title: Accelerated junctional rhythm and nonalternans repolarization lability precede ventricular tachycardia in Casq2-/- mice.
abstract: BACKGROUND
  Calsequestrin-2 (CASQ2) is a Ca(2+) buffering protein of myocardial sarcoplasmic reticulum. CASQ2 mutations underlie a form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The CPVT phenotype is recapitulated in Casq2 -/- mice. Repolarization lability (RL)-beat-to-beat variability in the T wave morphology-has been reported in long-QT syndrome, but has not been evaluated in CPVT.
  
  
  RESULTS
  ECG from Casq2 -/- mice was evaluated with respect to heart rate (HR) and RL changes prior to onset of ventricular tachycardia (VT) to gain insight into arrhythmogenesis in CPVT. Telemetry from unrestrained mice (3-month-old males, 5 animals of each genotype) and ECG before and after isoproterenol administration in anesthetized mice was analyzed. Average HR in sinus rhythm (SR), occurrence of nonsinus rhythm and RL were quantified. HR was slower in Casq2 -/- animals. Accelerated junctional rhythm (JR) occurred more frequently in Casq2 -/- mice and often preceded VT. In Casq2 -/- mice, HR increased prior to VT onset, prior to onset of JR and on transition from JR to VT. RL increased during progression from SR to VT and after isoproterenol administration in Casq2 -/-, but not in Casq2+/+ animals. Isoproterenol did not increase repolarization alternans in either genotype.
  
  
  CONCLUSIONS
  Accelerated JR, likely caused by triggered activity in His/Purkinje system, occurs frequently in Casq2 -/- mice. The absence of CASQ2 results in increased RL. The increase in HR and in RL precede onset of arrhythmias in this CPVT model. Nonalternans RL precedes ventricular arrhythmia in wider range of conditions than previously appreciated.
authors.affiliation: Heart and Vascular Institute, School of Medicine, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
authors.forename: Ure L
authors.initials: UL
authors.lastname: Mezu
authors.forename: Prabhpreet
authors.initials: P
authors.lastname: Singh
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shusterman
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Hwang
authors.forename: Bjorn C
authors.initials: BC
authors.lastname: Knollmann
authors.forename: Jan
authors.initials: J
authors.lastname: Němec
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002155:Calsequestrin / Q000378:metabolism*; D004562:Electrocardiography; D006329:Heart Conduction System / Q000503:physiopathology*; D006339:Heart Rate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000503:physiopathology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D002155:Calsequestrin; C514388:casq2 protein, mouse; D002118:Calcium