Gap junction remodeling is an arrhythmogenic substrate during the development of heart failure in cardiomyopathic hamster

Abstract

Differences in the distribution of gap junctions are considered to be an important factor in the origin of reentrant arrhythmias. We investigated the alterations in connexin (Cx)43 during development of heart failure in UM-X7.1 cardiomyopathic hamster (CM). We analyzed Cx43 expressions of the left ventricular (LV) myocardium at age of 6, 10, and 20w. Echocardiographic and ECG monitoring data were obtained. Results: In CM, LV hypertrophy had developed at 10w, and LV global hypokinesis at 20w. QRS interval was markedly prolonged compared with golden hamster (G), and polymorphic ventricular tachycardia was easily induced by burst pacing at 20w of CM. The interstitial fibrosis was significantly increased in CM (8.5 ± 2.6%) compared with G (1.9 ± 1.1%, p < 0.05) 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. Serine255-phosphorylated Cx43 was overexpressed at cytoplasmic area in CM. Conclusions: In cardiomyopathic hearts, in addition to 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.