Human iPSC-derived engineered heart tissue model of diastolic dysfunction in heart failure with preserved ejection fraction.

The prognosis for heart failure (HF) with preserved ejection fraction (HFpEF) remains poor, with treatment evidence and studies at the human cellular level limited. Here, we aimed to model HFpEF-associated diastolic dysfunction in vitro by generating human engineered heart tissues (hEHTs) using human induced pluripotent stem cells and culturing the tissues under high fatty acid and L-NG-nitroarginine methyl ester supplementation. Medium-loaded hEHTs showed a marked reduction in relaxation function while preserving contraction function; secreted high levels of the HF marker, BNP; exhibited abnormal calcium transients; and showed structural and functional features of HF. After treatment with several existing HF drugs, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) improved the decline in relaxation function and contributed to an improvement in the diastolic dysfunction phenotype. This mechanism exhibited an anti-inflammatory effect mediated by the recovery of the eNOS-NO-cGMP-PKG signaling pathway. These findings serve as a basis for elucidating the pathogenesis and mechanisms of improvement in HFpEF.