Aldosterone Receptor Antagonists in Cardiovascular Disease: A Review of the Recent Literature and Insight Into Potential Future Indications

Authors


Abstract

Randomized controlled trials demonstrate the efficacy of aldosterone receptor antagonists (spironolactone and eplerenone) as a useful pharmacologic intervention specifically in patients with New York Heart Association (NYHA) class III and IV heart failure, in patients with an ejection fraction <40% after myocardial infarction, and most recently in patients with mildly symptomatic heart failure. However, aldosterone receptor antagonists may be beneficial in a broader patient population. Aldosterone receptor antagonists can potentially serve as an antiarrhythmic pharmacologic agent for atrial and ventricular arrhythmias, an anti-ischemic medication in coronary artery disease through prevention of myocardial fibrosis and vascular damage, and as an agent in people with asymptomatic and mild heart failure (NYHA classes I and II) and diastolic heart failure. However, many clinicians remain reluctant to prescribe this highly efficacious pharmacologic therapy for a variety of reasons, including concerns about polypharmacy and hyperkalemia. Recent observational analysis demonstrates that less than one-third of eligible patients hospitalized with heart failure actually received aldosterone antagonist therapy. This article will review the current and potential future uses of aldosterone receptor antagonists across the entire spectrum of cardiovascular disease.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

Randomized controlled trials have shown the efficacy of aldosterone receptor antagonists (spironolactone and eplerenone) as a useful pharmacologic intervention specifically in patients with New York Heart Association (NYHA) class III and IV heart failure as well as patients with an ejection fraction (EF) <40% after myocardial infarction (MI).1,2 However, many clinicians remain reluctant to prescribe this highly efficacious pharmacologic therapy for a variety of reasons, including concerns about polypharmacy and hyperkalemia; recent observational analysis demonstrates that less than one-third of eligible patients hospitalized with heart failure actually received aldosterone antagonist therapy.3

In addition to patients with severely symptomatic heart failure and post-MI systolic dysfunction, there is evidence that aldosterone receptor antagonists may be beneficial in a much broader population of patients with a myriad of cardiovascular disorders, including those with mild systolic dysfunction, diastolic dysfunction, coronary artery disease, and arrhythmias. This article will review the current and potential future uses of aldosterone receptor antagonists across the entire spectrum of cardiovascular disease.

Aldosterone and the Pathophysiology of Cardiovascular Disease

The renin angiotensin aldosterone system (RAAS) is a neurohormonal cascade that begins with the formation of angiotensinogen in the liver. Renin, secreted by the juxtaglomerular apparatus in the kidney, subsequently cleaves angiotensinogen to angiotensin I. The angiotensin I peptide is then cleaved by angiotensin-converting enzyme (ACE) to form angiotensin II, which stimulates the formation of aldosterone in the adrenal gland.4 In addition to this pathway, recent evidence suggests local, extra-adrenal production of aldosterone by endothelial cells and vascular smooth muscle cells in the blood vessels and myocardium.4,5 The exact role of local aldosterone production is not yet clear, but it may contribute to vascular inflammation and injury locally.5

Aldosterone has been identified to have an important role in the pathogenesis of heart failure. Elevated levels of aldosterone occur after a perceived drop in intravascular volume, specifically in states of reduced cardiac output and systolic dysfunction. In addition to its role in sodium and fluid retention, aldosterone may help mediate key maladaptive mechanisms in heart failure including activation of the sympathetic nervous system, endothelial dysfunction, reduction of baroreceptor sensitivity, and activation of myocyte apoptosis (programmed cell death).5–7 Aldosterone has also been implicated in oxidative stress, and it decreases the bioavailability of nitric oxide.6,7

Aldosterone is secreted in response to angiotensin II, hyperkalemia, and corticotropin. Despite attempts to completely suppress aldosterone production with ACE inhibitors in heart failure, studies demonstrate that long-term therapy with ACE inhibitors does not entirely inhibit formation of aldosterone, and levels may return to baseline despite therapy (aldosterone escape).8 The addition of aldosterone receptor antagonists to ACE inhibitors may help prevent the impact of aldosterone escape, and thereby potentiate blockade of the RAAS system.

