Omega-3 PUFA as Biomarkers: Plasma Levels Predict Mortality, CV Events in CHS Analysis

April 03, 2013

BOSTON — The highest levels of plasma phospholipid omega-3 polyunsaturated fatty acids (PUFA), as measured in >2500 older adults initially without coronary heart disease or a history of stroke, predicted the lowest mortality in the observational, prospective Cardiovascular Health Study (CHS)[1].

In comparisons of the highest quintile of omega-3 PUFA levels vs the lowest quintile, all-cause mortality fell by 27%, with most of the benefit due to a reduction in cardiovascular death. The rate of arrhythmic death, in particular, fell by nearly one-half.

Such cardiovascular-outcome effects are consistent with abundant evidence from laboratory and clinical studies that omega-3 PUFA intake may benefit heart rate, blood pressure, myocardial contractile function and electrical stability, and endothelial, autonomic, and hemostatic function, write the study's authors, led by Dr Dariush Mozaffarian (Harvard School of Public Health, Boston, MA). Their analysis was published in the April 2, 2013 issue of the Annals of Internal Medicine.

The CHS longitudinal data allowed the group not only to link plasma omega-3 PUFA levels with survival, Mozaffarian told heartwire , it allowed them to estimate the benefit: in this population, starting at age 65, he said, about 2.2 extra years for people in the highest compared with the lowest plasma-level quintile.

Outcomes also varied by individual omega-3 PUFAs. For a number of end points, importantly heart-disease mortality and arrhythmic mortality, there was a pattern of greater benefit from highest levels of docosahexaenoicacid (DHA) vs highest levels of eicosapentaenoic acid (EPA) and an even greater benefit from highest levels of total omega-3 PUFA.

For the end point of heart-disease death, "DHA seems to have stronger association" than EPA, according to Mozaffarian; the effect, he noted, appears to be dominated by a difference in arrhythmic death. But EPA at the highest levels vs the lowest levels showed a weakly significant trend (p=0.04) of benefit for nonfatal MI, while DHA and total omega-3 PUFA were unquestionably nonsignificant. Still, he said, given the "borderline" p value for EPA, "maybe none of them are significantly associated" with respect to nonfatal MI.

That outcomes varied by type of omega-3 PUFA has implications for dietary recommendations as well as therapeutic preparations of omega-3 PUFA.

"I think that our results support DHA, in particular, being important for heart-disease death and leaves open the question of whether EPA . . . [has] additional benefit." Consuming both together is probably wise, as there appear to be "complementary effects," Mozaffarian said. Based on the current analysis, "If you're going to consume omega-3s, you should at least be sure you're getting DHA. EPA alone might not have the same benefit; I think that's fair to say."

Clinical Outcomes Hazard Ratio* (HR, 95% CI) for Quintile 5 vs Quintile 1 of Plasma Phospholipid Omega-3 PUFA Levels, by PUFA Type

End point EPA DHA Total omega-3 PUFA
Total mortality 0.83 (0.71–0.98) 0.80 (0.67–0.94) 0.73 (0.61–0.86)
Total CV mortality 0.72 (0.54–0.96) 0.66 (0.49–0.89) 0.65 (0.48–0.87)
Total CHD mortality 0.77 (0.54–1.11) 0.60 (0.41–0.87) 0.60 (0.42–0.87)
Arrhythmic CHD mortality 0.76 (0.47–1.23) 0.55 (0.33–0.93) 0.52 (0.31–0.86)
Stroke mortality 0.84 (0.47–1.48) 0.62 (0.32–1.20) 0.60 (0.32–1.12)
Ischemic stroke 1.09 (0.76–1.57) 0.74 (0.50–1.10) 0.63 (0.43–0.94)
Hemorrhagic stroke 0.70 (0.30–1.67) 1.24 (0.52–2.94) 1.23 (0.53–2.89)

PUFA=polyunsaturated fatty acid

EPA=eicosapentaenoic acid

DHA=docosahexaenoic acid

*Adjusted for age, sex, race, education, enrollment site, fatty-acid-measurement batch (1994–1996 or 2007–2010), smoking status, diabetes, atrial fibrillation, drug-treated hypertension, physical activity, body-mass index, waist circumference, alcohol use, and consumption of tuna or other broiled or baked fish, fried fish, red meat, fruits, vegetables, and dietary fiber

As previously covered by heartwire , the CHS enrolled 5201 adults aged >65 years in four US communities, two in the East and one in California from 1989 to 1990, plus 687 additional African Americans from 1992 to 1993. The current analysis includes 2692 without CHD, stroke, or heart failure at baseline who were not taking fish-oil supplements and in whom levels of plasma phospholipid omega-3 PUFA were measured in 1992–1993. Their mean age at baseline was 74 years, 64% were women, and 88% were white; they were followed until 2000.

The adjusted hazard ratio (HR) for total mortality was 0.83 for the highest quintile of EPA vs the lowest quintile (p=0.005), 0.80 for DHA (p=0.006), and 0.73 for total omega-3 PUFA (p<0.001).

Decreases in HR for total heart-disease mortality were significant only for DHA (p=0.003) and total omega-3 PUFA (p=0.002). The same was true for arrhythmic death: DHA (p=0.028) and total omega-3 PUFA (p=0.008).

Acknowledging that "this is an observational study--it doesn't prove cause and effect," Mozaffarian said that it at least supports high plasma levels of omega-3 PUFAs as directly affecting survival. "If there was confounding--if it was just that people were more educated or had healthy lifestyles--you'd expect that higher [omega-3 PUFA plasma levels] would relate very similarly to a lower risk of every kind of death: [including] respiratory death, infectious death, cancer death, and stroke death. But the bulk of the association seems to be from heart-disease death, and [especially] heart disease death from arrhythmia."

As for the possible advantage high plasma DHA levels may have over high EPA levels with respect to total and heart-disease mortality, which would conceivably conflict with the higher elevations in LDL cholesterol observed with DHA vs EPA supplementation, Mozaffarian said doesn't see a paradox.

"The LDL-raising effect of omega-3s is very modest." If there is any such effect, he said, "it's to make the particles larger and fluffier and therefore potentially less atherogenic." According to Mozaffarian, "it's just hype" to say that an omega-3 PUFA supplement that delivers only EPA should be preferred over a mixed EPA/DHA supplement because of a difference in LDL effects.

In addition to many brands of nonprescription mixed EPA/DHA supplements on the market, in the US there is the prescription-only mixed formulationLovaza (GlaxoSmithKline); and just last year, the FDA approved the synthetic EPA-only preparation Vascepa (Amarin), which contains ethyl eicosapentaenoic acid.

The CHS was funded by the National Institutes of Health; disclosures for Mozaffarian et al are available here.

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