Ou Guangyang, Zhang Yi, Cai Huzhi, Yao Kunpeng, Qiu Zerui, Chen Yaowu, Yang Yang, Chen Qingyang, Chen Xinyu
The First Clinical College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China.
Department of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou Medical University, Jinzhou, China.
Front Cardiovasc Med. 2024 Nov 5;11:1446610. doi: 10.3389/fcvm.2024.1446610. eCollection 2024.
Previous studies have shown an association between lipid-lowering drugs, circulating inflammatory factors, and atrial fibrillation (AF), but the specific effects of lipid-lowering drugs on AF and whether they can be mediated by circulating inflammatory factors remain unclear.
We collected 10 genetic variants encoding lipid-lowering drug targets (LDLR, HMGCR, PCSK9, NPC1L1, APOB, APOB, ABCG5, ABCG8, LPL, APOC3, and PPARA) and AF based on genome-wide association study (GWAS) summary statistics. Drug target Mendelian randomization (MR) was used to explore the causal relationship between lipid-lowering drugs and AF. In addition, we performed a mediation analysis of 91 circulating inflammatory factors to explore potential mediators. Sensitivity analyses were performed to verify the reliability of the MR Results by MR-Egger intercept test, Cochran's Q test and leave-one-out test.
The results of IVW method showed that LPL agonist had a protective effect on AF(OR = 0. 854, 95%CI: 0.816-0.894, = 1.844E-11). However, the other nine lipid-lowering drug targets had no significant effect on AF. Notably, we found a mediator role of Fibroblast Growth Factor 5 (FGF5) in the protective effect of LPL agonist on AF with a mediator ratio of 9.22%. Sensitivity analyses supported the robustness of our findings, indicating a possible mediating pathway by which LPL agonists affect the risk of AF.
Our study provides new insights into the complex interactions among lipid-lowering agents, circulating inflammatory factors and AF, and also identified a potential mediating role of FGF5 in the pathogenesis of AF. Our findings highlight the potential of LPL agonists and targeting specific inflammatory factors for therapeutic intervention in AF, providing promising avenues for future research and clinical strategies for the management and prevention of AF.
既往研究表明降脂药物、循环炎症因子与心房颤动（AF）之间存在关联，但降脂药物对AF的具体影响以及它们是否可由循环炎症因子介导仍不清楚。
基于全基因组关联研究（GWAS）汇总统计数据，我们收集了10个编码降脂药物靶点（低密度脂蛋白受体、3-羟基-3-甲基戊二酰辅酶A还原酶、前蛋白转化酶枯草溶菌素9、尼曼匹克C1样蛋白1、载脂蛋白B、载脂蛋白B、ATP结合盒转运体G5、ATP结合盒转运体G8、脂蛋白脂肪酶、载脂蛋白C3和过氧化物酶体增殖物激活受体α）的基因变异和AF相关数据。采用药物靶点孟德尔随机化（MR）方法探讨降脂药物与AF之间的因果关系。此外，我们对91种循环炎症因子进行了中介分析，以探索潜在的中介因素。通过MR-Egger截距检验、 Cochr an Q检验和留一法检验进行敏感性分析，以验证MR结果的可靠性。
逆方差加权（IVW）法结果显示，脂蛋白脂肪酶（LPL）激动剂对AF具有保护作用（比值比=0.854，95%置信区间：0.816-0.894，P=1.844E-11）。然而，其他9个降脂药物靶点对AF无显著影响。值得注意的是，我们发现成纤维细胞生长因子5（FGF5）在LPL激动剂对AF的保护作用中起中介作用，中介比例为9.22%。敏感性分析支持了我们研究结果的稳健性，表明LPL激动剂影响AF风险的可能中介途径。
我们的研究为降脂药物、循环炎症因子和AF之间的复杂相互作用提供了新的见解，同时也确定了FGF5在AF发病机制中的潜在中介作用。我们的研究结果突出了LPL激动剂以及靶向特定炎症因子在AF治疗干预中的潜力，为未来研究以及AF管理和预防的临床策略提供了有前景的途径。
