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| Item Type: | Article |
|---|---|
| Title: | Myeloid cell expansion propels right ventricular dysfunction in HFpEF through sterile inflammation |
| Creators: |
Jaeschke, Lara  ORCID: https://orcid.org/0009-0004-1847-5378, Koçana, Ceren ORCID: https://orcid.org/0000-0001-5863-2447, Chitroceanu, Alexandra Maria, Winkler, Annika ORCID: https://orcid.org/0009-0007-9434-3862, Kleitke, Hannah ORCID: https://orcid.org/0009-0006-9991-6044, Fahjen, Pauline ORCID: https://orcid.org/0000-0002-5015-0643, Kamp, Justus ORCID: https://orcid.org/0009-0009-4088-3796, Faidel, David ORCID: https://orcid.org/0000-0001-9606-9595, Asmus, Erik ORCID: https://orcid.org/0000-0003-4740-7724, Meiser, Martin, Stamatiades, Efstathios G. ORCID: https://orcid.org/0000-0002-2785-9005, Hublitz, Karolin W. ORCID: https://orcid.org/0000-0003-4840-4496, Zach, Veronika, Kretzler, Lucie, Zurkan, Daniela ORCID: https://orcid.org/0009-0000-1016-439X, Perret, Paul-Lennard, von der Ohe, Leonardo A. ORCID: https://orcid.org/0009-0004-7626-3146, Beckschulte, Kai, Simmons, Szandor ORCID: https://orcid.org/0000-0002-5309-9863, Gillan, Jonathan L. ORCID: https://orcid.org/0000-0002-9017-253X, Franz, Kristina ORCID: https://orcid.org/0000-0002-3819-9671, Alasfar, Lina, Hahn, Virginia S. ORCID: https://orcid.org/0000-0002-0578-2668, Sharma, Kavita ORCID: https://orcid.org/0000-0002-3012-1765, Reynolds, Edwardo ORCID: https://orcid.org/0000-0002-5148-1479, Schiattarella, Gabriele G. ORCID: https://orcid.org/0000-0002-7582-7171, van Linthout, Sophie ORCID: https://orcid.org/0000-0002-7581-7870, Pieske, Burkert ORCID: https://orcid.org/0000-0002-6466-5306, Beyhoff, Niklas ORCID: https://orcid.org/0000-0001-9140-2336, Ott, Christiane ORCID: https://orcid.org/0000-0002-3199-0655, Hegemann, Niklas ORCID: https://orcid.org/0000-0002-2898-0798, Mertins, Philipp ORCID: https://orcid.org/0000-0002-2245-528X, Edelmann, Frank ORCID: https://orcid.org/0000-0003-4401-5936, Kuebler, Wolfgang M. ORCID: https://orcid.org/0000-0003-4100-2961 and Grune, Jana ORCID: https://orcid.org/0000-0001-6209-7416
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| Abstract: | BACKGROUND: The role of leukocytes in the pathogenesis of right ventricular (RV) dysfunction (RVD) associated with heart failure with preserved ejection fraction (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: Young (<20-week-old) and aged (>80-week-old) male and female C57BL/6J mice were divided into 4 experimental groups: chow, HFpEF (L-NAME [Nω-nitro-L-arginine methyl ester] plus a high-fat diet), chronic hypoxia (10% O(2)), and HFpEF plus hypoxia (RV-HFpEF). Biventricular function and myeloid cell dynamics were assessed across groups. 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 left ventricular diastolic dysfunction, indicated by increased E/E' ratio, reduced global longitudinal peak strain, smaller end-diastolic diameters, and increased isovolumetric relaxation time compared with chow. RV-HFpEF animals developed RV hypertrophy and RVD, evident as increased Fulton index as well as elevated RV systolic pressure and reduced tricuspid annular plane systolic excursion, respectively. Total leukocyte, monocyte, and macrophage counts were elevated in RV tissue from RV-HFpEF mice compared with RV tissue from chow mice and left ventricular tissue from young and aged RV-HFpEF animals. These findings were confirmed by unbiased proteomic analyses of RV tissue from RV-HFpEF mice, demonstrating an increased abundance of proteins involved in activation of the innate immune system, macrophage chemotaxis, and leukocyte migration when compared with left ventricular tissue and the 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 with controls. In RV biopsies from patients with HFpEF, we found increased expression of adhesion molecules, fibrotic markers, and inflammatory transcripts, as well as an association between RVD and CD68(+) cells. CONCLUSIONS: We demonstrate that dysregulated myeloid cell dynamics are associated with, and directly contribute to, the pathogenesis of RVD associated with HFpEF in humans and mice. |
| Keywords: | Heart Failure, Heart Ventricles, Inflammation, Macrophages, Myeloid Cells, Animals, Mice |
| Source: | Circulation |
| ISSN: | 0009-7322 |
| Publisher: | American Heart Association |
| Date: | 18 August 2026 |
| Official Publication: | https://doi.org/10.1161/circulationaha.125.078476 |
| PubMed: | View item in PubMed |
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