Abstract Body: Heart failure with preserved ejection fraction (HFpEF) represents a significant and growing clinical challenge, particularly in patients with Type 1 diabetes (T1D), who exhibit a higher prevalence and mortality rate. This study investigates the mechanistic difference in murine diabetic-HFpEF by comparing it to obesity-related HFpEF (Two-hit model) using multi-omics approaches, including metabolomics, gut microbiome profiling, and single-cell multiome analysis.

A T1D-like HFpEF mouse model was established using a high-fat, high-sucrose diet (HFHSD) combined with L-NAME (a nitric oxide synthase inhibitor) in drinking water and streptozotocin (STZ) via intraperitoneal injection. Both diabetic- and obesity-related HFpEF models exhibited elevated left ventricular (LV) filling pressure and cardiac hypertrophy, possibly through differing pathophysiological pathways. Diabetic-HFpEF mice demonstrated severe metabolic disorders, exacerbated dysbiosis, renal dysfunction, and immune dysregulation, whereas obesity-related HFpEF was characterized by pronounced cardiomyocyte remodeling and fibroblast activation.

Notably, diabetic HFpEF was associated with greater endothelial dysfunction and systemic inflammation, whereas obesity-related HFpEF exhibited more extensive alterations in cardiomyocyte homeostasis and fibroblast-driven fibrosis. Epigenomic and transcriptomic profiling at the single-cell level revealed distinct chromatin accessibility changes, differentially expressed genes, and transcriptional regulatory networks in cardiomyocytes, endothelial cells, and immune cells. Metabolomic and microbiome analyses further demonstrated unique metabolic disturbances and gut microbial deficiencies in each model.

Overall, these findings highlight the distinct molecular and physiological mechanisms driving HFpEF progression between T1D and obese-related metabolic syndromes, emphasizing their differential impacts on cardiac remodeling, inflammation, and systemic metabolism and providing novel insights into potential therapeutic targets.