Effects Of Exercise On Immune Profiles In Mice With Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of all new cases of heart failure. The obesity-HFpEF phenotype is associated with dysregulated immunity, which contributes to the progression of HFpEF. Exercise attenuates inflammation associated with obesity, but it has not been evaluated in obesity-HFpEF. PURPOSE: Characterize the effects of voluntary wheel running (VWR) on immune profiles in a murine two-hit model of HFpEF. METHODS: C57BL/6 N male mice were placed on a chow diet and water (Control C) or a 60% high-fat diet and water supplemented with 0.5 g/L N(G)-Nitro-L-arginine methyl ester (L-NAME) (HFpEF) for 10 weeks. At the 5-week timepoint, the mice were randomized into sedentary (Sed) (C n = 3, HFpEF n = 6) or VWR (C n = 3, HFpEF n = 4) groups for the rest of the study. After 10 weeks, mice were sacrificed, and blood was collected. T-cells were stained for CD3/CD4 or CD8/CD62L/PD-1 and monocytes for LyC6/CD43/CCR2/CXCR3. All were analyzed by flow cytometry. A mixed-effects ANOVA was used to test the main effects of group (C vs HFpEF), exercise (Sed vs VWR), and their interaction. RESULTS: Sed Control mice had a greater body weight than VWR Control mice (Sed 31.2 ± 2.3 g, VWR 26.5 ± 1.2 g; p < 0.05). Sed and VWR HFpEF mice had similar body weights (Sed 39.7 ± 5.0 g and VWR 36.5 ± 7.2 g). VWR Control mice ran significantly more (11.3 ± 4.3 km/day) than VWR HFpEF mice (4.8 ± 1.7 km/day; p < 0.05). After 10 weeks, when Sed and VWR mice were grouped by Control or HFpEF, the percentage of CD4+ low differentiated T-cells was greater in the Control mice than in HFpEF mice (C 35.4% ± 11.9%, HFpEF 10.2% ±2.8%; p = 0.031). Furthermore, the HFpEF mice had a greater proportion of pro-inflammatory mid-differentiated T-cells than Control mice (CD4+/CD62L+/PD1+ HFpEF 49.5% ± 9.2%, C 18.1% ± 5.8 %; p = 0.027). Similarly, there was a trend for HFpEF mice having higher inflammatory monocytes than Control mice (HFpEF 15.5% ± 4.2%, C 5.2% ± 1.6%; p = 0.06). VWR did not impact the immune cell profiles in either Control or HFpEF groups. CONCLUSION: HFpEF mice exhibited increased mid-differentiated T-cells and inflammatory monocytes, suggesting a low-grade inflammatory state. However, VWR did not improve the profiles. The low sample size and reduced VWR in HFpEF mice may explain the lack of improvement in immune profiles. Supported by NIH 5P20GM135002-03