A novel genotype-based clinicopathology classification of arrhythmogenic cardiomyopathy provides novel insights into disease progression
A novel genotype-based clinicopathology classification of arrhythmogenic cardiomyopathy provides novel insights into disease progression
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DOI：
10.1093/eurheartj/ehz172
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发表时间：
2019-06-01
影响因子：
39.3
通讯作者：
Hu, Shengshou
中科院分区：
文献类型：
--
作者：
Chen, Liang;Song, Jiangping;Hu, Shengshou
目的 致心律失常性心肌病 (AC) 在其临床、遗传和病理表现上表现出很大的异质性。本研究旨在提供终末期AC的综合图谱，并阐明该疾病患者的临床特征、基因型和病理特征之间的关系。方法和结果我们收集了60颗摘除的AC心脏并进行了标准病理学检查。评估患者的临床特征、基因型和心脏磁共振成像结果以及病理特征。对每颗心脏的六个代表性切片进行马森染色。数字病理学与图像分割相结合，被用来计算心肌、纤维化和脂肪组织的分布。构建了基于包含四种亚型的纤维脂肪分布的无监督聚类。集群1中的患者主要携带桥粒突变（桥粒斑蛋白除外），并且在年轻时接受了移植；该组与经典的“桥粒心肌病”一致。簇 2 大多具有非桥粒突变，并显示右心室区域纤维脂肪替代。第 3 组中的患者表现出平行进展，其中包括桥粒斑蛋白突变的患者。第 4 组是典型的左侧显性 AC，尽管这些患者的遗传背景尚不清楚。多变量回归分析显示心前区 QRS 电压是右心室残余心肌的独立指标，在预测死亡和移植事件方面在验证队列 (n = 92) 中得到了验证。 结论 这项研究提供了一种新的 AC 分类，具有不同的遗传背景，表明不同的潜在发病机制。簇 1 的基因型和临床病理学不同，可定义为“桥粒心肌病”。心前区QRS波幅是反映右心室重构的独立指标，可能能够预测AC患者的移植/死亡事件。
Aims Arrhythmogenic cardiomyopathy (AC) shows large heterogeneity in its clinical, genetic, and pathological presentation. This study aims to provide a comprehensive atlas of end-stage AC and illustrate the relationships among clinical characteristics, genotype, and pathological profiles of patients with this disease.Methods and results We collected 60 explanted AC hearts and performed standard pathology examinations. The clinical characteristics of patients, their genotype and cardiac magnetic resonance imaging findings were assessed along with pathological characteristics. Masson staining of six representative sections of each heart were performed. Digital pathology combined with image segmentation was developed to calculate distribution of myocardium, fibrosis, and adipose tissue. An unsupervised clustering based on fibrofatty distribution containing four subtypes was constructed. Patients in Cluster 1 mainly carried desmosomal mutations (except for desmoplakin) and were subjected to transplantation at early age; this group was consistent with classical 'desmosomal cardiomyopathy'. Cluster 2 mostly had nondesmosomal mutations and showed regional fibrofatty replacement in right ventricle. Patients in Cluster 3 showed parallel progression, and included patients with desmoplakin mutations. Cluster 4 is typical left-dominant AC, although the genetic background of these patients is not yet clear. Multivariate regression analysis revealed precordial QRS voltage as an independent indicator of the residual myocardium of right ventricle, which was validated in predicting death and transplant events in the validation cohort (n = 92).Conclusion This study provides a novel classification of AC with distinct genetic backgrounds indicating different potential pathogenesis. Cluster 1 is distinct in genotype and clinicopathology and can be defined as 'desmosomal cardiomyopathy'. Precordial QRS amplitude is an independent indicator reflecting the right ventricular remodelling, which may be able to predict transplant/death events for AC patients.