Advances in arrhythmogenic cardiomyopathy modeling using human-induced pluripotent stem cell-based models.

Arrhythmogenic cardiomyopathy (ACM) is a hereditary and life-threatening cardiac disease that primarily affects young individuals and athletes. Given that ACM is difficult to distinguish from other cardiac disorders, it is challenging to diagnose, and the first clinical manifestation is often sudden cardiac death. Pathophysiologically, ACM is characterized by cardiomyocyte loss, fibrofatty replacement, contractile and electrical dysfunction, and inflammation. Although significant progress has been made in identifying the genetic underpinnings of ACM, the molecular mechanisms driving ACM development and progression remain poorly understood, limiting therapeutic strategies to symptom management and arrhythmia prevention rather than disease modification. To address this gap, advanced ACM models that accurately recapitulate human (patho)physiology are urgently needed. In this review, we examine the current landscape of 2-dimensional and 3-dimensional human-induced pluripotent stem cell (hiPSC)-derived ACM models, highlighting their ability to replicate key pathologic features and uncover disease mechanisms. We discuss emerging insights from hiPSC-based platforms, their contributions to understanding ACM pathophysiology, and the challenges that remain in modeling this complex disease. Finally, we outline future directions for advancing hiPSC-based ACM research, emphasizing the need for more physiologically relevant models to facilitate mechanistic discoveries and therapeutic development.