Heterogeneous Cx43 expression in chimeric mice significantly reduced fractional shortening (26.6% vs 36.5%; P<0.05) and caused highly irregular epicardial conduction patterns.
Does heterogeneous Cx43 expression cause conduction defects and depress cardiac performance in a murine model?
Heterogeneous expression of Cx43 gap junctions in a murine model directly causes conduction defects and depresses cardiac contractile function.
Absolute Event Rate: 26.6% vs 36.5%
p-value: p=<0.05
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.
Gutstein et al. (2001) studied Conduction defects and ventricular dysfunction (n=12). Heterogeneous Cx43 expression (chimeric mice) vs. Wild-type controls was evaluated on Fractional shortening (p=<0.05). Heterogeneous Cx43 expression in chimeric mice significantly reduced fractional shortening (26.6% vs 36.5%; P<0.05) and caused highly irregular epicardial conduction patterns.