Abstract
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. Twenty-six Wistar rats were subjected to transverse aortic constriction (TAC) (n = 13) or sham operation (n = 13). Four weeks postoperative, 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. TAC rats showed significant hypertrophy with preserved left ventricular (LV) function. Epicardial conduction velocity (CV) was similar, but more dispersed in TAC. Transmural CV was slowed in TAC (37.6 ± 2.9 cm s(-1)) compared to sham (58.5 ± 3.9 cm s(-1); 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 reentrant activation was sporadically observed. Collagen deposition was significantly higher in TAC compared to sham, but not different between arrhythmogenic and non-arrhythmogenic TAC animals. Connexin43 (Cx43) expression was heterogeneous with a higher prevalence of non-phosphorylated Cx43 in arrhythmogenic TAC animals. 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.
Highlights
During cardiac pathophysiology, both the compensated and decompensated heart is characterized by structural and electrical remodeling, which is accompanied by a high vulnerability to ventricular arrhythmias and sudden cardiac death [1,2,3,4]
The main and novel results from this study are 1) polymorphic tachycardias can be induced by programed stimulation from the LV in 62% of rat hearts in which compensated hypertrophy was induced by transverse aortic constriction (TAC). 2) Activation patterns during polymorphic tachycardias were more complex in LV than right ventricle (RV) showing areas of conduction slowing and conduction block, unstable reentrant circuits, and multiple sites of epicardial breakthrough in LV
Conduction delay and epicardial reentrant activation were observed in later phases of the tachycardias, which indicate that the reentry might play a role in perpetuation of the arrhythmia
Summary
Both the compensated and decompensated heart is characterized by structural and electrical remodeling, which is accompanied by a high vulnerability to ventricular arrhythmias and sudden cardiac death [1,2,3,4]. In more advanced stages of cardiac disease, heterogeneous distribution of Cx43 has strongly been associated with the occurrence of arrhythmias in both patients and mice [11, 12]. Adding to this aspect of heterogeneous remodeling, Cx43 is a phosphoprotein with several phosphorylation states, which determine its gating properties. We hypothesized that in compensated stages of cardiac remodeling, inhomogeneous dephosphorylation of Cx43 and heterogeneous spatial differences in Cx43 distribution would primarily lead to more dispersed ventricular impulse conduction and an increased propensity for ventricular arrhythmias. 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
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