Orthostatic intolerance, which includes vasovagal syncope and postural orthostatic tachycardia syndrome, is common in children and adolescents. Elevated plasma homocysteine levels might participate in the pathogenesis of orthostatic intolerance. This study was designed to analyze the plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine. Plasma samples from 34 orthostatic intolerance children with a plasma homocysteine concentration > 9 µmol/L and 10 healthy children were subjected to ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry analysis. A total of 875 metabolites were identified, 105 of which were significantly differential metabolites. Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, 1-(1Z-octadecenyl)-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, histidine, isocitric acid, and DL-glutamic acid and its downstream metabolites were upregulated, whereas 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-sn-glycerol 3-phosphocholine, sphingomyelin (d18:1/18:0), betaine aldehyde, hydroxyproline, and gamma-aminobutyric acid were downregulated in the orthostatic intolerance group compared with the control group. All these metabolites were related to choline and glutamate. Heatmap analysis demonstrated a common metabolic pattern of higher choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid, and lower sphingomyelin (d18:1/18:0), 1-stearoyl-sn-glycerol 3-phosphocholine, and 1-palmitoyl-sn-glycero-3-phosphocholine in patients with certain notable metabolic changes (the special group) than in the other patients (the common group). The maximum upright heart rate, the change in heart rate from the supine to the upright position, and the rate of change in heart rate from the supine to the upright position of vasovagal syncope patients were significantly higher in the special group than in the common group (P < 0.05). Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid were positively correlated with the rate of change in heart rate from the supine to the upright position in vasovagal syncope patients (P < 0.05). The levels of choline-related metabolites and glutamate–related metabolites changed significantly in orthostatic intolerance children with high levels of plasma homocysteine, and these changes were associated with the severity of illness. These results provided new light on the pathogenesis of orthostatic intolerance.

中文翻译：

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血浆同型半胱氨酸水平高的直立不耐受儿童的血浆代谢组学特征

直立性不耐受，包括血管迷走性晕厥和直立性心动过速综合征，在儿童和青少年中很常见。血浆同型半胱氨酸水平升高可能参与直立不耐受的发病机制。本研究旨在分析血浆同型半胱氨酸水平高的直立不耐受儿童的血浆代谢组学特征。对34例血浆同型半胱氨酸浓度>9μmol/L的直立不耐受儿童和10例健康儿童的血浆样本进行超高压液相色谱和四极杆飞行时间质谱分析。共鉴定出 875 种代谢物，其中 105 种为显着差异代谢物。胆碱，1-硬脂酰-2-亚油酰-sn-甘油-3-磷酸胆碱，1-(1Z-十八烯基)-2-(4Z,7Z,10Z,13Z,16Z,19Z-二十二碳六烯酰)-sn-甘油-3-磷酸胆碱、组氨酸、异柠檬酸和 DL-谷氨酸及其下游代谢物上调，而 1-棕榈酰-sn-甘油-3-磷酸胆碱、1-硬脂酰-sn-甘油 3-磷酸胆碱、鞘磷脂 (d18:1/18 :0)，与对照组相比，立位不耐受组中甜菜醛、羟脯氨酸和γ-氨基丁酸的表达下调。所有这些代谢物都与胆碱和谷氨酸有关。热图分析表明，较高的胆碱、1-硬脂酰-2-亚油酰-sn-甘油-3-磷酸胆碱和 DL-谷氨酸以及较低的鞘磷脂 (d18:1/18:0)、1-硬脂酰-在具有某些显着代谢变化的患者（特殊组）中，sn-甘油3-磷酸胆碱和1-棕榈酰-sn-甘油-3-磷酸胆碱的使用量高于其他患者（普通组）。特殊组血管迷走性晕厥患者的最大直立位心率、仰卧位至直立位心率变化率、仰卧位至直立位心率变化率均显着高于普通组（P<0.05）。胆碱、1-硬脂酰-2-亚油酰-sn-甘油-3-磷酸胆碱、DL-谷氨酸与血管迷走性晕厥患者仰卧位至直立位心率变化率呈正相关（P < 0.05） 。在血浆同型半胱氨酸水平高的直立不耐受儿童中，胆碱相关代谢物和谷氨酸相关代谢物的水平发生显着变化，并且这些变化与疾病的严重程度相关。这些结果为直立不耐受的发病机制提供了新的线索。