Beneficial Effects of FPR Agonists on an Animal Model of Early Stage Heart Failure with Preserved Ejection Fraction

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Heart failure (HF) is the most common cause of Medicare hospitalizations. About 50% of HF patients suffer from HF with low ejection fraction (HFrEF) for which there are treatments. The other 50% suffer from HFpEF, (preserved ejection fraction) characterized by the inability of the left ventricle (LV) to accommodate larger filling volumes upon greater demands in cardiac output. Currently, no treatments are available for HFpEF and studies demonstrate a female predominance (2:1 vs. men). Noteworthy, the VA has identified as a research priority Women Veteran’s health. HFpEF pathophysiology is complex and the cause for female predominance is unclear. However, studies strongly suggest a role for LV fibrosis in the development of HFpEF which, appears accentuated in post-menopausal women. Thus, there is a need to identify, evaluate and develop novel treatments in pre- or later stage HFpEF female animal models targeting fibrosis leading to improved LV function. Cardiac fibrosis is preceded and orchestrated by dysregulated inflammation where macrophages are key. Systemic inflammation derived from the presence of kidney disease, obesity, type 2 diabetes and/or hypertension leading to the activation of pro-inflammatory cytokines was identified as a likely key contributor to HFpEF. Pharmacologic approaches that non-specifically inhibit inflammation so as to attenuate fibrosis, are poorly tolerated. However, selective and targeted modulation of inflammation has emerged as a concept whereby the dysregulated process may be physiologically controlled leading to reduced fibrosis. The discovery of pro-resolution mediators such as lipoxins and resolvins as well as the identification of their receptors such as the formyl peptide receptor (FPR), has led to new insights towards addressing unresolved inflammation. Macrophages express FPR that when stimulated, induce their M2 like polarization to a pro-resolution phenotype. We utilized FPR agonists in rodent models of myocardial infarction where treatment significantly improves LV function and reduces non-infarcted area fibrosis. However, no studies have assessed their potential use in pre- clinical female models of HFpEF. We propose that: “Treatment with FPR agonists polarizes macrophages to a pro-resolution phenotype limiting adverse left ventricular remodeling and fibrosis in animal models mimicking HFpEF in women, leading to improved chamber function”. Aim 1 will test if the oral administration of an FPR agonist (compound 43) to a female animal model of early stage HFpEF prevents the development of fibrosis leading to the preservation of optimal myocardial material properties and thus, improved left ventricular diastolic and systolic function. Aim 2 if the oral administration of an FPR agonist to a female animal model of HFpEF compounded by renal injury ameliorates tissue fibrosis leading to the preservation of optimal myocardial material properties and thus, improved left ventricular diastolic and systolic function. Aim 3 if the oral administration of an FPR agonist to female animal models of early stage or compounded HFpEF normalizes blood levels of pro- inflammatory cytokines and triggers the polarization of macrophages to a pro-resolution phenotype. We will also perform a broader characterization of the infiltrating leucocyte population as well as macrophage derived conditioned media treatment of culture cardiac fibroblasts to assess its effects on cell phenotype.