Focal gap junction uncoupling and spontaneous ventricular ectopy

David E. Gutstein, Stephan B. Danik, Steve Lewitton, David France, Fangyu Liu, Franklin L. Chen, Jie Zhang, Newsha Ghodsi, Gregory E. Morley, Glenn I. Fishman

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Genetic studies in the mouse have demonstrated that conditional cardiac-restricted 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 wild-type 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 change of pressure over time, P < 0.01). Chimeras had significantly more spontaneous arrhythmic events than controls (P < 0.01), including frequent runs of nonsustained 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.

Original languageEnglish
Pages (from-to)H1091-H1098
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number3 58-3
StatePublished - Sep 2005
Externally publishedYes


  • Chimera
  • Connexin43
  • Ventricular dysfunction


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