Patient-Derived hiPSC-Cardiomyocytes and Engineered Heart Tissues Reveal Distinct Functional Phenotypes in Inherited Cardiomyopathies

Hypertrophic and dilated cardiomyopathies (HCM and DCM) are the most prevalent inherited forms of this condition. However, the specific molecular and functional characteristics of cardiomyocytes, as well as their responses to certain stimulants, remain not fully understood. In this study, researchers used three human-induced pluripotent stem cell (hiPSC) lines: one normal, one derived from a patient with HCM carrying a MYBPC3 mutation, and one from a patient with DCM carrying an LMNA mutation.

These hiPSCs were transformed into cardiomyocytes, which were then subjected to two different treatments: one involving the hormone endothelin-1 and the compound 3i-1262, which targets the GATA4 gene; the other involved electrical stimulation with the drug isoprenaline. The researchers then examined the resulting transcriptional and protein levels, as well as the performance of engineered heart tissues (EHTs) generated from these cardiomyocytes. The EHTs were cultured for 40 days, with the second treatment applied during the final 20 days.

The results showed that the cardiomyocytes from patients with HCM or DCM responded differently to endothelin-1 at both the transcriptional and protein levels. Moreover, when analyzed in the context of engineered heart tissues, it was observed that DCM-derived EHTs eventually fractured due to loss of structural integrity, while those derived from HCM cells exhibited a gradual decline in force production.

These findings demonstrate the value of using hiPSC-based cardiac models to study the molecular and functional aspects of cardiomyopathies and their responses to specific treatments.