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

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.