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

Abstract

Diastolic dysfunction (DD) is a hallmark of heart failure with preserved ejection fraction (HFpEF), a huge burden on healthcare systems worldwide. Using heart-on-a-chip (HOC) Biowire technology, we have generated a human-relevant model of DD. DD was induced by treatment of cardiac microtissues generated from human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and cardiac fibroblasts with endothelin-1 (ET-1) and transforming growth factor beta-1 (TGF-β). This resulted in increased passive tension, cardiomyocyte hypertrophy, diffuse fibrosis, impaired calcium handling, and slowed relaxation, without changes in active force of contraction. While empagliflozin treatment had no effect on DD HOCs, treatment with dasatinib and quercetin (D+Q) or with ranolazine (RAN) partially reversed the disease phenotype. This human HOC model of DD recapitulates several key hallmarks of the disease and may improve our understanding of the pathways that contribute to DD while serving as a drug discovery platform. Statement of significance: This work describes the generation of a 3D in vitro model of diastolic dysfunction (DD). Tissue-engineered DD models are lacking, despite the fact that DD is a universal feature of heart failure with preserved ejection fraction (HFpEF). Human stem cell derived cardiomyocytes (hPSC-CMs) and cardiac fibroblasts were seeded in a heart-on-a-chip (HOC) device, which enables the live readout of contractile function. We leveraged this platform to induce DD in HOCs, shown by impaired diastole with preserved force of contraction. Additionally, we demonstrated that the senolytic drug combination dasatinib + quercetin was able to improve function in DD HOCs. Overall, this shows the potential for this disease model to be useful both in mechanistic and drug-screening studies of DD.