Heart failure (HF) is the most common cause of Medicare hospitalizations. About 50% of HF patients suffer from HF with reduced ejection fraction (HFrEF) and 50% suffer from HFpEF (preserved ejection fraction). HFpEF pathophysiology is complex, but studies suggest a role of cardiac fibrosis that is often caused by systemic inflammation. Pro-resolution mediators (e.g. lipoxins and resolvins) and their receptors such as the formyl peptide receptor (FPR), have led to new insights toward addressing unresolved inflammation. We hypothesize that FPR agonists polarize macrophages to a pro-resolution phenotype limiting adverse left ventricular remodeling in a rat HFpEF model. 18-month-old female Fisher F344 rats were obtained from the NIH/NIA aging colony, underwent bilateral ovariectomy, and were exposed to 10% fructose in drinking water (OVF). After two months, animals were randomly divided into three groups and treated daily by gavage with the FPR agonist compound 43 (C43) at 1/kg/day (C43-LD, n=10), 10 mg/kg/day (C43-HD, n=10) or vehicle (Ctrl, 0.5% carboxymethylcellulose in H 2 0, n=20) for 2 months. Before OVF, and monthly post-OVF plasma collection, body weight assessment (BWs), and echocardiography were performed. 4-month-post OVF hearts were arrested in diastole, fixed with 10% formalin, paraffin-embedded, and Trichrome stained. Compared to baseline, BWs increase comparable in all treatment groups at 4-months-post OVF. 4 animals in the Ctrl group, 2 in the LD group, and one in the HD group were excluded due to tumors or sudden death. Echocardiography 4-months-post OVX shows preserved %EF in all groups, but reduced E’/A’ ratios in Ctrl, compared to C43 treated rats. No difference in diastolic function is found between rats treated with C43-LD or C43-HD. Trichrome staining in mid-ventricular cross sections does not reveal changes in cardiac fibrosis (% area in RV and LV) between all groups. Our early-stage HFpEF animal model combines aging, excess body weight, ovarian hormone depletion, and preserved systolic function with impaired chamber relaxation. Daily oral administration of the FPR agonist C43 does not reduce cardiac fibrosis but improves left ventricular diastolic function in aged female rats with HFpEF. Ongoing biochemical studies assess novel pathways responsible for the C43-induced cardioprotection during HFpEF. We aim to generate preclinical evidence for the prospect of using this class of agents as potential HFpEF therapeutics.
Zemljic‐Harpf et al. (Fri,) studied this question.
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