Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction.

Summary

Using human samples and complementary mouse models, the authors show that cardiometabolic HFpEF is characterized by elevated circulating hematopoietic stem cells, niche remodeling, and maladaptive myeloid fatty acid metabolism that fuels systemic inflammation and diastolic dysfunction. Multi-omics and isotope tracing support a cell-intrinsic macrophage metabolic program as a causal driver.

Key Findings

• Patients with cardiometabolic HFpEF exhibited elevated peripheral blood hematopoietic stem cells; this phenotype was conserved in a high-fat diet plus hypertension mouse model.
• Hematopoietic stem cell proliferation was coupled with remodeling of the peripheral stem cell niche and increased expression of a macrophage adhesion molecule.
• Macrophage fatty acid metabolism was implicated as a causal driver of systemic inflammation and diastolic dysfunction, supported by isotope tracing and ex vivo assays.

Clinical Implications

While not immediately practice-changing, the work suggests potential biomarkers (circulating hematopoietic stem cells) and therapeutic targets (myeloid fatty acid metabolic pathways) for HFpEF, a condition with limited options.

Limitations

• Some mechanistic links remain inferential in humans and require interventional validation
• Assay-specific sample sizes and details are not provided in the abstract, limiting appraisal of power

Future Directions

Test pharmacologic or genetic modulation of myeloid fatty acid metabolism in HFpEF models and evaluate circulating hematopoietic stem cells as biomarkers in longitudinal human cohorts.