Mark R. Etherton, MD, PhD

Saber H, Yakoob MY, Shi P, Longstreth Jr. WT, Lemaitre RN, Siscovick D, et al. Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts. Stroke. 2017

In this entry, I discuss a recent publication by Hamidreza Saber and colleagues regarding the relationship of circulating omega-3 fatty acids levels and incident ischemic stroke.

The authors set out to clarify the impact of omega-3 fatty acids on ischemic stroke incidence. Observational studies of self-reported omega-3 fatty acid consumption and omega-3 fatty acid supplementation trials have previously produced disparate results. As such, the authors quantified circulating omega-3 fatty acid levels in association with ischemic stroke incidence from 3 separate prospective cohort studies.

The authors used data from the Cardiovascular Health Study (CHS), Nurses’ Health Study (NHS), and Health Professionals Follow-Up Study (HPFS). Each of these three cohort studies represent distinct patient populations, which does influence the overall generalizability of these results. CHS is a prospective cohort study of adults aged 65 years and older. The NHS is a prospective cohort study of female registered nurses 30 to 55 years of age. Lastly, HPFS is a cohort study of U.S. male health professionals 40 to 75 years of age. Most participants in each study were white (88% in CHS, for example). The analysis of NHS and HPFS was based on a nested case-control study of age and vascular-risk factor matched controls. Ischemic stroke was subdivided into atherothrombotic, cardioembolic, or other. At the time of enrollment in the studies, blood samples were collected and stored for later analysis of omega-3 fatty acid levels. Of note, there were some differences in collection and storage of blood samples for fatty acid analysis between the three studies.

Over the follow-up period, 953 incident ischemic strokes were identified, with 408 and 256 attributed to atherothrombotic and cardioembolic etiologies, respectively. After adjusting for age, sex, and various dietary and vascular risk factors, the risk of incident ischemic stroke was reduced with higher circulating levels of docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA), but not eicosapentaenoic acid (EPA) (Figure). When the authors investigated stroke subtype, participants in the highest quartile of DHA had reduced risk of stroke secondary to atherothrombotic etiologies (large- and small-vessel) compared to the lowest quartile (pooled HR, 0.53; 95% CI 0.34-0.83). In contrast, when cardioembolic stroke was evaluated, a significant risk reduction was observed in participants in the highest quartile of DPA versus the lowest quartile (pooled HR, 0.58; 95% CI 0.37-0.92).

Risk of incident ischemic stroke according to the circulating phospholipid n-3 polyunsaturated fatty acid biomarkers in CHS (Cardiovascular Health Study), NHS (Nurses’ Health Study), and HPFS (Health Professionals Follow-Up Study).

Figure: Risk of incident ischemic stroke according to the circulating phospholipid n-3 polyunsaturated fatty acid biomarkers in CHS (Cardiovascular Health Study), NHS (Nurses’ Health Study), and HPFS (Health Professionals Follow-Up Study).

In total, the authors present data from 3 large prospective cohort studies performed in the United States and demonstrate an inverse relationship between circulating levels of DPA and DHA and incident ischemic stroke. Moreover, they suggest a preferential effect of select omega-3 fatty acids on incident risk of specific stroke subtypes.

This study is important for several reasons. First, rather than look at self-reported or dietary supplementation of omega-3 fatty acids, the authors quantified serum levels with respect to incident stroke risk. Secondly, the authors demonstrate that higher circulating levels of DHA and DPA inversely affect incident risk of atherothrombotic and cardioembolic stroke, respectively. This result, in combination with our present understanding of omega-3 fatty acid biochemical pathways, allows for interesting speculation on the protective mechanisms of these fatty acids.

There are several limitations of this study that warrant consideration. First, the time-period between blood sample collection and incident stroke was significant (median 8.3 years in NHS and HPFS), which invokes a major assumption on the longitudinal circulating serum fatty acid profile. Going forward, it would be useful for future studies to quantify circulating serum fatty acid levels at the time of ischemic stroke. Secondly, while stroke subtypes were divided into atherothrombotic and cardioembolic for the purposes of this analysis, there are important distinctions within these subgroups with regards to stroke pathophysiology (e.g. small-vessel occlusive/lacunar syndrome versus large-artery disease) that merit further investigation. Studies exploring the relationship of circulating omega-3 fatty acid levels and stroke attributed to small-vessel disease, large-artery disease, and, specifically, atrial fibrillation would therefore be informative.