Aldosterone-Related Cardiovascular Disease and Benefits of Mineralocorticoid Receptor Antagonists in Clinical Practice

Abstract

High levels of aldosterone are associated with vascular and cardiac remodeling, myocardial fibrosis, and endothelial dysfunction with consequent increased risk of cardiovascular events and cardiovascular mortality. Indeed, mineralcorticoid receptor antagonists (MRAs) are recommended in the treatment of arterial hypertension, heart failure, alone or associated with chronic kidney disease. Nevertheless, molecular pathways underlying aldosterone-induced cardiac remodeling are poorly investigated. High levels of aldosterone induce reactive oxygen species with consequent oxidative stress and mitochondrial dysfunction. Moreover, aldosterone induces myocardial hypertrophy through increase of sarcomere mass mediated by pro-hypertrophic effect mediated by a G protein-coupled receptor kinase 5 cytosolic signaling and retention of ions and water regulated by aquaporins. Aim of this review is to report the data from the literature regarding excessive aldosterone signaling in mediating cardiovascular disease, also highlighting the morphostructural and molecular pathways correlated to myocardial damage and the role of MRAs in clinical practice.

Keywords: aldosterone; cardiomyopathy; endomyocardial biopsy; heart failure; mineralocorticoid receptor antagonists; molecular biology.

Graphical abstract

Central Illustration

MRAs Have Favorable Effects on the Kidney, Heart, and Vessels by Reducing Inflammation, Remodeling, and Fibrosis High levels of aldosterone lead to hyperactivation of the MR with consequent negative effects on the kidney, heart, and vessels. Both steroid and nonsteroid MRAs block the vicious cycle, with beneficial effects in terms of reduced fibrosis, remodeling, and inflammation. Abbreviations as in Figure 2.

Figure 1

Histologic and Ultrastructural Changes of Cardiomyocytes in a Patient With Heart Failure Caused by Myocarditis and After Cardiac Recovery by Immunosuppression LV EMB showing vacuolar degeneration of myocytes (A) corresponding at electron microscopy to water accumulation in clear cisternae in the endoplasmic reticulum (B). Optical microscopy shows reduction of cardiomyocytes with disappearance of vacuoles and decrease of extracellular spaces following cardiac recovery (C), hypertrophic/hyperfunctioning Golgi apparatus with enlarged vesicles for water/ion extrusion at electron microscopy (D). Adapted from Frustaci et al. EMB = endomyocardial biopsy; LV = left ventricular.

Figure 2

Schematic Representation of the RAA Axis and the Effects on the Heart, Kidney, and Vessels Resulting From Its Hyperactivation On the right are represented the diseases in which hyperactivation of the MR is implicated. MR = mineralocorticoid receptor; MRA = MR antagonist.