Downregulation of Immunodetectable Connexin43 and Decreased Gap Junction Size in the Pathogenesis of Chronic Hibernation in the Human Left Ventricle

Abstract

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.

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

“…[4][5][6] In the hibernating myocardium, the structural remodeling of gap junctions and reduced Cx43 protein expression has been found and implicated a possible link between disease-related gap junction remodeling and impaired cardiac contraction. 8 The downregulation of Cx43 protein expression has also been demonstrated in the left ventricles of transplant patients with end-stage congestive heart failure, irrespective of whether heart failure is due to idiopathic dilated cardiomyopathy or ischemic heart disease. 9 Data from quantitative immunoconfocal microscopy of tissue from by-pass patients suggest that in ischemic heart disease, reduction in ventricular Cx43 develops long before terminal heart failure.…”

“…8,24,27 For each specimen, 10 randomly selected areas were examined. Mouse anti-rabbit immunoglobulin conjugated to CY3 (Chemicon) was used to visualize immunolabeled Cx43.…”

“…5,6 Alterations in the organization of cardiac gap junctions and expression of Cx43 can cause predisposition to arrhythmia, uncoordinated contraction, and overall diminished myocardial function in various pathologic conditions. [5][6][7][8][9] Using chimeric mice created from Cx43-deficient stem cells and blastocysts, Gutstein et al 10 have demonstrated that spatially heterogeneous Cx43 downregulation is indeed linked to disturbances in electromechanical function in terms of both irregular epicardial conduction patterns and contractile dysfunction. 10 Dietary hypercholesterolemia has been also shown to induce contractile dysfunction independent of vascular disease, characterized by a decrease in the maximum rate of shortening and relaxation in a papillary muscle preparation, 11 although this finding has not been confirmed in isolated intact hearts.…”

Regulation of intercellular coupling in acute and chronic heart disease

“…The morphological picture of the myocyte survival response is nonspecific. The same structural changes occur in response to diverse forms of sub-lethal injury and include partial or nearly complete loss of sarcomeres, accumulation of glycogen and disorganization and loss of sarcoplasmic reticulum (13)(14)(15), as well as a reduction in gap junction protein expression and loss of large gap junctions (16)(17)(18). These stereotypical morphological changes, referred to as myocytolysis, are universally observed, at least to some extent, in dysfunctional ventricular wall segments in patients with chronic ischemic heart disease (18) and in diverse forms of cardiomyopathy in patients with heart failure (13-15,19).…”

Do Alterations in Intercellular Coupling Play a Role in Cardiac Contractile Dysfunction?

“…In this issue of Circulation, Kaprielian et al 5 provide evidence for a novel mechanism involving alterations in intercellular coupling that might contribute to the pathogenesis of contractile dysfunction in hibernating myocardium. Using digital image processing techniques and confocal immunofluorescence microscopy, they measured the amount of the major cardiac gap junction protein connexin43 (Cx43) in left ventricular samples obtained from patients at the time of coronary artery bypass graft surgery.…”