Heart failure and atrial fibrillation are common coexisting disease states;data from the Framingham study indicate that heart failure is associated with a 4.5- to 5.9-fold increase in the risk of atrial fibrillation. In patients with advanced heart failure, atrial fibrillation significantly increases the risk of death. Experimental studies have shown that heart failure produces atrial electrophysiologic changes which promote atrial fibrillation;furthermore heart failure induces significant increases in myocardial oxidants. Using a chronic model of nonischemic heart failure, we have preliminary evidence of specific oxidatively-modulated forms of atrial electrophysiologic changes. In this chronic heart failure model, there is a substrate for atrial fibrillation, and in pilot experiments we are able to induce sustained (months) atrial fibrillation. Thus, we can study how both heart failure and atrial fibrillation contribute to the pathogenesis of atrial fibrillation. The purpose of this proposal is to understand the mechanistic bases of atrial fibrillation during heart failure, with a long-term goal of identifying specific targeted therapeutic interventions to effectively prevent or treat atrial fibrillation during heart failure. The central hypothesis of this proposal is that during chronic HF, and chronic HF with superimposed chronic AF, there are specific forms of oxidatively-mediated pathologic atrial remodeling. A combination of in vivo (electrophysiologic and non-invasive imaging techniques) and in vitro (cellular electrophysiology, electron paramagnetic resonance spectroscopy, HPLC analyses, immunohistochemistry and proteomics) techniques will be used to test the central hypothesis, through the following aims.
Specific Aim 1 will test the hypothesis that during HF-, and HF with AF-, discrete forms of atrial remodeling occur. Oxidative modulation of atrial myocyte remodeling will be examined.
Specific Aim 2 will test the hypothesis that during HF, and HF with AF, specific forms of atrial oxidative stress occur which result in specific alterations in atrial electrophysiology.
Specific Aim 3 will test the hypothesis that attenuation of a specific source of oxidative stress will reduce atrial fibrillation and pathologic atrial electrophysiologic remodeling.

Public Health Relevance

Heart failure (resulting from impaired contraction of the heart muscle) and atrial fibrillation (abnormal rhythm of the upper chambers of the heart) are increasingly common causes of disability and death in the U.S. population. Information from this study may result in improved treatments for the prevention and treatment of atrial fibrillation during heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Lathrop, David A
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Ohio State University
Schools of Pharmacy
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Bonilla, Ingrid M; Nishijima, Yoshinori; Vargas-Pinto, Pedro et al. (2016) Chronic Omega-3 Polyunsaturated Fatty Acid Treatment Variably Affects Cellular Repolarization in a Healed Post-MI Arrhythmia Model. Front Physiol 7:225
Long 3rd, Victor P; Bonilla, Ingrid M; Vargas-Pinto, Pedro et al. (2015) Heart failure duration progressively modulates the arrhythmia substrate through structural and electrical remodeling. Life Sci 123:61-71
Bonilla, Ingrid M; Long 3rd, Victor P; Vargas-Pinto, Pedro et al. (2014) Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure. PLoS One 9:e108824
Bonilla, Ingrid M; Vargas-Pinto, Pedro; Nishijima, Yoshinori et al. (2014) Ibandronate and ventricular arrhythmia risk. J Cardiovasc Electrophysiol 25:299-306
Lou, Qing; Hansen, Brian J; Fedorenko, Olga et al. (2014) Upregulation of adenosine A1 receptors facilitates sinoatrial node dysfunction in chronic canine heart failure by exacerbating nodal conduction abnormalities revealed by novel dual-sided intramural optical mapping. Circulation 130:315-24
Radwa?ski, Przemys?aw B; Belevych, Andriy E; Brunello, Lucia et al. (2013) Store-dependent deactivation: cooling the chain-reaction of myocardial calcium signaling. J Mol Cell Cardiol 58:77-83
Belevych, Andriy E; Radwanski, Przemyslaw B; Carnes, Cynthia A et al. (2013) 'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure. Cardiovasc Res 98:240-7
Belevych, Andriy E; Ho, Hsiang-Ting; Terentyeva, Radmila et al. (2013) Dietary omega-3 fatty acids promote arrhythmogenic remodeling of cellular Ca2+ handling in a postinfarction model of sudden cardiac death. PLoS One 8:e78414
DeGrande, Sean T; Little, Sean C; Nixon, Derek J et al. (2013) Molecular mechanisms underlying cardiac protein phosphatase 2A regulation in heart. J Biol Chem 288:1032-46
Lou, Qing; Glukhov, Alexey V; Hansen, Brian et al. (2013) Tachy-brady arrhythmias: the critical role of adenosine-induced sinoatrial conduction block in post-tachycardia pauses. Heart Rhythm 10:110-8

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