Reduction of fibrosis-related arrhythmias by chronic renin-angiotensin-aldosterone system inhibitors in an aged mouse model

Abstract

Myocardial fibrosis increases arrhythmia vulnerability of the diseased heart. The renin-angiotensin-aldosterone system (RAAS) governs myocardial collagen synthesis. We hypothesized that reducing cardiac fibrosis by chronic RAAS inhibition would result in reduced arrhythmia vulnerability of the senescent mouse heart. Wild-type mice (52 wk old) were treated for 36 wk: 1) untreated control (C); 2) eplerenone (E); 3) losartan (L); and 4) cotreatment with eplerenone and losartan (EL). Ventricular epicardial activation mapping was performed on Langendorff-perfused hearts. Arrhythmia inducibility was tested by one to three premature stimuli and burst pacing. Longitudinal and transverse conduction velocity and dispersion of conduction were determined during pacing at a basic cycle length of 150 ms. Sirius red staining (collagen) was performed. As a result, in the RV of mice in the E, L, and EL groups, transverse conduction velocity was significantly increased and anisotropic ratio was significantly decreased compared with those values of mice in the C group. Anisotropic reentrant arrhythmias were induced in 52% of untreated mice and significantly reduced to 22%, 26%, and 16% in the E, L, and EL groups, respectively. Interstitial fibrosis was significantly decreased in both the RV and LV of all treated groups. Scattered patches of replacement fibrosis were found in 90% of untreated hearts, which were significantly reduced in the E, L, and EL groups. A strong correlation between the abundance of patchy fibrosis and arrhythmia inducibility was found. In conclusion, chronic RAAS inhibition limited aging-related interstitial fibrosis. The lower arrhythmogeneity of treated mice was directly correlated to the reduced amount of patchy fibrosis.

Effect of spironolactone on ventricular arrhythmias in patients with left ventricular systolic dysfunction and implantable cardioverter defibrillators

“…4,5 Animal studies have shown that chronic aldosterone-overload induces structural and electrical remodelling of the myocardium increasing the risk for malignant ventricular arrhythmia 24 and the use of AA attenuated electrical remodelling and suppressed the inducibility of ventricular arrhythmia. 9,25,26 The use of AA causes a delay or reversal of myocardial fibrosis as noted by a decreased turnover of extracellular markers in the treatment arm of RALES trial. 27 Spironolactone has also been shown to reduce plasma levels of metalloproteinases in ischaemic HF indicating its role in reversing collagen dysregulation that plays a role in cardiac remodelling.…”

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Similarly, spironolactone treatment prevents gap junction remodeling and restores the decreased transverse conduction velocity in a thoracic aortic constriction model (Qu et al, 2009). Likewise, eplerenone reduces fibrosis-related arrhythmias in aged mice (Stein et al, 2010). Both spironolactone and eplerenone reduce the prolongation of QT intervals and diminishes the occurrence of ventricular premature beats or nonsustained ventricular tachycardia in aldosterone-infused rats (Dartsch et al, 2013).…”

Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease

“…Direct evidence for the role of Ang II in cardiac aging came in 2007, when Basso, et al reported that inhibition of Ang II signaling by either angiotensin converting enzyme inhibitor enalapril or angiotensin receptor type I inhibitor losartan extended the lifespan of normal male Wistar rats and slowed the onset of agerelated cardiovascular pathologies (22). These drugs have also been shown to reduce myocardial fibrosis and fibrosis-related arrhythmias in aged mice (304). This was confirmed by a study which demonstrated that mice with disruption of angiotensin receptor type I prolong mouse survival (29).…”