Reduced protein expression of the cardiac ryanodine receptor type 2 (RyR2) is thought to affect the susceptibility to stress-induced ventricular tachyarrhythmia (VT) and cardiac alternans, but direct evidence for the role of RyR2 protein expression in VT and cardiac alternans is lacking. Here, we used a mouse model (crrm1) that expresses a reduced level of the RyR2 protein to determine the impact of reduced RyR2 protein expression on the susceptibility to VT, cardiac alternans, cardiac hypertrophy, and sudden death. Electrocardiographic analysis revealed that after the injection of relatively high doses of caffeine and epinephrine (agents commonly used for stress test), wild-type (WT) mice displayed long-lasting VTs, whereas the crrm1 mutant mice exhibited no VTs at all, indicating that the crrm1 mutant mice are resistant to stress-induced VTs. Intact heart Ca2+ imaging and action potential (AP) recordings showed that the crrm1 mutant mice are more susceptible to fast-pacing induced Ca2+ alternans and AP duration alternans compared with WT mice. The crrm1 mutant mice also showed an increased heart-to-body-weight ratio and incidence of sudden death at young ages. Furthermore, the crrm1 mutant hearts displayed altered Ca2+ transients with increased time-to-peak and decay time (T50), increased ventricular wall thickness and ventricular cell area compared with WT hearts. These results indicate that reduced RyR2 protein expression suppresses stress-induced VTs, but enhances the susceptibility to cardiac alternans, hypertrophy, and sudden death.
Reduced expression of cardiac ryanodine receptor protects against stress-induced ventricular tachyarrhythmia, but increases the susceptibility to cardiac alternans
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Xiaowei Zhong, Alexander Vallmitjana, Bo Sun, Zhichao Xiao, Wenting Guo, Jinhong Wei, Mingke Ni, Yongxiang Chen, Edward R. O'Brien, Anne M. Gillis, Masahiko Hoshijima, Hiroshi Takeshima, Leif Hove-Madsen, Raul Benitez, Darrell Belke, S.R. Wayne Chen; Reduced expression of cardiac ryanodine receptor protects against stress-induced ventricular tachyarrhythmia, but increases the susceptibility to cardiac alternans. Biochem J 15 January 2018; 475 (1): 169–183. doi: https://doi.org/10.1042/BCJ20170631
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