Abstract Body: Background Urinary thromboxane B2 metabolites (TXB₂) are biomarkers of systemic thromboxane A2 (TXA₂) activity, an eicosanoid synthesized from arachidonic acid (AA) that is recognized to contribute to cardiovascular disease (CVD) independent of its platelet effects. The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), produce downstream molecules that can suppress TXA₂. Whether circulating EPA+DHA or AA may influence TXB₂ levels or modify its association with incident CVD is unknown.
Aims To investigate the relations of circulating EPA, DHA, and AA to urinary TXB₂ and to assess whether these fatty acids may modify the association between TXB₂ and incident CVD.
Methods We studied 2,524 participants in the Framingham Heart Study Offspring/Omni cohorts, who were free of CVD at baseline, with measurements of urinary TXB₂ and circulating EPA, DHA, and AA. Incident CVD included a composite of coronary heart disease, stroke, peripheral artery disease, heart failure, and cardiovascular mortality. Hazard ratio (HR) and 95% confidence interval (CI) of the association between urinary TXB₂ (comparing high vs low using pre-determined cut-offs) and CVD, were calculated using multivariable-adjusted Cox models. We analyzed the cross-sectional relationship between circulating EPA, DHA, and AA with TXB₂ and assessed the relation between a per-1 standard deviation increment in TXB₂ and CVD stratified by tertiles of EPA+DHA or AA.
Results Among non-aspirin users, median TXB₂ decreased across tertiles of EPA (T3 vs T1: 3696 vs 4486 pg/mg creatinine) and DHA (T3 vs T1: 3670 vs 4497) (P_trend<0.0005 for each) (Table 1). On the other hand, TXB₂ increased with higher AA (T3 vs T1: 4378 vs 3857 (P_trend=0.009). Similar trends were seen among aspirin users. After a median 12.9 years of follow-up, 428 incident CVD events occurred. Higher urinary TXB₂ was associated with incident CVD, with HR (95% CI) of 1.61 (1.19, 2.18) for aspirin non-users and 1.36 (1.02, 1.81) for users. Higher EPA+DHA or AA did not appear to modify the association between TXB₂ and incident CVD (P_interaction>0.05 for each).
Conclusion Urinary TXB₂ is associated with incident CVD after accounting for standard CVD risk factors. While circulating EPA and DHA are inversely related to TXB₂, the association of TXB₂ with incident CVD is consistent across levels of EPA+DHA, suggesting likely separate biological pathways linking TXB₂ and omega-3 fatty acids with CVD development.