PhyMedExp, INSERM U1046, CNRS UMR9214, Université de Montpellier, Montpellier, France.
Neuromyogene Institut, Claude Bernard University, Lyon 1, Villeurbanne, France.
Clin Transl Med. 2021 Mar;11(3):e319. doi: 10.1002/ctm2.319.
Severe ventricular rhythm disturbances are the hallmark of arrhythmogenic cardiomyopathy (ACM), and are often explained by structural conduction abnormalities. However, comprehensive investigations of ACM cell electrical instability are lacking. This study aimed to elucidate early electrical myogenic signature of ACM.
We investigated a 41-year-old ACM patient with a missense mutation (c.394C>T) in the DSC2 gene, which encodes desmocollin 2. Pathogenicity of this variant was confirmed using a zebrafish DSC2 model system. Control and DSC2 patient-derived pluripotent stem cells were reprogrammed and differentiated into cardiomyocytes (hiPSC-CM) to examine the specific electromechanical phenotype and its modulation by antiarrhythmic drugs (AADs). Samples of the patient's heart and hiPSC-CM were examined to identify molecular and cellular alterations.
A shortened action potential duration was associated with reduced Ca current density and increased K current density. This finding led to the elucidation of previously unknown abnormal repolarization dynamics in ACM patients. Moreover, the Ca mobilised during transients was decreased, and the Ca sparks frequency was increased. AAD testing revealed the following: (1) flecainide normalised Ca transients and significantly decreased Ca spark occurrence and (2) sotalol significantly lengthened the action potential and normalised the cells' contractile properties.
Thorough analysis of hiPSC-CM derived from the DSC2 patient revealed abnormal repolarization dynamics, prompting the discovery of a short QT interval in some ACM patients. Overall, these results confirm a myogenic origin of ACM electrical instability and provide a rationale for prescribing class 1 and 3 AADs in ACM patients with increased ventricular repolarization reserve.
严重的心室节律紊乱是心律失常性心肌病（ACM）的标志，通常由结构性传导异常来解释。然而，ACM 细胞电不稳定性的综合研究仍然缺乏。本研究旨在阐明 ACM 的早期电肌源性特征。
我们研究了一位 41 岁的 ACM 患者，其 DSC2 基因（编码桥粒蛋白 2）存在错义突变（c.394C>T）。该变体的致病性使用斑马鱼 DSC2 模型系统得到了确认。使用控制和 DSC2 患者来源的多能干细胞重编程并分化为心肌细胞（hiPSC-CM），以检查特定的机电表型及其对抗心律失常药物（AAD）的调节。检查患者心脏和 hiPSC-CM 的样本以识别分子和细胞改变。
动作电位持续时间缩短与 Ca 电流密度降低和 K 电流密度增加有关。这一发现导致阐明了 ACM 患者以前未知的异常复极动力学。此外，瞬变期间动员的 Ca 减少，Ca 火花频率增加。AAD 测试显示：（1）氟卡尼使 Ca 瞬变正常化，并显著降低 Ca 火花发生频率；（2）索他洛尔显著延长动作电位并使细胞的收缩特性正常化。
对源自 DSC2 患者的 hiPSC-CM 的彻底分析显示出异常的复极动力学，提示某些 ACM 患者存在 QT 间期缩短。总体而言，这些结果证实了 ACM 电不稳定性的肌源性起源，并为增加心室复极储备的 ACM 患者开处方 1 类和 3 类 AAD 提供了依据。
