A New HOPE for Aldosterone Blockade?

Abstract

A ldosterone is increasingly recognized to play an important role in the pathophysiology of heart failure due to systolic left ventricular dysfunction (SLVD) and aldosterone blockade (AB) to be effective in reducing mortality and morbidity in patients with severe chronic heart failure and heart failure due to SLVD after myocardial infarction. 1,2 AB has also been shown to reduce blood pressure and target-organ damage in patients with essential hypertension. 3 The effect of AB on mortality and morbidity will soon be investigated in patients with mild to moderate heart failure due to SLVD and in patients with heart failure with preserved left ventricular systolic function. Although AB has been shown to be effective in patients with SLVD and in those with essential hypertension without SLVD, increasing evidence suggests that it may have an even greater role in patients with atherosclerosis of the coronary and other vascular beds. See p 1819 Role of Aldosterone in Vascular Damage and Its ConsequencesIt is reasonable to assume that aldosterone influences vascular function because mineralocorticoid receptors are expressed in vascular endothelial and smooth muscle cells as well as in cardiac fibroblasts and cardiomyocytes. 4 Many of the pathophysiological effects of angiotensin II on the myocardium and vascular wall may, in a large part, be due to aldosterone and can be blocked by AB as well as by an angiotensinconverting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB); however, it appears that the combination of an AB with an ACE-I or ARB may be more effective than either alone in preventing myocardial and vascular inflammation and remodeling. Although angiotensin II is a major stimulus for the production of aldosterone, other stimuli such as potassium are also important ("aldosterone escape"), as illustrated by the ability to stimulate aldosterone production in the angiotensinogen-knockout mouse. 5 These data suggest that AB could add to the benefits of ACE-I in reducing mortality and morbidity in patients with vascular disease without known SLVD, as shown in the Heart Outcomes Prevention Evaluation (HOPE) 6 and European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) 7 studies. To date, several mechanisms have been evaluated to understand the adverse effects of aldosterone on vascular function. Aldosterone has been shown to increase NAD(P)H oxidase activity and reactive oxygen species (ROS) generation and AB to improve endothelial function in a high-lipiddiet rabbit model. 8 Aldosterone has also been shown to decrease tetrahydrobiopterin, an important cofactor for endothelial nitric oxide (NO) synthase activity and NO production, and AB to improve tetrahydrobiopterin levels and restore NO synthesis. 9 Aldosterone stimulates, and AB blocks, nuclear factor-␤ and activator protein-1 signaling pathways. 10 Clinically, AB is additive to an ACE-I in improving endothelial function in patients with heart failure due to SLVD. 11 Because endothelial function has ...

Aldosterone, atherosclerosis and vascular events in patients with stable coronary artery disease

“…As a component of the RAAS, aldosterone is classically known to play a regulatory role in body fluid and electrolyte homeostasis, thus contributing to the development of hypertension. Recent findings from experimental and clinical studies have indicated that aldosterone might be involved in cardiovascular disease through a mechanism distinct from its contribution to hypertension [1][2][3]. Under controlled experimental conditions, RAAS activation and administration of aldosterone resulted in myocardial and vascular fibrosis, inflammation, and endothelial dysfunction; such physiologic perturbations are known to complicate the atherosclerotic process [4][5][6][7][8].…”