Molecular biology and clinical management of arrhythmogenic right ventricular cardiomyopathy/dysplasia
Molecular biology and clinical management of arrhythmogenic right ventricular cardiomyopathy/dysplasia
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DOI：
10.1136/hrt.2010.193276
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发表时间：
2011-04-01
期刊：
影响因子：
5.7
通讯作者：
Thiene, Gaetano
中科院分区：
文献类型：
--
作者：
Corrado, Domenico;Basso, Cristina;Thiene, Gaetano
在过去的二十年中，致心律失常性右心室心肌病/发育不良（ARVC/D）分子生物学的巨大进展为我们对该疾病病因学的理解提供了重要的见解，表明它是心脏桥粒的遗传性疾病，并且细胞-细胞粘附的机械破坏和桥粒介导的细胞内信号传导缺陷之间的相互作用可能与 ARVC/D 表型的发病机制有关。 ARVC/D 致病基因的发现为在潜在恶性临床表型发生之前识别受遗传影响的个体提供了可能性。此外，通过对心内膜心肌活检样本进行免疫组织化学分析来评估桥粒蛋白的异常定位，为 ARVC/D 诊断提供了一种有前景的测试。通过受影响家庭的分子遗传学筛查可以改善 ARVC/D 的早期发现和对心源性猝死风险最高的年轻人的预防性治疗，并可能改变患者的临床管理。然而，目前基因分型的临床应用受到对致病突变的不完全了解和疾病复杂的遗传背景的限制，这导致了外显率不完全和表型表达的显着变异。这篇综述讨论了 ARVC/D 分子生物学的进展，特别是该疾病的遗传基础，以及这些进展如何影响疾病发病机制的理解、诊断和制定管理策略。
In the last two decades the extraordinary advances in molecular biology of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) have provided significant insights into our understanding of the disease aetiology by showing that it is a genetic disorder of the cardiac desmosomes and that interactions between mechanical disruption of cell-cell adhesion and defects of desmosomal-mediated intracellular signalling are likely to be involved in the pathogenesis of the ARVC/D phenotype. The discovery of the causative genes for ARVC/D offers the possibility of identifying genetically-affected individuals before potentially malignant clinical phenotype occurs. Moreover, the evaluation of abnormal localisation of desmosomal proteins by immunohistochemical analysis on endomyocardial biopsy samples represents a promising test for ARVC/D diagnosis. Early detection of ARVC/D and preventive therapy of young individuals at highest risk of experiencing sudden cardiac death may be improved by molecular genetic screening within affected families and may alter the clinical management of patients. At present, however, the clinical use of genotyping is limited by the incomplete knowledge of causative mutations and the complex genetic background of the disease, which accounts for the incomplete penetrance and the marked variability of the phenotype expression. This review addresses the advances in the molecular biology of ARVC/D, with particular reference to the genetic basis of the disease, and how these advances have impacted on understanding the disease pathogenesis, on diagnosis and in establishing management strategies.