Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43

Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribut e to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice w ith cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactiva tion of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months o f age. Optical mapping of the epicardial electrical activation pattern in C x43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic rati o compared with control littermates (2.1+/-0.13 versus 1.66+/-0.06; P<0.01) . This novel genetic murine model of primary sudden cardiac death defines g ap junctional abnormalities as a key molecular feature of the arrhythmogeni c substrate.