Myeloid Cells in HFpEF Right Ventricles

This single-study briefing examines a translational investigation of whether myeloid-cell expansion and sterile inflammation are linked to right-ventricular remodeling and dysfunction in heart failure with preserved ejection fraction (HFpEF). The authors studied a murine model with manifest right-ventricular dysfunction alongside prospectively enrolled human HFpEF cohorts at a single center. pmid:42610249

Evidence

The reported design was translational. Young (<20-week-old) and aged (>80-week-old) male and female C57BL/6J mice were assigned to chow, HFpEF, chronic-hypoxia, and HFpEF-plus-hypoxia (RV-HFpEF) groups. HFpEF was modeled with L-NAME plus a high-fat diet, and the RV-HFpEF model additionally used chronic hypoxia at 10% O 2. The supplied packet did not locate a sample size. pmid:42610249

The investigators assessed biventricular function and myeloid-cell dynamics across the mouse groups. They also performed proteomic analysis of mouse right-ventricular tissue and fate-mapping experiments to assess the source of cardiac macrophages. To test myeloid cells in the model, RV-HFpEF mice received a colony-stimulating factor 1 receptor inhibitor intended to deplete myeloid cells. pmid:42610249

RV-HFpEF mice developed left-ventricular diastolic dysfunction, right-ventricular hypertrophy, and right-ventricular dysfunction. Compared with chow mice, the reported right-ventricular findings included increased Fulton index and elevated right-ventricular systolic pressure, with reduced tricuspid annular plane systolic excursion. The supplied findings do not provide an exact effect estimate, confidence interval, or p-value for these outcomes. pmid:42610249

Total leukocyte, monocyte, and macrophage counts were elevated in right-ventricular tissue from RV-HFpEF mice compared with right-ventricular tissue from chow mice and left-ventricular tissue from young and aged RV-HFpEF animals. Proteomic analysis identified increased abundance of proteins involved in innate-immune-system activation, macrophage chemotaxis, and leukocyte migration in RV-HFpEF right-ventricular tissue relative to left-ventricular tissue and the other experimental groups. pmid:42610249

Fate mapping found that recruited monocyte-derived macrophages became the main source of total cardiac macrophages in right-ventricular tissue from RV-HFpEF mice. In the depletion experiment, myeloid-cell depletion was associated with lower right-ventricular systolic-pressure profiles in RV-HFpEF mice compared with controls. pmid:42610249

For human validation, right-ventricular biopsies from patients with HFpEF showed increased expression of adhesion molecules, fibrotic markers, and inflammatory transcripts, along with an association between right-ventricular dysfunction and CD68 + cells. Participants in the described clinical cohort were over 18 years old, provided written informed consent, and were recruited at a single center. pmid:42610249

Analysis — Mechanistic interpretation

The study’s central interpretation is mechanistic but should be separated into its mouse-model and human-observation components. In RV-HFpEF mice, the convergence of right-ventricular dysfunction, increased right-ventricular leukocyte and macrophage counts, proteomic immune signals, fate-mapped monocyte-derived macrophages, and the depletion result supports the authors’ conclusion that dysregulated myeloid-cell dynamics directly contribute to right-ventricular dysfunction in that model. The human biopsy findings extend the association to HFpEF patients, but the supplied evidence describes an association between right-ventricular dysfunction and CD68 + cells rather than a human intervention result. pmid:42610249

The study is therefore most useful as evidence that immune-cell recruitment and sterile inflammation may be relevant to right-ventricular disease biology in HFpEF. It does not establish that a particular immune-targeting strategy improves clinical outcomes in people. Lower right-ventricular systolic-pressure profiles after myeloid-cell depletion are a model-specific experimental finding, and statistical significance, clinical significance, and patient benefit are distinct questions. pmid:42610249

Limitations

Human validation was limited by the availability of fresh human right-ventricular free-wall tissue for validating leukocyte accumulation in HFpEF patients. This constrains how broadly the biopsy observations can be assessed from the supplied study description. pmid:42610249

The investigators did not selectively block monocyte recruitment in RV-HFpEF mice because pharmacological CCR2 inhibition failed to reduce monocyte recruitment, with compensatory upregulation of other chemotactic pathways. They also found increased macrophage accumulation in aged animals independent of HFpEF. These limitations underscore the complexity of immune-cell recruitment in this model and limit conclusions about a single recruitment pathway. pmid:42610249