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Spatial Heterogeneity of Cx43 Is an Arrhythmogenic Substrate of Polymorphic Ventricular Tachycardias during Compensated Cardiac Hypertrophy in Rats

By Mohamed eBoulaksil, Mohamed eBoulaksil, Mohamed eBoulaksil, Marti F.A. Bierhuizen, Markus A.B. Engelen, Markus A.B. Engelen, Mera eStein, Mera eStein, Bart J.M. Kok, Shirley C.M. van Amersfoorth, Marc A Vos, Harold V.M. Van Rijen, Jacques MT De Bakker, Jacques MT De Bakker, Jacques MT De Bakker and Toon A.B. Van Veen

Abstract

Background. Ventricular remodeling increases the propensity of ventricular tachyarrhythmias and sudden death in patients. We studied the mechanism underlying these fatal arrhythmias, electrical and structural cardiac remodeling as well as arrhythmogeneity during early, compensated hypertrophy in a rat model of chronic pressure overload.Methods. Twenty six Wistar rats were subjected to transverse aortic constriction (TAC, n=13) or sham operation (n=13). Four weeks post-operative, echo- and electrocardiography was performed. Epicardial (208 or 455 sites) and transmural (30 sites) ventricular activation mapping was performed on Langendorff perfused hearts. Subsequently, hearts were processed for (immuno)histological and molecular analyses.Results. TAC rats showed significant hypertrophy with preserved left ventricular (LV) function. Epicardial conduction velocity was similar, but more dispersed in TAC. Transmural conduction velocity was slowed in TAC (37.6±2.9 cm/s) compared to sham (58.5±3.9 cm/s; P<0.01). Sustained polymorphic ventricular tachycardias were induced from LV in 8/13 TAC, and in 0/13 sham rats. During VT, electrical activation patterns showed variable sites of earliest epicardial activation and altering sites of functional conduction block. Wandering epicardial re-entrant activation was sporadically observed. Collagen deposition was significantly higher in TAC compared to sham, but not different between arrhythmogenic and non-arrhythmogenic TAC animals. Cx43 expression was heterogeneous with a higher prevalence of non-phosphorylated Cx43 in arrhythmogenic TAC animals. Conclusions. In TAC rats with compensated cardiac hypertrophy, dispersion of conduction correlated to arrhythmogenesis, an increased heterogeneity of Cx43 and a partial substitution with non-phosphorylated Cx43. These alterations may result in the increased vulnerability to polymorphic VTs

Topics: Electrophysiology, Gap Junctions, Hypertrophy, arrhythmia, sudden death, Diseases of the circulatory (Cardiovascular) system, RC666-701
Publisher: Frontiers Media S.A.
Year: 2016
DOI identifier: 10.3389/fcvm.2016.00005
OAI identifier: oai:doaj.org/article:a1571332b93c4b159dfbc93175f0989b
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