Besides heart failure, multiple prior studies demonstrate that aldosterone plays a broad role in cardiovascular disease. Elevated aldosterone levels have been associated with left ventricular hypertrophy, MI, and adverse outcomes.9,10 Aldosterone has also been implicated in endothelial dysfunction, decreasing vascular reactivity, activation of inflammatory mediators, and promotion of tissue fibrosis.5–7 Furthermore, aldosterone contributes to adverse myocardial remodeling through collagen deposition and increasing myocardial stiffness.5–7

Given these broad pleitropic effects of aldosterone on the cardiovascular system, it follows that aldosterone receptor blockade may benefit patients with cardiovascular disease in a variety of ways. Aldosterone receptor antagonists have been shown to prevent many of the maladaptive effects of aldosterone on the cardiovascular system. For instance, spironolactone prevents the aldosterone-mediated collagen synthesis that contributes to adverse left ventricular remodeling.11 Rats with postinfarction heart failure treated with aldosterone receptor antagonists have improved left ventricular (LV) diastolic and systolic function, a reduction of reactive fibrosis, and reduced myocardial norepinephrine content.12 Eplerenone inhibits superoxide formation and enhances nitric oxide-dependent relaxation in experimental studies.13

Aldosterone Receptor Antagonists in Heart Failure

The strongest evidence for clinical usefulness of aldosterone receptor antagonists exists for patients with class III/IV or stage C/D heart failure and reduced LV function. The American College of Cardiology/American Heart Association guidelines recommend use of these medications in this patient population if normal renal function and normal plasma potassium levels are present.14 In addition to the Randomized ALdactone Evaluation Study (RALES) trial, which established the role for aldosterone antagonists in chronic severe (NYHA class III/IV) systolic heart failure, Eplerenone Post-myocardial infarction Heart failure Efficacy and Survival Study (EPHESUS) demonstrated the benefit of aldosterone receptor antagonists in patients with an EF <40% after MI.1,2

Recently published evidence from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study suggests that patients with mild heart failure benefit substantially from aldosterone receptor antagonist therapy.15 Patients with NYHA class II systolic heart failure (left ventricular ejection fraction ≤35%) had significantly reduced risk of both death and hospitalization when treated with eplerenone in addition to standard medical therapy. EMPHASIS-HF is the first randomized controlled trial to suggest that even patients with mildly symptomatic systolic heart failure benefit from this therapy.15 Future guidelines for treatment of mild heart failure will likely include recommendations for treatment with aldosterone receptor antagonists. Clinical data from magnetic resonance imaging demonstrate that the addition of spironolactone to angiotensin-receptor blocker (ARB) therapy substantially decreases LV size, improves systolic function, and reverses LV hypertrophy.16 This reverse remodeling may contribute to the significant reduction in adverse clinical outcomes observed in EMPHASIS.

The next logical question after the observed marked benefit for aldosterone antagonists in mortality in the EMPHASIS-HF is whether there is a role for aldosterone receptor antagonists in the class I heart failure patients. Future research will be necessary to evaluate the use of aldosterone receptor antagonists in this patient population.

The usefulness of aldosterone receptor antagonists in the setting of acute decompensated heart failure has not been determined. Current evidence from RALES and EPHESUS supporting the use of aldosterone receptor antagonists is based on long-term clinical outcome data, but the acute effects of these agents are less established. Evidence suggests that aldosterone antagonists may improve cardiac vagal control (including heart rate variability and baroreflex sensitivity) immediately after intravenous administration, an effect that may be beneficial in decompensated heart failure and MIs.17

Blockade of the RAAS system in diastolic heart failure is a potential therapeutic option in this condition known for its limited treatment options. Aldosterone promotes synthesis of collagen and contributes to myocardial fibrosis, which has a deleterious effect on myocardial relaxation.18 Because aldosterone mediates myocardial fibrosis and the inflammatory response to tissue injury, increased aldosterone may ultimately increase LV hypertrophy, reduce vascular compliance, and impair diastolic function. Therefore, aldosterone blockade may have a role in reversing the underlying pathogenesis of diastolic heart failure.18 Small studies suggest that aldosterone antagonism may improve echocardiographic measurements of myocardial relaxation in patients with exertional dyspnea and abnormal LV filling patterns.19 This benefit in diastolic heart failure is likely independent of the antihypertensive effects of these agents, because improvement in diastolic parameters have been demonstrated independent of blood pressure effect.20 The results of the large, randomized, controlled trial TOPCAT (Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart) will provide clinical insight into the potential use of aldosterone antagonists in diastolic heart failure.18–20

