Abstract: Human iPSC-derived cardiomyocytes are increasingly used to assess drug toxicity through effects on ion channels and electrophysiology, yet contractility is not always evaluated. There is growing interest in including both electrophysiology and contractility data from engineered heart tissue to more comprehensively assess human cardiac responses. In this study, we developed a scalable platform for generating engineered heart tissue without the use of collagen or fibrin gels. The iPSC-CMs self-organized into 3D heart tissue with a thickness of over 100 µm within 10 days. This device is compatible with commercial multi-electrode array systems, enabling the simultaneous recording of electrophysiology and contractility data. A range of drugs with varying torsade de pointes risks were used to validate the system, underscoring the advantage of comprehensive, multi-parameter readouts over single-parameter analyses. We found that drug-induced arrhythmias not only affect heart rhythm but also significantly reduce force output. Additionally, we used this device to model myosin-binding protein C deficiency, successfully replicating contractile deficits in engineered heart tissues. Collectively, this platform demonstrates that simultaneously measuring electrophysiological and mechanical properties is crucial for evaluating drug-induced cardiotoxicity, holding promise for regulatory authorities, pharmaceutical companies, and research institutions in the comprehensive assessment of drug efficacy and toxicity in humans.
