Focal gap junction uncoupling and spontaneous ventricular ectopy.
Genetic studies in the mouse have demonstrated that conditional cardiac-restricted loss of connexin43 (Cx43), the major ventricular gap junction protein, is highly arrhythmogenic. However, whether more focal gap junction remodeling, as is commonly seen in acquired cardiomyopathies, influences the propensity for arrhythmogenesis is not known. We examined electrophysiological properties and the frequency of spontaneous and inducible arrhythmias in genetically engineered chimeric mice derived from injection of Cx43-deficient embryonic stem cells into wild-type recipient blastocysts. Chimeric mice had numerous well-circumscribed microscopic Cx43-negative foci in their hearts, comprising approximately 15% of the total surface area as determined by immunohistochemical analysis. Systolic function in the chimeric mice was significantly depressed as measured echocardiographically (19.0% decline in fractional shortening compared with controls, P < 0.05) and by invasive hemodynamics (17.6% reduction in change of pressure over time, P < 0.01). Chimeras had significantly more spontaneous arrhythmic events than controls (P < 0.01), including frequent runs of nonsustained ventricular tachycardia in some of the chimeric mice. However, in contrast to mice with conditional cardiac-resricted loss of Cx43 in the heart, no sustained ventricular tachyarrhythmias were observed. We conclude that focal areas of uncoupling in the myocardium increase the likelihood of arrhythmic triggers, but more widespread uncoupling is required to support sustained arrhythmias.
Gutstein
David E
DE
The Leon H. Charney Div. of Cardiology, New York Univ. School of Medicine/VA Harbor Medical Ctr., 423 E. 23rd St., 6 W.-6005BW, New York, NY 10010, USA. david.gutstein@med.nyu.edu
Danik
Stephan B
SB
Lewitton
Steve
S
France
David
D
Liu
Fangyu
F
Chen
Franklin L
FL
Zhang
Jie
J
Ghodsi
Newsha
N
Morley
Gregory E
GE
Fishman
Glenn I
GI
D000818:Animals; D015139:Blotting, Southern; D002678:Chimera; D018031:Connexin 43 / Q000235:genetics; D003971:Diastole; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D006321:Heart / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013599:Systole; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000503:physiopathology*; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology*
D018031:Connexin 43