Scales Tip Toward 'Fish Oil' PUFA Intake for Heart Failure Prevention

Marlene Busko

July 16, 2019

High plasma levels of the kinds of fatty acids found in fish oil were associated with a lower long-term risk for new heart failure (HF), whether with reduced or preserved ejection fraction (HFrEF or HFpEF), in a community-based cohort of more than 6000 people.

The greater the plasma levels of eicosapentaenoic acid (EPA), a prevalent n-3 polyunsaturated fatty acid (n-3 PUFA, also called omega-3 PUFA), the lower the risk for both forms of HF during a median follow-up of 13 years.

Similar independent observations were made for plasma levels of docosahexaenoic acid (DHA) and of EPA and DHA combined, suggesting that increased levels of n-3 PUFA in general may confer cardiovascular (CV) benefits, observe the study's authors, led by Robert C. Block, MD, MPH, University of Rochester School of Medicine and Dentistry, New York.

The findings from the Multi-Ethnic Study of Atherosclerosis (MESA), published July 10 in JACC: Heart Failure, add to a literature of abundant but diverse observations on the CV effects of elevated levels of n-3 PUFA, whether achieved by diet or fish oil–based supplements or prescriptions.

The MESA cohort consists of initially middle-aged adults and is noteworthy for being about evenly divided between women and men and including large proportions of African Americans and other non-white groups.

The analysis "may reopen the discussion on the role of omega-3 fatty acids in the context of prevention and treatment of heart failure," writes Aldo P. Maggioni, MD, Heart Care Foundation, Florence, Italy, in an accompanying editorial.

"This study clearly demonstrated a significant independent inverse correlation between circulating levels of omega-3 fatty acids, specifically eicosapentaenoic acid, and the occurrence of HF over a long median follow-up period of 13 years," he writes.

To reap such benefits, "shall we have to go to the fish market or to the pharmacy to elevate our circulating levels of omega-3 fatty acids and, in this way, to try to prevent (or treat) heart failure?" Maggioni asks.

He argues in favor of the pharmacy. Cardiovascular outcomes from OMEGA-REMODEL and REDUCE-IT, the current results, and studies in mice "suggest that just with very high plasma levels of omega-3 fatty acids we can obtain a reduction of major CV events, a prevention of HF occurrence, and a favorable effect on the left ventricular remodeling processes."

Moreover, "High plasma levels of omega-3 fatty acids can be probably achieved just with the use of purified pharmacological preparations."

"Most Americans, regardless of race or ethnicity," have insufficient levels of n-PUFAs and "would benefit from increased intake," senior author Gregory C. Shearer, PhD, Pennsylvania State University, University Park, said in emailed comments to theheart.org | Medscape Cardiology.

Fish-oil supplements would likely be more effective than eating more fish to achieve the n-3 PUFA levels that may be of benefit, Shearer and coauthor Timothy D O'Connell, PhD, University of Minnesota, Minneapolis, speculated in a joint interview.

As both the report and editorial note, n-3 PUFA treatment at the fairly low dosage of 1 g/day, added to standard therapy, was associated with reduced all-cause mortality and HF hospitalization rates over about 4 years in the 2008 GISSI-HF trial.

In the 2015 OMEGA-REMODEL trial, patients who took a proprietary n-PUFA preparation (Lovaza, GlaxoSmithKline) at 4 g/day for 6 months after a myocardial infarction (MI) showed reductions in ventricular remodeling, fibrosis, and inflammatory markers.

More recently, in the REDUCE-IT trial, patients with high triglyceride levels and CV disease or diabetes plus one other CV risk factor showed a 25% reduction in the composite outcome of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina over 5 years while taking icosapent ethyl (Vascepa, Amarin) at 4 g/day. The agent acts as a precursor of EPA.

The current analysis classified 65,632 high-risk MESA participants according to their plasma percent-EPA levels.

Levels were <1.0%, or "insufficient," compared to adjusted levels that prevented HF in animal models, in 73.1% of participants.

They were 1% to 2.5%, or "marginally sufficient," in 22.4% of participants; and 4.5% of the cohort had "sufficient" levels, at >2.5%.

Only 1.4% of Hispanic participants had sufficient percent-EPA levels; the proportions were 4.4% for African Americans, 4.9% for whites, and 9.8% for participants of Asian descent.

There were 292 HF events — 128 involving HFrEF, 110 in HFpEF, and 54 in people whose ejection fractions were unknown — during a median of 13 months. The mean percent-EPA level was 0.76% for participants who did not develop HF, vs 0.69% for participants who did develop HF (P = .005).

In an analysis adjusted for age, sex, race, body-mass index, smoking status, type 2 diabetes, blood pressure, lipids, lipid-lowering therapy, albuminuria, and types of PUFA, percent-EPA was inversely associated with risk for HF at a hazard ratio (HR) of 0.73 for each log-unit difference (P = .001).

"Clinical trials using 1 g/day omega-3 fatty acids," such as GISSI-HF, "seem to reduce HF risk by about 10%," said Shearer. But this dose would likely only increase the average percent-EPA from 0.7% to the marginally sufficient range, between 1% and 1.5%.

Any forthcoming trials should be designed "to achieve a goal of greater than 3.5% EPA, or greater than 12% EPA plus DHA," he said.

"Based on the results from MARINE and ANCHOR, we are optimistic that a larger dose such as 4 g/day" would result in an average percent-EPA of 4% and about a 35% reduced risk for HF.

"If we want to move from hypotheses to more reliable evidences," Maggioni agrees, "it is probably the time to design again adequately sized randomized clinical trials testing high dosages of omega-3 fatty acids on top of current optimized pharmacological and non-pharmacological therapies."

Their goals, he writes, should be to determine whether the intervention has an effect on clinical outcomes in patients with overt HF and the ability to avert HF in patients with structural heart disease but who do not have signs or symptoms of HF.

"Considering the very favorable tolerability and safety profile of this therapeutic approach, any positive results of these trials could provide us with an additional strategy to improve the outcomes of patients with HF or at high risk to develop it," he writes.

Block has disclosed no relevant financial relationships. Shearer has received honoraria from Amarin Pharmaceuticals. Disclosures for the other authors are listed in the report. Maggioni has received honoraria for participation in committees of studies sponsored by Bayer, Novartis, and Fresenius outside the scope of the current study.

JACC: Heart Fail. Published online July 10, 2019. Abstract, Editorial

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Editor's note: This article has been corrected to more clearly distinguish the types of orally administered PUFA mentioned as dietary supplements or those available only by prescription.

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