Submitted on August 17, 2007
Accepted on December 6, 2007
Altered expression of connexin43 contributes to the arrhythmogenic substrate during the development of heart failure in cardiomyopathic hamster
Takashi Sato1, Tomoko Ohkusa1*, Haruo Honjo2, Shinsuke Suzuki1, Masa-aki Yashida1, Yuko Sato Ishiguro3, Harumichi Nakagawa3, Masatoshi Yamazaki3, Masafumi Yano, Itsuo Kodama4, and Masunori Matsuzaki
1 Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan
2 Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
3 Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya, Japan
4 Univ. Nagoya, Japan
* To whom correspondence should be addressed. E-mail: ohkusa{at}yamaguchi-u.ac.jp.
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 6~10w, and showed a moderate reduction in LV contractility at age 20w. Appreciable interstitial fibrosis was recognized at these stages. LV mRNA and protein levels of Cx43 in UM-X7.1 were unaffected at age 10w, but significantly reduced at 20w. The expression level of Ser255-phosphorylated Cx43 in UM-X7.1 at age 20w was significantly greater than that in control golden hamster at the same age. In UM-X7.1 at age 10w, almost normal LV conduction was preserved, whereas the dispersion of action potential duration (APD) was significantly increased. UM-X7.1 at age 20w showed significant reduction of cardiac space constant (
), significant decrease in conduction velocity, marked distortion of activation fronts and pronounced increase in APD dispersion. Programmed stimulation resulted in sustained ventricular tachycardia (VT) or fibrillation in UM-X7.1. LV activation during polymorphic VT was characterized by multiple phase singularities or wavebreaks. During the development of heart failure in 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.
