Cardiac Organoids for Modeling Inherited Cardiomyopathies

Background: Inherited cardiomyopathies, including hypertrophic, dilated, and arrhythmogenic subtypes, are leading causes of heart failure and sudden cardiac death in young individuals. Understanding their pathogenesis and testing precision therapies have been limited by the lack of human-relevant models that recapitulate the structural, electrophysiological, and genetic complexity of diseased myocardium. Cardiac organoids—three-dimensional, multicellular constructs derived from human pluripotent stem cells—have emerged as powerful platforms for disease modeling, drug screening, and mechanistic discovery. These miniaturized tissue models reproduce key aspects of cardiac development, tissue architecture, and patient-specific genetic backgrounds. Methods and Results: This review summarizes recent advances in the generation and application of cardiac organoids for modeling inherited cardiomyopathies. Protocols integrating cardiomyocytes, fibroblasts, endothelial cells, and extracellular matrix components allow formation of contractile, vascularized organoids with electrophysiological and metabolic maturity. Genome editing tools such as CRISPR/Cas9 are used to introduce or correct disease-causing mutations in sarcomeric and desmosomal genes including MYH7, TNNT2, LMNA, and PKP2. Functional readouts—such as contractility, calcium flux, arrhythmic behavior, and response to stress—enable characterization of disease phenotypes and identification of genotype-phenotype correlations. Organoids also serve as testbeds for evaluating gene therapies, small-molecule drugs, and antisense oligonucleotides targeting pathogenic pathways. Integration with single-cell transcriptomics and imaging enhances resolution and mechanistic insights. Conclusion: Cardiac organoids provide a physiologically relevant and genetically tractable model system for studying inherited cardiomyopathies. Their ability to recapitulate patient-specific disease features and enable high-content screening makes them invaluable for translational research and precision therapy development. Continued refinement in organoid complexity, scalability, and functional integration will accelerate their clinical impact in inherited cardiac disease.