Eicosapentaenoic Acid Prevents Interstitial Cardiac Fibrosis in a Mouse Model of Hypertensive Heart Disease

Abstract

Heart failure with preserved ejection fraction (HFpEF) is ~50% of all heart failure (HF) diagnoses, however, standard HF therapies show no efficacy in HFpEF. Omega‐3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), improve outcomes in coronary heart disease and HF with reduced ejection fraction, but whether this benefit extends to HFpEF is unclear. Here, we examined the effect of EPA and DHA on remodeling following transverse aortic constriction (TAC) in mice. TAC induced concentric hypertrophy, interstitial fibrosis, and diastolic and systolic dysfunction similar, in several respects, to remodeling in HFpEF. Diastolic dysfunction correlated with the extent of interstitial fibrosis and hypertrophy after TAC (R2=0.39, P=0.02; R2 = 0.34, P=0.04, respectively), but systolic dysfunction did not (R2=0.19, P = 0.14; R2=0.07, P=0.40). Interestingly, blood levels of EPA (n=58, P=0.04), but not DHA (n=58, P=0.63), inversely correlated with interstitial fibrosis after TAC. However, EPA, unlike DHA, was not incorporated into cardiac fibroblast membranes, a traditional mechanism of action for long‐chain fatty acids. Alternatively, expression of free fatty acid receptor 4 (FFAR4), a G‐protein coupled receptor for long‐chain fatty acids, was detected in cardiac fibroblasts, suggesting an alternate mechanism of action. Our data suggest that EPA prevents interstitial fibrosis following TAC, potentially through FFAR4 in cardiac fibroblasts, which could have implications for the management of HFpEF.