Connexin-40, bundle-branch block, and propagation at the Purkinje-myocyte junction.

Genetic engineering in mice has created unprecedented opportunities to define the contributions of specific proteins in complex cardiological processes, but these opportunities also present significant challenges in characterizing murine cardiac function and relating insights gained into the human heart. These challenges are especially keen in defining electrophysiological phenotypes. Elucidation of the role of specific gene products in impulse propagation or arrhythmogenesis in mice requires advanced technology, particularly if the gene of interest is expressed in a restricted pattern or distribution. Such is the case in the study by Tamaddon et al appearing in this issue of Circulation Research. This study is focused on connexin40 (Cx40), a protein that forms gap junction channels responsible for intercellular current flux. Cx40 expression in the adult heart is restricted to atrial myocytes, coronary vascular endothelium, and the His-Purkinje system. In addition to Cx40, cardiac myocytes express 2 other connexins, Cx43 and Cx45, in different amounts and combinations. A major goal of present research is to understand the biological roles of individual connexins. Previously, Simon et al from Harvard and Kirchhoff et al from the University of Bonn independently produced Cx40 knockout mice and characterized phenotypes by electrocardiography. As predicted by the pattern of Cx40 distribution, Cx40 mice show prolongation of the PR interval and evidence of bundle branch block. However, going the next step to define mechanisms responsible for these alterations in the surface ECG requires a more sophisticated approach, and this is the basis for the study by Tamaddon et al. These investigators, led by Dr José Jalife, have pioneered the development and application of optical mapping to characterize electrical activation and arrhythmogenesis. Now, in a technical tour de force, optical mapping has been used to delineate patterns of ventricular activation in Cx40 hearts and directly visualize and characterize impulse propagation in the right bundle branch of the murine His-Purkinje system. In wild-type mice, Tamaddon et al observed that the anterior right ventricular epicardium was activated first, followed by epicardial breakthrough on the anterior left ventricle (LV), a pattern similar to that observed in larger experimental animals and humans. In contrast, earliest breakthrough occurred in the LV in Cx40 mice, with later activation of the right ventricle (RV). Moreover, multiple highly variable breakthrough sites were observed on both the LV and RV surfaces of Cx40 mice. To additionally define mechanisms underlying these abnormal patterns of ventricular activation, Tamaddon et al mapped the activation sequence of the mouse right bundle branch for the first time. They observed that absence of Cx40 reduced propagation velocity in the right bundle branch by '40% without apparent delay in the left bundle branch or detectable slowing in ventricular propagation velocities. Thus, altered patterns of epicardial activation seemed to be directly attributable to conduction slowing in the right bundle branch. Several aspects of this study raise intriguing questions. Although experts may disagree on the exact interpretation of the ECG findings in Cx40 mice, the prolonged QRS duration, notching of the R wave, and increased duration of the S wave in lead I suggest right bundle-branch block (RBBB). This condition may occur in human patients without apparent heart disease and, under these circumstances, is considered a normal variant. With increasing age, patients may progress from incomplete to complete RBBB without demonstrable alterations in the left conduction system. Therefore, the findings of RBBB without apparent abnormalities in the left bundle branch in Cx40 mice are reminiscent of idiopathic RBBB and raise the testable hypothesis that alterations in Cx40 expression could play a role in the pathogenesis of RBBB in patients. RBBB is a characteristic feature of the Brugada syndrome. Although the mechanism underlying this syndrome is associated, at least in some patients, with mutations in Na channels, it is noteworthy that RBBB but not LBBB occurs in Brugada syndrome patients, even in those in whom bundle branch block is not present under basal conditions but can be induced by administration of lidocaine. The marked slowing of conduction in the right bundle branch without a similar change in the left bundle branch in Cx40 mice raises provocative questions about the determinants of impulse propagation in these 2 major divisions of the His-Purkinje system, not only in Cx40 mice but also in clinical syndromes characterized by RBBB but not LBBB. As far as we know, Cx40 is expressed in both left and right bundle branches, and it seems unlikely that functional differences observed in Cx40 mice are attributable to disparate patterns of connexin expression in the His-Purkinje system. Tamaddon et al suggest that because the right bundle branch is anatomically thinner than the left bundle branch and action potential durations are more prolonged in the right bundle branch, a lower safety factor for antegrade conduction may The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Pathology and Surgery and the Center for Cardiovascular Research, Washington University, St. Louis, Mo. Correspondence to Jeffrey E. Saffitz, MD, PhD, Department of Pathology, Box 8118, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110. E-mail [email protected] (Circ Res. 2000;87:835-836.) © 2000 American Heart Association, Inc.