timing of ventricular repolarization: significance for cardiac arrhythmias. Ann N Y Acad Sci. 1992;644:1–22.

    Article  PubMed  CAS  Google Scholar 

  24. 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;11:3025–33.

    Article  Google Scholar 

  25. Pieske B, Maier LS, Piacentino V, et al. Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium. Circulation. 2002;106:447–53.

    Article  PubMed  CAS  Google Scholar 

  26. Mihailidou AS, Bungaard H, Mardini M, et al. Hyperaldosteronemia in rabbits inhibits the cardiac sarcolemmal Na + -K + pump. Circ Res. 2000;86:37–42.

    PubMed  CAS  Google Scholar 

  27. Komentiani P, Li J, Gnudi L, et al. Multiple signal transduction pathways link Na+/K + -ATPase to growth-related genes in cardiac myocytes. J Biol Chem. 1998;24:15249–56.

    Article  Google Scholar 

  28. Kent RL, Hoober K, Cooper IV G. Load responsiveness of protein synthesis in adult mammalian myocardium: role of cardiac deformation linked to sodium influx. Circ Res. 1989;64:74–85.

    PubMed  CAS  Google Scholar 

  29. Huang L, Kometiani P, Xie Z. Differential regulation of Na/K-ATPase a-subunit isoform gene expressions in cardiac myocytes by ouabain and other hypertrophic stimuli. J Mol Cell Cardiol. 1997;29:3157–67.

    Article  PubMed  CAS  Google Scholar 

  30. •Ivanes F, Susen S, Mouquet F, et al. Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure. Eur Heart J. 2012;33:191–202. This study shows that plasma aldosterone levels measured in patients with coronary artery disease without MI or heart failure predict future cardiovascular events.

    Article  PubMed  CAS  Google Scholar 

  31. Rousseau MF, Gurne O, Duprez D, et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure. J Am Coll Cardiol. 2002;40:1596–601.

    Article  PubMed  CAS  Google Scholar 

  32. • Le TYL, Ashton A, Mardini M, Funder JW, Mihailidou AS. Cardioprotective action of mineralocorticoid receptor antagonists during experimental myocardial infarction: role of Apoptosis Repressor with Caspase recruitment domain (ARC). Hypertension. 2011;58:117 (Abstract 13). This study provides a novel mechanism for the cardioprotective action of low doses of MR antagonists during ischemia-reperfusion.

    Google Scholar 

  33. Krozowski ZS, Funder JW. Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity. Proc Natl Acad Sci. 1983;80:6056–60.

    Article  PubMed  CAS  Google Scholar 

  34. Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science. 1987;237:268–75.

    Article  PubMed  CAS  Google Scholar 

  35. Nagata K, Obata K, Xu J, et al. Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. Hypertension. 2006;47:656–64.

    Article  PubMed  CAS  Google Scholar 

  36. Mihailidou, AS, Mardini M, Fraser T, et al. Agonist/antagonist activity of cortisol in cardiomyocyte mineralocorticoid receptors is determined by redox state. Presented at the International Aldosterone Conference, New Orleans, 2004.

  37. •• Mihailidou AS, Le TYL, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension. 2009;54:1306–1312. This study provides direct evidence that during tissue damage, cortisol mimics the action of aldosterone in the heart. It is also shown that spironolactone acts as an inverse agonist, which may provide a mechanism for the beneficial effects of low doses of spironolactone in the RALES study.

    Article  PubMed  CAS  Google Scholar 

  38. Mihailidou AS, Buhagiar KA, Rasmussen HH. Na + influx and Na + -K + pump activation during short-term exposure of cardiac myocytes to aldosterone. Am J Physiol Cell Physiol. 1998;274:C175–81.

    CAS  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Department of Cardiology & Kolling Institute of Medical Research, Royal North Shore Hospital & University of Sydney, Pacific Highway, St. Leonards, Sydney, NSW, Australia, 2065

    Anastasia S. Mihailidou

Authors
  1. Anastasia S. Mihailidou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anastasia S. Mihailidou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mihailidou, A.S. Aldosterone in Heart Disease. Curr Hypertens Rep 14, 125–129 (2012). https://doi.org/10.1007/s11906-012-0256-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-012-0256-9

Keywords

Search

Navigation