Julie A Eclov, Qingwen Qian, Rebecca Redetzke, Quanhai Chen, Steven C Wu, Chastity L Healy, Steven B Ortmeier, Erin Harmon, Gregory C Shearer, Timothy D O'Connell

Heart failure with preserved ejection fraction (HFpEF) is half of all HF, but standard HF therapies are ineffective. Diastolic dysfunction, often secondary to interstitial fibrosis, is common in HFpEF. Previously, we found that supra-physiologic levels of ω3-PUFA produced by 12 weeks of ω3-dietary supplementation prevented fibrosis and contractile dysfunction following pressure overload (TAC), a model that resembles aspects of remodeling in HFpEF. This raised several questions regarding ω3-concentration-dependent cardioprotection, the specific role of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the relationship between prevention of fibrosis and contractile dysfunction. To achieve more clinically relevant ω3-levels and test individual ω3-PUFA, we shortened the ω3-diet regimen and used EPA- and DHA-specific diets to examine remodeling following TAC. The shorter diet regimen produced ω3-PUFA levels closer to western clinics. Further, EPA, but not DHA, prevented fibrosis following TAC. However, neither ω3-PUFA prevented contractile dysfunction, perhaps due to reduced uptake of ω3-PUFA. Interestingly, EPA did not accumulate in cardiac fibroblasts. However, free fatty acid receptor 4, a G-protein coupled receptor for ω3-PUFA, was sufficient and required to block TGFβ1-fibrotic signaling in cultured cardiac fibroblasts suggesting a novel mechanism for EPA. In summary, EPA-mediated prevention of fibrosis could represent a novel therapy for HFpEF.