Eicosanoid Inflammatory Mediators Are Robustly Associated with Blood Pressure in the General Population

Background: Epidemiologic and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid derived eicosanoids serve as mediators of inflammation and have been suggested to also regulate renal vascular tone, peripheral resistance, renin-angiotensin system, and endothelial function. We therefore hypothesize that specific pro- and anti-inflammatory eicosanoids modulate BP. Methods: In N=8099 FINRISK 2002 cohort participants randomly drawn from the Finnish population register (53% women, mean age 48±13 years), we profiled 545 distinct high-quality eicosanoids and related oxylipin mediators in plasma using non-targeted liquid chromatography-mass spectrometry. In models adjusted for conventional hypertension risk factors, we analyzed the associations of eicosanoids and eicosanoid profiles with systolic BP and hypertension. We used the Framingham Heart Study (FHS) Offspring study (N=2859) as the replication cohort. Results: We observed 187 eicosanoids (34%) significantly associated with systolic BP (P < Bonferroni-corrected threshold of 0.05/545). 175 of these associations were positive and 12 were negative. Due to strong correlations between the eicosanoids, we used forward selection linear regression modeling to identify six eicosanoids independently related to systolic BP. A risk score based on these six eicosanoids was related to 40% (95% confidence interval [CI], 33-48%) and 32% (95% CI, 21-44%) greater odds of hypertension in FINRISK and FHS, respectively, per 1-SD score increase. Individuals in the upper quartile of the six-eicosanoid risk score had 2.26-fold greater odds (95% CI, 1.96-2.62) of prevalent hypertension in FINRISK, compared with those in the lowest quartile. These findings were successfully replicated in an independent cohort of FHS participants. Conclusions: Plasma eicosanoids demonstrate strong associations with BP in the general population. Intriguingly, we observed specific protective molecules as well as harmful molecules. As eicosanoid compounds affect numerous physiological processes that are central to BP regulation, they may offer new insights regarding pathogenesis of hypertension, as well as serve as new targets for therapeutic intervention.