Epidemiological studies, clinical trials (patients with myocardial infarction), and animal studies have demonstrated that fish consumption, or diets enriched with fish oil (omega-3 polyunsaturated fatty acids, n-3 PUFAs) supplements, significantly reduced the incidence of sudden cardiac death. However, the mechanisms underlying the relationship between n-3 PUFAs and a reduced risk for cardiac arrhythmias remain to be determined. Therefore, we propose to investigate the safety and efficacy of n-3 PUFAs using a well-established canine model of lethal ventricular arrhythmias. The mechanisms altering cardiac electrophysiology will be examined in cardiac myocytes isolated from the hearts of these animals. The central hypothesis is that chronic treatment with n-3 PUFAs attenuates the electrophysiological abnormalities contributing to sudden cardiac death in a post-myocardial infarction canine model of sudden cardiac death. The following specific aims will be used to test this hypothesis:
Specific Aim #1 will test the hypothesis that the chronic ingestion of n-3 PUFA supplements will prevent ischemia-induced tachyarrhythmias (by preventing re-entrant and/or triggered arrhythmias).
Specific Aims #2 and #3 will investigate the effects of the chronic administration of n-3 PUFAs on the electrophysiology and calcium regulation of cardiomyocytes prepared from the hearts of the dogs, respectively. In particular, Specific Aim 2 will test the following hypotheses: n-3 PUFAs will a) normalize the sarcolemmal ion currents improving the ventricular myocyte action potential and b) reduce both early and delayed afterdepolarizations in dogs susceptible to ventricular fibrillation. Finally, Specific Aim #3 will test the following hypotheses: a) n-3 PUFAs will block L-type calcium current reducing calcium entry and thereby preventing calcium overload-induced spontaneous calcium release in dogs susceptible to ventricular fibrillation;b) n-3 PUFAs will alter ryanodine receptor function, restoring a more normal sarcoplasmic reticular calcium release in dogs susceptible to ventricular fibrillation;and c) n-3 PUFAs will alter the sarcoplasmic reticular (SR) calcium load, restoring a more normal SR calcium load in the dogs susceptible to ventricular fibrillation. Lay summary: This project will examine the safety of fish oil supplements after a heart attack. This project will also determine the effectiveness of fish oil supplements in reducing sudden death due to a lethal abnormal heart rhythm after a heart attack.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086700-04
Application #
7872853
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2007-08-15
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$493,004
Indirect Cost
Name
Ohio State University
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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
Canan, Benjamin D; Haizlip, Kaylan M; Xu, Ying et al. (2016) Effect of exercise training and myocardial infarction on force development and contractile kinetics in isolated canine myocardium. J Appl Physiol (1985) 120:817-24
Ardell, J L; Andresen, M C; Armour, J A et al. (2016) Translational neurocardiology: preclinical models and cardioneural integrative aspects. J Physiol 594:3877-909
Billman, George E; Cagnoli, Kristen L; Csepe, Thomas et al. (2015) Exercise training-induced bradycardia: evidence for enhanced parasympathetic regulation without changes in intrinsic sinoatrial node function. J Appl Physiol (1985) 118:1344-55
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
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
Glukhov, Alexey V; Hage, Lori T; Hansen, Brian J et al. (2013) Sinoatrial node reentry in a canine chronic left ventricular infarct model: role of intranodal fibrosis and heterogeneity of refractoriness. Circ Arrhythm Electrophysiol 6:984-94
Belevych, Andriy E; Terentyev, Dmitry; Terentyeva, Radmila et al. (2012) Shortened Ca2+ signaling refractoriness underlies cellular arrhythmogenesis in a postinfarction model of sudden cardiac death. Circ Res 110:569-77
Billman, George E (2012) Effect of dietary omega-3 polyunsaturated Fatty acids on heart rate and heart rate variability in animals susceptible or resistant to ventricular fibrillation. Front Physiol 3:71
Billman, George E; Carnes, Cynthia A; Adamson, Philip B et al. (2012) Dietary omega-3 fatty acids and susceptibility to ventricular fibrillation: lack of protection and a proarrhythmic effect. Circ Arrhythm Electrophysiol 5:553-60

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