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Cited by 18Fatty Acid Research and HealthNutritional Studies and DietAquaculture Nutrition and Growth

Higher docosahexaenoic acid levels lower the protective impact of eicosapentaenoic acid on long-term major cardiovascular events

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Le, Viet T., Knight, Stacey, Watrous, Jeramie D., Najhawan, Mahan, Dao, Khoi, McCubrey, Raymond O., Bair, Tami L., Horne, Benjamin D. +7 more·2023·Frontiers in Cardiovascular Medicine
DOI 10.3389/fcvm.2023.1229130PMC PMC10482040
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Abstract

Introduction: Long-chain omega-3 polyunsaturated fatty acids (OM3 PUFA) are commonly used for cardiovascular disease prevention. High-dose eicosapentaenoic acid (EPA) is reported to reduce major adverse cardiovascular events (MACE); however, a combined EPA and docosahexaenoic acid (DHA) supplementation has not been proven to do so. This study aimed to evaluate the potential interaction between EPA and DHA levels on long-term MACE. Methods: We studied a cohort of 987 randomly selected subjects enrolled in the INSPIRE biobank registry who underwent coronary angiography. We used rapid throughput liquid chromatography-mass spectrometry to quantify the EPA and DHA plasma levels and examined their impact unadjusted, adjusted for one another, and fully adjusted for comorbidities, EPA + DHA, and the EPA/DHA ratio on long-term (10-year) MACE (all-cause death, myocardial infarction, stroke, heart failure hospitalization). Results: The average subject age was 61.5 ± 12.2 years, 57% were male, 41% were obese, 42% had severe coronary artery disease (CAD), and 311 (31.5%) had a MACE. The 10-year MACE unadjusted hazard ratio (HR) for the highest (fourth) vs. lowest (first) quartile (Q) of EPA was HR = 0.48 (95% CI: 0.35, 0.67). The adjustment for DHA changed the HR to 0.30 (CI: 0.19, 0.49), and an additional adjustment for baseline differences changed the HR to 0.36 (CI: 0.22, 0.58). Conversely, unadjusted DHA did not significantly predict MACE, but adjustment for EPA resulted in a 1.81-fold higher risk of MACE (CI: 1.14, 2.90) for Q4 vs. Q1. However, after the adjustment for baseline differences, the risk of MACE was not significant for DHA (HR = 1.37; CI: 0.85, 2.20). An EPA/DHA ratio ≥1 resulted in a lower rate of 10-year MACE outcomes (27% vs. 37%, adjusted p -value = 0.013). Conclusions: Higher levels of EPA, but not DHA, are associated with a lower risk of MACE. When combined with EPA, higher DHA blunts the benefit of EPA and is associated with a higher risk of MACE in the presence of low EPA. These findings can help explain the discrepant results of EPA-only and EPA/DHA mixed clinical supplementation trials.

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  • A recent retrospective study of 987 randomly selected patients from the INSPIRE biobank registry suggested that higher DHA serum levels may blunt beneficial actions of EPA and are associated with higher incidence of adverse cardiovascular events when serum EPA levels are low.

    “a recent retrospective study of 987 randomly selected patients from the INSPIRE biobank registry suggested that higher DHA serum levels may blunt beneficial actions of EPA, and are associated with higher incidence of adverse cardiovascular events when serum EPA levels are low.38”

    From Effects of Eicosapentaenoic Acid vs Eicosapentaenoic/Docosahexaenoic Acids on Cardiovascular Mortality (2025) · cites this paper as [38]

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Authors
Le, V. T., Knight, S., Watrous, J. D., Najhawan, M., Dao, K., McCubrey, R. O., Bair, T. L., Horne, B. D., May, H. T., Muhlestein, J. B., Nelson, J. R., Carlquist, J. F., Knowlton, K. U., Jain, M., & Anderson, J. L.
Affiliations
  • Intermountain Medical Center (US)
  • University of Utah (US)
  • University of California San Diego (US)
Corresponding author
Le, Viet T.
ORCID
Venue
Frontiers in Cardiovascular Medicine
Publisher
Frontiers Media SA
Published
2023-08-23
Volume
10
Pages
1229130-1229130
ISSN
2297-055X (ISSN-L)
DOI
10.3389/fcvm.2023.1229130
PMC
PMC10482040
OpenAlex
W4386085743
Cited by
18
References
59
Citations by year
2026: 3 · 2025: 8 · 2024: 7
FWCI
3.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cardiovascular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
  • Life Sciences › Agricultural and Biological Sciences › Aquatic Science › Aquaculture Nutrition and Growth
Keywords
docosahexaenoic acid, eicosapentaenoic acid, omega-3 polyunsaturated fatty acids, major adverse cardiovascular events, EPA/DHA ratio, plasma fatty acids, coronary artery disease, cardiovascular risk, long-term cardiovascular outcomes, omega-3 supplementation, heart failure hospitalization, stroke, myocardial infarction, all-cause mortality, lipidomics

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