title: Spatial Heterogeneity of Cx43 is an Arrhythmogenic Substrate of Polymorphic Ventricular Tachycardias during Compensated Cardiac Hypertrophy in Rats.
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 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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands; Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands; Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boulaksil
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Marti F A
authors.initials: MF
authors.lastname: Bierhuizen
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands; Division of Cardiology, Department of Cardiovascular Medicine, University of Muenster, Muenster, Germany.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Engelen
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands; Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Mèra
authors.initials: M
authors.lastname: Stein
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Bart J M
authors.initials: BJ
authors.lastname: Kok
authors.affiliation: Heart Failure Research Center, Academic Medical Center , Amsterdam , Netherlands.
authors.forename: Shirley C M
authors.initials: SC
authors.lastname: van Amersfoorth
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
authors.affiliation: Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands; Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands; Heart Failure Research Center, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
keywords: arrhythmia; electrophysiology; hypertrophy; sudden death