Key result
This comprehensive review summarizes the molecular and cellular mechanisms of arrhythmogenic cardiomyopathy pathogenesis, including abnormal calcium homeostasis and inflammatory/autoimmune responses.
Why the study?
Understanding of the molecular mechanisms in ACM and the cell source of fibroadiposis remains incomplete, and no effective targeted therapy currently exists.
This review summarizes the molecular and cellular mechanisms underlying arrhythmogenic cardiomyopathy, highlighting abnormal calcium homeostasis, inflammatory responses, and potential targeted therapeutic approaches.
Hypothesis-generating for arrhythmogenic cardiomyopathy therapies; leaves open clinical translation pending validation.
Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.
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Gao et al. (2020) conducted a review in Arrhythmogenic cardiomyopathy (ACM). This comprehensive review summarizes the molecular and cellular mechanisms of arrhythmogenic cardiomyopathy pathogenesis, including abnormal calcium homeostasis and inflammatory/autoimmune responses.
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