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

项目摘要：妊娠期间发生先兆子痫的妇女， 随后的动脉粥样硬化性心血管疾病（ASCVD），但生物学机制， 介导这种风险尚未阐明。先兆子痫是否引发独特的病理生理学 导致ASCVD的过程，或加剧潜在的脆弱血管状态，它提供了一个 这是一个独特的机会，可以识别出晚期ASCVD风险增加的女性，并提供有关ASCVD的见解。 致病途径和潜在的治疗靶点。我们提出，高维生物标志物 先兆子痫的特征在女性的生命过程中是明显的，并且与 心血管异常：从怀孕，通过立即和后期产后期间， 在发展ASCVD的女性中。我们建议利用三个大的，嗯- 特点，正在进行的妇女队列（斯坦福大学3月的迪姆斯怀孕研究， 丹麦国家生物库和妇女健康倡议），并采用先进的方法， 收集和分析高维“组学”数据，并最终确定新的病理生理学联系 先兆子痫和ASCVD之间的关系我们将定义生物标志物签名， 妊娠期和产后早期先兆子痫，基于高维度测量 蛋白质组、代谢组、转录组和关键细胞组分，使用新的 计算方法，并确定其与心血管异常的关系（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相关性 疾病（内皮功能障碍），5至20年后先兆子痫的妇女无临床 明显的ASCVD（目标2）;并鉴定和验证先兆子痫生物标志物特征， 与临床上明显的ASCVD（心肌梗死、缺血性卒中或 冠状动脉或颈动脉的血运重建）（目标3）。最后，我们将整合 整个生命过程的数据，以确定先兆子痫生物标志物的演变及其 与心血管疾病的关联，以深入了解因果途径，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（目的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