Abstract 1429: Defects in Connexin Signaling Underlie Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in a Novel Mouse Model
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic form of cardiomyopathy, which is typically characterized by right but also recently left ventricular dysfunction, fibrotic/fatty replacement of the ventricle and ventricular tachycardia leading to sudden cardiac death. The precise molecular mechanisms responsible for ARVD/C are currently unknown. However, compelling evidence from human genetic studies has linked these diseases to genetic deficiencies in components of a cell-cell junction within cardiac muscle known as the desmosomes. To understand the molecular mechanisms and the pathogenesis of ARVD/C we generated a mouse model of ARVD/C through conditional cardiac-specific ablation of the desmosomal component, desmoplakin, using a Cre/loxP strategy and the myosin light chain-2v Cre mouse line (desmo cKO). Homozygous desmo cKO mice exhibit early defects in desmosomal integrity, which lead to (i) histological defects including a thin, fibrotic, hypoplastic and dilated right and left ventricle, respectively, as well as accumulation of lipid/fat deposits within cardiac mucle, (ii) physiological defects including cardiac dysfunction, (iii) electrophysiological defects including spontaneous ventricular tachycardia as well as susceptibility to exercise and catecholamine induced arrhythmias and (iv) sudden cardiac death between one and five months of age. Desmo cKO mice also display unique effects on connexin signaling in the right ventricle in vivo, including right bundle branch block and loss of connexin43 expression, which precede the defects in desmosomal integrity. These studies provide evidence for a new mouse model of ARVD/C, which is reminiscent of the postnatal onset of human ARVD/C at the histological, physiological and electrophysiological levels as well as provide the basis for molecular mechanisms underlying ARVD/C.
This research has received full or partial funding support from the American Heart Association, AHA National Center.