Spironolactone improves the arrhythmogenic substrate in heart failure by preventing ventricular electrical activation delays associated with myocardial interstitial fibrosis and inflammation.

Abstract

INTRODUCTION:

Mineralocorticoid receptor antagonism reduces sudden cardiac death in heart failure, but the underlying mechanism is unclear. Our previous studies indicate that treatment with a mineralocorticoid receptor antagonist prevents adverse ventricular electrophysiological remodeling and reduces ventricular tachyarrhythmia inducibility in the rapid ventricular pacing-induced heart failure model. This study's aim was to determine whether chronic spironolactone treatment prevents formation of local electrical activation delays in the cardiomyopathic ventricle by attenuating inflammatory pathways and myocardial fibrosis.

METHODS AND RESULTS:

Dogs subjected to rapid ventricular pacing at 220 bpm for 5 weeks in the absence or presence of spironolactone treatment were assessed by echocardiography, electrophysiology study, ventricular fibrosis measurements and inflammatory cytokine mRNA expression analysis. Spironolactone failed to prevent LV systolic dysfunction or chamber enlargement in dogs that underwent rapid ventricular pacing. Spironolactone prevented ventricular electrogram widening after premature stimulation at short coupling intervals, electrogram fractionation, interstitial fibrosis, and inflammatory cytokine (interleukin-6, tumor necrosis factor-α) gene overexpression in ventricular paced dogs with heart failure.

CONCLUSIONS:

Our findings establish an important link between inflammatory cytokine gene expression, interstitial fibrosis and myocardial electrical activation delays during premature excitation and provide insight into the mechanisms by which mineralocorticoid receptor antagonism may prevent development of an arrhythmogenic ventricular substrate in systolic heart failure.

• Authors: Christine Tanaka Esposito, Subha Varahan, Darwin Jeyaraj, Yuan Lu, Bruce S Stambler
• Journal: Journal of cardiovascular electrophysiology (J Cardiovasc Electrophysiol) Vol. 24 Issue 7 Pg. 806-12 (Jul 2013) ISSN: 1540-8167 [Electronic] United States
• PMID: 23489714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Wiley Periodicals, Inc.

Chemical References

• Mineralocorticoid Receptor Antagonists
• Spironolactone

Topics

• Animals
• Arrhythmias, Cardiac (complications, prevention & control)
• Dogs
• Electrophysiological Phenomena
• Fibrosis (complications, prevention & control)
• Heart Failure (drug therapy, etiology)
• Heart Ventricles (physiopathology)
• Inflammation (complications, prevention & control)
• Mineralocorticoid Receptor Antagonists (therapeutic use)
• Myocardium (pathology)
• Spironolactone (therapeutic use)
• Ventricular Dysfunction (complications, prevention & control)