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Cardiovascular Research 2007 75(1):69-78; doi:10.1016/j.cardiores.2007.03.002
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Copyright © 2007, European Society of Cardiology

A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice

Wessel P. Dirksena, Veronique A. Lacombec, Mei Chia,1, Anuradha Kalyanasundarama,1, Serge Viatchenko-Karpinskia,b, Dmitry Terentyeva,b, Zhixiang Zhoua, Srikanth Vedamoorthyraoa,b, Ning Lie, Nipavan Chiamvimonvate, Cynthia A. Carnesc, Clara Franzini-Armstrongd, Sandor Györkea,b and Muthu Periasamya,*

aDepartment of Physiology and Cell Biology, 304 Hamilton Hall, 1645 Neil Ave, The Ohio State University College of Medicine, Columbus, OH 43210, United States
bDavis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, United States
cCollege of Pharmacy, The Ohio State University, Columbus, OH 43210, United States
dDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, United States
eDivision of Cardiovascular Medicine, University of California, Davis, CA 95616, United States

* Corresponding author. Tel.: +1 614 292 2310; fax: +1 614 292 4888. periasamy.1{at}osu.edu

Objective A naturally-occurring mutation in cardiac calsequestrin (CASQ2) at amino acid 307 was discovered in a highly inbred family and hypothesized to cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The goal of this study was to establish a causal link between CASQ2D307H and the CPVT phenotype using an in vivo model.

Methods and results Cardiac-specific expression of the CASQ2D307H transgene was achieved using the {alpha}-MHC promoter. Multiple transgenic (TG) mouse lines expressing CASQ2D307H from 2- to 6-fold possess structurally normal hearts without any sign of hypertrophy. The hearts displayed normal ventricular function. Myocytes isolated from TG mice had diminished ICa-induced Ca2+ transient amplitude and duration, as well as increased Ca2+ spark frequency. These myocytes, when exposed to isoproterenol and caffeine, displayed disturbances in their rhythmic Ca2+ oscillations and membrane potential, and delayed afterdepolarizations. ECG monitoring revealed that TG mice challenged with isoproterenol and caffeine developed complex ventricular arrhythmias, including non-sustained polymorphic ventricular tachycardia.

Conclusions The findings of the present study demonstrate that expression of mutant CASQ2D307H in the mouse heart results in abnormal myocyte Ca2+ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients.

KEYWORDS SR; Sarcoplasmic reticulum; CASQ2; Calsequestrin; CPVT; Catecholaminergic polymorphic ventricular tachycardia; WT; Wild-type; TG; Transgenic; RyR2; Cardiac ryanodine receptor.

1 Contributed equally.


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