Elsevier

Nutrition Research

Volume 36, Issue 9, September 2016, Pages 989-994
Nutrition Research

Original Research
Red blood cell oleic acid levels reflect olive oil intake while omega-3 levels reflect fish intake and the use of omega-3 acid ethyl esters: The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico–Heart Failure trial

https://doi.org/10.1016/j.nutres.2016.06.012Get rights and content

Abstract

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico–Heart Failure (GISSI-HF) study reported benefits of n-3 fatty acid (FA) treatment on cardiovascular (CV) events, but the effects of treatment on a putative CV disease risk factor, the red blood cell (RBC) n-3 FA level (the omega-3 index), have not been examined in this context. We hypothesized that treatment with prescription omega-3 acid ethyl esters (O3AEE) would increase the omega-3 index to the proposed cardioprotective value of 8%. RBCs were collected from a subset of patients participating in the GISSI-HF study (n = 461 out of 6975 randomized), at baseline and after 3 months of treatment with either an olive oil placebo or O3AEE (1 g/d). RBC FA levels were expressed as a percentage of total FA. Patients also reported their typical olive oil and fish intakes. RBC oleic acid levels were directly correlated with reported frequency of olive oil consumption, and the omega-3 index was correlated with reported fish intake (P for trends <0.001 for both). After treatment, the omega-3 index increased from 4.8 ± 1.7% to 6.7 ± 1.9% but was unchanged in the placebo group (4.7 ± 1.7 to 4.8 ± 1.5%) (P < .0001 for changes between groups). At 3 months, more patients reached the proposed target omega-3 index level of 8%-12% in the treated vs placebo group (22.6% vs. 1.3%, P < .0001), however, what omega-3 index levels were ultimately achieved after four years in this trial are unknown.

Introduction

There are multiple controversies surrounding the effects of saturated, mono-unsaturated and omega-6 polyunsaturated fatty acids (FAs) on coronary heart disease risk [1], [2], [3], [4], and even around the omega-3 FA, which for many years have enjoyed virtually universal support as being cardioprotective [5], [6]. In the Chowdhury et al meta-analysis [1], both intakes and blood levels of the long-chain, marine-derived omega-3 FAs (eicosapentaenoic [EPA], docosahexaenoic [DHA], and docosapentaenoic acids [DPAn-3]) were inversely related to risk, but randomized trials have, at least in recent years, not supported this relationship.

FA intakes and blood levels vary around the world, presumably driven by differences in dietary patterns. Omega-3 FA levels are typically low in most western countries where fish consumption is low, and high in cultures like Japan or Korea where consumption is high [7]. Among the European Mediterranean countries, Spain has the highest fish intake [8], but their red blood cell (RBC) omega-3 levels, although high [8] relative to the United States [9] and Germany [10] (ie, 7.1% versus 5.6% and 4.7%, respectively), have not been compared across Europe. The other FA family most commonly associated with Mediterranean diets, particularly in Italy, is oleic acid (OA), which is a major component of olive oil. Since OA levels are determined by both endogenous synthesis and exogenous consumption, its levels in the blood have not been considered to be good markers of dietary OA [11], but cross-cultural analyses using the same laboratory methods are few, and the possibility that chronically elevated intakes might be reflected in membrane OA levels has not been tested.

The primary hypotheses tested here were (1) treatment with omega-3 acid ethyl esters (O3AEE) will increase the RBC EPA + DHA level (ie, the Omega-3 Index) to the proposed cardioprotective level of 8% or greater, (2) the Omega-3 Index at baseline is directly associated with reported fish intake, and 3) RBC OA levels at baseline are directly associated with reported olive oil intake. These hypotheses were tested by measuring the RBC FA composition at baseline and after 3 months in a sub-cohort of Italian patients who participated in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico–Heart Failure (GISSI-HF) study and who were treated with 1 g/d of O3AEE (or placebo).

