Impact of EPA and DHA Supplementation on Plasma Biomarkers of Inflammation (n3)
Condition: Cardiovascular Disease, Inflammation
MeSH terms: Cardiovascular Diseases; Inflammation
Study type: Interventional

Summary: 
      Subclinical inflammation is now indisputably recognized as a key etiological factor in the
      development of atherosclerosis and subsequent cardiovascular disease. Obesity and related
      dysmetabolic states including metabolic syndrome (MetS) are highly prevalent causes of
      subclinical inflammation. Obesity and MetS are both diet and lifestyle-related and there is a
      growing body of literature suggesting that specific nutrients, such as long chain omega-3
      polyunsaturated fatty acids (LCn-3PUFA), may attenuate the pro-inflammatory state associated
      with these conditions. However, careful review of existing literature on this topic reveals
      important gaps in knowledge, the purported anti-inflammatory effects of LCn-3PUFA even being
      questioned by many. Significant confounding attributable to study design, sample size and
      biomarker selection may be responsible in part for inconsistencies in the literature on
      LCn-3PUFA and inflammation. We also found that evidence available to date (for and against)
      is based primarily on secondary analyses, as most of the studies published were not primarily
      designed to investigate inflammation as a primary outcome. It remains unclear whether the
      different LCn-3PUFA, primarily docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid
      (EPA, 20:5n-3), have similar effects on pro-inflammatory processes as almost all studies were
      undertaken using a mix of LCn-3PUFA. Whether efficacy of EPA and DHA is influenced by
      sex/gender is also unknown. Finally, a better understanding of the systemic and
      tissue-specific mechanisms underlying the anticipated anti-inflammatory effects of different
      LCn-3PUFA in MetS would also be of great value. Addressing these gaps has important public
      health implications, considering that LCn-3PUFA supplements are broadly and indiscriminately
      recommended for the prevention of cardiovascular disease.

      The overarching objective of the proposed research is to compare the anti-inflammatory
      effects of EPA and DHA in men and women with MetS.
    

Detailed description: 
      The proposed study will be undertaken according to a double-blind randomized placebo
      controlled cross-over design with 3 treatment phases: 1- high DHA, 2- High EPA, 3- Control.
      Each treatment phase will last 10 weeks and will be separated by 8-week washouts.
      Participants will be randomized to one of 6 treatment sequences while stratifying for sex.
      Treatments will provide 3 identical 1g capsules per day. During the 3 treatment periods,
      subjects will receive in random order 0g/d EPA+DHA (3g corn oil placebo), 3g/d EPA (>90%
      EPA), and 3g/d DHA (>90% DHA). Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA)
      will be provided in their re-esterified triacylglycerol form as studies have shown that
      bioavailability was greater when EPA and DHA were consumed as TG rather than as ethyl esters.
      The therapeutic dose that maximizes the anti-inflammatory effects of LCn-3PUFA in patients
      with inflammation has not been established, although data suggest that they may be
      dose-dependent. However, studies in healthy human volunteers suggest that an intake > 2 g EPA
      + DHA/day is required to affect inflammatory processes. Many of the available studies have
      used a dose of EPA+DHA that was lower than 2g/d, with no apparent anti-inflammatory effects.
      A study has shown that a dose of 1.8g/d of EPA+DHA induced significant changes in peripheral
      blood cell (PBC) inflammation gene expression, with no change in plasma CRP concentrations.
      In the present study, we propose to use a dose of 3 g/d for each individual LCn-3PUFA tested,
      which is at the higher end of the recommended intake for patients with high plasma TG, but
      which will maximize our chance to observe changes in inflammatory markers and to
      differentiate the effects of EPA and DHA, if they exist. Participants will be instructed to
      maintain a constant body weight during the course of the study. They will also be counselled
      on how to exclude fatty fish meals (including salmon, tuna, mackerel, and herring), fish-oil
      supplements, flax products, walnuts, and omega-3-enriched eggs during the study. Vitamin
      supplements and natural health products will be strictly forbidden during the entire
      experimental period, with the exception of calcium and vitamin D, which will be allowed at a
      stable dose. Although alcohol consumption will be permitted during the study with intakes not
      exceeding one serving (12-15 g alcohol) per day, it will be forbidden for the 4 days that
      precede the various tests at the end of each treatment phase. Subjects will also be
      instructed to maintain their usual physical activity except for the 4 days that precede blood
      sampling at the various stages of the study, during which they will be asked to remain
      sedentary.
    

Intervention name(s): High DHA; High EPA; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): 10 week supplementation period; 10 week supplementation period; 10 week supplementation period
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Cardiovascular disease; Inflammation; EPA/DHA supplementation