Fosheim Ingrid K, Jacobsen Daniel P, Sugulle Meryam, Alnaes-Katjavivi Patji, Fjeldstad Heidi E S, Ueland Thor, Lekva Tove, Staff Anne C
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, Ueland, and Staff); Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, and Staff).
Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, and Staff).
Am J Obstet Gynecol MFM. 2023 Jan;5(1):100794. doi: 10.1016/j.ajogmf.2022.100794. Epub 2022 Nov 9.
Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid-aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear.
We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis.
Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the Mann-Whitney U, chi-squared, or Fisher exact test as appropriate. Spearman's rho was calculated for assessing correlations.
In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 µg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 µg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 µg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fms-like tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein.
Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease.
妊娠高血压疾病（子痫前期、妊娠高血压和慢性高血压）、糖尿病和胎盘功能障碍会增加孕产妇发生长期心血管疾病的风险。子痫前期还与急性动脉粥样硬化有关，后者涉及子宫胎盘螺旋动脉病变，类似于动脉粥样硬化的早期阶段。血清淀粉样蛋白A1参与高凝状态和动脉粥样硬化，可能聚集成错误折叠蛋白的淀粉样聚集体。妊娠区蛋白可能抑制淀粉样蛋白聚集。淀粉样蛋白与阿尔茨海默病和心血管疾病有关；它已在子痫前期中被发现，但其在子痫前期病理生理学中的作用尚不清楚。
我们假设在妊娠高血压疾病和糖尿病妊娠中，血清淀粉样蛋白A1会升高而妊娠区蛋白会降低，并且血清淀粉样蛋白A1和妊娠区蛋白会与胎盘功能障碍标志物（胎儿生长受限和血管生成生物标志物失调）及急性动脉粥样硬化相关。
血清淀粉样蛋白A1在血清和血浆中均可测量。在我们的研究中，对549例妊娠的血浆（血压正常、血糖正常的对照组：258例；早发型子痫前期：71例；晚发型子痫前期：98例；妊娠高血压：30例；慢性高血压：9例；糖尿病：83例）进行了血清淀粉样蛋白A1和妊娠区蛋白检测。547例妊娠有血管生成生物标志物可溶性fms样酪氨酸激酶-1和胎盘生长因子的血清水平数据，313例妊娠有急性动脉粥样硬化评估结果。根据情况使用曼-惠特尼U检验、卡方检验或费舍尔精确检验对妊娠组之间的临床特征和循环生物标志物进行比较。计算斯皮尔曼相关系数以评估相关性。
在早发型子痫前期中，血清淀粉样蛋白A1较对照组升高（17.1对5.1μg/mL，P<0.001），而妊娠区蛋白降低（590对892μg/mL，P=0.002）。与对照组相比，糖尿病患者的妊娠区蛋白也降低（683对892μg/mL，P=0.01）。血清淀粉样蛋白A1与胎盘功能障碍（胎儿生长受限、可溶性fms样酪氨酸激酶-1与胎盘生长因子比值升高）相关。在所有研究组中，妊娠区蛋白与可溶性fms样酪氨酸激酶-1与胎盘生长因子比值呈负相关。急性动脉粥样硬化与血清淀粉样蛋白A1或妊娠区蛋白无关。
参与动脉粥样硬化、高凝状态和蛋白错误折叠的蛋白质在早发型子痫前期和胎盘功能障碍中失调，这将它们联系起来，并可能导致未来的孕产妇心血管疾病。
