Impact of Voluntary Exercise on Systemic Inflammation in a 2? Hit Model of Heart Failure With Preserved Ejection Fraction

hronic systemic inflammation is implicated in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). 1 Contrary to other forms of heart failure (ie, with reduced ejection fraction), HFpEF represents an outside-in mechanism of inflammation whereby systemic factors drive diastolic heart failure.Exercise training improves cardiorespiratory fitness, muscle function, and quality-of-life markers in patients with HFpEF. 2 Despite the agreement that chronic systemic inflammation is a driving factor for the development of cardiometabolic HFpEF and the emphasis on exercise therapy at the clinical level, studies are scarce on the impact of exercise on systemic inflammation.The data that support the findings of this study are available from the corresponding author (Dr Allerton) upon reasonable request.C57BL/6N male mice (9 weeks old) were randomly assigned to a control group where they were maintained on a chow diet (5001; Purina) with regular drinking water or a 60% high-fat diet (D12492; Research Diet, New Brunswick, NJ) and N()-nitro-Larginine methyl ester (Enzo Life Sciences) (0.5 g/L, pH to 7.4) in supplemented drinking water to induce HFpEF, as we have previously demonstrated. 3HFpEF mice were provided a standard cage with access to a running wheel after 5 weeks (Figure [A]).The Pennington Biomedical Research Center Institutional Animal Care and Use Committee approved all experiments, which were conducted according to ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines.After 10 weeks, the mice were euthanized, and whole blood was collected via cardiac puncture into EDTA microtainers.The red blood cells were lysed, and T cells were stained for PD-1-fluroescein isothiocyanate (FITC), cluster of differentiation (CD)4 or CD8-PE, CD62L-PerCP-Cy5.5, and CD3-APC.The monocytes were stained for (C-C motif chemokine receptor) CCR2-PE, CD43-PerCP-Cy5.5, and Ly6C-APC.Monocytes were identified as classical (CD43 Low /Ly6C High /CCR2+), intermediate (CD43+/Ly6C+/ CCR2+), or nonclassical (CD43 High /Ly6C Low /CCR2-).T-cell subsets were identified as CD3+/CD4+ or CD8+/ CD62L+/PD-1+.All samples were analyzed using a BD Accuri C6 flow cytometer.All data were analyzed using FCS Express Flow Research software.Cytokine concentrations of interferon (IFN), interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, keratinocyte chemoattractant and human growth-related oncogene (KC/GRO), IL-10, IL_12p70, and tumor necrosis factor (TNF) using the Meso Scale Discovery V-Plex Proinflammatory Panel 1 mouse kit according to the manufacturer's protocol.Classical (CD43 Low /Ly6c High ), intermediate (CD43 + / Ly6c + ), and nonclassical (CD43 High /Ly6c Low ) monocytes were not significantly altered by HFpEF (Figure [B]).The percentage of low differentiated (ie, nave) CD4+ cells (CD62L+/PD-1-) was reduced, whereas the proportion