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Carvedilol and its new analogs suppress arrhythmogenic store overload–induced Ca2+ release

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 Ca2+ waves, also called store overload–induced Ca2+ 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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Figure 1: Carvedilol inhibits SOICR in HEK293 cells.
Figure 2: Carvedilol modifies the gating of single RyR2 channels.
Figure 3: Carvedilol suppresses SOICR in mouse ventricular cardiomyocytes.
Figure 4: Effect of VK-II-86 on heart rate, SOICR and single RyR2 channels.
Figure 5: Effects of VK-II-86 on CPVT in R4496C-heterozygous or homozygous mice.
Figure 6: Effects of CS-I-34 and CS-I-59 on heart rate, SOICR and CPVT.

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (S.R.W.C.), the US National Institutes of Health (NIH; S.R.W.C., L.-S.S., M.F. and A.M.F.), the Heart and Stroke Foundation of Alberta (A.M.G. and H.J.D.) and the Intramural Research Program of the US National Institute on Aging (D.Y. and H. Cheng). D.J., W.C. and X.T. were supported by Alberta Innovates–Health Solutions (AIHS) studentship awards, C.D.S. by an AIHS fellowship award, P.P.J. by an AIHS and Heart and Stroke Foundation fellowship award and H.J.D. and S.R.W.C. by AIHS scientist awards. We thank the King family and the Libin Cardiovascular Institute of Alberta for their donations and S. Pogwizd and S. Priori for critical reading of the manuscript.

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Q.Z., J.X., D.J., R.W., K.V., A.W., C.D.S., W.Z., D.Y., J.C., A.M.G., H.J.D., H. Cheng, A.M.F., L.-S.S., M.F., T.G.B. and S.R.W.C. designed research; Q.Z., J.X., D.J., R.W., K.V., A.W., C.D.S., C.X., W.C., J.Z., W.Z., X.T., P.P.J., X.Z., A.G., H. Chen, L.Z., D.Y. and X.L. carried out research; Q.Z., J.X., D.J., C.X., W.C., J.Z., W.Z., X.T., P.P.J., X.Z., A.G., H. Chen, L.Z. and D.Y. analyzed data; and Q.Z., R.W., C.D.S., W.Z., M.F., T.G.B. and S.R.W.C. wrote the paper.

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Correspondence to S R Wayne Chen.

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Zhou, Q., Xiao, J., Jiang, D. et al. Carvedilol and its new analogs suppress arrhythmogenic store overload–induced Ca2+ release. Nat Med 17, 1003–1009 (2011). https://doi.org/10.1038/nm.2406

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