Abstract 566: Altered Expression of Connexin43 Contributes to the Arrhythmogenic Substrate in Early Stage Heart Failure of Cardiomyopathic Hamster

Abstract

Background: Heart failure is known to predispose life-threatening ventricular tachyarrhythmias even before compromising the systemic circulation, but the underlying mechanism is not well understood. Methods and Results : We investigated stage-dependent changes in connexin43 (Cx43) expression and consequent electrophysiological properties in UM-X7.1 cardiomyopathic hamster hearts. UM-X7.1 hamsters develop left ventricular (LV) hypertrophy by age 6~10w, and show more pronounced LV hypertrophy and a moderate reduction in LV contractility at age 20w. Appreciable interstitial fibrosis is recognized at these stages. LV mRNA and protein levels of Cx43 in UM-X7.1 were unaffected at 10w, but significantly reduced at 20w (by 33% and 55%, respectively from controls). The relative expression level of serin255-phosphorylated Cx43 was markedly increased in UM-X7.1 at age 20w (by 175%). Electrophysiological properties were examined by optical mapping. In UM-X7.1 at 10w, almost normal LV conduction was preserved, whereas the dispersion of action potential duration (APD) was significantly increased. UM-X7.1 at 20w showed significant reduction of conduction velocity (by 35~40%), significant prolongation of APD (by 68%), marked distortion of activation fronts and a pronounced increase in APD dispersion. Programmed stimulation resulted in no arrhythmias in controls, but sustained ventricular tachycardia or fibrillation (VT/VF >5s) in UM-X7.1 (1/11 at 10w and 5/6 at 20w). LV activation during polymorphic VT was characterized by multiple phase singularities or wavebreaks. Conclusions : In the early stage heart failure of cardiomyopathy, down-regulation and serine255-phosphorylation of Cx43 in addition to the interstitial fibrosis may contribute to the arrhythmogenic substrate through the inhibition of cell-to-cell communication.