Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in cx43-deficient mice

Background-Myocardial ischemia causes profound changes in both active membr ane currents and passive electrical properties. Because these complex chang es develop and progress concomitantly, it has not been possible to elucidat e the relative contributions of any one component to arrhythmogenesis induc ed by acute ischemia. Cx43+/- mice express 50% of the normal level of conne xin43 (Cx43), the major ventricular electrical coupling protein, but are ot herwise identical to wild-type (Cx43+/+) mice. Comparison of arrhythmogenes is in Cx43+/- and +/+ mice can provide insights into the role of changes in electrical coupling as an independent variable in the complex setting of a cute ischemia. Methods and Results-Acute ischemia was induced in isolated perfused mouse h earts by occlusion of the left anterior descending coronary artery. Spontan eous ventricular tachyarrhythmias (VT) occurred in more than twice as many Cx43+/- hearts than Cx43 +/+ hearts. VT was induced in nearly 3 times as ma ny Cx43+/- hearts. Multiple runs and prolonged runs of spontaneous VT were more frequent in Cx43+/- hearts. Onset of the first run of VT occurred sign ificantly earlier in Cx43+/- hearts. Premature ventricular beats were also more frequent in Cx43+/- hearts. The size of the hypoperfused region was eq uivalent in both groups. Conclusions-Reduced expression of Cx43 accelerates the onset and increases the incidence, frequency, and duration of ventricular tachyarrhythmias afte r coronary artery occlusion. Thus diminished electrical coupling per se pla ys a critical role in arrhythmogenesis induced by acute ischemia.