Dalal Darshan, Molin Lorraine H, Piccini Jonathan, Tichnell Crystal, James Cynthia, Bomma Chandra, Prakasa Kalpana, Towbin Jeffrey A, Marcus Frank I, Spevak Philip J, Bluemke David A, Abraham Theodore, Russell Stuart D, Calkins Hugh, Judge Daniel P
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Circulation. 2006 Apr 4;113(13):1641-9. doi: 10.1161/CIRCULATIONAHA.105.568642. Epub 2006 Mar 20.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations.
DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28+/-11 years) than in those without (36+/-16 years) (P<0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P<0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P<0.05).
Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.
致心律失常性右室发育不良/心肌病（ARVD/C）是一种遗传性心肌病，其特征为右室功能障碍和室性心律失常。最近一项研究报道了编码桥粒蛋白盘状球蛋白-2的PKP2基因突变与ARVD/C有关。我们研究的目的是在另一大组ARVD/C患者中验证PKP2基因突变的频率，并研究与PKP2基因突变相关的表型特征。
对58例ARVD/C患者的DNA进行测序，以确定PKP2基因中是否存在突变。将ARVD/C患者分为两组：有PKP2基因突变的患者和未检测到PKP2基因突变的患者，并比较两组患者的临床特征。在25例（43%）患者中鉴定出13种不同的PKP2基因突变。其中6种突变以前未被报道；4种发生在多个明显无亲缘关系的家族中。有PKP2基因突变的患者出现症状时的平均年龄（28±11岁）低于无突变的患者（36±16岁）（P<0.05）。有PKP2基因突变的患者累积无症状生存中位数年龄（32岁对42岁）和累积无心律失常生存中位数年龄（34岁对46岁）低于无PKP2基因突变的患者（P<0.05）。仅在无PKP2基因突变的患者中，电生理研究中室性心律失常的可诱导性、右室疾病的弥漫性以及既往自发性室性心动过速的存在被确定为植入式心脏复律除颤器（ICD）干预的预测因素（P<0.05）。
我们的研究强调了PKP2基因突变在ARVD/C中的临床相关性。ARVD/C患者中PKP2基因突变的存在与症状和心律失常的较早发作相关。有PKP2基因突变的患者接受ICD干预，而不考虑决定ARVD/C患者ICD干预的经典危险因素。
