title: Cardiomyocyte calcium cycling in a naturally occurring German shepherd dog model of inherited ventricular arrhythmia and sudden cardiac death.
abstract: OBJECTIVE
  To further characterize arrhythmic mechanisms in German shepherd dogs (GSDs) affected with inherited ventricular arrhythmias by evaluating intracellular calcium cycling and expression of calcium handling genes.
  
  
  METHODS
  Twenty five GSDs, 9 backcross dogs, and 6 normal mongrel dogs (controls) were studied. The GSDs and backcross dogs were from a research colony of inherited ventricular arrhythmias. The control research dogs were purchased.
  
  
  METHODS
  Action potentials (APs) and pseudo-electrocardiograms (ECG) were recorded from left ventricular (LV) wedge preparations of GSDs and normal dogs. Midmyocardial (Mid) LV cells from GSDs and normal mongrels were isolated by enzymatic digestion. Cells were either field stimulated or voltage clamped and calcium transients were measured by confocal microscopy using the indicator Fluo-3AM. Expression of calcium handling genes was measured by quantitative RT-PCR.
  
  
  RESULTS
  Mean calcium transient decay (tau) was not different between affected GSDs and control dogs, but striking cell-to-cell variability for tau was observed within affected GSDs and between affected GSDs and controls (P < 0.0001 each); within-dog variability accounted for 75% of total variability. Calcium sparks and afterdepolarizations occurred in GSD but not control cells. ATP2A2/SERCA2a expression was significantly reduced (P = 0.0063) in affected GSDs and inversely correlated (P = 0.0006) with severity of ventricular arrhythmias.
  
  
  CONCLUSIONS
  German shepherd dogs with inherited ventricular arrhythmias have electrophysiologic abnormalities in calcium cycling associated with reduced ATP2A2/SERCA2a expression. These animals provide a unique opportunity to study calcium remodeling at the genetic and molecular level in familial ventricular arrhythmias.
authors: Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14850, USA. sjesty@utk.edu
authors: Sophy A
authors: SA
authors: Jesty
authors: Seung Woo
authors: SW
authors: Jung
authors: Jonathan M
authors: JM
authors: Cordeiro
authors: Teresa M
authors: TM
authors: Gunn
authors: José M
authors: JM
authors: Di Diego
authors: Shari
authors: S
authors: Hemsley
authors: Bruce G
authors: BG
authors: Kornreich
authors: Giles
authors: G
authors: Hooker
authors: Charles
authors: C
authors: Antzelevitch
authors: N Sydney
authors: NS
authors: Moïse
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D016757:Death, Sudden, Cardiac / Q000662:veterinary*; D004283:Dog Diseases / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D032383:Myocytes, Cardiac / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium