DOWN-REGULATION OF IMMUNODETECTABLE CONNEXIN43 AND DECREASED GAP JUNCTION SIZE IN THE PATHOGENESIS OF CHRONIC HIBERNATION IN THE HUMAN LEFT-VENTRICLE

Background-The regional wall motion impairment and predisposition to a rrhythmias in human ventricular hibernation may plausibly result from abnormal intercellular propagation of the depolarizing wave front. Thi s study investigated the hypothesis that altered patterns of expressio n of connexin43, the principal gap junctional protein responsible for passive conduction of the cardiac action potential, contribute to the pathogenesis of hibernation. Methods and Results-Patients with poor ve ntricular function and severe coronary artery disease underwent thalli um scanning and MRI to predict regions of normally perfused, reversibl y ischemic, or hibernating myocardium. Twenty-one patients went on to coronary artery bypass graft surgery, during which biopsies representa tive of each of the above classes were taken. Hibernation was confirme d by improvement in segmental wall motion at reassessment 6 months aft er surgery. Connexin43 was studied by quantitative immunoconfocal lase r scanning microscopy and PC image software. Analysis of en face proje ction views of intercalated disks revealed a significant reduction in relative connexin43 content per unit area in reversibly ischemic (76.7 +/-34.6%, P<.001) and hibernating (67.4+/-24.3%, P<.001) tissue compar ed with normal (100+/-30.3%); ANOVA P<.001. The hibernating regions we re further characterized by loss of the larger gap junctions normally seen at the disk periphery, reflected by a significant reduction in me an junctional plaque size in the hibernating tissues (69.5+/-20.8%) co mpared with reversibly ischemic (87.4+/-31.2%, P=.012) and normal (100 +/-31.5%, P<.001) segments; ANOVA P<.001. Conclusions-These results in dicate progressive reduction and disruption of connexin43 gap junction s in reversible ischemia and hibernation. Abnormal impulse propagation resulting from such changes may contribute to the electromechanical d ysfunction associated with hibernation.