HEART RHYTHM :致心律失常性心肌病患者或存在心肌信号传导紊乱

　　来自荷兰的一项研究表明，大部分的致心律失常性心肌病（AC）可以观察到其闰盘组织PKG，Cx43和NaV1.5免疫反应信号水平的下降。Nav1.5水平的下降可能有助于确定心律失常的易感性，在未来可能作为一个新的临床相关工具指标，用于风险评估策略。研究在2012年11月26日在线发表于《心脏节律》（Heart Rhythm）杂志。

　　在大多数患者中，AC与桥粒突变存在紧密的相关性。AC患者的心律失常可能与心脏缝隙连接的重塑和纤维化水平的提高相关。研究者最近采用实验模型研究证实，钠离子通道功能障碍可继发于桥粒功能障碍。该研究旨在评价AC患者心肌标本中钠通道蛋白NaV1.5以及缝隙连接蛋白43和盘状球蛋白的Plakoglobin免疫反应信号水平。研究从5 例AC患者和5例年龄和性别匹配的对照受试者的尸体标本取材左心室和右心室游离壁（LVFW / RVFW）组织。从另外的15 例AC患者的活组织中取材RV间隔的切片（RVSB）。所有患者均符合2010年修订的AC强制诊断标准。使用抗缝隙连接蛋白43（Cx43蛋白），Plakoglobin，NaV1.5，Plakophilin-2和N-钙粘蛋白抗体进行免疫组织化学分析。

　　结果表明，与对照组相比，AC患者的N-钙粘蛋白和桥粒斑蛋白的免疫反应信号和分布是正常的。Plakophilin-2信号亦没有受到影响，除非存在一个预测单倍剂量不足的PKP2基因突变。与对照组比较，信号分布无变化。分别有74％，70％和65％患者的PKG，Cx43和NaV1.5免疫反应信号存在紊乱。

Remodeling of the cardiac sodium channel, Connexin43 and Plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy

Background

Arrhythmogenic cardiomyopathy (AC) is tightly associated with desmosomal mutations in the majority of patients. Arrhythmogenesis in AC patients is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction. The aim of the present study was to assess the immunoreactive signal levels of the sodium channel protein NaV1.5, as well as Connexin43 and Plakoglobin, in myocardial specimens obtained from AC patients. Methods: Left and right ventricular free wall (LVFW/RVFW) post-mortem material was obtained from 5 AC patients and 5 age and sex-matched controls. RV septal biopsies (RVSB) were taken from another 15 AC patients. All patients fulfilled the 2010 revised Task Force Criteria for AC diagnosis. Immunohistochemical analyses were performed using antibodies against Connexin43 (Cx43), Plakoglobin, NaV1.5, Plakophilin-2 and N-Cadherin.

Results

N-Cadherin and Desmoplakin immunoreactive signals and distribution were normal in AC patients compared to control. Plakophilin-2 signals were unaffected unless a PKP2 mutation predicting haploinsufficiency was present. Distribution was unchanged compared to control. Immunoreactive signal levels of PKG, Cx43 and NaV1.5 were disturbed in 74%, 70% and 65% of the patients, respectively.

Conclusions

Reduced immunoreactive signal of PKG, Cx43 and NaV1.5 at the intercalated disks can be observed in a large majority of the patients. Decreased levels of Nav1.5 might contribute to arrhythmia vulnerability and, in the future, potentially could serve as a new clinically relevant tool for risk assessment strategies.