Abstract 3861: Histone Deacetylase Inhibitors Ameliorate Cardiac Electrical Competence In Dystrophic Mice
INTRODUCTION & BACKGROUND: Many Duchenne patients (DMD) develop dilated cardiomyopathy and heart failure. In addition, ECG abnormalities can also be detected in up to 60% of 10-year-old DMD patients and among those, conduction defects are frequent. Recently, we have demonstrated the morphological and functional recovery of skeletal muscles in dystrophic mice treated with histone deacetylase inhibitors (DIs) suggesting histone deacetylases (HDACs) as potential novel pharmacological targets for the treatment of DMD downstream of its genetic defect. Little or no information, however, is currently available about possible effects of DIs on the dystrophic heart function.
METHODS: To gain mechanistic insight into cardiomyopathy associated with DMD, we compared cardiac electrophysiological, structural and molecular features observed in the MDX mice model of DMD, treated with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (5 mg/kg for 90 days, SAHA mice) to untreated (MDX) and wild type (WT) mice. In 5-month old WT (n=14), MDX (n=16) and SAHA-treated MDX (n=15) mice we determined:
heart rate and heart-rate-based indices of cardiac autonomic control (SDRR and r-MSSD) and propensity to stress induced (restraint test) ventricular arrhythmias (VAs) by telemetry ECG,
post-transcriptional expression of Cx 40, 43, 32, and Nav 1.5 Sodium channel,
intercellular Cx organization by confocal microscopy.
RESULTS: VAs were negligible at rest in all animals. During restraint, SAHA treatment reduced the high incidence of VAs detected in untreated MDX mice to WT values (p<0.01). Heart rate, SDRR and r-MSSD were similar in the three groups at rest and during restraint. SAHA administration induced in MDX mice the decrease of Cx 40 protein level, the up-regulation of Cx 32 while the level of Cx 43 was unchanged. Finally, SAHA increase Nav 1.5 expression in treated MDX mice.
CONCLUSIONS: The SAHA-induced remodelling of the Na-channel and that of different connexins suggests a novel HDACi-dependent mechanism of action active in the heart and indicates these molecules as important contributors to arrhythmogenesis and ventricular instability in DMD cardiomyopathy.