| Literature DB >> 21743453 |
Qiang Zhou1, Jianmin Xiao, Dawei Jiang, Ruiwu Wang, Kannan Vembaiyan, Aixia Wang, Chris D Smith, Cuihong Xie, Wenqian Chen, Jingqun Zhang, Xixi Tian, Peter P Jones, Xiaowei Zhong, Ang Guo, Haiyan Chen, Lin Zhang, Weizhong Zhu, Dongmei Yang, Xiaodong Li, Ju Chen, Anne M Gillis, Henry J Duff, Heping Cheng, Arthur M Feldman, Long-Sheng Song, Michael Fill, Thomas G Back, S R Wayne Chen.
Abstract
Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Spontaneous Ca(2+) waves, also called store overload-induced Ca(2+) release (SOICR), evoke ventricular tachyarrhythmias in individuals with heart failure. Here we show that carvedilol is the only beta blocker tested that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. To enable optimal titration of carvedilol's actions as a beta blocker and as a suppressor of SOICR separately, we developed a new SOICR-inhibiting, minimally beta-blocking carvedilol analog, VK-II-86. VK-II-86 prevented stress-induced ventricular tachyarrhythmias in RyR2-mutant mice and did so more effectively when combined with either of the selective beta blockers metoprolol or bisoprolol. Combining SOICR inhibition with optimal beta blockade has the potential to provide antiarrhythmic therapy that can be tailored to individual patients.Entities:
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Year: 2011 PMID： 21743453 PMCID： PMC3268079 DOI： 10.1038/nm.2406
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440