Effects of dietary omega–3 fatty acids on ventricular function in dogs with healed myocardial infarctions: in vivo and in vitro studies George E. Billman,1,2 Yoshinori Nishijima,2,3 Andriy E. Belevych,1,2 Dmitry Terentyev,1,2 Ying Xu,1 Kaylan M. Haizlip,1 Michelle M. Monasky,1 Nitisha Hiranandani,1 William S. Harris,4 Sandor Gyorke,1,2 Cynthia A. Carnes,1–3 and Paul M. L. Janssen1,2 1 Department of Physiology and Cell Biology, 2 Davis Heart and Lung Research Institute, 3 College of Pharmacy, The Ohio State University, Columbus, Ohio; and 4 Sanford Research Institute, University of South Dakota, Sioux Falls, South Dakota Submitted 9 November 2009; accepted in final form 21 January 2010 Billman GE, Nishijima Y, Belevych AE, Terentyev D, Xu Y, Haizlip KM, Monasky MM, Hiranandani N, Harris WS, Gyorke S, Carnes CA, Janssen PM. Effects of dietary omega–3 fatty acids on ventricular function in dogs with healed myocardial infarctions: in vivo and in vitro studies. Am J Physiol Heart Circ Physiol 298: H1219–H1228, 2010. First published January 22, 2010; doi:10.1152/ajpheart.01065.2009.—Since omega–3 polyunsaturated fatty acids (n-3 PUFAs) can alter ventricular myocyte calcium handling, these fatty acids could adversely affect cardiac contractile function, particularly following myocardial infarc- tion. Therefore, 4 wk after myocardial infarction, dogs were randomly assigned to either placebo (corn oil, 1 g/day, n 16) or n-3 PUFAs supplement [docosahexaenoic acid (DHA) eicosapentaenoic acid (EPA) ethyl esters; 1, 2, or 4 g/day; n 7, 8, and 12, respectively] groups. In vivo, ventricular function was evaluated by echocardiog- raphy before and after 3 mo of treatment. At the end of the 3-mo period, hearts were removed and in vitro function was evaluated using right ventricular trabeculae and isolated left ventricular myocytes. The treatment elicited significant (P 0.0001) dose-dependent increases (16.4-fold increase with 4 g/day) in left ventricular tissue and red blood cell n-3 PUFA levels (EPA DHA, placebo, 0.42 0.04; 1 g/day, 3.02 0.23; 2 g/day, 3.63 0.17; and 4 g/day, 6.97 0.33%). Regardless of the dose, n-3 PUFA treatment did not alter ventricular function in the intact animal (e.g., 4 g/day, fractional shortening: pre, 42.9 1.6 vs. post, 40.1 1.7%; placebo: pre, 39.2 1.3 vs. post, 38.4 1.6%). The developed force per cross-sectional area, changes in length- and frequency-dependent behavior in contractile force, and the inotropic response to -adrenoceptor activation were also similar for trabeculae obtained from placebo- or n-3 PUFA-treated dogs. Finally, calcium currents and calcium transients were the same in myocytes from n-3 PUFA- and placebo-treated dogs. Thus dietary n-3 PUFAs did not adversely alter either in vitro or in vivo ventricular contractile function in dogs with healed infarctions. contractility; Frank-Starling mechanism; force-frequency relation- ship; heart failure; sudden cardiac death; diet THE CARDIOVASCULAR BENEFITS of dietary omega–3 polyunsatu- rated fatty acids (n-3 PUFA) have been actively investigated for over 30 years. In the late 1970s, Dyerberg et al. (23) documented that age-adjusted mortality from myocardial in- farction (MI) among the Greenland Inuit was 10 to 40% of that noted for Danes, despite similar consumption of dietary fat and cholesterol. Dietary analysis revealed that most of the fat and calories in the Inuit diet were from fish and marine mammals rich in long-chain n-3 PUFAs, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), whereas typical Western diets contain twice as much saturated fatty acids and more n-6 PUFAs (2). This initial observation has been con- firmed by numerous epidemiological studies that provide fur- ther evidence for a strong inverse relationship between fatty fish consumption and cardiac mortality (18, 38, 41). In contrast to these observational studies, interventional studies using n-3 PUFAs for the secondary prevention of adverse cardiovascular events in patients recovering from MI have yielded conflicting results (14, 15, 43, 69). The Diet and Reinfarction Trial (DART) (14) and Gruppo Italiano per la Sperimentazione della Streptochinasi nell’Infarto Miocardico (GISSI)-Prevenzione trial (43) reported 10 to 20% reductions in all-cause mortality with up to a 45% reduction in sudden cardiac death (43). In marked contrast, the DART-2 study (15) reported that n-3 PUFAs increased, rather than decreased, all-cause mortality (26% increase over a 9-yr follow-up period, with a 54% increase sudden cardiac death), whereas the Japan Eicosapen- taneoic Acid Lipid Intervention (JELIS) found that EPA sup- plements did not alter either sudden death or fatal MI despite decreasing nonfatal coronary events (69). Meta-analyses of trials in which subjects ingested either fish or fish oil supple- ments also yielded inconsistent results; some studies reported a reduced cardiovascular mortality (39, 70), whereas others did not find a reduced risk for sudden death (12, 35). An explana- tion for these conflicting results remains largely to be deter- mined. The acute application of n-3 PUFAs to cardiac myocytes has been shown to alter intracellular calcium handling by inhibiting both sarcolemmal calcium entry via the L-type calcium chan- nels (24, 33, 67) and calcium release from the sarcoplasmic reticulum (34, 49, 52, 60). Dietary n-3 PUFAs have also been shown to alter intracellular calcium dynamics. Coronel and coworkers (64) found that myocytes from healthy pigs fed diets enriched with fish oil exhibited decreased L-type calcium (15%) and sodium/calcium exchanger currents (60%). Since calcium is critical for excitation-contraction coupling, these alterations in calcium homeostasis could provoke reduc- tions in myocardial contractile performance that become par- ticularly important in patients with compromised cardiac function. As such, it is possible that the consumption of n-3 PUFAs could reduce ventricular function and thereby increase the risk for adverse cardiac events in patients in whom cardiac function had been compromised by MI (13). Indeed, calcium channel antagonists have been shown to increase mortality in post-MI patients with left ventricular (LV) dysfunction (11, 28). The effects of n-3 PUFA supplements on ventricular function, particularly following MI, have not been extensively investi- gated. Address for reprint requests and other correspondence: G. E. Billman, Dept. of Physiology and Cell Biology, The Ohio State Univ., 304 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210-1218 (e-mail:
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