A major cause of sudden death in patients with heart failure (HF) is ventricular arrhythmia. Disappointingly, large clinical trials have recently demonstrated that most of the anti-arrhythmic drugs have little or no survival benefits. Surprisingly, ?-blockers, once thought to be dangerous and contraindicated for patients with HF, have consistently been shown to reduce the risk of sudden death. However, the molecular mechanisms underlying ?-blockers'survival benefits are unknown. The overall objective of this proposal is to understand the beneficial effects of ?-blockers and to develop novel anti-arrhythmic agents. It is well known that spontaneous Ca2+ release, also known as store-overload-induced-Ca2+-release (SOICR), can cause delayed afterdepolarizations (DADs), which in turn can trigger arrhythmias. Importantly, enhanced SOICR activity and DAD-associated ventricular arrhythmias are common in HF and in cardiac ryanodine receptor (RyR2)-associated ventricular arrhythmias. Hypotheses: the beneficial effects of ?-blockers are, in part, attributable to SOICR inhibition, and that SOICR inhibitors are effective in suppressing cardiac arrhythmias.
Three specific aims are proposed. 1. To Assess the Impact of Different ?-blockers on Spontaneous Ca2+ Release or SOICR and RyR2-Associated Arrhythmias. The impact of a number of ?- blockers on SOICR, the activity of RyR2, and stress-induced ventricular arrhythmias will be determined using various approaches. 2. To Design, Synthesize, and Characterize Novel Carvedilol Analogues for Suppressing Arrhythmias. Our preliminary data demonstrate that carvedilol is uniquely effective among ?- blockers in suppressing SOICR. To improve its efficacy and to produce a novel class of anti-arrhythmic agents, a number of carvedilol derivatives will be synthesized in order to reduce or diminish its ?-blocking activity, while retaining or increasing its SOICR inhibition. 3. To Understand the Molecular Basis of SOICR. Site-directed mutagenesis in conjunction with single channel analysis will be used to test our hypothesis that SOICR is governed by a luminal Ca2+ sensor located within the RyR2 channel pore. Significance: These proposed studies will not only shed novel mechanistic insight into the molecular basis of cardiac arrhythmias, but also lead to the development of a new and promising class of anti-arrhythmic agents, and have direct implications for the prevention and treatment of cardiac arrhythmias.

Public Health Relevance

A major cause of sudden death in patients with heart failure is ventricular arrhythmia. Consequently, a variety of anti-arrhythmic therapies have been developed over the past 3-4 decades. However, recent large clinical trials have demonstrated that the majority of these drugs have little or no survival benefits. Beta-blockers have consistently been shown to reduce the risk of sudden death. However, the molecular mechanisms underlying beta-blockers'survival benefits are unknown. This proposal seeks to identify the mechanisms responsible for beta-blockers'beneficial effects, and to develop novel anti-arrhythmic therapies that target these mechanisms. These proposed studies will not only shed novel mechanistic insight into the molecular basis of cardiac arrhythmias, but also lead to the development of a new and promising class of anti-arrhythmic agents, and have direct implications for the prevention and treatment of cardiac arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075210-08
Application #
8317617
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
2009-08-21
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$345,174
Indirect Cost
$101,719
Name
Rush University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Liu, Yingjie; Wang, Ruiwu; Sun, Bo et al. (2014) Generation and characterization of a mouse model harboring the exon-3 deletion in the cardiac ryanodine receptor. PLoS One 9:e95615
Bai, Yunlong; Jones, Peter P; Guo, Jiqing et al. (2013) Phospholamban knockout breaks arrhythmogenic Caýýýýý waves and suppresses catecholaminergic polymorphic ventricular tachycardia in mice. Circ Res 113:517-26
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Wang, Ruiwu; Zhong, Xiaowei; Meng, Xing et al. (2011) Localization of the dantrolene-binding sequence near the FK506-binding protein-binding site in the three-dimensional structure of the ryanodine receptor. J Biol Chem 286:12202-12

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