To Genetics And Clinical Characteristics Of Right Ventricular Cardiomyopathy Arrhythmia Sex Correlation Studies

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable cardiac disease predominantly caused by mutations in desmosomal protein genes. Previous genetic analyses of Chinese ARVC population are limited to small size and single gene. This study was aimed to investigate the genotype in a large series of Chinese patients with ARVC through comprehensively screening nine ARVC-causing genes.MethodsA total of100unrelated ARVC patients and300age, gender and ethnicity-matched healthy controls were genetically tested for9previously reported ARVC-causing genes, including plakophilin-2(PKP2), desmoplakin (DSP), desmoglein-2(DSG2), desmocollin-2(DSC2), and plakoglobin (JUP), transforming growth factor beta-3(TGFJ33), transmembrane protein43(TMEM43), desmin (DES) and Lamin A/C (LMNA), with multiplexing targeted resequencing. Clinical characteristics were compared between the two groups of mutation carriers and non-carriers.ResultsFifty-nine mutations were identified in64%of the patients, among which,93%were located in desmosomal protein genes. PKP2mutation accounted for54%of the total and58%of the desmosomal mutations, with truncating mutation type occupied about2/3of the PKP2mutations. Only4mutations were found in non-desmosomal genes:2in TMEM43and2in TGFβ3. Two of them (one of each gene) appeared as single missense mutation. No mutation was identified in DES or LMNA. Multiple mutations were found in23%of the patients, with PKP2being found in57%of the multi-mutation carriers. Genotype-phenotype analysis showed that ventricular tachycardia history occurred more in mutation carriers than non-carriers (86%vs.58%, P=0.003), especially the clinical ventricular tachycardia shaped as left bundle-branch block with superior axis (72%vs.50%, P=0.033).ConclusionPKP2is the most common gene that identified in64%of Chinese ARVC patients. Ventricular tachycardia history occurs more in mutation carriers than non-carriers. Non-desmosomal genes should be added to desmosomal protein genes when performing molecular genetic screening in patients with suspected ARVC. BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is mainly caused by mutation of genes encoding desmosomal proteins. It is supposed that both ventricles should be involved in the disease since the effect of ultrastructural and molecular dysfunction of desmosome plays an equal role on both ventricles. This study was aimed to identify the clinical and genotype characteristics of ARVC with left ventricular (LV) involvement.MethodsA total of172ARVC patients were enrolled for clinical evaluation. LV involvement was defined by echocardiography with at least one of the followings:LV end-diastolic diameter>57mm, LV ejection fraction≤50%, LV wall being thin, or LV dyskinesis. One hundred patients of the total sample underwent genetic screening for9reported ARVC-causing genes. The genotype-phenotype correlation of the patients with LV involvement was analyzed.ResultsThirty-one (18%) patients were found to have LV involved. Compared with patients without LV involvement, the involved group had similar sex ratio, onset age, duration between onset and diagnosis, clinical manifestations, except more severe right ventricular structural impairment (58%vs.32%, P=0.008). Among the64mutation carriers, LV involvement was found in11(17%) patients. The involved group had more multi-mutation carriers (64%vs.30%, P=0.046), but less plakophilin-2mutation carriers (36%vs.72%, P=0.037).ConclusionIn Chinese ARVC patients,18%has echocardiography identified LV involvement, which is related to multi-mutation and right ventricular structural impairment progression. BackgroundVentricular arrhythmia is the most common clinical manifestation in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, which may lead to serious consequences (eg. cardiac arrest and sudden death). However, the relationship between genotype and the electrophysiological features of ARVC remains unclear.MethodsNinety ARVC patients who underwent electrophysiological study and substrate mapping were recruited and9well-accepted disease genes were genotyped with targeted resequencing and Sanger sequencing.ResultsA total of53mutations were identified in57patients (63%). Mutation carriers had higher chance for clinical ventricular tachycardia (VT)(89%vs.55%, P<0.001) and negative T waves in V1to V3or beyond (61%vs.33%, P=0.016) than the subjects without mutation. So did patients with plakophilin-2(PKP2) mutations than those without PKP2mutation. Syncope history was more common in multi-mutations carriers (58%vs.21%, P=0.003). During electrophysiological study, VT was significantly more often induced in mutation carriers (75%vs.39%, P=0.001) and PKP2mutation carriers (80%vs.48%, P=0.002). Among induced VTs, a rate≥200bpm was more often documented in mutations carriers (88%vs.54%, P=0.013), as well as PKP2mutations carriers (91%vs.67%, P=0.041). In substrate mapping, mutation carriers were more likely to have the low voltage areas in the basal free-wall (90%vs.68%, P=0.028) and inferior wall (44%vs.18%, P=0.026) than those without mutation.ConclusionsPathogenic gene mutations were found in nearly2/3of ARVC patients. Mutations carriers, especially PKP2, had a higher proportion of a history of VT and more inducible fast VT. The right ventricular basal free-wall and inferior wall as substrates was more frequently present in mutation carriers.