Aldosterone Receptor Antagonists in Arrhythmias

Although mechanistically unclear, aldosterone receptor antagonists decrease the frequency of ventricular arrhythmias.21 Spironolactone decreases QT dispersion, mediates the sympathetic nervous system, and conserves total body potassium and magnesium, which may underlie an antiarrhythmic effect.21,22 Furthermore, prior research showed that aldosterone receptor antagonists may decrease collagen synthesis after MI and positively affect LV remodeling, 2 potential sources that participate in ventricular arrhythmias in patients with heart failure.21,22 Both the RALES and EPHESUS trials demonstrate that aldosterone blockade decreased sudden death events.1,2 The exact mechanism of possible arrhythmia prevention leading to sudden cardiac death reduction remains unclear, although prevention of hypokalemia and reversal of the adverse LV remodeling, which serves as the substrate for adverse arrhythmias, are the leading hypotheses. Finally, it is possible that the mineralocorticoid receptor may directly affect arrhythmogenesis. Mice models demonstrate that the receptor itself may assist in mediating the electrical stability of the left ventricle.23 Although not traditionally considered antiarrhythmic medications, aldosterone receptor antagonists may be grouped with other nonantiarrhythmic medications including statins, known for their ability to reduce the incidence of ventricular fibrillation and ventricular tachycardia without the proarrhythmic potential of the traditional antiarrhythmic medications.24

Further clinical trials are needed to establish the clinical efficacy of aldosterone receptor antagonists in the prevention of arrhythmias. It is possible that aldosterone receptor blockade may serve as a primary prevention agent of sudden cardiac death in patient populations at risk, including long QT syndrome, Brugada syndrome, and hypertrophic cardiomyopathy. At this point in time, however, future studies remain necessary to prove the efficacy of aldosterone receptor blockade in these areas.25

In addition to its potential role in prevention of ventricular arrhythmias, there may be a role for aldosterone receptor antagonism in prevention of atrial arrhythmias.26–31 Atrial fibrillation is the most common sustained arrhythmia in congestive heart failure. The adverse structural changes that occur in congestive heart failure, including atrial fibrosis and atrial remodeling, may be attenuated by spironolactone in rat models.26 Eplerenone has been shown to suppresses the inducibility of atrial tachyarrhythmias in dog models.27 Although our current management of atrial fibrillation in congestive heart failure relies on both rate and rhythm control after the development of the arrhythmia, medications with a positive effect on atrial remodeling, and atrial fibrosis may limit the substrate that underlies the arrhythmia.28 Meta-analysis of prior studies demonstrates that ARBs and ACE-inhibitors are associated with less atrial fibrillation. It is possible that additional blockade of the RAAS system may also be particularly useful to prevent recurrence of atrial fibrillation after cardioversion as well.29–31 The aldosterone receptor may serve a potential therapeutic target as a preventative measure for patients at high risk for atrial fibrillation, as well as patients with known paroxysmal atrial fibrillation.

Aldosterone Receptor Antagonists in Coronary Artery Disease

Aldosterone receptor antagonists may have clinical utility in patients with coronary artery disease.32 Aldosterone mediates effects that enhance the progression of coronary artery disease (eg, endothelial dysfunction, collagen deposition, vascular inflammation, increasing oxidant stress, disruption of fibrinolysis, and activation of the sympathetic nervous system).32–34 All of these effects remain current targets for therapeutic intervention in patients with coronary artery disease, including patients with chronic stable angina and post- MI. Furthermore, mineralocorticoid receptor blockade improves the bioavailability of nitric oxide and enhances vasorelaxation.33,34 Plasma aldosterone level is an independent predictor of in-stent restenosis in patients with prior percutaneous interventions, possibly secondary to its role in vascular inflammation and endothelial dysfunction.35 Aldosterone may also serve as a mediator in the pathogenesis of atherosclerosis. Although the exact role of aldosterone in the formation of an atherosclerotic lesion remains unknown, mice treated with eplerenone have inhibited atherosclerotic formation.36,37 These observations justify studies of aldosterone receptor antagonists in the chronic setting.35

