Fig. 2: Enhancing cardiac drug discovery in hPSC-CMs.

Diverse cardiac disorders have been successfully modeled in hPSC-CMs, beyond merely the patient-specific mutations for which this technology was first used, with broad applicability now demonstrated for the widespread, acquired forms of human heart disease. Concurrently, the readouts relevant to cardiac drug development have expanded beyond the arrhythmias first studied, to encompass the full spectrum of molecular and functional cardiomyocyte phenotypes including mechanical performance, energetics, myocyte formation, and myocyte loss. The impact on drug development has been manifested initially through more predictive safety pharmacology (including the improved profiling of non-cardiac drugs) and through human preclinical studies of approved agents, toward novel applications. In the development of novel agents, hPSC-CMs can augment not only target-based approaches, as platforms for validation by gene silencing and the investigation of new chemical series, but also as a human substrate for mechanistically agnostic, phenotype-driven screens. Diverse approaches promote cardiomyocyte maturation and fidelity to the adult human heart itself, which remains an acknowledged limitation of these models.