Section snippets

Subjects

The GISSI-HF trial was a randomized, double-blind, placebo-controlled, multicenter study that enrolled 6975 patients with clinical evidence of chronic, stable HF, as previously described [12]. The trial investigated the effect of taking 1 g/day of O3AEE providing about 850 to 882 mg of EPA and DHA combined (in the average ratio of 1:1.2) or an olive oil placebo for about 4 years. In a prospectively planned biomarker substudy, blood samples were collected at randomization and 3 months later from

Results

The mean (SD) age of the 461 patients comprising the GISSI-HF subcohort was 67.1 (11.5) years, 77% were male, the mean (SD) body mass index was 26.8 (4.6) and omega-3 index was 4.7% (1.7%). The effects of treatment with O3AEE (1 g/d) or placebo for 3 months on RBC FA composition are shown in Table. O3AEE increased the omega-3 index by 2 percentage points (a 42% increase), and levels of DPAn-3 by 30%. Treatment also lowered levels of all long chain omega-6 FAs downstream of linoleic acid

Discussion

The purposes of this study were to estimate the effects of 1 capsule of O3AEE per day on RBC FA composition in the GISSI-HF study, and to determine the extent to which RBC omega-3 and OA levels correlated with reported fish and olive oil intakes, respectively. Based on our findings, we reject the hypothesis that 3 months of treatment would result in a mean omega-3 index of ≥8%, but accept the hypotheses that the omega-3 index and RBC OA levels would be directly correlated with reported intakes

Acknowledgment

The authors wish to thank Joe McConnell and Jennie Ward and the staff at Health Diagnostic Laboratory, Inc. (HDL) for the complimentary analysis of RBC fatty acids. During the performance of this study, WSH was an employee of HDL and is the President of OmegaQuant Analytics, LLC, both of which offer blood fatty acid testing. None of the other authors has any potential conflict to disclose. The GISSI-HF study was funded by Società Prodotti Antibiotici (SPA; Italy), Pfizer, Sigma Tau, and

References (48)

  • ML Burr et al.

    Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART)

    Lancet

    (1989)
  • C von Schacky

    Omega-3 fatty acids in cardiovascular disease--an uphill battle

    Prostaglandins Leukot Essent Fat Acids

    (2015)
  • WS Harris et al.

    Comparison of the effects of fish and fish-oil capsules on the n 3 fatty acid content of blood cells and plasma phospholipids

    Am J Clin Nutr

    (2007)
  • AC Salisbury et al.

    Predictors of omega-3 index in patients with acute myocardial infarction

    Mayo Clin Proc

    (2011)
  • R Chowdhury et al.

    Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis

    Ann Intern Med

    (2014)
  • MS Farvid et al.

    Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies

    Circulation

    (2014)
  • VS Malik et al.

    Circulating very-long chain saturated fatty acids and incident coronary heart disease in U.S. men and women

    Circulation

    (2015)
  • JH Wu et al.

    Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the cardiovascular health study

    Circulation

    (2014)
  • JH Lee et al.

    Omega-3 fatty acids: cardiovascular benefits, sources and sustainability

    Nat Rev Cardiol

    (2009)
  • A Sala-Vila et al.

    Determinants of the omega-3 index in a Mediterranean population at increased risk for CHD

    Br J Nutr

    (2011)
  • A Kohler et al.

    Effects of a convenience drink fortified with n-3 fatty acids on the n-3 index

    Br J Nutr

    (2010)
  • GISSI Heart Failure Investigators

    Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial

    Lancet

    (2008)
  • S Masson et al.

    Plasma n-3 polyunsaturated fatty acids in chronic heart failure in the GISSI-heart failure trial: relation with fish intake, circulating biomarkers, and mortality

    Am Heart J

    (2013)
  • F Barzi et al.

    Mediterranean diet and all-causes mortality after myocardial infarction: results from the GISSI-Prevenzione trial

    Eur J Clin Nutr

    (2003)
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    1

    A complete list of centers participating in the GISSI-HF substudy and their investigators was published in the European Journal of Heart Failure 2010;12:338–347.

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