The Omega-3 Index: a new risk factor for death from coronary heart disease? $, $$ William S. Harris, Ph.D. a, * and Clemens von Schacky, M.D. b a Lipid and Diabetes Research Center, Mid America Heart Institute of Saint Luke’s Hospital, University of Missouri-KC School of Medicine, Kansas City, MO 64111, USA b Medizinische Klinik and Poliklinik Innenstadt, University of Munich, Munich, Germany Available online 2 April 2004 Abstract Background. Low intakes or blood levels of eicosapentaenoic and docosahexaenoic acids (EPA + DHA) are independently associated with increased risk of death from coronary heart disease (CHD). In randomized secondary prevention trials, fish or fish oil have been demonstrated to reduce total and CHD mortality at intakes of about 1 g/day. Red blood cell (RBC) fatty acid (FA) composition reflects long-term intake of EPA + DHA. We propose that the RBC EPA + DHA (hereafter called the Omega-3 Index) be considered a new risk factor for death from CHD. Methods. We conducted clinical and laboratory experiments to generate data necessary for the validation of the Omega-3 Index as a CHD risk predictor. The relationship between this putative marker and risk for CHD death, especially sudden cardiac death (SCD), was then evaluated in several published primary and secondary prevention studies. Results. The Omega-3 Index was inversely associated with risk for CHD mortality. An Omega-3 Index of z 8% was associated with the greatest cardioprotection, whereas an index of V 4% was associated with the least. Conclusion. The Omega-3 Index may represent a novel, physiologically relevant, easily modified, independent, and graded risk factor for death from CHD that could have significant clinical utility. D 2004 The Institute for Cancer Prevention and Elsevier Inc. All rights reserved. Keywords: Omega-3 fatty acids; Eicosapentaenoic acid; Docosahexaenoic acid; Coronary heart disease; Sudden cardiac death; Risk factors Introduction Coronary heart disease (CHD) claims roughly 500,000 deaths/year in the USA. Of these, about 50% are sudden cardiac deaths (SCDs) [1]. Recent evidence from second- ary prevention trials suggests that supplementation with 850 mg/day of omega-3 fatty acids (FA), that is, eicosa- pentaenoic acid (EPA; C20:5 N-3) and docosahexaenoic acid (DHA: C22:6 N-3), can reduce the risk of CHD death by 25% and SCD by about 45% [2]. The American Heart Association (AHA) now recommends about 1.0 g/day of EPA + DHA to reduce risk for death from CHD in the secondary prevention setting [3]. In addition, for individ- uals without known disease (primary prevention), the AHA recommends the consumption of at least two, preferably oily, fish meals per week. This amount of fatty fish would provide about 500 mg of EPA + DHA per day. Because red blood cell (RBC) membranes reflect cardiac membrane omega-3 FA content, we propose that the content of EPA + DHA in RBC membranes (expressed as a percent of total FA) be considered a new risk factor for death from CHD and especially SCD. This biomarker is hereafter called the ‘‘Omega-3 Index’’. The goals of this study were (1) to explore the potential utility of the Omega-3 Index as a risk factor for CHD mortality and (2) to define ranges for the Omega-3 Index corresponding to high, medium, or low 0091-7435/$ - see front matter D 2004 The Institute for Cancer Prevention and Elsevier Inc. All rights reserved. doi:10.1016/j.ypmed.2004.02.030 $ Conflicts of interest for sponsored work. Roche Vitamins provided a research grant to conduct the dose-ranging study presented in this paper. However, the data herein included on RBC fatty acid composition were derived from an independent analysis of the blood samples collected in that study and were not a part of the funded protocol. $$ Conflict of interest for authors and their institutions. The Mid America Heart Institute, UMKC, W.S. Harris and C. von Schacky have interests in OmegaMetrix, a company that offers blood omega-3 fatty acid analyses. * Corresponding author. Lipid and Diabetes Research Center, Mid America Heart Institute of Saint Luke’s Hospital, University of Missouri- KC School of Medicine, 4320 Wornall Road, Suite 128, Kansas City, MO 64111. Fax: +1-816-932-8278. E-mail address: wharris@saint-lukes.org (W.S. Harris). www.elsevier.com/locate/ypmed Preventive Medicine 39 (2004) 212 – 220