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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. Ho...