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 language | English (US) |
|---|---|
| Pages (from-to) | 69-78 |
| Number of pages | 10 |
| Journal | Cardiovascular Research |
| Volume | 75 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 1 2007 |
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ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
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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 journal › Article
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TY - JOUR
T1 - A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice
AU - Dirksen, Wessel P.
AU - Lacombe, Veronique A.
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
PY - 2007/7/1
Y1 - 2007/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34249878775&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34249878775&partnerID=8YFLogxK
U2 - 10.1016/j.cardiores.2007.03.002
DO - 10.1016/j.cardiores.2007.03.002
M3 - Article
C2 - 17449018
AN - SCOPUS:34249878775
VL - 75
SP - 69
EP - 78
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 1
ER -