Eicosanoid and Eicosanoid-Related Inflammatory Mediators and Exercise Intolerance in Heart Failure with Preserved Ejection Fraction

Abstract

Abstract Background: Systemic inflammation has been implicated in the pathobiology of HFpEF. We examined the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Methods: We studied 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing (CPET). We examined the association of 890 eicosanoid and eicosanoid-related metabolites ascertained using mass spectrometry with HFpEF status (defined as abnormal rest or exercise PCWP) using multivariable logistic regression (FDR q-value <0.1 deemed significant). In secondary analyses, we examined eicosanoid profiles of specific exercise traits, including cardiac vs extra-cardiac organ reserve using principal component analysis. To corroborate findings, significant metabolites were tested against incident HF in 5192 MESA participants. Results: Among 510 participants (mean age 56±16 years, 63% women), 257 had physiologic evidence of HFpEF. We found 70 eicosanoid and eicosanoid-related metabolites were associated with HFpEF status including 17 named and 53 putative eicosanoids and eicosanoid-related metabolites. Specific prostaglandin (15R-PGF2a and 11ß-dhk-PGF2a) and linoleic acid derivatives (12,13 EpOME) were associated with greater odds of HFpEF, whereas epoxide (8(9)-EpETE), docosanoid (13,14-DiHDPA), and oxylipin (12-OPDA) derivatives were associated with lower odds of HFpEF(P<0.008 for all). Eicosanoid profiles showed heterogeneous associations across cardiac vs extra-cardiac contributors to exercise intolerance. In the MESA sample, we found that 18 eicosanoids and eicosanoid-related metabolites were associated with the development of future heart failure (P<0.05 for all). Conclusions: We found 70 pro- and anti-inflammatory eicosanoid and eicosanoid-related metabolites that were associated with physiologic HFpEF, including prostaglandin, linoleic acid, and epoxide derivatives. Among these, 18 were associated with future development of heart failure in the community. Further, eicosanoid profiles highlighted contributions to exercise intolerance. Specific eicosanoid and eicosanoid-related metabolites may contribute to the pathogenesis of HFpEF and may serve as potential therapeutic targets for intervention.