Peters Stacey, Thompson Bryony A, Perrin Mark, James Paul, Zentner Dominica, Kalman Jonathan M, Vandenberg Jamie I, Fatkin Diane
Department of Cardiology (S.P., M.P., D.Z., J.M.K.), Royal Melbourne Hospital.
Department of Genomic Medicine (S.P., B.A.T., M.P., P.J., D.Z.), Royal Melbourne Hospital.
Circ Genom Precis Med. 2022 Feb;15(1):e003432. doi: 10.1161/CIRCGEN.121.003432. Epub 2021 Dec 24.
Variants in the gene, that encodes the cardiac sodium channel, Nav1.5, are associated with a highly arrhythmogenic form of dilated cardiomyopathy (DCM). Our aim was to review the phenotypes, natural history, functional effects, and treatment outcomes of DCM-associated rare variants.
A systematic review of reported DCM-associated rare variants was undertaken using PubMed and Embase.
Eighteen rare variants in 29 families with DCM (173 affected individuals) were identified. Eleven variants had undergone experimental evaluation, with 7 of these resulting in increased sustained current flow during the action potential (eg, increased window current) and at resting membrane potentials (eg, creation of a new gating pore current). These variants were located in transmembrane voltage-sensing domains and had a consistent phenotype characterized by frequent multifocal narrow and broad complex ventricular premature beats (VPB; 72% of affected relatives), ventricular arrhythmias (33%), atrial arrhythmias (32%), sudden cardiac death (13%), and DCM (56%). This VPB-predominant phenotype was not seen with 1 variant that increased late sodium current, or with variants that reduced peak current density or had mixed effects. In the latter groups, affected individuals mainly showed sinus node dysfunction, conduction defects, and atrial arrhythmias, with infrequent VPB and ventricular arrhythmias. DCM did not occur in the absence of arrhythmias for any variant. Twelve studies (23 total patients) reported treatment success in the VPB-predominant cardiomyopathy using sodium channel-blocking drug therapy.
variants can present with a diverse spectrum of primary arrhythmic features. A majority of DCM-associated variants cause a multifocal VPB-predominant cardiomyopathy that is reversible with sodium channel blocking drug therapy. Early recognition of the distinctive phenotype and prompt genetic testing to identify variant carriers are needed. Our findings have implications for interpretation and management of variants found in DCM patients with and without arrhythmias.
编码心脏钠通道Nav1.5的基因变异与一种高度致心律失常的扩张型心肌病（DCM）相关。我们的目的是回顾与DCM相关的罕见变异的表型、自然病史、功能影响和治疗结果。
使用PubMed和Embase对报道的与DCM相关的罕见变异进行系统综述。
在29个患有DCM的家族（173名受影响个体）中鉴定出18种罕见变异。11种变异已进行实验评估，其中7种导致动作电位期间持续电流增加（例如，窗电流增加）以及静息膜电位时增加（例如，产生新的门控孔电流）。这些变异位于跨膜电压传感结构域，具有一致的表型，其特征为频繁出现多灶性窄和宽复合室性早搏（VPB；72%的受影响亲属）、室性心律失常（33%）、房性心律失常（32%）、心源性猝死（13%）和DCM（56%）。增加晚期钠电流的1种变异、降低峰值电流密度或具有混合效应的变异未出现这种以VPB为主的表型。在后一组中，受影响个体主要表现为窦房结功能障碍、传导缺陷和房性心律失常，VPB和室性心律失常少见。对于任何变异，心律失常不存在时均未发生DCM。12项研究（共23例患者）报告使用钠通道阻滞剂药物治疗以VPB为主的心肌病取得成功。
变异可表现出多种原发性心律失常特征。大多数与DCM相关的变异导致以多灶性VPB为主的心肌病，钠通道阻滞剂药物治疗可使其逆转。需要早期识别独特的表型并及时进行基因检测以识别变异携带者。我们的发现对有或无心律失常的DCM患者中发现的变异的解释和管理具有重要意义。
