Aldosterone—An Independent Risk Factor in Cardiovascular Disease

James C. Melby

Department of Medicine and Evans, Department of Clinical Research, University Medical Center, Boston, Massachusetts 02118-2393

Address all correspondence and requests for reprints to: James C. Melby, M.D., Department of Medicine and Evans Department of Clinical Research, University Medical Center, Boston, Massachusetts 02118-2393.

Vascular lesions of the heart, brain, and kidneys have been noted in mineralocorticoid–NaCl-induced hypertension in experimental animals for the past half century. Recently, severe myocardial hypertrophy and fibrosis, which are not directly due to hypertension, have been demonstrated in experimental animals (1).

It is generally acknowledged that in the treatment of human hypertension with agents that reduce blood pressure also reduce cardiovascular mortality. However, congestive heart failure and end stage renal disease increase unless the renin-angiotensin-aldosterone system (RAAS) activation is interrupted by use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists. The observations in the study by Sawathiparnich et al. (2), in this issue of JCEM, are of great interest with respect to the role of aldosterone blockade in preventing the fibrogenic stimulation of the plasminogen activator inhibitors (PAI-I). Although myocardial infarction and stroke have decreased with antihypertensive treatment as a result of blood pressure lowering, heart failure rate and end stage renal disease have not. Activation of the RAAS occurs in treatment regiments that include agents such as diuretics. An enormous literature has accumulated on studies (clinical and experimental) in which blockade of the RAAS with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have markedly improved cardiovascular function. Although the maladaptive effects of angiotensin II per se have been clearly demonstrated in cardiovascular disease, the role of aldosterone has not been defined, except only indirectly due to its effects on sodium and potassium metabolism. Aldosterone is thought to act exclusively through its epithelial receptors, however, growing evidence suggests that mineralocorticoid receptors exist in nonepithelial tissues such as the heart. Several laboratory studies support the profibrinogenic effect of aldosterone in such tissues as the heart.

The study reported by Sawathiparnich et al. (2) found that aldosterone antagonism with spironolactone was not associated with a rise in PAI-I, whereas treatment with hydrochlorothiazide did increase profibrotic activity although both compounds lowered systolic blood pressure; furthermore, t-PA antigen increased to the same extent with spironolactone as it did with hydrochlorothiazide. These finding are of particular interest because in human studies with low-dose spironolactone reduced congestive heart failure and prolonged life independently of natriureses (3). Brown et al. (4) had previously demonstrated that aldosterone modulated PAI-I in glomerulosclerosis in vivo, thus profibrotic effects may have humoral basis.

It is nearly a half century since the mineralocorticoid antagonist spironolactone has been used in the treatment of hypertension and also in the management of primary aldosteronism. The results (outcomes) of the Randomized Aldosterone Evaluation Study markedly reduced morbidity and mortality in patients with severe congestive heart failure independent of effects on blood pressure or potassium retention.

In the Randomized Aldosterone Evaluation Study the dose of spironolactone was low, and the reduction of morbidity and mortality of congestive heart failure averaged 30%. It is tempting to assume that these remarkable effects of aldosterone antagonism in congestive heart failure are due in part to the nonfibrogenic effects of such treatment in preventing abnormal ventricular function.

It is of considerable importance that re-awakening of interest in aldosterone antagonists in the treatment of cardiac disease has been associated with the synthesis of the more potent aldosterone antagonist eplerenome, which is more selective than spironolactone and is antifibrotic and antineurohormonal. In preliminary studies by Pfeffer (5) in the EPHESUS trial, which randomized patients with heart failure due to impaired systolic function, eplerenome has been used in addition to standard therapy. Preliminary observations in the first 2.5 yr ought to be decisive in the cardiac antifibrotic effect of eplerenome in this study, which will randomize 6200 patients.

Denolle et al. (3) have studied eplerenome in myocardial remodeling after experimental myocardial infarction and demonstrated a protective effect of eplerenome at 28 d.

Thus, the blockade of receptors in the heart of both aldosterone and angiotensin II may have salutary effects in preventing or reducing myocardial fibrosis after myocardial infarction remodeling, hence reducing heart failure and prolonging life.

Footnotes

Abbreviations: PAI-I, Plasminogen activator inhibitor(s); RAAS, renin-angiotensin-aldosterone system.

Received October 19, 2001.

Accepted October 22, 2001.

References

  1. Rocha R, Stier Jr CT 2001 Pathophysiological effects of aldosterone in cardiovascular tissues. Trends Endocrinol Metab 12:308–314[CrossRef][Medline]
  2. Sawathiparnich P, Kumar S, Vaughan DE, Brown NJ 2002 Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans. J Clin Endocrinol Metab 87:448–452[Abstract/Free Full Text]
  3. Denolle T, Chatellier G, Julien J, Battaglia C, Luo P, Plouin PF 1993 Left ventricular mass and geometry before and after etiologic treatment in renovascular hypertension, aldosterone-producing adenoma and pheochromocytoma. Am J Hypertens 6:907–913[Medline]
  4. Brown NJ, Nakamura S, Ma L, Nakamura I, Donnert E, Freeman M, Vaughan DE, Fogo AB 2000 Aldosterone modulates plasminogen activator inhibitor-I and glomerulosclerosis in vivo. Kidney Int 58:1219–1227[CrossRef][Medline]
  5. Pfeffer MA 2001 New treasures from old? EPHESUS. Eplerenome post-AHI heart failure effic survival study. Cardiovasc Drugs Ther 15:11–13[CrossRef][Medline]




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