Myeloid cell expansion propels right ventricular dysfunction in HFpEF via sterile inflammation

Abstract

Background Leukocyte’s role in frequently occurring right ventricular dysfunction (RVD) secondary to HFpEF remains poorly defined, partially due to the lack of suitable small animal models. Here, we followed a translational research approach by establishing a murine HFpEF model developing manifest RVD and analyzed human HFpEF cohorts to study the mechanistic link between leukocytes and RVD in HFpEF. Methods <20-week-old (young) and >80-week-old (aged) male and female C57BL/6J mice were divided into four experimental groups: i) chow, ii) HFpEF (N[ω]-nitro-l-arginine methyl ester (L-NAME), high-fat diet), iii) chronic hypoxia (10% O2) and iv) HFpEF and hypoxia (RV-HFpEF) to assess bi-ventricular function and myeloid cell dynamics. To test whether myeloid cells are causally involved in the development of RV remodeling in HFpEF, we treated RV-HFpEF mice with a colony stimulating factor 1 receptor inhibitor to deplete myeloid cells. Results RV-HFpEF resulted in LV diastolic dysfunction indicated by increased E/E’ ratio, reduced global longitudinal peak strain, smaller end-diastolic diameters and increased isovolumetric relaxation time compared to chow. RV-HFpEF animals developed RV hypertrophy and RVD evident as increased Fulton’s index as well as elevated RV systolic pressures and reduced tricuspid annular plane systolic excursion, respectively. Total leukocyte, monocyte, and macrophage counts were elevated in RV tissue of RV-HFpEF compared to chow or LV tissue from young and aged RV-HFpEF animals. These data were confirmed by unbiased proteomic analyses of RV tissue from RV-HFpEF mice, demonstrating increased abundance of proteins involved in activation of the innate immune system, macrophage chemotaxis and leukocyte migration when compared to LV tissue or other experimental groups. Fate mapping experiments revealed that recruited monocyte-derived macrophages became the main source of total cardiac macrophages in RV tissue from RV-HFpEF mice. Depletion of myeloid cells was associated with lower RVSP profiles in RV-HFpEF mice compared to controls. In RV biopsies from HFpEF patients, we found increased expression of adhesion molecules, fibrotic markers, inflammatory transcripts and an association between RVD and CD68+ cells. Conclusion We demonstrate that dysregulated myeloid cell dynamics are associated with, and directly contribute to, the pathogenesis of RVD-HFpEF in humans and mice.