Zhang Siqi, Chen Tielong
Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China.
Department of Cardiology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China.
Medicine (Baltimore). 2025 Jun 6;104(23):e42713. doi: 10.1097/MD.0000000000042713.
Myocarditis is a self-limiting inflammatory disease with a high prevalence of severe arrhythmogenic cardiomyopathy and sudden death. Although studies have emphasized the strong association between myocarditis and immune cells and blood metabolites, the establishment of a causal relationship between these associations has yet to be clarified. Data on 731 immune cells (N = 3757), 1400 blood metabolites (N = 8299), and myocarditis were derived from the genome-wide association studies catalog database. Two-way two-sample Mendelian randomization studies first assessed genetic associations between exposures and outcomes. Mendelian randomization (MR) analyses were performed primarily using inverse variance weighting supplemented with MR-Egger, weighted median, weighted mode and simple models, using Cochran Q-test to detect heterogeneity and MR-Egger intercept to assess horizontal pleiotropy, in addition to leave-one-out for sensitivity analyses to ensure robust results. Finally, we used a two-step mediation analysis to identify pathways from immune cells to myocarditis mediated by blood metabolites. MR analysis identified genetic relationships between 27 immune cells and myocarditis, with no strong evidence that myocarditis can affect 25 circulating immune cells. In addition, 50 blood metabolites were screened for causal associations with myocarditis, and finally 19 mediating associations were obtained by two-step MR, of which 5 immune cells mediated strong causal associations between 6 blood metabolites and myocarditis. Notably, levels of 4-ethylphenyl sulfate and methyl-4-hydroxybenzoate sulfate mediated the association between circulating CCR2 on monocytes and FSC-A on NKT cells with myocarditis, with the effect ratio of 4-ethylphenyl sulfate at 19.4% (P = .003) and that of methyl-4-hydroxybenzoate sulfate at 13.9% (P = .007). Our results clarify the causal relationship between 13 circulating immune cells and 15 blood metabolites and myocarditis. This provides new biological markers for early prevention, diagnosis and treatment of myocarditis. It also facilitates real-time monitoring of the metabolic status of immune responses in myocarditis patients, which contributes to individual precision therapy.
心肌炎是一种自限性炎症性疾病，严重心律失常性心肌病和猝死的患病率很高。尽管研究强调了心肌炎与免疫细胞和血液代谢物之间的密切关联，但这些关联之间因果关系的建立仍有待阐明。来自全基因组关联研究目录数据库的731个免疫细胞（N = 3757）、1400种血液代谢物（N = 8299）和心肌炎的数据。双向双样本孟德尔随机化研究首先评估暴露与结局之间的遗传关联。孟德尔随机化（MR）分析主要使用逆方差加权法，并辅以MR-Egger、加权中位数、加权模式和简单模型，使用 Cochr an Q检验检测异质性，使用MR-Egger截距评估水平多效性，此外还采用留一法进行敏感性分析以确保结果的稳健性。最后，我们使用两步中介分析来确定从免疫细胞到由血液代谢物介导的心肌炎的途径。MR分析确定了27种免疫细胞与心肌炎之间的遗传关系，没有强有力的证据表明心肌炎会影响25种循环免疫细胞。此外，筛选了50种血液代谢物与心肌炎的因果关联，最终通过两步MR获得了19种中介关联，其中5种免疫细胞介导了6种血液代谢物与心肌炎之间的强因果关联。值得注意的是，硫酸4-乙基苯酯和硫酸甲基-4-羟基苯酯的水平介导了单核细胞上循环CCR2与NKT细胞上FSC-A与心肌炎之间的关联，硫酸4-乙基苯酯 的效应比为19.4%（P = 0.003），硫酸甲基-4-羟基苯酯的效应比为13.9%（P = 0.007）。我们的结果阐明了13种循环免疫细胞和15种血液代谢物与心肌炎之间的因果关系。这为心肌炎的早期预防、诊断和治疗提供了新的生物标志物。它还有助于实时监测心肌炎患者免疫反应的代谢状态，这有助于个体化精准治疗。
