Human heart-on-a-chip model emulates structural and functional characteristics of diastolic dysfunction and reveals a beneficial role for senolytics

This study developed a human heart-on-a-chip (HOC) model of diastolic dysfunction (DD), a core feature of HFpEF, using Biowire-style engineered cardiac microtissues formed from human pluripotent stem cell-derived cardiomyocytes and cardiac fibroblasts. DD was induced by treating HOCs with endothelin-1 and TGF-β, which increased passive tension ~3-fold while preserving active contractile force. Disease tissues displayed cardiomyocyte hypertrophy, diffuse interstitial fibrosis (increased collagen deposition and lysyl oxidase expression), impaired calcium handling, and slowed relaxation. Drug testing demonstrated that empagliflozin did not improve the DD phenotype, whereas the senolytic combination dasatinib + quercetin and ranolazine partially reversed or prevented passive-tension abnormalities (with timing-dependent efficacy), supporting this platform for mechanistic studies and therapeutic screening in DD/HFpEF.