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Aldosterone and Its Cardiovascular Effects


Key Points

  • Aldosterone and mineralocorticoid receptor activation exert cardiovascular effects above and beyond effects on blood pressure

  • Several large clinical trials have shown that mineralocorticoid receptor antagonists, in addition to usual therapy that includes angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, improve clinical outcomes in heart failure

  • Accumulating data also suggest potential beneficial effects of mineralocorticoid receptor antagonists in vascular conditions related to diabetes mellitus and renal failure

  • Mechanisms that explain the role of aldosterone in cardiovascular disease and provide a rationale for use of mineralocorticoid receptor antagonists include inflammation, oxidative stress, cardiac and vascular fibrosis, and endothelial dysfunction

1

Introduction

In recent years, our understanding of aldosterone has changed from considering it to be a hormone mainly responsible for fluid and electrolyte balance to a hormone with widespread cardiovascular and metabolic effects. A large body of literature demonstrates that activation of the mineralocorticoid receptor by aldosterone increases oxidative stress, inflammation, insulin resistance, and vascular dysfunction, leading to renovascular and cardiovascular injury and stroke. Further, clinical studies using either the selective mineralocorticoid receptor antagonist eplerenone or the nonselective antagonist spironolactone have demonstrated beneficial cardiovascular and renovascular effects in patients with heart failure, diabetes, and hypertension. The cardiovascular actions of mineralocorticoid receptor involve both genomic and nongenomic mechanisms. This chapter discusses these evolving concepts of aldosterone action.

2

Aldosterone and the Heart

2.1

Clinical Evidence Supporting a Role for Aldosterone in the Pathophysiology of Cardiac Disease

2.1.1

Heart Failure

At the turn of the century, approximately 50 years after the discovery of aldosterone, several large-scale clinical studies revealed potent beneficial effects of aldosterone receptor antagonists on the heart. The Randomized Aldactone Evaluation Study (RALES) was the first large randomized clinical trial that tested the effect of a mineralocorticoid receptor antagonist on mortality in patients with severe heart failure due to systolic left ventricular dysfunction. In this trial, 1663 patients were randomized in a double-blind fashion to 25 mg spironolactone or placebo given once daily, in addition to standard therapy including angiotensin-converting enzyme (ACE) inhibitors. The follow-up was initially planned for 3 years but the trial was stopped prematurely after a mean follow-up period of 2 years due to clear benefits of spironolactone on mortality (30% reduction in relative risk of death). Hospitalization rate for worsening heart failure was lowered by 35% in the spironolactone group as compared to the placebo group. Patients with an elevation in procollagen type III amino-terminal peptide, a marker of fibrosis, were the most likely to benefit from spironolactone in this study. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial tested the benefits of mineralocorticoid receptor antagonism in patients with systolic heart failure with mild symptoms. In this trial, 2737 patients with New York Heart Association class II heart failure were randomized to receive either eplerenone (up to 50 mg daily) or placebo, in addition to the standard therapy. The trial was also stopped early because the primary outcome, a composite of death from cardiovascular causes or hospitalization for heart failure, showed significant benefits of eplerenone. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group ( P < .001). Mortality was significantly lower in the eplerenone group (12.5%) as compared to the standard treatment group (15.5%) ( P = .008). The most feared complication of mineralocorticoid receptor antagonists when used with ACE inhibitors, i.e., hyperkalemia, was uncommon in these trials. Further, the beneficial effect of mineralocorticoid receptor antagonists was observed without significant effects on blood pressure. The benefits of mineralocorticoid receptor blockade in heart failure were further demonstrated in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). This randomized, double blind, controlled trial was designed to test the effect of eplerenone, a selective mineralocorticoid receptor antagonist, on mortality and hospitalization rates in patients with left ventricular dysfunction and heart failure after acute myocardial infarction. The patients received standard medical therapy, including ACE inhibitors or angiotensin receptor blocker (ARB) therapy and were randomly assigned to receive additional eplerenone (25 mg/day initially, titrated to a maximum of 50 mg/day) or placebo. During a mean follow-up of 16 months, there was a 15% relative risk reduction in overall mortality and 17% relative risk reduction in cardiovascular mortality with eplerenone. Hospitalization rates were also significantly lower in the eplerenone group.

