Heterogeneous expression of Gap junction channels in the heart leads to conduction defects and ventricular dysfunction.
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
D E
DE
Section of Myocardial Biology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Morley
G E
GE
Vaidya
D
D
Liu
F
F
Chen
F L
FL
Stuhlmann
H
H
Fishman
G I
GI
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D015153:Blotting, Western; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D015870:Gene Expression; D005838:Genotype; D049452:Green Fluorescent Proteins; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D018031:Connexin 43; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase