Background: Sex differences in cardiovascular disease (CVD) risk remain poorly understood. Because inflammation-related pathways are implicated in the pathogenesis of CVD, we examined the relation of eicosanoids, the upstream mediators of system inflammation, with the sexual dimorphism in CVD risk.
Methods: In N=2420 Framingham Heart Study offspring cohort participants (57% women, mean age 67 years), we profiled 523 distinct eicosanoids in plasma. In multivariable-adjusted models, we analyzed the associations of all eicosanoids with sex, and the relation of sex-associated eicosanoids with incident CVD (N= 226 events, mean follow up 7.1 years).
Results: We observed that 246 eicosanoids (47%) were significantly associated with sex (P<1.0E-5) (Figure 1A). Of the 20 eicosanoids most highly associated with sex (P<1.0E-60), 5 were higher and 15 were lower in men compared with women. These 20 eicosanoids displayed substantial inter-correlations. (Figure 1B). Of the eicosanoids significantly associated with sex, 5 eicosanoids represent pathways previously implicated in the development of CVD (prostaglandins, leukotrienes, octadecanoids, lipoxins). One leukotriene, m/z 493.241180, was positively associated with male sex (P=4.7E-20) and also with greater risk for CVD after adjustment for traditional cardiovascular risk factors (P=0.01).
Conclusion: Plasma eicosanoids vary substantially by sex, represent pathways with biologically plausible roles in CVD pathogenesis, and are related to incident CVD. Thus, eicosanoids offer new insights regarding sexual dimorphism in CVD risk, and may contribute to the persistently greater risk seen in men versus women.