Modifiable Correlates With Systemic Thromboxane Generation and Association With Cardiovascular Outcomes: Results From...

Systemic thromboxane A₂ generation, assessed via measurement of its urinary metabolites, is associated with cardiovascular disease (CVD) risk. Modifiable correlates with thromboxane A₂ generation, including potential nonplatelet sources not readily affected by aspirin, are poorly understood.

We investigated 2655 FHS (Framingham Heart Study) participants with measurements of urinary thromboxane B₂ metabolites normalized for renal function (TXB₂-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 TXB₂-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 TXB₂-M_GFR.

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 TXB₂-M_GFR. Higher omega-3 fatty acids (eicosapentaenoic acid+docosahexaenoic acid) and lower arachidonic acid were associated with lower TXB₂-M_GFR (P<0.005 for each). Higher TXB₂-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 TXB₂-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 TXB₂-M_GFR and high LE8.

Our findings suggest several modifiable factors that may impact systemic thromboxane A₂ generation. Higher systemic thromboxane A₂ generation also appears to modulate the association of lifestyle measures (as assessed by LE8 score) with CVD and heart failure.