To gain mechanistic insight into cardiomyopathy associated with DMD, we compared cardiac electrophysiological, structural and molecular features observed in mdx mice treated with HDACi suberoylanilide hydroxamic acid (5 mg/kg for 90 days, SAHA mice, n=22) to untreated (mdx, n=24) and wild type (WT, n=20) mice. By telemetry ECG recording, a higher proneness to ventricular arrhythmias (Vas) was detected in mdx mice under stress condition (restraint test), mostly prevented by SAHA. Aconitine precipitated VAs by 83% in WT mice, and 11% and 57% in mdx and SAHA mice. Epicardial multiple lead recording revealed a slowing down of impulse propagation and reduced ability to elicit a propagated response in mdx mice in comparison to WT, together with a prolongation of QRS complex. The changes were largely counteracted by SAHA. In addition, SAHA: (i) reverted a marked lateralization of Cx43 in mdx mice and (ii) determined a decrease of Cx40 and up-regulation of Cx37 and 32 while expression levels of Cx43 and 45 as well as dystrophin were unaltered. We propose that SAHA counteract the dystrophin-dependent reduction in the sodium channel Na_v1.5 protein level via its ability to inhibit proteasome activity and the ubiquitin-driven degradation of the channel. The SAHA-induced remodelling of Na_v1.5 and different connexins suggests a novel HDACi-dependent mechanism of action active in the heart and indicates histone deacetylase as important contributor to arrhythmogenesis in DMD cardiomyopathy.