血清VAP-1在妊娠期高血壓的角色

Abstract

在已開發國家，妊娠期高血壓位居孕期母親死亡原因的首位。此外，患有嚴重妊娠期高血壓的母親產下的胎兒約四分之一呈現胎兒窘迫，三分之一為早產兒。早期預測妊娠期高血壓的發生一直是產前檢查的重點之一。已有證據指出，在懷孕早期給予阿斯匹靈可有效降低子癲前症的發生率。學界一直致力於發展能預期妊娠期高血壓的生物指標。 血管黏附蛋白-1 (Vascular adhesion protein-1) 是分子量為170000道爾頓的糖蛋白。位於血管內皮的VAP-1其主要作用為輔助白血球移動，穿越血管至發炎組織。研究指出，血清VAP-1的濃度與活性在許多心血管疾病會發生變化。此外，多個研究也發現VAP-1參與了血管新生的病理機轉。 我們於是假設VAP-1可能是妊娠期高血壓的致病因子之一。希望藉由血清中的VAP-1預測妊娠期高血壓的發生。 我們於2013年至2015年之間針對在台大醫院產檢的孕婦進行一項前瞻性的世代研究。加入研究的541位病患之中，480位有完整的懷孕與生產記錄。26病患發生妊娠期高血壓（佔5.42%），其中12位(佔2.50%)診斷為妊娠高血壓，14位(佔2.92%)診斷為子癲前症。 發生妊娠期高血壓的病患，其發病前第二孕期的平均VAP-1血清濃度（267.92ng/ml, SD=72.84）較正常懷孕病患的數值（307.20 ng/ml, SD=61.14, p=0.0023）為低。第一孕期的平均VAP-1血清濃度也觀測到同樣的情況(313.2 ng/ml vs. 359.5 ng/ml)，然而其差異不具統計顯著(p=0.11)。我們使用ROC曲線分析來評估第二孕期的平均VAP-1血清濃度對於妊娠期高血壓的預測能力。結果顯示其ROC曲線下方的面積(AUC)為0.64（95% CI, 0.57-0.80）。若再加上母親是否有高血壓病史，是否曾發生過子癲前症，是否為雙胞胎妊娠，及懷孕前身體質量指數（BMI）等參數，則AUC可達0.83（95% CI, 0.74-0.92）。 總結而言，本研究顯示利用VAP-1血清濃度，母親病史與身體質量指數，可有效預測之後發生妊娠期高血壓的機會。

Hypertensive disorders of pregnancy (HDP) are the leading causes of maternal mortality in developed countries. Additionally, one quarter of the babies born to mothers with preeclampsia, a severe HDP, are growth restricted and one third are premature. Early identification of HDP remains one of the major focuses of antenatal care. Evidence suggests that early administration of low-dose aspirin could reduce the incidence of preeclampsia. Much effort has been made to identify biomarkers that predict hypertensive disorders of pregnancy. Vascular adhesion protein-1 (VAP-1), a 170-kDa transmembrane homodimer glycoprotein, is a vascular endothelial adhesion molecule involved in leukocyte rolling, adhesion, and transmigration into sites of inflammation. Changes in both serum VAP-1 concentration and activity have been reported in various vascular diseases. VAP-1 is also thought to be involved in neo-angiogenesis of various disease states. We hypothesized that VAP-1 expression may be involved in the development of HDP and that serum VAP-1 concentration may be used as a predictive biomarker of HDP. We conducted a prospective cohort study of pregnant women who underwent prenatal examination at National Taiwan University Hospital (NTUH) from 2013 through 2015. Among 541 patients recruited into the study, pregnancy outcome data were available in 480 patients. HDP developed in 26 (5.42%) subjects, of whom 12 (2.50%) had gestational hypertension and 14 (2.92%) had preeclampsia. Mean VAP-1 serum concentration during the second trimester, before diagnosis of HDP, was significantly lower in HDP cases (267.92 ng/ml, SD=72.84) than in non-affected cases (307.20 ng/ml, SD = 61.14, P = 0.0023). First trimester VAP-1 serum concentration also showed a similar trend but with borderline significance (P = 0.11). The predictive value of second trimester VAP-1 serum concentration was evaluated by receiver-operating characteristic (ROC) curve analysis. When used alone, the area under the ROC curve (AUC) is 0.64 (95% CI, 0.57–0.80) for predicting HDP. When combined with a history of preeclampsia, history of hypertension, higher body mass index (BMI) before pregnancy, and twin pregnancy, AUC scored 0.83 (95% CI, 0.74–0.92) for predicting HDP. In conclusion, effective screening for HDP can be provided by a combination of serum VAP-1 and maternal characteristics.