Omega-3 fatty acids, subclinical atherosclerosis, and cardiovascular events: Implications for primary prevention

Abdulhamied Alfaddagh, Karan Kapoor, Zeina A. Dardari, Deepak L. Bhatt, Matthew J. Budoff, Khurram Nasir, Michael Miller, Francine K. Welty, Michael D. Miedema, Michael D. Shapiro, Michael Y. Tsai, Roger S. Blumenthal, Michael J. Blaha

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Background and aims: High-dose eicosapentaenoic acid (EPA) therapy was beneficial in high-risk patients without clinical cardiovascular disease (CVD). Whether higher plasma levels of EPA and docosahexaenoic acid (DHA) have similar benefits in those without subclinical CVD is unclear. We aim to evaluate the interplay between plasma omega-3 fatty acids and coronary artery calcium (CAC) in relation to CVD events. Methods: We examined 6568 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with plasma EPA and DHA levels and CAC measured at baseline. The primary outcome was incident CVD events (myocardial infarction, angina, cardiac arrest, stroke, CVD death). Hazard ratios for the primary outcome were adjusted for potential confounder using Cox regression. Results: Mean ± SD age was 62.1 ± 10.2 years and 52.9% were females. The median follow-up time was 15.6 years. Higher loge(EPA) (adjusted hazard ratio, aHR = 0.83; 95% CI, 0.74–0.94) and loge(DHA) (aHR = 0.79; 95% CI, 0.66–0.96) were independently associated with fewer CVD events. The difference in absolute CVD event rates between lowest vs. highest EPA tertile increased at higher CAC levels. The adjusted HR for highest vs. lowest EPA tertile within CAC = 0 was 1.02 (95% CI, 0.72–1.46), CAC = 1–99 was 0.71 (95% CI, 0.51–0.99), and CAC≥100 was 0.67 (95% CI, 0.52–0.84). A similar association was seen in tertiles of DHA by CAC category. Conclusions: In an ethnically diverse population free of clinical CVD, higher plasma omega-3 fatty acid levels were associated with fewer long-term CVD events. The absolute decrease in CVD events with higher omega-3 fatty acid levels was more apparent at higher CAC scores.

Original languageEnglish (US)
Pages (from-to)11-19
Number of pages9
StatePublished - Jul 2022

Bibliographical note

Funding Information:
This research was supported by contracts HHSN268201500003I , N01-HC-95159 , N01-HC-95160 , N01-HC-95161 , N01-HC-95162 , N01-HC-95163 , N01-HC-95164 , N01-HC-95165 , N01-HC-95166 , N01-HC-95167 , N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute , and by grants UL1-TR-000040 , UL1-TR-001079 , and UL1-TR-001420 from the National Center for Advancing Translational Sciences . The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at .

Funding Information:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. Dr. Michael Miller is a scientific advisor to Amarin. Dr. Michael D Shapiro has the following disclosures: Scientific Advisory Board activities with Amgen, Regeneron, Esperion, and Alexion. Consultant activities with Novartis. Dr. Michael J Blaha received grant support from the National Institutes of Health, the Food and Drug Administration, the American Heart Association, Aetna Foundation, Amgen; has served on the advisory board for Amgen, Sanofi, Regeneron, Novartis, Novo Nordisk, Bayer, Kowa, Akcea, 89Bio. The other authors have no disclosures.

Publisher Copyright:
© 2022 Elsevier B.V.


  • Cardiovascular disease
  • Coronary artery calcium
  • Docosahexaenoic acid
  • Eicosapentaenoic acid
  • Primary prevention


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