DYNLT1 Deficiency Induces Atrial Fibrillation: Insights into Cardiac Remodeling and Molecular Mechanisms

Atrial fibrillation (AF) is a prevalent arrhythmia characterized by high morbidity and mortality, yet its molecular underpinnings remain poorly understood. This study investigates the role of DYNLT1 in AF by generating a DYNLT1-knockout (KO) mouse model via CRISPR/Cas9 technology. Molecular analyses revealed significant disruptions in key pathways, including reduced expression of gap junction proteins connexin 40 and 43, increased cardiomyocyte apoptosis as indicated by TUNEL staining, and heightened inflammatory responses characterized by elevated IL-6, CRP, and TNF-α levels. These molecular changes were accompanied by structural remodeling, including atrial enlargement and fibrosis, as demonstrated by histological analyses and echocardiography. Electrocardiographic recordings showed prolonged PR intervals, irregular RR intervals, and reduced P-wave amplitude, confirming electrophysiological remodeling. Pharmacological testing highlighted the model’s sensitivity to antiarrhythmic drugs such as amiodarone and propafenone, which effectively restored sinus rhythm. These findings establish DYNLT1 as a key regulator in AF pathogenesis and underscore the KO mouse model as a valuable tool for exploring the molecular and cellular mechanisms of AF and for screening potential therapeutic agents.心房颤动（Atrial fibrillation, AF）是一种高发心律失常，兼具高发病率与高致死率，但其分子机制迄今尚未被充分阐明。本研究通过CRISPR/Cas9基因编辑技术构建DYNLT1基因敲除（KO）小鼠模型，以此探究DYNLT1在房颤发病过程中的作用。分子生物学分析显示，核心通路出现显著紊乱，包括缝隙连接蛋白connexin 40与connexin 43的表达下调、经TUNEL染色证实的心肌细胞凋亡水平升高，以及以IL-6、CRP、TNF-α水平升高为特征的炎症反应加剧。上述分子改变同时伴随结构重构，经组织学分析与超声心动图证实，该重构表现为心房扩大与纤维化。心电图记录显示PR间期延长、RR间期不规则以及P波振幅降低，证实存在电生理重构。药物实验结果表明，该模型对胺碘酮、普罗帕酮等抗心律失常药物具有响应性，此类药物可有效恢复窦性心律。本研究结果证实DYNLT1是房颤发病机制中的关键调控因子，同时证明该基因敲除小鼠模型可作为探究房颤分子与细胞机制、筛选潜在治疗药物的有效工具。