Abstract Body: Background: Heart failure with preserved ejection fraction (HFpEF) remains a major unmet clinical challenge and accounts for approximately half of HF cases. However, effective therapies are limited due to incomplete understanding of its pathogenesis. Increasing evidence suggests that inflammation and vascular dysfunction are not only late features of HFpEF, but early mediators of disease pathogenesis.
Hypothesis: Endothelial cells (ECs) play a central role in initiating and sustaining inflammatory signaling during HFpEF development.
Goals: To investigate the EC transcriptional dynamics and intracellular signaling networks across HFpEF progression.
Methods: A temporal study was performed to characterize HFpEF development at 0, 1, 4, and 8 weeks using a ‘two-hit’ mouse model (high-fat diet (HFD) plus N(gamma)-nitro-L-arginine methyl ester (L-NAME)). Cardiac function and systemic metabolic phenotypes were assessed at the designated timepoints. Cardiac non-cardiomyocytes were isolated and subjected to single cell RNA sequencing (ScRNA-seq) and bulk RNA-sequencing to delineate cellular heterogeneity and temporal interactions.
Results: Cardiac dysfunction at whole heart and single cardiomyocyte levels, as well as impaired metabolic manifestations, were observed as early as 1 week of HFD+L-NAME and persisted through 8 weeks. ScRNA-seq revealed substantial EC cellular heterogeneity, and ECs exhibited the highest transcriptional responsiveness during HFpEF development. Integrated ScRNA-seq and bulk RNA-seq demonstrated progressive inflammatory reprogramming of HFpEF ECs, determined by the upregulation of inflammatory mediators and adhesion molecules. Cell-to-cell communication analysis predicted strong EC-immune cell interactions as a dominant feature of HFpEF progression.
Conclusion: These findings suggest that EC dysfunction is not merely a consequence of HFpEF, but rather an upstream driver of disease progression. Targeting early EC activation and intercellular signaling may provide novel therapeutic opportunities.