title: Spironolactone improves the arrhythmogenic substrate in heart failure by preventing ventricular electrical activation delays associated with myocardial interstitial fibrosis and inflammation.
abstract: BACKGROUND
  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.
  
  
  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.affiliation: University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Christine Tanaka
authors.initials: CT
authors.lastname: Esposito
authors.forename: Subha
authors.initials: S
authors.lastname: Varahan
authors.forename: Darwin
authors.initials: D
authors.lastname: Jeyaraj
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Stambler
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000517:prevention & control*; D004285:Dogs; D055724:Electrophysiological Phenomena; D005355:Fibrosis / Q000150:complications / Q000517:prevention & control; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology; D006352:Heart Ventricles / Q000503:physiopathology*; D007249:Inflammation / Q000150:complications / Q000517:prevention & control*; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D009206:Myocardium / Q000473:pathology*; D013148:Spironolactone / Q000627:therapeutic use*; D018754:Ventricular Dysfunction / Q000150:complications / Q000517:prevention & control*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone
keywords: aldosterone; fibrosis; heart failure; inflammatory markers; ventricular tachycardia