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

Wessel P. Dirksen, Veronique A. Lacombe, Mei Chi, Anuradha Kalyanasundaram, Serge Viatchenko-Karpinski, Dmitry Terentyev, Zhixiang Zhou, Srikanth Vedamoorthyrao, Ning Li, Nipavan Chiamvimonvat, Cynthia A. Carnes, Clara Franzini-Armstrong, Sandor Györke, Muthu Periasamy

Research output: Contribution to journalArticle

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Abstract

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 α-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.

Original languageEnglish (US)
Pages (from-to)69-78
Number of pages10
JournalCardiovascular Research
Volume75
Issue number1
DOIs
StatePublished - Jul 1 2007

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Calsequestrin
Sarcoplasmic Reticulum
Muscle Cells
Transgenic Mice
Cardiac Arrhythmias
Caffeine
Isoproterenol
Mutation
Phenotype
Ventricular Function
Ventricular Tachycardia
Transgenes
Membrane Potentials
Hypertrophy
Electrocardiography
Amino Acids
Handling (Psychology)
Polymorphic catecholergic ventricular tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Dirksen, W. P., Lacombe, V. A., Chi, M., Kalyanasundaram, A., Viatchenko-Karpinski, S., Terentyev, D., ... Periasamy, M. (2007). A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice. Cardiovascular Research, 75(1), 69-78. https://doi.org/10.1016/j.cardiores.2007.03.002

A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice. / Dirksen, Wessel P.; Lacombe, Veronique A.; Chi, Mei; Kalyanasundaram, Anuradha; Viatchenko-Karpinski, Serge; Terentyev, Dmitry; Zhou, Zhixiang; Vedamoorthyrao, Srikanth; Li, Ning; Chiamvimonvat, Nipavan; Carnes, Cynthia A.; Franzini-Armstrong, Clara; Györke, Sandor; Periasamy, Muthu.

In: Cardiovascular Research, Vol. 75, No. 1, 01.07.2007, p. 69-78.

Research output: Contribution to journalArticle

Dirksen, WP, Lacombe, VA, Chi, M, Kalyanasundaram, A, Viatchenko-Karpinski, S, Terentyev, D, Zhou, Z, Vedamoorthyrao, S, Li, N, Chiamvimonvat, N, Carnes, CA, Franzini-Armstrong, C, Györke, S & Periasamy, M 2007, 'A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice', Cardiovascular Research, vol. 75, no. 1, pp. 69-78. https://doi.org/10.1016/j.cardiores.2007.03.002
Dirksen, Wessel P. ; Lacombe, Veronique A. ; Chi, Mei ; Kalyanasundaram, Anuradha ; Viatchenko-Karpinski, Serge ; Terentyev, Dmitry ; Zhou, Zhixiang ; Vedamoorthyrao, Srikanth ; Li, Ning ; Chiamvimonvat, Nipavan ; Carnes, Cynthia A. ; Franzini-Armstrong, Clara ; Györke, Sandor ; Periasamy, Muthu. / A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice. In: Cardiovascular Research. 2007 ; Vol. 75, No. 1. pp. 69-78.
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AU - Chi, Mei

AU - Kalyanasundaram, Anuradha

AU - Viatchenko-Karpinski, Serge

AU - Terentyev, Dmitry

AU - Zhou, Zhixiang

AU - Vedamoorthyrao, Srikanth

AU - Li, Ning

AU - Chiamvimonvat, Nipavan

AU - Carnes, Cynthia A.

AU - Franzini-Armstrong, Clara

AU - Györke, Sandor

AU - Periasamy, Muthu

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