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Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Fuel Heart Failure with Preserved Ejection Fraction

ABSTRACT: Background: Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. While inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear. Methods: Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry, and single cell RNA sequencing. After identification of transcriptional and cell signatures, we implemented a high fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells (HSCs) during HFpEF. Contributions of macrophage metabolism were also evaluated, including via mass spectrometry and carbon labelling. Primary macrophages were studied ex vivo to gain insight into complementary cell- intrinsic mechanisms. Results: Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells (HSCs). This phenotype was conserved across species in a murine mode of high fat diet and hypertension. HSC proliferation was coupled to striking remodeling of the peripheral HSC niche, and expression of the macrophage adhesion molecule Vcam1. This could be partially inhibited by SGLT2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the Vcam1 promoter to enhance its expression. Conclusion: These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE288048 | GEO | 2025/03/20

REPOSITORIES: GEO

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Project description:Aims: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods&Results: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF.

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Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Fuel Heart Failure with Preserved Ejection Fraction

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