© 2001 American Heart Association, Inc.
Integrative Physiology |
Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43
From the Section of Myocardial Biology, Cardiovascular Institute, Departments of Medicine (D.E.G., G.I.F.), Biochemistry and Molecular Biology (H.S., G.I.F.), and Physiology and Biophysics (G.I.F.), Mount Sinai School of Medicine, New York, NY; Department of Pharmacology (G.E.M., H.T., D.V.), SUNY Upstate Medical University, Syracuse, NY; Center for Cardiovascular Development (M.D.S.), Baylor College of Medicine, Houston, Tex; and UCSD-Salk NHLBI Program in Molecular Medicine (J.C., K.R.C.), Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif. Present address for H.S. is Department of Vascular Biology, The Scripps Research Institute, La Jolla, Calif.
Correspondence to Dr Glenn I. Fishman, Mount Sinai School of Medicine, One Gustave L. Levy Pl, Box 1269, New York, NY 10029. E-mail fishmg01{at}doc.mssm.edu
Abstract—Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation 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 of age. Optical mapping of the epicardial electrical activation pattern in Cx43 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 ratio 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 gap junctional abnormalities as a key molecular feature of the arrhythmogenic substrate.
Key Words: gap junction • connexin43 • arrhythmia • conduction
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