title: Conduction slowing contributes to spontaneous ventricular arrhythmias in intrinsically active murine RyR2-P2328S hearts.
abstract: BACKGROUND
  The familial condition catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic bidirectional ventricular tachycardia (BVT), polymorphic ventricular tachycardia (PVT), and ventricular fibrillation following adrenergic challenge. It is associated with mutations involving the cardiac ryanodine receptor (RyR2).
  
  
  RESULTS
  We explored for a slowing of myocardial conduction that could potentially result in a substrate for the spontaneous arrhythmogenesis that was observed following introduction of isoproterenol and caffeine in intrinsically beating murine RyR2-P2328S hearts. Such pharmacological challenge increased the number of arrhythmic episodes in electrocardiographic recordings from intact anesthetized mice, with the greatest effects in the homozygote RyR2(S/S). Arrhythmias took the form of bigeminy, BVT, monomorphic ventricular tachycardia, and PVT, as found in human CPVT. Ventricular epicardial conduction velocities (CVs) measured using multielectrode array recordings and maximum action potential upstroke rates, (dV/dt)(max), measured using intracellular microelectrodes were indistinguishable in untreated wild-type (WT) and RyR2(S/S). Pharmacological challenge of RyR2(S/S), but not WT hearts, then reduced CV and (dV/dt)(max) and also revealed a strongly arrhythmic phenotype. There was no evidence of gross structural or fibrotic changes in either RyR2(+/S) or RyR2(S/S) hearts on light microscopy.
  
  
  CONCLUSIONS
  We associate altered ventricular myocardial CV potentially resulting in arrhythmogenic substrate with arrhythmic properties associated with genetic RyR2 alterations for the first time.
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: JingJing
authors.initials: J
authors.lastname: Wu
authors.forename: Kamalan
authors.initials: K
authors.lastname: Jeevaratnam
authors.forename: James H
authors.initials: JH
authors.lastname: King
authors.forename: Laila
authors.initials: L
authors.lastname: Guzadhur
authors.forename: XiaoLei
authors.initials: X
authors.lastname: Ren
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
authors.forename: James A
authors.initials: JA
authors.lastname: Fraser
mesh_terms: D000818:Animals; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006329:Heart Conduction System / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009431:Neural Conduction; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel