Abstract Body: Background: Heart failure with preserved ejection fraction (HFpEF) exhibits important sex differences in clinical presentation and outcomes, yet the cellular mechanisms underlying these differences remain poorly understood. Experimental models that capture clinically observed sex differences in disease severity and reversibility are limited.
Hypothesis: We hypothesized that biological sex shapes cell-type-specific transcriptional remodeling and recovery in HFpEF.
Aims: To define the cellular basis of sex-specific remodeling and recovery in HFpEF and to develop a framework to quantitatively assess recovery across cell types.
Methods: We generated a comprehensive single-nucleus transcriptomic atlas of 29,282 nuclei from mouse left ventricles using a long-term dietary HFpEF model incorporating male, female, and ovariectomized C57BL/6 mice under chow, high-fat sucrose-containing diet, and dietary regression conditions.
Results: We found that biological sex influences cell-type-specific transcriptional remodeling and recovery in HFpEF. Sex- and diet-dependent shifts in cellular composition, including higher percentages of fibroblast and myeloid populations and lower percentages of endothelial cells in males and ovariectomized females compared with females, were accompanied by pronounced transcriptional differences in these populations. Male hearts exhibited exaggerated inflammatory and fibrotic programs with altered vascular permeability, whereas female hearts displayed recovery-associated transcriptional features, including endothelial transcripts such as Esrrg and Park2 and enrichment of PPAR and FOXO signaling pathways. Ovariectomized females recapitulated male-like transcriptional responses, highlighting the impact of ovarian hormone loss. To assess recovery, we developed a recovery score framework integrating directional transcriptional changes across disease and regression states, revealing sex-specific reversal patterns and cell-type-dependent recovery.
Conclusion: These findings establish a clinically relevant experimental framework for metabolic HFpEF and suggest that sex-specific remodeling and recovery trajectories should be considered in precision therapeutic strategies.