Muller Steven A, Bertoli Giorgia, Wang Jianan, Gasperetti Alessio, Cox Moniek G P J, Calkins Hugh, Riele Anneline S J M Te, Judge Daniel P, Delmar Mario, Hauer Richard N W, Boink Gerard J J, Cerrone Marina, Tintelen J Peter van, James Cynthia A
Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
J Cardiovasc Electrophysiol. 2024 Dec 2. doi: 10.1111/jce.16519.
Arrhythmogenic cardiomyopathy (ACM) is a genetically heterogeneous inherited cardiomyopathy with an estimated prevalence of 1:5000-10 000 that predisposes patients to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD). ACM diagnostic criteria and risk prediction models, particularly for arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common form of ACM, are typically genotype-agnostic, but numerous studies have established clinically meaningful genotype-phenotype associations. Early signs of ACM onset differ by genotype indicating the need for genotype-specific diagnostic criteria and family screening paradigms. Likewise, risk factors for SCD vary by genetic subtype, indicating that genotype-specific guidelines for management are also warranted. Of particular importance, genotype-specific therapeutic approaches are being developed. Results from a randomized controlled trial for flecainide use in ARVC patients are currently pending. Research in a plakophilin-2-deficient mouse model suggests this antiarrhythmic drug may be particularly useful for patients with likely pathogenic or pathogenic (LP/P) PKP2 variants. Additionally, the first gene therapy clinical trials in ARVC patients harboring LP/P PKP2 variants are currently underway. This review aims to provide clinicians caring for ACM patients with an up-to-date overview of the current literature in genotype-specific natural history of disease and management of ACM patients and describe scientific advances that have led to upcoming clinical trials.
致心律失常性心肌病（ACM）是一种遗传异质性遗传性心肌病，估计患病率为1:5000 - 10000，使患者易发生危及生命的室性心律失常（VA）和心源性猝死（SCD）。ACM的诊断标准和风险预测模型，特别是对于最常见的ACM形式致心律失常性右室心肌病（ARVC），通常不考虑基因型，但大量研究已建立了具有临床意义的基因型 - 表型关联。ACM发病的早期迹象因基因型而异，这表明需要特定基因型的诊断标准和家族筛查模式。同样，SCD的危险因素因遗传亚型而异，这表明也需要特定基因型的管理指南。特别重要的是，正在开发特定基因型的治疗方法。目前，关于氟卡尼用于ARVC患者的随机对照试验结果尚未得出。在一种缺失盘状球蛋白2的小鼠模型中的研究表明，这种抗心律失常药物可能对可能具有致病性或致病性（LP/P）PKP2变异的患者特别有用。此外，目前正在对携带LP/P PKP2变异的ARVC患者进行首例基因治疗临床试验。本综述旨在为照顾ACM患者的临床医生提供关于ACM患者特定基因型自然病史和管理的当前文献的最新概述，并描述导致即将进行的临床试验的科学进展。
