Abstract Body: Background: Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are the two major forms of heart failure and remain the leading causes of morbidity and mortality. While therapeutic advances have improved outcomes in HFrEF, effective treatments for HFpEF remain limited. Emerging evidence suggests that non-cardiomyocytes (NCMs) contribute critically to HF initiation and progression.
Hypothesis: Distinct NCM populations drive phenotype-specific pathogenic processes in HFpEF and HFrEF.
Goals: To define early cell-type-specific alterations and intercellular signaling networks in NCMs to better distinguish the mechanisms underlying HFpEF and HFrEF.
Methods: Single-cell RNA sequencing (scRNA-seq) was performed to generate transcriptomic profiles of NCMs in mouse HFpEF and HFrEF models. HFpEF data were developed by our laboratory using a ‘two-hit’ model (high-fat diet (HFD) plus N(gamma)-nitro-L-arginine methyl ester (L-NAME)), while HFrEF data were obtained from a publicly available dataset. Integrated analyses enabled cross-model comparisons of cellular composition, functional programs, and intercellular communication.
Results: Comparative single-cell analyses revealed distinct pathogenic programs between HFpEF and HFrEF. HFpEF was characterized by prominent inflammatory activation, particularly within endothelial cells, accompanied by endothelial activation signatures. Intercellular communication analysis revealed predominant endothelial-macrophage inflammatory signaling. In contrast, HFrEF demonstrated enhanced fibrotic remodeling and extracellular matrix programs, with fibroblasts serving as key effector cells in fibroblast-macrophage crosstalk.
Conclusion: Our study reveals divergent NCM pathogenic hubs in HF. HFpEF is characterized by inflammation-driven endothelial dysfunction, whereas HFrEF is dominated by fibrosis-associated fibroblast remodeling. These findings provide a cellular framework for HF heterogeneity.