Cardiomyocyte Metabolism and Maturation in In Vitro Models of Arrhythmogenic Cardiomyopathy: Current Progress and Challenges

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a disease that affects adult hearts and causes heart problems and heart muscle damage. Heart cells, cardiomyocytes, were made from stem cells to study ACM and test new medication. However, these lab-grown cardiomyocytes are immature cells and have a metabolism that resembles a foetal heart. To address this, researchers have explored various methods to promote these cells to mature metabolically and structurally. Treatments with small molecules such as thyroid hormone (T3), ZLN005, and retinoic acid (RA) have shown potential by improving mitochondrial function and shifting the cells’ metabolism toward fatty acid use, which is typical of adult cardiomyocytes. Inhibiting cathepsin K (CatK) also influences energy pathways and may protect the cells during disease progression. Moreover, optimizing the cell culture environment by using fatty acid-rich media, human plasma-like medium, and three-dimensional (3D) tissue cultures further supports the development of more adult-like features. Combining these approaches, including metabolic modulators and hormonal treatments, appears necessary to advance the maturation process. Despite promising results, no single strategy fully matures these stem cell-derived cardiomyocytes across all important features. Continued research is needed to develop integrated protocols that produce adult-like heart cells. Such advances are essential to improve the study of diseases like ACM and to develop effective therapies.