Abstract P329: Eicosanoids and Heart Failure Risk in the Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Eicosanoids play an important role in regulating inflammation response, which influences the development of heart failure (HF). However, the association between eicosanoids and the risk of HF remains unclear. Hypothesis: We hypothesize that eicosanoid metabolites are associated with incident HF and may improve HF prediction. Methods: We measured plasma eicosanoids via liquid chromatography-mass spectrometry among HF-free participants at visit 2 (1990-1992) from the Atherosclerosis Risk in Communities (ARIC) study. The Cox proportional hazard regression was performed to evaluate the relationship between eicosanoids and incident HF controlling for clinical risk factors. The least absolute shrinkage and selection operator was applied to identify a representative subset of eicosanoids towards constructing an eicosanoid risk score (ERS). We further conducted genome-wide association analyses to examine the genetic determinants for HF related eicosanoids in black and white participants respectively. Results: During an average of 21 years of follow up, 2,202 (28.0 % blacks, 50.3% women) out of 9,519 participants developed HF. Out of 200 eicosanoids analyzed, six with hazard ratio between 0.89 to 1.10 were found associated with the risk of HF (FDR <0.05) per SD change, namely 11-dehydro-2,3-dinor-TXB2, 5-hydroperoxyicosa-6,8,11,14,17-pentaenoic acid, 13-hydroperoxyoctadeca-9,11-dienoic acid, eicosapentaenoic acid (EPA) [M-H], and EPA [M-H+Acetate]. Genetic loci were identified for six HF related eicosanoids (p<8.3e-9). One locus, rs6600888, an intronic variant of UGT2B7 , where its T allele was associated with lower EPA [M-H+Acetate] level while positively affect the risk of HF and systolic blood pressure level. ERS constructed from 52 eicosanoids showed a 39% increase in HF risk per SD increment and twice the risk between the highest and the lowest ERS quartile (p < 0.001). The addition of ERS to the HF 10-years prediction model modestly improved the C-statistics from 0.799 to 0.808, 95%CI ΔC : 0.004-0.015. Conclusion: We identified a set of eicosanoids that significantly associated with increased risk of HF. The contributing genetic variation of eicosanoids may depict the biological pathways related to HF.