Background-Connexin 43 (Cx43) is a major determinant of conduction in the ventricular working myocardium of mammals. We investigated the effect of decreased Cx43 expression on conduction velocity and arrhythmogenesis using adult mice with inducible deletion of Cx43. Methods and Results-Cx43Cre-ER(T)/ϩ mice, in which 1 coding region of the Cx43 gene was replaced by Cre-ER(T), were mated to Cx43 fl/fl mice, generating Cx43 Cre-ER(T)/fl mice. Application of 4-hydroxytamoxifen (4-OHT) induced Cre-ER(T)-mediated deletion of the floxed Cx43 allele. Epicardial ventricular mapping using a 13ϫ19 multiterminal electrode grid (300-m spacing) was performed on Langendorff-perfused hearts from Cx43 fl/fl plus carrier (nϭ10), Cx43 fl/fl plus 4-OHT (nϭ10), Cx43Cre-ER(T)/fl plus carrier (nϭ9), and Cx43Cre-ER(T)/fl plus 4-OHT (nϭ10). Cx43 protein amount in group 3 hearts was decreased by Ϸ50% compared with group 1. 4-OHT did not affect cardiac protein amounts in group 2 but decreased Cx43 expression up to 95% in group 4 compared with group 3. Epicardial activation of both left ventricle (LV) and right ventricle (RV) during sinus rhythm was similar in all groups. Conduction velocity (CV) changed only in group 4 animals. For RV (LV), longitudinal CV decreased from 38 (35) to 31.6 (33.6) and transverse CV from 24.4 (16.8) to 10.1 (11.3) cm/s. Dispersion of conduction in RV (LV) was increased by 91% (38%). Programmed stimulation resulted in ventricular arrhythmias in group 4 (7 of 10 mice) but never in groups 1 through 3. Conclusions-Heterozygous expression of Cx43 did not affect ventricular conduction velocity. Up to 95% decrease of Cx43 protein in 4-OHT-treated Cx43 Cre-ER(T)/fl mice reduced conduction velocity and increased dispersion of conduction and propensity for ventricular arrhythmias.

Abstract-Connexins, the protein molecules forming gap junction channels, are reduced in number or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases. This "gap junction remodeling" is considered to be arrhythmogenic. Using a simple model of human ventricular myocardium, we found that quantitative remodeling data extracted from the literature gave rise to only small to moderate changes in conduction velocity and the anisotropy ratio. Especially for longitudinal conduction, cytoplasmic resistivity (and thus cellular geometry) is much more important than commonly realized. None of the remodeling data gave rise to slow conduction on the order of a few centimeters per second. (Circ Res. 2000;86:1193-1197.)Key Words: connexins Ⅲ conduction velocity Ⅲ arrhythmia Ⅲ computer simulation G ap junctions, specialized membrane structures consisting of arrays of intercellular channels, connect adjacent cells in many tissues and organs, thereby providing chemical and electrical communication. In the heart, gap junctions provide the pathways for intercellular current flow, enabling coordinated action potential propagation. Recently, numerous reports have been published suggesting that changes in gap junction distribution, density, and properties may be involved in the initiation and persistence of various cardiac arrhythmias. In the present review, we summarize the data presented in these reports and discuss functional implications. Structure and Properties of Gap Junction ChannelsIn the past decade, the structure and properties of gap junction channels have been extensively documented, as discussed in several recent reviews. [1][2][3][4] Mammalian gap junction channels are built of connexins encoded by a family of closely related genes. All connexins consist of 4 highly conserved ␣-helical membrane-spanning segments separated by 2 extracellular and 1 intracellular loop. The amino and carboxy terminals are located intracellularly. Fifteen members of the mammalian connexin family have been identified. They differ mainly in the sequence of their intracellular loops and carboxy terminals. Between cardiomyocytes, 3 connexins have been detected at the protein level: connexin40 (Cx40), connexin43 (Cx43), and connexin45 (Cx45) (named by their putative molecular mass in kilodaltons).One gap junction channel is formed by head-to-head docking of 2 hemichannels (connexons), each composed of 6 connexin molecules hexagonally arranged around an aqueous pore. Because docking is mediated by relatively conserved extracellular loops, many connexons composed of one kind of connexin can combine with connexons made of other connexins to form heterotypic gap junction channels. A connexon may also be composed of different connexins 5 (heteromeric connexon). In the heart, different connexins colocalize in gap junction plaques, but it is unknown whether heterotypic and/or heteromeric gap junction channels exist in the cardiovascular system.Gap junction channels are permeable to substances with a molecular weig...

Abstract-Atrial standstill (AS) is a rare arrhythmia that occasionally appears to be genetically determined. This study investigates the genetic background of this arrhythmogenic disorder in a large family. Forty-four family members were clinically evaluated. One deceased and three living relatives were unambiguously affected by AS. All other relatives appeared unaffected. Candidate gene screening revealed a novel mutation in the cardiac sodium channel gene SCN5A (D1275N) in all three affected living relatives and in five unaffected relatives, and the deceased relative was an obligate carrier. In addition, two closely linked polymorphisms were detected within regulatory regions of the gene for the atrial-specific gap junction protein connexin40 (Cx40) at nucleotides Ϫ44 (G3 A) and ϩ71 (A3 G). Eight relatives were homozygous for both polymorphisms, which occurred in only Ϸ7% of control subjects, and three of these relatives were affected by AS. The three living AS patients exclusively coinherited both the rare Cx40 genotype and the SCN5A-D1275N mutation. SCN5A-D1275N channels showed a small depolarizing shift in activation compared with wild-type channels. Rare Cx40 genotype reporter gene analysis showed a reduction in reporter gene expression compared with the more common Cx40 genotype. In this study, familial AS was associated with the concurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene. We propose that, although the functional effect of each genetic change is relatively benign, the combined effect of genetic changes eventually progresses to total AS. (Circ Res. 2003;92:14-22.)