Abstract Wed089: Deciphering transcriptome and cell-cell communication signature in heart failure with preserved ejection fraction at single cell resolution

Heart failure with preserved ejection fraction (HFpEF) has limited effective therapies so far. Diabetes and insulin resistance increases the risk of HFpEF. We hypothesized that changes in myocardial insulin signaling could contribute to HFpEF development. We generated insulin receptor loxp inserted ( Insr f/f , IR_Flox) or myofibroblast specific knockout mice ( Insr f/f , Postn :Cre +/- , IR_mfKO). 15 weeks of high fat diet with L-NAME (HFDL) induced obesity, hyperglycemia and cardiac hypertrophy in IR_Flox and IR_mfKO mice relative to mice fed normal chow (NC). While ejection fraction was preserved, diastolic dysfunction exemplified in HFDL_IR_Flox relative to NC_IR_Flox. HFDL_IR_mfKO mice shown improved diastolic function relative to HFDL_IR_Flox mice. We assessed transcriptional profiles using single nuclei RNA sequencing. While HFDL altered the transcriptome in multiple cell types, in HFDL_IR_mfKO, transcriptional changes were rescued indicating intercellular compartment communication mechanisms. We inferred top changed pathways in NC_Flox and HFDL_Flox hearts by CellChat , included Neurexin, Vitronectin, Fibronectin and Semaphorin. We observed recovered patterns of these pathways in HFDL_IR_mfKO vs HFDL_IR_Flox. These results indicate the contribution of insulin signaling in HFpEF development via organ-wide cell-cell communication.