Given the broad effects of aldosterone on vascular pathophysiology, it follows that aldosterone receptor antagonists may ultimately have similar pleitropic effects to statins for patients with known coronary artery disease. Aldosterone itself may also play a unique role in the acute phase of a MI. Evidence indicates that elevated plasma aldosterone levels are associated with adverse clinical outcomes, including mortality, in the setting of ST-elevation MI.38 Because aldosterone plays a role in promoting thrombosis, endothelial dysfunction, oxidative stress, and extracellular collagen deposition, the use of aldosterone antagonists may be particularly useful early in the setting of MI. This association between aldosterone levels and mortality was present independent of the presence of congestive heart failure, further suggesting that aldosterone antagonists may possess a unique role in the treatment of MIs.38

Although EPHESUS established the clinical utility of aldosterone receptor antagonists after MI with concomitant heart failure, the role of aldosterone antagonists after MI in the absence of heart failure has not yet been established in clinical trials. High aldosterone levels are a poor prognostic indicator after MI, independent of the presence of congestive heart failure.39 Results of future clinical trials such as ALBATROSS (Aldosterone Lethal effects Blocked in Acute myocardial infarction Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up) will help elucidate whether aldosterone receptor blockade will provide additional benefit to patients after acute MI, independent of the presence of heart failure.39

Aldosterone Receptor Antagonists in Primary Prevention

The presence of excess aldosterone frequently exists long before a patient presents with decompensated heart failure or an MI. Even before the presence of cardiovascular disease, research suggests that aldosterone contributes to insulin resistance, endothelial dysfunction, and the maladaptive vascular remodeling present in metabolic syndrome.40,41 Plasma aldosterone levels are elevated in one-third of patients with metabolic syndrome.40,41 Blockade of aldosterone early in the disease process may prevent the development of symptomatic heart failure and atherosclerosis. Recent evidence indicates that mineralocorticoid receptor blockade may improve the detrimental endocrine and vascular abnormalities that characterize metabolic syndrome by increasing pancreatic insulin release, improving utilization of glucose, as well as increasing vasorelaxation of the endothelium.40,41 Furthermore, obesity has been associated with an inappropriate activation of the mineralocorticoid receptor, suggesting the endocrine and vascular effects of the hormone are intimately related.40 Clinical trials are necessary to help elucidate the possible role of aldosterone receptor antagonists in primary prevention of atherosclerotic disease in metabolic syndrome.41

Hypertension is 1 of the leading risks for the development of congestive heart failure, and the pathogenesis leading from hypertension to structural heart failure includes left ventricular remodeling, hypertrophy, and interstitial fibrosis. Because mineralocorticoid receptor blockade may inhibit these structural abnormalities, these agents may alter the progression from hypertension to congestive heart failure.42 Recent evidence indicates that eplerenone demonstrates equal efficacy in blood pressure control and regression of ventricular hypertrophy in hypertensive patients with known LV hypertrophy.43 Furthermore, it has been previously proposed that mineralocorticoid receptor blockers in patients with essential hypertension may help prevent further ventricular hypertrophy and myocardial fibrosis, and thereby preserve the cardiac conduction system.

Conclusion

Aldosterone receptor antagonists have been shown to be a highly efficacious pharmacologic intervention in treatment of heart failure patients. Despite a plethora of clinical trials demonstrating their utility in decreasing morbidity and mortality in heart failure, the adoption of these medications into clinical practice and standard of care has been faced with reluctance by clinicians. Although congestive heart failure remains 1 of the leading causes of morbidity, mortality, and hospitalizations, medications like aldosterone receptor antagonists continue to be under prescribed. With the recent results of the EMPHASIS-HF study, perhaps this class of medications will establish itself with the same importance in clinical treatment as ACE inhibitors and ARBs. The pleitropic effects of this class of medications may extend their clinical utility to a broader cardiovascular patient population. The current major clinical trials may have only scratched the surface in terms of the patient population that may benefit from this therapy, and the results of future and ongoing clinical trials are eagerly awaited.

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