Plasma Omega-3 Fatty Acids and the Risk of Cardiovascular Events in Patients After an Acute Coronary Syndrome in MERLIN-TIMI 36

Abstract

Background Plasma omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been shown to be inversely correlated with the risk of cardiovascular death in primary prevention. The risk relationship in the setting of an acute coronary syndrome is less well established. Methods and Results Baseline plasma ω3-PUFA composition (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) was assessed through gas chromatography with flame ionization detection in a case-cohort study involving 203 patients with cardiovascular death, 325 with myocardial infarction, 271 with ventricular tachycardia, and 161 with atrial fibrillation, and a random sample of 1612 event-free subjects as controls from MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation-Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36), a trial of patients hospitalized with non-ST-segment-elevation -acute coronary syndrome. After inverse-probability-weighted multivariable adjustment including all traditional risk factors, a higher relative proportion of long-chain ω3-PUFAs (eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid) were associated with 18% lower odds of cardiovascular death (adjusted [adj] odds ratio [OR] per 1 SD, 0.82; 95% CI, 0.68-0.98) that was primarily driven by 27% lower odds of sudden cardiac death (adj OR per 1 SD, 0.73; 95% CI, 0.55-0.97). Long-chain ω3-PUFA levels in the top quartile were associated with 51% lower odds of cardiovascular death (adj OR 0.49; 95% CI, 0.27-0.86) and 63% lower odds of sudden cardiac death (adj OR, 0.37; 95% CI, 0.16-0.56). An attenuated relationship was seen for α-linolenic acid and subsequent odds of cardiovascular (adj OR, 0.92; 95% CI, 0.74-1.14) and sudden cardiac death (adj OR, 0.91; 95% CI, 0.67-1.25). No significant relationship was observed between any ω3-PUFAs and the odds of cardiovascular death unrelated to sudden cardiac death, myocardial infarction, atrial fibrillation, or early post-acute coronary syndrome ventricular tachycardia. Conclusions In patients after non-ST-segment-elevation-acute coronary syndrome, plasma long-chain ω3-PUFAs are inversely associated with lower odds of sudden cardiac death, independent of traditional risk factors and lipids. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00099788.

Keywords: acute coronary syndrome; omega‐3 polyunsaturated fatty acids; sudden cardiac death.

Conflict of interest statement

Dr Zelniker was supported by a research grant of the Deutsche Forschungsgemeinschaft (DFG, ZE 1109/1‐1) and has received consulting fees and honoraria from AstraZeneca and Boehringer Ingelheim. Dr Morrow reports grants from Anthos Therapeutics, Daiichi Sankyo, Eisai, GlaxoSmithKline, Medicines Company, Pfizer, Quark, Regeneron, Siemens, Takeda, and Zora Biosciences; grants and personal fees from AstraZeneca, Merck & Co, Novartis, and Roche Diagnostics; and personal fees from Bayer Pharma, and InCarda, outside the submitted work. Dr Morrow is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Regeneron, Roche, Siemens, Takeda, The Medicines Company, and Zora Biosciences. Dr Scirica reports institutional research grants to Brigham and Women's Hospital from AstraZeneca, Eisai, Merck, Novartis, NovoNordisk, and Pfizer; consulting fees from AbbVie, Allergan, AstraZeneca, Boehringer Ingelheim, Eisai, Elsevier Practice Update Cardiology, Esperion, Hamni, Lexicon, Medtronic, Merck, and NovoNordisk; and equity in HEALTH[at]SCALE. Dr Scirica is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Dr Furtado reports no conflicts of interest related to this article. J. Guo is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Regeneron, Roche, Siemens, Takeda, The Medicines Company, and Zora Biosciences. Dr Mozaffarian reports research funding from the National Institutes of Health, the Gates Foundation, and the Rockefeller Foundation; personal fees from GOED, Danone, Indigo Agriculture, Motif FoodWorks, Amarin, Acasti Pharma, Cleveland Clinic Foundation, and America's Test Kitchen; has been a member of the scientific advisory boards of Beren Therapeutics, Brightseed, Calibrate, DayTwo, Elysium Health, Filtricine, Foodome, HumanCo, January.ai, and Tiny Organics; and received chapter royalties from UpToDate; all outside the submitted work. Dr Sabatine reports the following conflicts of interest: research grant support through Brigham and Women's Hospital from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi‐Sankyo, Eisai, Intarcia, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Takeda; and has been a consultant for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol‐Myers Squibb, CVS Caremark, DalCor, Dr Reddy's Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis. Dr O'Donoghue has received grant funding via Brigham and Women's Hospital from Amgen, Medicines Company, Novartis, Merck, Eisai, AstraZeneca and Medimmune, as well as consulting fees from Amgen, AstraZeneca, Novartis, and Janssen.

Figures

Figure 1. Relative proportion of ω3‐polyunsaturated fatty acids subtypes as compared with total ω3‐PUFA content and total fatty acid (FA) content overall.

ALA indicates α‐linolenic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; EPA, eicosapentaenoic acid; and ω3‐PUFA, ω3‐polyunsaturated fatty acids.

Figure 2. Multivariable adjusted odds ratios per 1‐SD increase in ω3‐polyunsaturated fatty acid subtype content for cardiovascular death (A) and sudden cardiac death (B).

The models were adjusted for age, sex, estimated glomerular filtration rate, hypertension, prior myocardial infarction, heart failure, diabetes mellitus, smoking, statin use, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, triglycerides, body mass index, race, region, index diagnosis, and randomized treatment arm. The long chain ω3‐polyunsaturated fatty acids include EPA, DPA, and DHA. Adj. OR indicated adjusted odds ratio; ALA, α‐linolenic acid; CV, cardiovascular; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; and EPA, eicosapentaenoic acid.

Figure 3. Multivariable adjusted odds ratios for quartiles of ω3‐polyunsaturated fatty acid (ω3‐PUFA) subtypes for sudden cardiac death.

The models were adjusted for age, sex, estimated glomerular filtration rate, hypertension, prior myocardial infarction, heart failure, diabetes mellitus, smoking, statin use, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, triglycerides, body mass index, race, region, index diagnosis, and randomized treatment arm. ALA indicates α‐linolenic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; and EPA, eicosapentaenoic acid.

Figure 4. Multivariable adjusted splines for long‐chain marine‐based ω3‐polyunsaturated fatty acid (ω3‐PUFA) content (EPA, DHA, DPA) and sudden cardiac death.

The x axis is truncated at the 99.5 percentile of the distribution. Adjusted for age, sex, estimated glomerular filtration rate, hypertension, prior myocardial infarction, heart failure, diabetes mellitus, smoking, statin use, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, triglycerides, body mass index, race, region, index diagnosis, and randomized treatment arm. ALA indicates α‐linolenic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; and EPA, eicosapentaenoic acid. P‐linearity = 0.87 (indicating that non‐linearity cannot be rejected).