Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression
Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression
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DOI：
10.1161/circulationaha.106.660241
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发表时间：
2007-04-03
期刊：
影响因子：
37.8
通讯作者：
McKenna, William J.
中科院分区：
文献类型：
--
作者：
Sen-Chowdhry, Srijita;Syrris, Petros;McKenna, William J.
背景-根据临床病理相关性研究，致心律失常性右心室发育不良/心肌病的自然病程据称是从局部右心室功能障碍进展为整体右心室功能障碍，随后出现左心室（LV）受累和双心室泵衰竭。然而，对猝死受害者和移植受者的不可避免的关注可能会造成对遗传病的偏见。我们假设，要公正地表示致心律失常性右心室发育不良/心肌病的疾病表达谱，需要对遗传异质人群中的家庭进行体内评估。方法和结果-对满足工作组或修改后的致心律失常性右心室发育不良/心肌病诊断标准的200名先证者和亲属组成的队列进行了全面的临床评估。在来自 20 个不同家族的 39 名个体中发现了桥粒突变。结构严重性指数与年龄增长相关，并且在长期耐力运动员中增加。满足修改后的标准表明表型为轻度疾病，而无症状状态则不然。在 > 80% 的患者中，心电图、节律监测和/或钆增强心血管磁共振提示左心室受累，其程度通常在患有链终止突变和/或桥粒斑蛋白疾病的个体中表现出来。确定了三种疾病表达模式：（1）经典型，孤立性右心室疾病或左心室受累，伴有明显的右心室损害； (2) 左心占优势，左心室表现早期且明显，右侧病变相对较轻； (3)双心室，其特征是两个心室平行受累。结论：致心律失常性右心室发育不良/心肌病中左心室受累可能先于严重右心室功能障碍的发生。对早期和/或主要左心室受累的疾病变异的认识支持采用更广泛的术语致心律失常性心肌病。
Background-According to clinical-pathological correlation studies, the natural history of arrhythmogenic right ventricular dysplasia/cardiomyopathy is purported to progress from localized to global right ventricular dysfunction, followed by left ventricular (LV) involvement and biventricular pump failure. The inevitable focus on sudden death victims and transplant recipients may, however, have created a skewed perspective of a genetic disease. We hypothesized that unbiased representation of the spectrum of disease expression in arrhythmogenic right ventricular dysplasia/cardiomyopathy would require in vivo assessment of families in a genetically heterogeneous population.Methods and Results-A cohort of 200 probands and relatives satisfying task force or modified diagnostic criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy underwent comprehensive clinical evaluation. Desmosomal mutations were identified in 39 individuals from 20 different families. Indices of structural severity correlated with advancing age and were increased in long-term endurance athletes. Fulfillment of modified criteria indicated phenotypically mild disease, whereas asymptomatic status did not. In > 80%, ECG, rhythm monitoring, and/or gadolinium-enhanced cardiovascular magnetic resonance were suggestive of LV involvement, the extent of which often was marked among individuals with chain-termination mutations and/or desmoplakin disease. Three patterns of disease expression were identified: (1) classic, with isolated right ventricular disease or LV involvement in association with significant right ventricular impairment; (2) left dominant, with early and prominent LV manifestations and relatively mild right-sided disease; and (3) biventricular, characterized by parallel involvement of both ventricles.Conclusions-LV involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy may precede the onset of significant right ventricular dysfunction. Recognition of disease variants with early and/or predominant LV involvement supports adoption of the broader term arrhythmogenic cardiomyopathy.