PDF(Pubmed)
Abstract：
Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease characterized by the progressive substitution of myocardium with fibro-fatty tissue. Clinically, ACM shows wide variability among patients; symptoms can include syncope and ventricular tachycardia but also sudden death, with the latter often being its sole manifestation. Approximately half of ACM patients have been found with variations in one or more genes encoding cardiac intercalated discs proteins; the most involved genes are plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP). Cardiac intercalated discs provide mechanical and electro-metabolic coupling among cardiomyocytes. Mechanical communication is guaranteed by the interaction of proteins of desmosomes and adheren junctions in the so-called area composita, whereas electro-metabolic coupling between adjacent cardiac cells depends on gap junctions. Although ACM has been first described almost thirty years ago, the pathogenic mechanism(s) leading to its development are still only partially known. Several studies with different animal models point to the involvement of the Wnt/β-catenin signaling in combination with the Hippo pathway. Here, we present an overview about the existing murine models of ACM harboring variants in intercalated disc components with a particular focus on the underlying pathogenic mechanisms. Prospectively, mechanistic insights into the disease pathogenesis will lead to the development of effective targeted therapies for ACM.
摘要：
心律失常性心肌病（ACM）是一种罕见的遗传性心脏病，其特征是心肌逐渐被纤维脂肪组织取代。临床上,ACM在患者中表现出广泛的变异性；症状可能包括晕厥和室性心动过速，也包括猝死，后者往往是其唯一的表现。已经发现大约一半的ACM患者在编码心脏插入椎间盘蛋白的一个或多个基因中存在变异;最涉及的基因是plakophilin2(PKP2),desmoglein2(DSG2),和desmoplakin(DSP)。心脏插层盘在心肌细胞之间提供机械和电代谢耦合。在所谓的复合区域中，桥粒和附着点的蛋白质相互作用保证了机械通讯，而相邻心脏细胞之间的电代谢耦合取决于间隙连接。虽然ACM在近三十年前就已经被首次描述过，导致其发展的致病机制仍然仅部分已知。对不同动物模型的若干研究指出Wnt/β-连环蛋白信号与Hippo途径的组合的参与。这里,我们对现有的ACM小鼠模型进行了概述，这些模型在插入的椎间盘组件中具有变体，特别关注潜在的致病机制。Prospective,对疾病发病机制的机械见解将导致ACM的有效靶向治疗的发展。
