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

Viet T Le; Stacey Knight; Jeramie D Watrous; Mahan Najhawan; Khoi Dao; Raymond O McCubrey; Tami L Bair; Benjamin D Horne; Heidi T May; Joseph B Muhlestein; John R Nelson; John F Carlquist; Kirk U Knowlton; Mohit Jain; Jeffrey L Anderson

doi:10.3389/fcvm.2023.1229130

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

Front Cardiovasc Med. 2023 Aug 23:10:1229130. doi: 10.3389/fcvm.2023.1229130. eCollection 2023.

Authors

Viet T Le^{1

2}, Stacey Knight^{1

3}, Jeramie D Watrous⁴, Mahan Najhawan⁴, Khoi Dao⁴, Raymond O McCubrey¹, Tami L Bair¹, Benjamin D Horne^{1

5}, Heidi T May¹, Joseph B Muhlestein^{1

3}, John R Nelson⁶, John F Carlquist^{1

3}, Kirk U Knowlton^{1

3

4}, Mohit Jain⁴, Jeffrey L Anderson^{1

3}

Affiliations

¹ Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT, United States.
² Department of Physician Assistant Studies, Rocky Mountain University of Health Professions, Provo, UT, United States.
³ The University of Utah, School of Medicine, Salt Lake City, UT, United States.
⁴ Department of Medicine, University of California San Diego, San Diego, CA, United States.
⁵ Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, United States.
⁶ California Cardiovascular Institute, Fresno, CA, United States.

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.

Keywords: DHA; EPA; major adverse cardiovascular events; omega-3; outcomes.

Grants and funding

This research was funded by an unrestricted grant that was provided through the philanthropy of the Dell Loy Hansen Heart Foundation.