Preeclampsia to cardiovascular disease: Life course analysis of biomarkers and risk

项目摘要：怀孕期间患先兆子痫的女性患子痫前期的风险增加 随后的动脉粥样硬化性心血管疾病（ASCVD），但其生物学机制 介导这种风险的机制尚未阐明。先兆子痫是否引发独特的病理生理学 导致 ASCVD 或加剧潜在的脆弱血管状态的过程，它提供了 识别后期 ASCVD 风险增加的女性的独特机会，并提供见解 因果途径和潜在的治疗靶点。我们建议高维生物标志物 先兆子痫的特征在女性的一生中都很明显，并且与 心血管异常：从怀孕到产后早期和晚期， 几十年后，在患有 ASCVD 的女性中。我们建议利用三个大型、良好的 持续进行的女性群体特征研究（斯坦福大学关于怀孕的 March of Dimes 研究、 丹麦国家生物银行和妇女健康倡议），并应用尖端方法 收集和分析高维“组学”数据，并最终定义新的病理生理学联系 先兆子痫和 ASCVD 在整个生命过程中之间的关系。我们将定义生物标志物签名 怀孕期间和产后早期的先兆子痫，基于高维测量 使用新颖的方法分析蛋白质组、代谢组、转录组和关键细胞成分 计算方法，并确定它们与心血管异常的关联（目标 1）； 评估先兆子痫生物标志物特征及其与亚临床心血管疾病的关联 疾病（内皮功能障碍），无临床症状的女性在先兆子痫后五到二十年 明显的 ASCVD（目标 2）；识别并验证先兆子痫生物标志物特征 与临床明显的 ASCVD（心肌梗塞、缺血性中风或 冠状动脉或颈动脉的血运重建）在晚年（目标 3）。最后，我们将整合 整个生命周期的数据来定义先兆子痫生物标志物特征及其演变 与心血管疾病的关联，深入了解因果途径并指导预防 以及降低与先兆子痫相关的 ASCVD 过度风险的治疗策略（目标 4）。 1

Project Summary: Women who develop preeclampsia during pregnancy are at increased risk for subsequent atherosclerotic cardiovascular disease (ASCVD), but the biological mechanisms that mediate this risk have not been elucidated. Whether preeclampsia initiates unique pathophysiologic processes that lead to ASCVD, or exacerbates an underlying vulnerable vascular state, it provides a unique opportunity to identify women at increased risk for later ASCVD, and to provide insights into causal pathways and potential therapeutic targets. We propose that high dimensional biomarker signatures of preeclampsia will be evident across a woman's life-course, and will be associated with cardiovascular abnormalities: from pregnancy, through the immediate and late postpartum periods, to many decades later in women who develop ASCVD. We propose to leverage three large, well- characterized, ongoing cohorts of women (the Stanford March of Dimes study of pregnancy, the Danish National Biobank, and the Women's Health Initiative), and to apply cutting edge methods to gather and analyze high dimensional “omics” data, and ultimately define novel pathophysiologic links between preeclampsia and ASCVD across the life-course. We will define biomarker signatures of preeclampsia during pregnancy and early post-partum, based on high dimensional measurements of the proteome, metabolome, transcriptome, and key cellular components, analyzed using novel computational methods, and determine their association with cardiovascular abnormalities (Aim 1); assess preeclampsia biomarker signatures, and their association with subclinical cardiovascular disease (endothelial dysfunction), five to twenty years after preeclampsia in women free of clinically evident ASCVD (Aim 2); and identify and validate a preeclampsia biomarker signature that is associated with development of clinically evident ASCVD (myocardial infarction, ischemic stroke, or revascularization of the coronary or carotid arteries) in later life (Aim 3). Finally, we will integrate the data across the life-course to define the evolution of preeclampsia biomarker signatures and their association with cardiovascular disease, to gain insight into causal pathways, and guide preventive and therapeutic strategies to reduce the excess risk of ASCVD associated with preeclampsia (Aim 4). 1