Molecular to Clinical Perspectives in Arrhythmogenic Cardiomyopathy: Current Understanding and Future Therapeutic Directions

Arrhythmogenic cardiomyopathy (ACM), a genetic heart muscle disease that affects primarily the right ventricle, can lead to sudden cardiac death. Although ACM was initially classified as a dysplasia due to a congenital abnormality in the growth of the right ventricle, it was later demonstrated to be caused by a genetic defect in the cardiac desmosomes. Mutations in genes that encode components of the desmosomes, that is, the adhesive junctions that connect cardiomyocytes, are the most common cause of ACMs. However, the specific molecular mechanisms that lead to myocardial destruction, remodeling, and arrhythmogenic predisposition are unclear. Recent advances in the understanding of the pathogenic mechanisms of ACM have focused on mechanisms including cardiomyocyte loss, fibrosis, and adipogenesis, which occur through different signaling pathways such as Wnt signaling, PPARγ signaling, and the Hippo-Yes-associated protein pathway. Inflammation also plays a role in the development of ACM. Regarding the diagnosis of ACM, the International Task Force Criteria distinguish between minor and major ACM criteria, with an emphasis on family history, conduction defects, morphological and microstructural changes, repolarization defects, and arrhythmias. In the management and prevention of sudden cardiac death and ventricular tachyarrhythmias, epicardial and endocardial ablation with electromagnetic mapping and the use of an implantable cardiac defibrillator have emerged as useful approaches. We provide an overview of the genetics, histological features, molecular mechanisms, clinical presentation, diagnosis, biomarkers and treatment advances of ACM, including gene therapy, small-molecule and drug-based therapies, implantable cardioverter defibrillators, radiofrequency ablation, lifestyle interventions, heart transplantation and prognosis.