Vahdat Juliette, Sauer Jakob, Marksteiner Jessica, Hilber Karlheinz, Miquerol Lucile
Aix-Marseille Université, CNRS UMR 7288, Developmental Biology Institute of Marseille, Marseille, France.
Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Front Physiol. 2025 Jun 26;16:1607916. doi: 10.3389/fphys.2025.1607916. eCollection 2025.
Duchenne muscular dystrophy (DMD) is a severe X-chromosomal disease characterised by progressive muscle weakness and degeneration. Cardiac involvement is inevitable in DMD patients and ventricular arrhythmias are a high-risk factor for mortality in these patients. Ventricular arrhythmias are often triggered by a dysfunctional ventricular conduction system, which serves as an electrical circuit in the heart to ensure the synchronization of the heartbeat. This system includes Purkinje fibers which are susceptible to degeneration in DMD patients, leading to cardiac conduction disorders. To unravel whether a defective ventricular conduction system may account for arrhythmogenesis in a DMD mouse model, we performed a longitudinal study of the cardiac electrical activity in mice. ECG recordings showed a progressive increase in PR interval over time and a prolonged QRS in compared to wild-type (WT) mice. At baseline, only mice presented premature ventricular complexes (PVC), and a greater prevalence of PVC was observed after β-adrenergic stimulation in these mice. These conduction defects and arrhythmias occurred while no defects in the morphology and maturation of the Purkinje fiber network were observed. However, mice had a larger heart and showed signs of fibrosis and hypertrophy. Furthermore, conduction defects in mice were associated with ventricular dyssynchrony and sodium current (I) reduction in ventricular myocytes and Purkinje fibers. Altogether, these data demonstrated that mice develop a progressive arrhythmogenic cardiomyopathy in association with I loss, ventricular fibrosis but without degeneration of the ventricular conduction system.
杜兴氏肌肉营养不良症（DMD）是一种严重的X染色体疾病，其特征为进行性肌肉无力和退化。DMD患者不可避免地会出现心脏受累，室性心律失常是这些患者死亡的高危因素。室性心律失常通常由功能失调的心室传导系统引发，该系统作为心脏中的电路，确保心跳同步。这个系统包括浦肯野纤维，在DMD患者中浦肯野纤维易发生退化，导致心脏传导障碍。为了弄清楚有缺陷的心室传导系统是否可能是DMD小鼠模型中心律失常发生的原因，我们对小鼠的心脏电活动进行了纵向研究。心电图记录显示，与野生型（WT）小鼠相比，随着时间的推移，PR间期逐渐增加，QRS波增宽。在基线时，只有小鼠出现室性早搏复合波（PVC），在这些小鼠中，β肾上腺素能刺激后观察到PVC的发生率更高。这些传导缺陷和心律失常出现时，未观察到浦肯野纤维网络的形态和成熟存在缺陷。然而，小鼠心脏更大，并显示出纤维化和肥大的迹象。此外，小鼠的传导缺陷与心室不同步以及心室肌细胞和浦肯野纤维中的钠电流（I）减少有关。总之，这些数据表明，小鼠会发生与I丢失、心室纤维化相关的进行性心律失常性心肌病，但心室传导系统无退化。
