Introduction: The associations of individual seafood n-3 polyunsaturated fatty acids with incident ischemic stroke, and its subtypes (atherothrombotic and cardioembolic stroke), are not well-established. Individual n-3 fatty acids, which are best assessed by circulating biomarkers, may also have differential effects on atherothrombotic vs. cardioembolic stroke.
Objective: To prospectively investigate the relationship of circulating eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke.
Methods: We measured circulating phospholipid fatty acids (erythrocyte or plasma) at baseline in the Cardiovascular Health Study (CHS), Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). Ischemic stroke was prospectively adjudicated and classified into atherothrombotic (large and small vessel infarctions) or cardioembolic (cardiac mural thrombi, valvular heart disease, atrial fibrillation, other sources) stroke by imaging studies and medical records. Risk was assessed using conditional logistic regression (for prospective nested case-control studies: NHS, HPFS) or Cox proportional hazards model (full cohort: CHS). Findings were pooled by fixed-effects meta-analysis.
Results: A total of 953 incident ischemic strokes were identified that included 408 atherothrombotic and 256 cardioembolic strokes, during mean follow-up of 11.4 (CHS) and 8.3 (NHS,HPFS) years (the remaining 289 ischemic strokes could not be sub-classified). After adjustment for age, race, sex, smoking, physical activity, alcohol intake, family history of MI and diabetes, menopausal status, BMI, aspirin use and intakes of fruits, vegetables, and meats, lower risk of total ischemic stroke was seen with DPA (highest vs. lowest-quartiles, pooled HR=0.74, 95%CI=0.58-0.92) and DHA (0.80, 0.64-1.00), but not EPA (0.94, 0.77-1.19). Among stroke subtypes, DHA was associated with substantially lower risk of atherothrombotic (0.53, 0.34-0.83), but not cardioembolic stroke; and DPA with substantially lower risk of cardioembolic (0.58, 0.37-0.92), but not atherothrombotic stroke. Findings in each individual cohort were similar to the pooled results.
Conclusions: In 3 US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke, and DPA, with cardioembolic stroke. EPA was not associated with ischemic stroke. These novel findings highlight the importance of separately evaluating ischemic stroke subtypes as well as specific individual fatty acids, and suggest differential pathways of benefit for DHA, DPA, and EPA.