%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 }