Chen Liang, Hu Yuxiao, Saguner Ardan M, Bauce Barbara, Liu Yaxin, Shi Anteng, Guan Fu, Chen Zhongli, Bueno Marinas Maria, Wu Lingmin, Foltran Deborah, Hermida Alexis, Fressart Veronique, Pinci Serena, Celeghin Rudy, Chen Zixian, Zhang Baowei, Lin Yubi, Liu Xiaorui, Cason Marco, Martini Marika, Rigato Ilaria, Brunckhorst Corinna, Biller Ruth, Basso Cristina, Yang Bing, Zhao Xiaoyan, Cadrin-Tourigny Julia, Gasperetti Alessio, James Cynthia A, Zhou Xianliang, Gandjbakhch Estelle, Pilichou Kalliopi, Duru Firat, Hu Shengshou
State Key Laboratory of Cardiovascular Disease, National Clinical Research Center for Cardiovascular Diseases (L.C., Y.H., Y. Liu, A.S., Zhongli Chen, L.W., X.L., X. Zhou, S.H.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Cardiac Surgery (L.C., A.S., X.L., S.H.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Circulation. 2025 Apr 29;151(17):1213-1230. doi: 10.1161/CIRCULATIONAHA.124.072226. Epub 2025 Mar 24.
Genetic variants in desmosomal cadherins, desmoglein 2 () and desmocollin 2 (), cause a distinct form of arrhythmogenic right ventricular cardiomyopathy (ARVC), which remains poorly reported. In this study, we aimed to provide a comprehensive description of the phenotypic expression, natural history, and clinical outcomes of patients with this ARVC subset.
Genetic and clinical data of and variant carriers were collected from 5 countries in Europe and Asia. We assessed the phenotypic profile of these patients and their clinical outcomes, focusing on heart failure and ventricular arrhythmia events.
Overall, 271 subjects, 254 with variants, were included in this study (median age, 38 years [interquartile range, 25-52]; 62.7% male). Of these, 165 were probands, and 200 were diagnosed with definite ARVC. A total of 181 (66.8%) individuals carried missense variants, mainly distributed in the extracellular domains. Notably, we included 78 (28.8%) individuals with multiple variants. Of the 200 cases with diagnosed ARVC, 41 (20.5%) experienced premature cardiac death before the age of 65. Among the 81 individuals for whom both left ventricular ejection fraction and right ventricular fractional area change data were available at presentation, 29 (35.8%) had isolated right ventricular dysfunction, and 16 (19.8%) had biventricular dysfunction. Single-variant carriers who engaged in intense physical exercise were younger at disease onset compared with those who did not (=0.001). Compared with single-variant carriers, those with multiple variants were more likely to be diagnosed with ARVC (96.2% versus 64.8%; <0.001) and exhibited more severe left ventricular dysfunction (44.4% versus 22.1%; =0.001) and right ventricular dilation (88.9% versus 55.8%, <0.001). Multiple-variant carriers were significantly younger at ARVC diagnosis compared with single-variant carriers (33 [18-49] years versus 42 [27-54] years; <0.001]. During follow-up, end-stage heart failure (<0.001) and malignant ventricular arrhythmias (=0.004) were significantly more frequent in multiple-variant compared with single-variant carriers. Compared with patients, patients exhibited a significantly higher risk of end-stage heart failure (<0.001).
ARVC attributable to variants in desmosomal cadherins mostly present with right ventricular or biventricular disease. Multiple variants are common in these patients and are associated with more frequent clinical penetrance, earlier onset of disease, and adverse clinical outcomes.
桥粒钙黏蛋白中的基因变异，即桥粒芯糖蛋白2（DSG2）和桥粒胶蛋白2（DSC2），会引发一种特殊形式的致心律失常性右室心肌病（ARVC），但相关报道仍较少。在本研究中，我们旨在全面描述这一ARVC亚组患者的表型表达、自然病史及临床结局。
从欧洲和亚洲5个国家收集了DSG2和DSC2变异携带者的基因及临床数据。我们评估了这些患者的表型特征及其临床结局，重点关注心力衰竭和室性心律失常事件。
总体而言，本研究纳入了271名受试者，其中254名携带DSG2变异（中位年龄38岁[四分位间距，25 - 52岁]；62.7%为男性）。其中，165名是先证者，200名被诊断为明确的ARVC。共有181名（66.8%）个体携带错义变异，主要分布在细胞外结构域。值得注意的是，我们纳入了78名（28.8%）携带多个变异的个体。在200例诊断为ARVC的病例中，41例（20.5%）在65岁之前发生心源性猝死。在81名就诊时同时有左心室射血分数和右心室面积变化数据的个体中，29名（35.8%）有孤立性右心室功能障碍，16名（19.8%）有双心室功能障碍。与未进行剧烈体育锻炼的单变异携带者相比，进行剧烈体育锻炼的单变异携带者发病年龄更小（P = 0.001）。与单变异携带者相比，携带多个变异的个体更易被诊断为ARVC（96.2%对64.8%；P < 0.001），且表现出更严重的左心室功能障碍（44.4%对22.1%；P = 0.001）和右心室扩张（88.9%对55.8%，P < 0.001）。与单变异携带者相比，携带多个变异的个体在诊断为ARVC时年龄显著更小（33[18 - 49]岁对42[27 - 54]岁；P < 0.001）。在随访期间，与单变异携带者相比，携带多个变异的个体发生终末期心力衰竭（P < 0.001）和恶性室性心律失常（P = 0.004）的频率显著更高。与DSG2患者相比，DSC2患者发生终末期心力衰竭的风险显著更高（P < 0.001）。
由桥粒钙黏蛋白变异引起的ARVC大多表现为右心室或双心室疾病。多个变异在这些患者中很常见，且与更频繁的临床外显率、更早的发病以及不良临床结局相关。
