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1 The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA
2 Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, USA
* To whom correspondence should be addressed. E-mail: david.gutstein{at}med.nyu.edu.
Genetic studies in the mouse have demonstrated that conditional cardiac-resticted loss of connexin43 (Cx43), the major ventricular gap junction protein, is highly arrhythmogenic. However, whether more focal gap junction remodeling, as is commonly seen in acquired cardiomyopathies, influences the propensity for arrhythmogenesis is not known. We examined electrophysiological properties and the frequency of spontaneous and inducible arrhythmias in genetically engineered chimeric mice derived from injection of Cx43-deficient embryonic stem cells into wildtype recipient blastocysts. Chimeric mice had numerous well-circumscribed microscopic Cx43-negative foci in their hearts, comprising ~ 15% of the total surface area as determined by immunohistochemical analysis. Systolic function in the chimeric mice was significantly depressed as measured echocardiographically (19.0% decline in fractional shortening compared with controls, p < 0.05) and by invasive hemodynamics (17.6% reduction in dP/dT, p < 0.01). Chimeras had significantly more spontaneous arrhythmic events than controls (p < 0.01), including frequent runs of non-sustained ventricular tachycardia in some of the chimeric mice. However, in contrast to mice with conditional cardiac-resticted loss of Cx43 in the heart, no sustained ventricular tachyarrhythmias were observed. We conclude that focal areas of uncoupling in the myocardium increase the likelihood of arrhythmic triggers, but more widespread uncoupling is required to support sustained arrhythmias.
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