Altered expression of connexin43 contributes to the arrhythmogenic substrate during the development of heart failure in cardiomyopathic hamster

Abstract

Heart failure is known to predispose to life-threatening ventricular tachyarrhythmias even before compromising the systemic circulation, but the underlying mechanism is not well understood. The aim of this study was to clarify the connexin43 (Cx43) gap junction remodeling and its potential role in the pathogenesis of arrhythmias during the development of heart failure. We investigated stage-dependent changes in Cx43 expression in UM-X7.1 cardiomyopathic hamster hearts and associated alterations in the electrophysiological properties using a high-resolution optical mapping system. UM-X7.1 hamsters developed left ventricular (LV) hypertrophy by ages 6 approximately 10 wk and showed a moderate reduction in LV contractility at age 20 wk. Appreciable interstitial fibrosis was recognized at these stages. LV mRNA and protein levels of Cx43 in UM-X7.1 were unaffected at age 10 wk but significantly reduced at 20 wk. The expression level of Ser255-phosphorylated Cx43 in UM-X7.1 at age 20 wk was significantly greater than that in control golden hamsters at the same age. In UM-X7.1 at age 10 wk, almost normal LV conduction was preserved, whereas the dispersion of action potential duration was significantly increased. UM-X7.1 at age 20 wk showed significant reduction of cardiac space constant, significant decrease in conduction velocity, marked distortion of activation fronts, and pronounced increase in action potential duration dispersion. Programmed stimulation resulted in sustained ventricular tachycardia or fibrillation in UM-X7.1. LV activation during polymorphic ventricular tachycardia was characterized by multiple phase singularities or wavebreaks. During the development of heart failure in the cardiomyopathic hamster, alterations of Cx43 expression and phosphorylation in concert with interstitial fibrosis may create serious arrhythmogenic substrate through an inhibition of cell-to-cell coupling.

Bepridil Facilitates Early Termination of Spiral-Wave Reentry in Two-Dimensional Cardiac Muscle Through an Increase of Intercellular Electrical Coupling

“…The space constant (λ) was measured by the previously described method (24,25). In brief, a single cathodal subthreshold stimulus (20 ms in duration, approximately 0.8 times threshold) was delivered during electrical diastole after regular (BCL, 400 ms) suprathreshold stimuli (2.0 ms in duration, approximately 1.2 times the threshold intensity) through a teflon-coated platinum wire electrode (diameter, 0.1 mm) placed at the center of the anterior LV free wall.…”

Spontaneous high-frequency action potential

“…Connexin 43 (Cx43) predominates in virtually all myocytes of the working atrialand ventricular mammalian myocardium [1][2][3][4]. The severe reduction of Cx43 in the connecting-end had been generally regarded as the sign of the occurrence of tachyarrhythmias by immunolabeling in a large number of reports [5][6][7][8][9][10][11][12][13][14][15].…”

“…End-stage heart failure was characterized by the changes in conduction velocity that predisposed to arrhythmias, reported by Akar et al [5][6][7]. In pace-induced heart failure model (the myocardia in pace-induced heart failure are of volume-hypertrophy, i.e., high compliance hypertrophy), two stages were divided by conduction velocity: (i) In the early stage, conduction velocity was preserved first and then slightly decreased, concomitant with the gradual reduction of Cx43 in the longitudinal ends (i.e., the connecting-ends of myocardiocytes); (ii) in the late stage of conduction defect, conduction velocity was significantly decreased, preceded by the severe reduction of Cx43 in the longitudinal ends, leading to the sustained ventricular tachyarrhythmias.…”

Animal models of arrhythmogenic cardiomyopathy

“…Moreover, downregulation of connexin-43 may contribute to heterogeneity in repolarization and an increased likelihood of ventricular arrhythmias (Boukens et al, 2009). Likewise, reduced expression of connexin-43 in a Syrian cardiomyopathic hamster model of HCM was shown to lead to increased action potential dispersion and a propensity to develop VT at 20 weeks of age (Sato et al, 2008).…”