Cardiomyocyte calcium cycling in a naturally occurring German shepherd dog model of inherited ventricular arrhythmia and sudden cardiac death

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• 作者：Sophy A. Jesty ; DVM^a ; ^e ; ^h ; ^{sjesty@utk.edu} ; Seung Woo Jung ; DVM ; PhD^b ; ^f ; ^h ; Jonathan M. Cordeiro ; PhD^c ; Teresa M. Gunn ; PhD^b ; ^g ; José ; M. Di Diego ; MD^c ; Shari Hemsley ; LVT^a ; Bruce G. Kornreich ; DVM ; PhD^a ; Giles Hooker ; PhD^d ; Charles Antzelevitch ; PhD ; FHRS^c ; N. Sydney Mo&iuml ; se ; DVM ; MS^a
• 关键词：Familial ; ATP2A2 ; SERCA2
• 刊名：Journal of Veterinary Cardiology
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：15
• 期：1
• 页码：5-14
• 全文大小：912 K

文摘

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.

Animals

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 (m>Pm>?<?0.0001 each); within-dog variability accounted for 75 % of total variability. Calcium sparks and afterdepolarizations occurred in GSD but not control cells.?m>ATP2A2m>/SERCA2a expression was significantly reduced (m>Pm>?=?0.0063) in affected GSDs and inversely correlated (m>Pm>?=?0.0006) with severity of ventricular arrhythmias.

Conclusions

German shepherd dogs with inherited ventricular arrhythmias have electrophysiologic abnormalities in calcium cycling associated with reduced m>ATP2A2m>/SERCA2a expression. These animals provide a unique opportunity to study calcium remodeling at the genetic and molecular level in familial ventricular arrhythmias.