2.1.2

Hypertensive Heart Disease

Clinical studies have also demonstrated a role for the mineralocorticoid receptor in the pathophysiology of hypertensive heart disease. In a double-blind study, eplerenone along with the ACE inhibitor enalapril caused a very significant reduction in hypertension-related cardiac hypertrophy as compared to either drug used alone. This study suggests a direct role of aldosterone in the pathophysiology of left ventricular hypertrophy in patients with hypertension. Consistent with the result of this study, patients with primary hyperaldosteronism have increased left ventricular hypertrophy and evidence of diastolic dysfunction compared to patients with essential hypertension. Surgical removal of the aldosterone-producing adenoma leads to regression of hypertrophy.

2.1.3

Cardiovascular Disease Associated With Insulin Resistance and Diabetes

Recent evidence also suggests a role of mineralocorticoid receptor activation in cardiac disease associated with insulin resistance and diabetes. Increased aldosterone production was present in overweight and obese individuals and was associated with an increase in insulin resistance. Aldosterone levels also associated with insulin resistance in healthy people. In individuals with HIV infection, there was an association between increased aldosterone levels, visceral adiposity, and insulin resistance. Further, support for an effect of aldosterone on insulin resistance comes from studying patients with primary hyperaldosteronism. Insulin resistance was present in patients with tumoral and idiopathic hyperaldosteronism, and treatment with surgery or mineralocorticoid receptor antagonists improved sensitivity to insulin. Finally, spironolactone reduced insulin resistance in patients with polycystic ovarian syndrome. In patients with type 2 diabetes mellitus without coronary artery disease, aldosterone was associated with expansion of myocardial extracellular matrix which is a measure of cardiac fibrosis and inflammation and a predictor of cardiovascular morbidity and mortality in diabetes. Coronary flow reserve, the ratio of stimulated to baseline myocardial perfusion, is reduced in patients with type 2 diabetes and reductions in coronary flow reserve predicted cardiac mortality in individuals with diabetes without epicardial coronary artery disease. In the absence of epicardial coronary artery disease, coronary flow reserve is an indicator of coronary microcirculatory function. In a randomized, double-blind, controlled study, spironolactone improved coronary flow reserve in individuals with well-controlled type 2 diabetes mellitus without epicardial coronary artery disease. In this study, all individuals were receiving chronic ACE inhibition and the improvements in coronary function with spironolactone were not related to changes in blood pressure.

2.1.4

Diastolic Dysfunction

Two small clinical studies suggested a beneficial effect of mineralocorticoid receptor blockade on diastolic dysfunction. Treatment for 6 months with the mineralocorticoid receptor antagonist canrenone (50 mg/day) improved diastolic function, as compared to placebo treatment, in patients with hypertension and left ventricular diastolic dysfunction on ACE inhibitor and calcium channel blockade therapy. The improvements in diastolic function with canrenone were not mediated by changes in blood pressure or left ventricular mass, suggesting that mineralocorticoid blockade has a direct beneficial effect on diastolic function. In another study in patients with dilated cardiomyopathy, 12-month treatment with spironolactone was demonstrated to decrease myocardial collagen content, decrease myocardial stiffness, and ameliorate diastolic dysfunction. However, the “Aldosterone Antagonist Therapy for Adults with Heart Failure and Preserved Systolic Function” (TOPCAT) trial failed to show benefits of mineralocorticoid receptor blockade in patients with diastolic heart failure. This was a large clinical trial including 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more that were randomized either to spironolactone (15–45 mg daily) or placebo. After a mean follow-up of 3.3 years, the primary outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) [hazard ratio, 0.89; 95% confidence interval (CI), 0.77–1.04; P = .14]. Hospitalization for heart failure was significantly lower in the spironolactone group than in the placebo group [206 patients (12.0%) vs. 245 patients (14.2%); hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = .04]. A post hoc analysis of TOPCAT showed marked differences in outcomes of patients recruited from the Americas versus those recruited from Russia and Georgia. Spironolactone lowered the event rates in patients recruited in the Americas but not in Russia and Georgia, probably due to the fact that patients in Americas had more severe cardiac disease. Thus, benefits of mineralocorticoid antagonists in diastolic heart failure cannot be completely ruled out.

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