Prevention of Ventricular Arrhythmia and Calcium Dysregulation in a Catecholaminergic Polymorphic Ventricular Tachycardia Mouse Model Carrying Calsequestrin‐2 Mutation |
| |
Authors: | RONNY ALCALAI MD HIROKO WAKIMOTO MD PhD MICHAEL ARAD MD DAVID PLANER MD TETSUO KONNO MD LIBIN WANG MD PhD JON G SEIDMAN PhD CHRISTINE E SEIDMAN MD CHARLES I BERUL MD |
| |
Institution: | 1. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA;2. Heart Institute, Hadassah Hebrew University Medical Centre, Jerusalem, Israel;3. Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA;4. Heart Institute, Sheba Medical Centre and Tel Aviv University, Israel;5. Howard Hughes Medical Institute and Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA;6. Children's National Medical Center, Washington, DC, USA |
| |
Abstract: | Arrhythmia Prevention in CPVT . Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmic syndrome caused by mutations in genes encoding the calcium‐regulation proteins cardiac ryanodine receptor (RyR2) or calsequestrin‐2 (CASQ2). Mechanistic studies indicate that CPVT is mediated by diastolic Ca2+ overload and increased Ca2+ leak through the RyR2 channel, implying that treatment targeting these defects might be efficacious in CPVT. Method and results: CPVT mouse models that lack CASQ2 were treated with Ca2+‐channel inhibitors, β‐adrenergic inhibitors, or Mg2+. Treatment effects on ventricular arrhythmia, sarcoplasmic reticulum (SR) protein expression and Ca2+ transients of isolated myocytes were assessed. Each study agent reduced the frequency of stress‐induced ventricular arrhythmia in mutant mice. The Ca2+ channel blocker verapamil was most efficacious and completely prevented arrhythmia in 85% of mice. Verapamil significantly increased the SR Ca2+ content in mutant myocytes, diminished diastolic Ca2+ overload, increased systolic Ca2+ amplitude, and prevented Ca2+ oscillations in stressed mutant myocytes. Conclusions: Ca2+ channel inhibition by verapamil rectified abnormal calcium handling in CPVT myocytes and prevented ventricular arrhythmias. Verapamil‐induced partial normalization of SR Ca2+ content in mutant myocytes implicates CASQ2 as modulator of RyR2 activity, rather than or in addition to, Ca2+ buffer protein. Agents such as verapamil that attenuate cardiomyocyte calcium overload are appropriate for assessing clinical efficacy in human CPVT . (J Cardiovasc Electrophysiol, Vol. 22, pp. 316‐324, March 2011) |
| |
Keywords: | antiarrhythmia agents calcium calsequestrin‐2 CPVT mouse model sudden death |
|
|