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(Circulation. 2001;104:1194.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Heterogeneous Expression of Gap Junction Channels in the Heart Leads to Conduction Defects and Ventricular Dysfunction

David E. Gutstein, MD; Gregory E. Morley, PhD; Dhananjay Vaidya, PhD; Fangyu Liu, BS; Franklin L. Chen, BA; Heidi Stuhlmann, PhD; Glenn I. Fishman, MD

From the Section of Myocardial Biology and Departments of Medicine (D.E.G., G.E.M., F.L., F.L.C., G.I.F.), Physiology and Biophysics (G.I.F.), and Biochemistry and Molecular Biology (G.I.F.), Mount Sinai School of Medicine, New York, NY; the Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY (D.V.); and the Department of Vascular Biology, The Scripps Research Institute, La Jolla, Calif (H.S.).

Correspondence to Glenn I. Fishman, MD, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1269, New York, NY 10029. E-mail fishmg01{at}doc.mssm.edu

Background—— Heterogeneous remodeling of gap junctions is observed in many forms of heart disease. The consequent loss of synchronous ventricular activation has been hypothesized to result in diminished cardiac performance. To directly test this hypothesis, we designed a murine model of heterogeneous gap junction channel expression.

Methods and Results—— We generated chimeric mice formed from connexin43 (Cx43)-deficient embryonic stem cells and wild-type or genetically marked ROSA26 recipient blastocysts. Chimeric mice developed normally, without histological evidence of myocardial fibrosis or hypertrophy. Heterogeneous Cx43 expression resulted in conduction defects, however, as well as markedly depressed contractile function. Optical mapping of chimeric hearts by use of voltage-sensitive dyes revealed highly irregular epicardial conduction patterns, quantified as significantly greater negative curvature of the activation wave front (-1.86±0.40 mm in chimeric mice versus -0.86±0.098 mm in controls; P<0.01; n=6 for each group). Echocardiographic studies demonstrated significantly reduced fractional shortening in chimeric mice (26.6±2.3% versus 36.5±1.6% in age-matched 129/SvxC57BL/6F1 wild-type controls; P<0.05).

Conclusions—— These data suggest that heterogeneous Cx43 expression, by perturbing the normal pattern of coordinated myocardial excitation, may directly depress cardiac performance.

Key Words: ion channels • contractility • conduction • genes • arrhythmia

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