From Cardiac Medicine, Imperial College School of Medicine at the
National Heart and Lung Institute (R.R.K., M.G., E.D., S.M.R., P.A.P.-W.,
N.J.S.), and Royal Brompton Hospital (M.N.S., R.U., D.J.P., K.F., J.P.),
London, England.
Correspondence to Prof N.J. Severs, Cardiac Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, Sydney St, London SW3 6NP, England. E-mail n.severs{at}ic.ac.uk
Background—The regional wall motion
impairment and predisposition to arrhythmias in human
ventricular hibernation may plausibly result from abnormal
intercellular propagation of the depolarizing wave front. This study
investigated the hypothesis that altered patterns of expression 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 ventricular
function and severe coronary artery disease underwent thallium
scanning and MRI to predict regions of normally perfused, reversibly
ischemic, or hibernating myocardium. Twenty-one
patients went on to coronary artery bypass graft surgery,
during which biopsies representative of each of the
above classes were taken. Hibernation was confirmed by improvement in
segmental wall motion at reassessment 6 months after surgery.
Connexin43 was studied by quantitative immunoconfocal laser scanning
microscopy and PC image software. Analysis of en face
projection 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 compared with normal
(100±30.3%); ANOVA P<.001. The hibernating regions
were further characterized by loss of the larger gap junctions normally
seen at the disk periphery, reflected by a significant reduction in
mean junctional plaque size in the hibernating tissues (69.5±20.8%)
compared with reversibly ischemic (87.4±31.2%,
P=.012) and normal (100±31.5%, P<.001)
segments; ANOVA P<.001.
Conclusions—These results indicate progressive reduction and
disruption of connexin43 gap junctions in reversible ischemia
and hibernation. Abnormal impulse propagation resulting from such
changes may contribute to the electromechanical dysfunction associated
with hibernation.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Downregulation of Immunodetectable Connexin43 and Decreased Gap Junction Size in the Pathogenesis of Chronic Hibernation in the Human Left Ventricle
Key Words: junctions, gap • myocardial contraction • hibernation
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