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 CASQ2(D307H) and the CPVT phenotype using an in vivo
model. METHODS AND RESULTS: Cardiac-specific expression of the CASQ2(D307H)
transgene was achieved using the alpha-MHC promoter. Multiple transgenic
(TG) mouse lines expressing CASQ2(D307H) 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 I(Ca)-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
CASQ2(D307H) 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.
%0 Journal Article
%1 Dirk_2007_69
%A Dirksen, Wessel P
%A Lacombe, Veronique A
%A Chi, Mei
%A Kalyanasundaram, Anuradha
%A Viatchenko-Karpinski, Serge
%A Terentyev, Dmitry
%A Zhou, Zhixiang
%A Vedamoorthyrao, Srikanth
%A Li, Ning
%A Chiamvimonvat, Nipavan
%A Carnes, Cynthia A
%A Franzini-Armstrong, Clara
%A Gy�rke, Sandor
%A Periasamy, Muthu
%D 2007
%J Cardiovasc Res
%K Agents, Animal; Animals; Caffeine, Calcium Calcium, Calsequestrin, Cardiac, Cardiotonic Confocal; Death, Electrocardiography; Isoproterenol, Mice, Mice; Microscopy, Missense; Models, Mutation, Myocytes, Reticulum, Sarcoplasmic Signaling; Sudden, Tachycardia, Transgenic; Ventricular, etiology; genetics/metabolism/pathology genetics; metabolism/pathology; metabolism; pharmacology;
%N 1
%P 69--78
%R 10.1016/j.cardiores.2007.03.002
%T A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum
Ca2+ handling and causes complex ventricular arrhythmias in mice.
%U http://dx.doi.org/10.1016/j.cardiores.2007.03.002
%V 75
%X 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 CASQ2(D307H) and the CPVT phenotype using an in vivo
model. METHODS AND RESULTS: Cardiac-specific expression of the CASQ2(D307H)
transgene was achieved using the alpha-MHC promoter. Multiple transgenic
(TG) mouse lines expressing CASQ2(D307H) 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 I(Ca)-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
CASQ2(D307H) 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.
@article{Dirk_2007_69,
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 CASQ2(D307H) and the CPVT phenotype using an in vivo
model. METHODS AND RESULTS: Cardiac-specific expression of the CASQ2(D307H)
transgene was achieved using the alpha-MHC promoter. Multiple transgenic
(TG) mouse lines expressing CASQ2(D307H) 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 I(Ca)-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
CASQ2(D307H) 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.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Dirksen, Wessel P and Lacombe, Veronique A and Chi, Mei and Kalyanasundaram, Anuradha and Viatchenko-Karpinski, Serge and Terentyev, Dmitry and Zhou, Zhixiang and Vedamoorthyrao, Srikanth and Li, Ning and Chiamvimonvat, Nipavan and Carnes, Cynthia A and Franzini-Armstrong, Clara and Gy�rke, Sandor and Periasamy, Muthu},
biburl = {https://www.bibsonomy.org/bibtex/2589cb6f51e1f17e7a88cfb3268d6faa2/hake},
description = {The whole bibliography file I use.},
doi = {10.1016/j.cardiores.2007.03.002},
institution = {Department of Physiology and Cell Biology, 304 Hamilton Hall, 1645
Neil Ave, The Ohio State University College of Medicine, Columbus,
OH 43210, USA.},
interhash = {4172213c87089c9ad6e73720a445ca9c},
intrahash = {589cb6f51e1f17e7a88cfb3268d6faa2},
journal = {Cardiovasc Res},
keywords = {Agents, Animal; Animals; Caffeine, Calcium Calcium, Calsequestrin, Cardiac, Cardiotonic Confocal; Death, Electrocardiography; Isoproterenol, Mice, Mice; Microscopy, Missense; Models, Mutation, Myocytes, Reticulum, Sarcoplasmic Signaling; Sudden, Tachycardia, Transgenic; Ventricular, etiology; genetics/metabolism/pathology genetics; metabolism/pathology; metabolism; pharmacology;},
month = Jul,
number = 1,
pages = {69--78},
pii = {S0008-6363(07)00111-3},
pmid = {17449018},
timestamp = {2009-06-03T11:21:10.000+0200},
title = {A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum
Ca2+ handling and causes complex ventricular arrhythmias in mice.},
url = {http://dx.doi.org/10.1016/j.cardiores.2007.03.002},
volume = 75,
year = 2007
}