Gap Junction Remodeling is An Important Arrhythmogenic Substrate During the Development of Heart Failure in Cardiomyopathic Hamster

Abstract

Lethal ventricular arrhythmias often occur during the development of heart failure. Differences in the distribution of gap junction are considered to be an important factor in the origin of reentrant arrhythmias. We investigated the alterations in connexin (Cx)43 during the development of heart failure in UM-X7.1 cardiomyopathic hamster (CM) hearts. We analyzed Cx43 expressions (protein and mRNA) of the left ventricular (LV) myocardium by western blotting and RT-PCR. Echocardiographic and electrophysiological data were obtained. In CM, LV hypertrophy had developed at 10w, and LV global hypokinesis at 20w. In CM of 20w, random reentry was easily induced by programmed pacing, and conduction velocity was remarkably decreased in CM. The interstitial fibrosis was significantly increased in CM compared with G at 20w. The relative expression level of Cx43 protein and mRNA were significantly lower in CM at 20w than in G (0.52±0.29 vs 1.20±0.12, 0.58±0.14 vs 0.87±0.12, p<0.05, respectively). The relative expression level of serine255-phosphorylated Cx43, which initiates the down-regulation of gap junctional intercellular communication, was markedly increased in CM (1.1±0.4) compared with G (0.4±0.4, p<0.01) at 20w. Conclusions: In cardiomyopathic hamster hearts, in addition to an increase of interstitial fibrosis, downregulation and abnormal serine-phosphorylation of Cx43 may result in abnormal cell-to-cell communication and alter the electrophysiologic properties of the ventricle, leading to the initiation and perpetuation of ventricular arrythmias.