Human iPSC-Derived 3D Cardiac Models for Cardiomyopathies: Organoids, Spheroids, and Engineered Heart Tissues as Translational Platforms

Cardiomyopathies represent a substantial global health burden, yet progress in developing effective therapies was long constrained by the absence of physiologically relevant human models to understand molecular mechanisms and evaluating interventions. The advent of induced pluripotent stem cell (iPSC) technology has driven major advances in cardiomyopathy research, although important limitations persist. Current iPSC based systems exhibit incomplete cellular maturation, lack functional vasculature and chamber level architecture, and possess an immature extracellular matrix. These factors must be carefully weighed when interpreting disease phenotypes and drug response data. iPSC derived in vitro 3D cardiac tissues have significantly addressed these issues, thereby expanding our ability to model human cardiac disease, offering more physiologically relevant platforms for mechanistic studies, drug screening, and translational research. This concise review synthesizes recent advances in the development of iPSC-derived 3D cardiac systems, such as 3D spheroids, engineered heart tissues (EHTs) and cardiac organoids, their application to modeling various cardiomyopathies including hypertrophic cardiomyopathy, dilated cardiomyopathy, and amyloid-related cardiomyopathies, while discussing critical challenges including cellular maturation, vascularization, and standardization. In this review, emerging technologies and therapeutic strategies have been highlighted that bridge the gap between bench and bedside, demonstrating the translational potential of these models for precision medicine in cardiovascular disease.