Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release |
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Authors: | Zhou Qiang Xiao Jianmin Jiang Dawei Wang Ruiwu Vembaiyan Kannan Wang Aixia Smith Chris D Xie Cuihong Chen Wenqian Zhang Jingqun Tian Xixi Jones Peter P Zhong Xiaowei Guo Ang Chen Haiyan Zhang Lin Zhu Weizhong Yang Dongmei Li Xiaodong Chen Ju Gillis Anne M Duff Henry J Cheng Heping Feldman Arthur M Song Long-Sheng Fill Michael Back Thomas G Chen S R Wayne |
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Affiliation: | Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. |
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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. |
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