Abstract 13767: Cardiac Reprogramming Reduces Fibrosis and Improves Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a disease associated with high morbidity and mortality. Cardiac fibroblasts (CFs) contribute to HFpEF pathogenesis through interstitial/perivascular fibrosis and diastolic dysfunction; however, little is known regarding the mechanisms of the fibrosis, and therapies targeting it are lacking. Cardiac reprogramming is a promising approach for myocardial infarction by overexpressing Mef2c/Gata4/Tbx5/Hand2 (MGTH) in CFs, however, it remains undetermined whether cardiac reprogramming is effective in HFpEF. Aims: This study aims to determine the effectiveness of cardiac reprogramming in HFpEF. Methods: We generated a novel Tcf21iCre/Tomato/MGTH2A transgenic mouse system, where cardiac reprogramming can be induced in a druggable manner with lineage tracing. We first tested whether this system could improve the HFpEF mouse model. To determine the efficacy of cardiac reprogramming and the mechanisms of cardiac fibrosis in HFpEF, we performed multi-omics, including single cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and epigenome analysis. Finally, we generated mouse lines that induce each of the reprogramming factors and investigated whether overexpression of a single factor alone could improve HFpEF, which we also examined in human CF. Results: We found that cardiac reprogramming reduced fibrosis and improved diastolic dysfunction in HFpEF. scRNA-seq and spatial transcriptomics revealed that multiple CF clusters upregulated fibrotic profiles to induce diffuse interstitial fibrosis, whereas the distinct profibrotic CF cluster contributed to perivascular fibrosis, which were reversed with cardiac reprogramming. Mechanistically, cardiac reprogramming changed the epigenetic landscape by recruiting Gata4 to loci. Notably, overexpression of only Gata4 improved HFpEF by reducing fibrosis and suppressed profibrotic signatures in human CFs without generating cardiomyocytes. Conclusions: Cardiac reprogramming may be a promising approach for HFpEF via anti-fibrosis.