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.
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 humanpatients.
Authors: P J Laitinen; K M Brown; K Piippo; H Swan; J M Devaney; B Brahmbhatt; E A Donarum; M Marino; N Tiso; M Viitasalo; L Toivonen; D A Stephan; K Kontula Journal: Circulation Date: 2001-01-30 Impact factor: 29.690
Authors: H Lahat; M Eldar; E Levy-Nissenbaum; T Bahan; E Friedman; A Khoury; A Lorber; D L Kastner; B Goldman; E Pras Journal: Circulation Date: 2001-06-12 Impact factor: 29.690
Authors: H Lahat; E Pras; T Olender; N Avidan; E Ben-Asher; O Man; E Levy-Nissenbaum; A Khoury; A Lorber; B Goldman; D Lancet; M Eldar Journal: Am J Hum Genet Date: 2001-10-25 Impact factor: 11.025
Authors: Wen Zhao; Konrad F Frank; Guoxiang Chu; Michael J Gerst; Albrecht G Schmidt; Yong Ji; Muthu Periasamy; Evangelia G Kranias Journal: Cardiovasc Res Date: 2003-01 Impact factor: 10.787
Authors: Silvia G Priori; Carlo Napolitano; Mirella Memmi; Barbara Colombi; Fabrizio Drago; Maurizio Gasparini; Luciano DeSimone; Fernando Coltorti; Raffaella Bloise; Roberto Keegan; Fernando E S Cruz Filho; Gabriele Vignati; Abraham Benatar; Angelica DeLogu Journal: Circulation Date: 2002-07-02 Impact factor: 29.690