Engineered Heart Tissues in Preclinical Drug Testing: Toward Humanized Cardiac Models

Background: Preclinical cardiotoxicity screening remains a critical bottleneck in drug development, with conventional models often failing to predict human-specific cardiac responses. Engineered heart tissues (EHTs), composed of human pluripotent stem cell–derived cardiomyocytes embedded in biomimetic scaffolds, have emerged as a next-generation platform that recapitulates key structural, electrophysiological, and contractile features of native myocardium. These 3D constructs enable dynamic assessment of cardiac function in response to pharmacologic agents, offering a scalable and ethically sustainable alternative to animal models. Methods and Results: This review outlines the current landscape of EHT technologies in preclinical drug testing, with emphasis on tissue fabrication methods, cellular composition, biomechanical conditioning, and integration of biosensing platforms. Recent studies demonstrate that EHTs respond to β-adrenergic agonists, ion channel blockers, and pro-arrhythmic compounds with human-like fidelity, surpassing the predictive capacity of traditional monolayer assays. High-throughput EHT arrays coupled with optical mapping and force transduction systems allow multiplexed analysis of drug-induced changes in conduction velocity, calcium handling, and contractility. Integration of fibroblasts, endothelial cells, and immune components enhances physiological relevance and permits evaluation of inflammation-mediated cardiotoxicity. Case studies involving doxorubicin, sunitinib, and hERG-channel blockers validate EHTs as sensitive platforms for early cardiotoxicity screening. Conclusion: Engineered heart tissues represent a transformative advance in preclinical drug evaluation, bridging the translational gap between in vitro assays and human cardiac physiology. Their ability to model complex drug responses in a human-relevant system positions EHTs as essential tools in precision pharmacology, toxicology, and personalized medicine. Continued innovation in biofabrication and functional integration will drive the adoption of EHTs as standard components of cardiac safety assessment pipelines.