Abstract
BACKGROUND: Systemic thromboxane A(2) generation, assessed via measurement of its urinary metabolites, is associated with cardiovascular disease (CVD) risk. Modifiable correlates with thromboxane A(2) generation, including potentially nonplatelet sources not readily affected by aspirin, are poorly understood. METHODS: We investigated 2655 FHS (Framingham Heart Study) participants with measurements of urinary thromboxane B(2) metabolites normalized for renal function (TXB(2)-M(GFR)). Life's Essential 8 (LE8) score was constructed from 8 modifiable factors. We additionally examined erythrocyte omega-3 fatty acids and omega-6 fatty acid levels, namely, eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid. In a subset of participants, objective measurements of vascular stiffness and adiposity were obtained. We related these factors to TXB(2)-M(GFR) using linear models, adjusting for age, sex, and aspirin use. We also explored the association of LE8 or omega-3 fatty acids with total CVD or heart failure stratified by TXB(2)-M(GFR). RESULTS: Both total LE8 score (P<0.001) and individual LE8 components (P<0.05 for each), including favorable diet, physical activity, blood glucose, blood pressure, and nonsmoking, were associated with lower TXB(2)-M(GFR). Higher omega-3 fatty acids (eicosapentaenoic acid+docosahexaenoic acid) and lower arachidonic acid were associated with lower TXB(2)-M(GFR) (P<0.005 for each). Higher TXB(2)-M(GFR) was related to greater waist circumference, computed tomography-measured visceral adipose tissue, and hepatic steatosis (P<0.01 for each), and higher large artery vascular stiffness (P<0.001). Findings were generally consistent across aspirin use status. After median follow-up of 12.9 years (371 CVD and 214 heart failure events), individuals with both high TXB(2)-M(GFR) and low LE8 displayed an over 5-fold higher risk of heart failure (hazard ratio, 5.07 [95% CI, 3.26-7.89]) and 2.5-fold higher risk of CVD (hazard ratio, 2.74 [95% CI, 2.04-3.68]) compared with participants with low TXB(2)-M(GFR) and high LE8. CONCLUSIONS: Our findings suggest several modifiable factors that may impact systemic thromboxane A(2) generation. Higher systemic thromboxane A(2) generation also appears to modulate the association of lifestyle measures (as assessed by LE8 score) with CVD and heart failure.