Background and purpose Previous studies have found ischemic stroke is associated with atrial fibrillation. However, the causal association between ischemic stroke and atrial fibrillation is not clear. Furthermore, the network relationship among ischemic stroke, atrial fibrillation and its risk factors need further attention. This study aims to examine the potential causal association between ischemic stroke and atrial fibrillation and further to explore potential mediators in the causal pathway from ischemic stroke to atrial fibrillation. Methods Summary statistics from the ISGC (case = 10,307 and control = 19,326) were used as ischemic stroke genetic instruments, AFGen Consortium data (case = 65,446 and control = 522,744) were used for atrial fibrillation, and other consortia data were used for potential mediators (fasting insulin, white blood cell count, procalcitonin, systolic and diastolic blood pressure, body mass index, waist circumference, and height). Under the framework of network Mendelian randomization, two-sample Mendelian randomization study was performed using summary statistics from several genome-wide association studies. Inverse-variance weighted method was performed to estimate causal effect. Results Blood pressure mediates the causal pathways from ischemic stroke to atrial fibrillation. The total odds ratio of ischemic stroke on atrial fibrillation was 1.05 (95% confidence interval [CI], 1.02 to 1.07; P = 1.3 × 10 −5 ). One-unit increase of genetically determined ischemic stroke was associated with 0.02 (DBP: 95% CI, 0.001 to 0.034, P = 0.029; SBP: 95% CI, 0.006 to 0.034, P = 0.003) upper systolic and diastolic blood pressure levels. Higher genetically determined systolic and diastolic blood pressure levels were associated with higher atrial fibrillation risk (DBP: RR, 1.18; 95% CI, 1.03 to 1.35; P = 0.012. SBP: RR, 1.18; 95% CI, 1.01 to 1.38; P = 0.04). Specially, we also found the bidirectional causality between blood pressure and ischemic stroke. Conclusions Our study provided a strong evidence that raised blood pressure in stroke patients increases the risk of atrial fibrillation and active acute blood pressure lowering can improve the outcome in ischemic stroke patients.

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探索从缺血性中风到心房颤动的因果途径：网络孟德尔随机化研究


背景和目的先前的研究发现缺血性中风与心房颤动相关。然而，缺血性卒中与心房颤动之间的因果关系尚不清楚。此外，缺血性脑卒中、心房颤动及其危险因素之间的网络关系值得进一步关注。本研究旨在探讨缺血性卒中与心房颤动之间的潜在因果关系，并进一步探讨缺血性卒中与心房颤动因果途径中的潜在介质。方法 使用 ISGC 的汇总统计数据（病例 = 10,307 例，对照 = 19,326）作为缺血性中风遗传仪器，AFGen 联盟数据（病例 = 65,446 例，对照 = 522,744）用于心房颤动，其他联盟数据用于潜在介质（空腹胰岛素、白细胞计数、降钙素原、收缩压和舒张压、体重指数、腰围和身高）。在网络孟德尔随机化的框架下，利用多项全基因组关联研究的汇总统计数据进行双样本孟德尔随机化研究。采用逆方差加权法来估计因果效应。结果血压介导从缺血性中风到心房颤动的因果途径。缺血性卒中与房颤的总比值比为 1.05（95% 置信区间 [CI]，1.02 至 1.07；P = 1.3 × 10 -5 ）。基因决定的缺血性卒中增加 1 个单位与 0.02（DBP：95% CI，0.001 至 0.034，P = 0.029；SBP：95% CI，0.006 至 0.034，P = 0.003）上收缩压和舒张压水平相关。 基因决定的收缩压和舒张压水平越高，房颤风险越高（DBP：RR，1.18；95% CI，1.03 至 1.35；P = 0.012。SBP：RR，1.18；95% CI，1.01 至 1.38；P = 0.04）。特别地，我们还发现了血压与缺血性中风之间的双向因果关系。结论 我们的研究提供了强有力的证据，表明中风患者血压升高会增加心房颤动的风险，而积极的急性降压可以改善缺血性中风患者的预后。