Atrial fibrillation is the most common arrhythmia in the United States. The development of more effective new anti-arrhythmic drugs has been hampered by an incomplete understanding of the molecular mechanisms underlying these arrhythmias. Our research project focuses on studying the molecular mechanisms underlying AF, in particular the role of intracellular calcium-release channel dysfunction. Understanding how calcium channels in the heart are regulated and how new pharmacological compounds may normalize dysfunction of these channels may lead to improved therapeutic strategies for AF. Despite intense focus on understanding the molecular mechanisms that cause AF, and efforts to develop more effective and safer drug therapies to prevent AF, the need for better understanding of AF mechanisms and improved therapy is widely accepted. An emerging line of investigation has been the link between altered calcium (Ca2+) homeostasis and AF-initiation and perpetuation. It is hoped that a better understanding of the role of altered Ca2+ homeostasis in the genesis and maintenance of AF could lead to the development of novel, more effective and safer drug therapies. The applicant proposes to determine the mechanism underlying leaky RyR2 channels in atrial and pulmonary vein myocytes in animal models of AF, and test a novel drug S107 (a rycal), developed in the applicant's laboratory, that binds to RyR2 channels and prevents depletion of calstabin2 from the channel thereby inhibiting pathologic diastolic SR Ca2+ leak. A rycal is now in Phase II clinical studies for heart failure and sudden cardiac death and would be available for testing in AF patients.

Public Health Relevance

Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and mortality primarily due to stroke and cardiovascular events. There has been intense focus on understanding the molecular mechanisms that cause AF, and efforts to develop more effective and safer drug therapies to prevent AF. Nevertheless, the need for better understanding of AF mechanisms and improved therapy is widely accepted. An emerging line of investigation has been exploration of the role of altered calcium (Ca2+) homeostasis as a key element linked to AF-initiating focal activity and AF perpetuation due to rapid firing of foci and reentry. It is hoped that a better understanding of the role of altered Ca2+ homeostasis in the genesis and maintenance of AF could lead to the development of novel, more effective and safer drug therapies. The goal of the proposed studies is to use novel animal models of AF to study the molecular mechanisms that perturb Ca2+ homeostasis in AF. These same novel models of AF will be used to determine the efficacy of novel compounds that fix the leak in RyR2 channels and may be candidates for new therapeutics for AF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102040-02
Application #
8301586
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Boineau, Robin
Project Start
2011-07-15
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$400,000
Indirect Cost
$150,000
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Xie, Wenjun; Santulli, Gaetano; Reiken, Steven R et al. (2015) Mitochondrial oxidative stress promotes atrial fibrillation. Sci Rep 5:11427
Santulli, Gaetano; Marks, Andrew R (2015) Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging. Curr Mol Pharmacol 8:206-22
Santulli, Gaetano; Pagano, Gennaro; Sardu, Celestino et al. (2015) Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J Clin Invest 125:1968-78
Waning, David L; Mohammad, Khalid S; Reiken, Steven et al. (2015) Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat Med 21:1262-71
Xie, Wenjun; Santulli, Gaetano; Guo, Xiaoxiao et al. (2013) Imaging atrial arrhythmic intracellular calcium in intact heart. J Mol Cell Cardiol 64:120-3
Marx, Steven O; Marks, Andrew R (2013) Dysfunctional ryanodine receptors in the heart: new insights into complex cardiovascular diseases. J Mol Cell Cardiol 58:225-31
Shan, Jian; Xie, Wenjun; Betzenhauser, Matthew et al. (2012) Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia. Circ Res 111:708-17
Kushnir, Alexander; Marks, Andrew R (2012) Ryanodine receptor patents. Recent Pat Biotechnol 6:157-66
Meli, Albano C; Refaat, Marwan M; Dura, Miroslav et al. (2011) A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium. Circ Res 109:281-90
Kushnir, Alexander; Betzenhauser, Matthew J; Marks, Andrew R (2010) Ryanodine receptor studies using genetically engineered mice. FEBS Lett 584:1956-65