Journal article
Carvedilol and Its New Analogs Suppress Arrhythmogenic Store Overload-induced Ca2+ Release
Nature medicine, Vol.17(8), pp.1003-1009
08/01/2011
DOI: 10.1038/nm.2406
PMCID: PMC3268079
PMID: 21743453
Abstract
Carvedilol is one of the most effective beta-blockers for preventing ventricular tachyarrhythmias (VTs) in heart failure (HF), but the mechanisms underlying its favorable anti-arrhythmic benefits remain unclear. Spontaneous Ca
2+
waves, also termed store-overload-induced Ca
2+
release (SOICR), are known to evoke VTs in patients with HF. Here we show that carvedilol is the only beta-blocker 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 likely contributes to its favorable anti-arrhythmic effect. To allow individual and optimal titration of these beneficial activities, we developed a novel SOICR-inhibiting, minimally-beta-blocking carvedilol analogue VK-II-86. We found that VK-II-86 alone prevented stress-induced VTs in RyR2 mutant mice, and was more effective when combined with a selective beta-blocker metoprolol or bisoprolol. Thus, SOICR inhibition combined with optimal beta-blockade presents a new, promising and potentially patient-tailorable anti-arrhythmic approach.
Details
- Title: Subtitle
- Carvedilol and Its New Analogs Suppress Arrhythmogenic Store Overload-induced Ca2+ Release
- Creators
- Qiang Zhou - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaLong-Sheng Song - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IowaJianmin Xiao - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaDawei Jiang - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaRuiwu Wang - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaKannan Vembaiyan - Department of Chemistry, University of Calgary, Calgary, AB, CanadaAixia Wang - Department of Chemistry, University of Calgary, Calgary, AB, CanadaChris D Smith - Department of Chemistry, University of Calgary, Calgary, AB, CanadaCuihong Xie - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaWenqian Chen - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaJingqun Zhang - Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, ILXixi Tian - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaPeter P Jones - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaXiaowei Zhong - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaAng Guo - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IowaHaiyan Chen - Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, ILLin Zhang - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaWeizhong Zhu - Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PADongmei Yang - Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MDJu Chen - Department of Medicine, University of California at San Diego, La Jolla, CaliforniaXiaodong Li - Department of Medicine, University of California at San Diego, La Jolla, CaliforniaAnne M Gillis - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaHenry J Duff - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaHeping Cheng - Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MDArthur M Feldman - Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PAMichael Fill - Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, ILThomas G Back - Department of Chemistry, University of Calgary, Calgary, AB, CanadaS. R. Wayne Chen - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.17(8), pp.1003-1009
- DOI
- 10.1038/nm.2406
- PMID
- 21743453
- PMCID
- PMC3268079
- NLM abbreviation
- Nat Med
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Grant note
- R01 HL075210-08 || HL / National Heart, Lung, and Blood Institute : NHLBI
- Language
- English
- Date published
- 08/01/2011
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984094755402771
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