Electrophysiological basis of cardiac arrhythmia in a mouse model of myotonic dystrophy type 1.
Electrophysiological basis of cardiac arrhythmia in a mouse model of myotonic dystrophy type 1.
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DOI：
10.3389/fphys.2023.1257682
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发表时间：
2023
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
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简介：强直性肌营养不良1型（Myotonic dystrophy type 1，DM1）是由肌营养不良性肌强直蛋白激酶（DMPK）基因3′非编码区CTG重复序列增加引起的多系统遗传病。DM 1患者经历传导异常以及房性和室性心律失常，增加了对心源性猝死的易感性。这些电异常的离子基础知之甚少。 研究方法：我们评估了表面心电图（ECG）和动作电位（AP）的关键离子电流在小鼠模型DM1，DMSXL，表达超过1000个CTG重复。采用膜片钳技术记录钠电流（INa）、L型钙电流（ICaL）、瞬时外向钾电流（Ito）和AP。 结果如下：在DMSXL纯合子小鼠中观察到ECG上的心律失常事件，包括窦性心动过缓、传导缺陷以及室性和房性心律失常，但在WT小鼠中未观察到。在纯合子小鼠中观察到PR间期缩短，而ECG参数如QRS时限和QTc没有变化。此外，氟卡尼在DMSXL纯合子小鼠中视觉上延长了PR、QRS和QTc。在单个心室肌细胞水平上，我们观察到与WT小鼠相比，DMSXL纯合子小鼠中Ito和ICaL的电流密度降低，携带ICaL的L型钙通道稳态激活发生正向偏移。INa密度和动作电位时程在DMSXL和WT小鼠之间没有变化。 结论：Ito和ICaL的电流密度降低以及L型钙通道门控特性的改变可能导致DM1的DMSXL小鼠模型中的ECG异常。这些发现为新型靶向治疗开辟了新的途径。
Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3′ UTR of Dystrophia Myotonia Protein Kinase (DMPK) gene. DM1 patients experience conduction abnormalities as well as atrial and ventricular arrhythmias with increased susceptibility to sudden cardiac death. The ionic basis of these electrical abnormalities is poorly understood. Methods: We evaluated the surface electrocardiogram (ECG) and key ion currents underlying the action potential (AP) in a mouse model of DM1, DMSXL, which express over 1000 CTG repeats. Sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and APs were recorded using the patch-clamp technique. Results: Arrhythmic events on the ECG including sinus bradycardia, conduction defects, and premature ventricular and atrial arrhythmias were observed in DMSXL homozygous mice but not in WT mice. PR interval shortening was observed in homozygous mice while ECG parameters such as QRS duration, and QTc did not change. Further, flecainide prolonged PR, QRS, and QTc visually in DMSXL homozygous mice. At the single ventricular myocyte level, we observed a reduced current density for Ito and ICaL with a positive shift in steady state activation of L-type calcium channels carrying ICaL in DMSXL homozygous mice compared with WT mice. INa densities and action potential duration did not change between DMSXL and WT mice. Conclusion: The reduced current densities of Ito, and ICaL and alterations in gating properties in L-type calcium channels may contribute to the ECG abnormalities in the DMSXL mouse model of DM1. These findings open new avenues for novel targeted therapeutics.
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影响因子：
4
作者：
通讯作者：
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影响因子：
4.5
作者：
Huguet, Aline;Medja, Fadia;Gourdon, Genevieve
通讯作者：
Gourdon, Genevieve
DOI：
10.1111/j.1540-8167.2011.02032.x
发表时间：
2011-08-01
影响因子：
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通讯作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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