To characterize the role of the gap junction protein connexin43 (Cx43) in ventricular conduction, we studied hearts of mice with targeted deletion of the Cx43 gene. Mice homozygous for the Cx43 null mutation (Cx43 Ϫ / Ϫ ) die shortly after birth. Attempts to record electrical activity in neonatal Cx43 Ϫ / Ϫ hearts ( n ϭ 5) were unsuccessful. Ventricular epicardial conduction of paced beats, however, was 30% slower in heterozygous (Cx43 Ϫ / ϩ ) neonatal hearts (0.14 Ϯ 0.04 m/s, n ϭ 27) than in wild-type (Cx43 ϩ / ϩ ) hearts (0.20 Ϯ 0.07 m/s, n ϭ 32; P Ͻ 0.001). This phenotype was even more severe in adult mice; ventricular epicardial conduction was 44% slower in 6-9 mo-old Cx43 Ϫ / ϩ hearts (0.18 Ϯ 0.03 m/s, n ϭ 5) than in wild-type hearts (0.32 Ϯ 0.07 m/s, n ϭ 7, P Ͻ 0.001). Electrocardiograms revealed significant prolongation of the QRS complex in adult Cx43 Ϫ / ϩ mice (13.4 Ϯ 1.8 ms, n ϭ 13) compared with Cx43 ϩ / ϩ mice (11.5 Ϯ 1.4 ms, n ϭ 12, P Ͻ 0.01). Whole-cell recordings of action potential parameters in cultured disaggregated neonatal ventricular myocytes from Cx43 Ϫ / ϩ and ϩ / ϩ hearts showed no differences. Thus, reduction in the abundance of a major cardiac gap junction protein through targeted deletion of a Cx43 allele directly leads to slowed ventricular conduction. ( J. Clin. Invest. 99:1991-1998.)

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This study tests the hypothesis that moderate myocardial dysfunction is associated with altered myocardial anisotropic properties and structurally altered ventricular fibrillation (VF). Mongrel dogs were randomized to either a control group or a group that was rapidly paced at 250 beats/min until the left ventricular ejection fraction was < or = 40%. Changes in anisotropic properties and the electrical characteristics of VF associated with the development of moderate myocardial dysfunction were assessed by microminiature epicardial mapping studies. In vivo conduction, refractory periods, and repolarization times were prolonged in both longitudinal and transverse directions in myopathic animals versus controls. VF was different in myopathic versus control animals. There were significantly more conducted deflections during VF in normal hearts compared with myopathic hearts. Propagated deflection-to-deflection intervals during VF were significantly longer in myopathic hearts compared with controls (125.5 +/- 49.06 versus 103.4 +/- 32.9 ms, p = 0.009). There were no abnormalities in cell size, cell shape, or the number of intercellular gap junctions and there was no detectable change in the expression of the gap junction proteins Cx43 and Cx45. Moderate myocardial dysfunction is associated with significant electrophysiological abnormalities in the absence of changes in myocardial cell morphology or intercellular connections, suggesting a functional abnormality in cell-to-cell communication.