Supported by an independent research grant from Pfizer, Inc to B. Stambler. Spironolactone was donated by Pfizer, Inc. Pacemakers and pacemaker leads for this study were donated by Medtronic, Inc.
Spironolactone Improves the Arrhythmogenic Substrate in Heart Failure by Preventing Ventricular Electrical Activation Delays Associated with Myocardial Interstitial Fibrosis and Inflammation
Article first published online: 13 MAR 2013
© 2013 Wiley Periodicals, Inc.
Journal of Cardiovascular Electrophysiology
Volume 24, Issue 7, pages 806–812, July 2013
How to Cite
ESPOSITO, C. T., VARAHAN, S., JEYARAJ, D., LU, Y. and STAMBLER, B. S. (2013), Spironolactone Improves the Arrhythmogenic Substrate in Heart Failure by Preventing Ventricular Electrical Activation Delays Associated with Myocardial Interstitial Fibrosis and Inflammation. Journal of Cardiovascular Electrophysiology, 24: 806–812. doi: 10.1111/jce.12115
B.S. Stambler has received consulting fees and honoraria from Medtronic. Other authors: No disclosures.
- Issue published online: 1 JUL 2013
- Article first published online: 13 MAR 2013
- Accepted manuscript online: 15 FEB 2013 11:28AM EST
- Manuscript Accepted: 1 FEB 2013
- Manuscript Revised: 16 JAN 2013
- Manuscript Received: 16 NOV 2012
- heart failure;
- inflammatory markers;
- ventricular tachycardia
MR Blockade Reduces Electrical Delays and Fibrosis
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.
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.