PRegnancy OuTcomEs and subclinical Cardiovascular disease sTudy: (PROTECT)

摘要 该提案的目标是，预防性结局和亚临床心血管疾病研究（PREGRESS）， 是了解风险因素的轨迹和机制，将相互关联的不良妊娠结局联系起来， （APO）和亚临床心血管疾病（CVD）。妊娠期高血压疾病，早产， 和小于胎龄儿是常见的APO，发病率增加，目前并发症近1/5 在美国怀孕。这些APO与CVD的短期和长期风险增加有关， 这是最近NHLBI工作组的重点。尽管临床上存在表型异质性， APO亚型的临床表现（妊娠期高血压疾病、早产和小血管疾病） 这些APO被认为是相互关联的血管疾病， 与胎盘发育缺陷有关的病理生理学。导致异常的过程 胎盘形成开始的时间远早于APO的临床表现， 亚型（包括妊娠期高血压疾病）更有可能（但不普遍） 怀孕时血压会更高因此，目前尚不清楚APO是否反映了潜在的CVD风险， 他们是未来CVD的独立风险因素。此外，经历任何这些APO的女性 亚型在怀孕后5年内发生高血压的风险较高。然而，发展 APO后高血压和其他传统CVD危险因素可能只能部分解释APO后高血压和其他传统CVD危险因素的增加。 有以后CVD的风险。来自小规模生物标志物研究的初步数据表明， APOs和CVD可能与炎症和抗血管生成有关。因此，为了阐明 APO和CVD之间的通路，从女性第一次怀孕开始开始并将两者结合起来是至关重要的 妊娠期风险因素水平（APO上游）和妊娠后纵向随访（APO下游） APO）。我们建议利用正在进行的NHLBI资助的未产妊娠结局研究： 监测准妈妈心脏健康研究（nuMoM 2b-HHS）：一项种族/民族和地理上的 在第一次妊娠期间招募的具有严格判定的妊娠结局的多样化队列，广泛 暴露数据和纵向随访。我们将进行颈动脉超声检查，以评估标准和新的 成像参数，以检查有和没有经历过APO的妇女的差异。目标1： 将量化APO和亚临床CVD之间关联的强度和方向性，独立于 怀孕早期的BP在目标2中，我们将确定APO与 亚临床CVD由妊娠后BP介导。在目标3中，我们将鉴定早孕蛋白质组， 与APO和亚临床CVD相关的途径。实现这些目标将产生新的和 对亚临床CVD发展轨迹和机制的重要见解，为定制CVD提供信息 预防策略，并为APO后的女性提前发现新的治疗靶点。

ABSTRACT The goal of this proposal, PRegnancy OuTcomEs and subclinical Cardiovascular disease sTudy (PROTECT), is to understand the trajectory of risk factors and mechanisms linking interrelated adverse pregnancy outcomes (APOs) and subclinical cardiovascular disease (CVD). Hypertensive disorders of pregnancy, preterm delivery, and small for gestational age are common APOs, increasing in incidence, and currently complicate nearly 1 in 5 pregnancies in the United States. These APOs are associated with increased short- and long-term risk of CVD, which was the focus of a recent NHLBI Working Group. Despite phenotypic heterogeneity in the clinical manifestations of APO subtypes (hypertensive disorders of pregnancy, preterm delivery, and small for gestational age), these APOs are thought to be interrelated vascular disorders with shared underlying pathophysiology related to defective placental development. The processes leading to abnormal placentation begin long before APOs are clinically apparent, and women who later experience any of the APO subtypes (including and in addition to hypertensive disorders of pregnancy) are more likely (but not universally) to enter pregnancy with higher BP levels. Therefore, it is unclear whether APOs reflect latent CVD risk or are themselves independent risk factors for future CVD. Moreover, women who experience any of these APO subtypes have a higher risk of incident hypertension within 5 years post-pregnancy. However, development of hypertension and other traditional CVD risk factors following an APO may only partially explain the increased risk for later CVD. Preliminary data from small-scale biomarker studies suggest underlying mechanisms linking APOs and CVD may be related to inflammation and anti-angiogenesis. Therefore, in order to elucidate the pathways between APOs, and CVD, it is critical to begin with a woman’s first pregnancy and incorporate both intra-pregnancy risk factor levels (upstream of APOs) and longitudinal follow-up post-pregnancy (downstream of APOs). We propose to leverage the ongoing NHLBI-funded Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be Heart Health Study (nuMoM2b-HHS): a racially/ethnically and geographically diverse cohort recruited during the first pregnancy with rigorously adjudicated pregnancy outcomes, extensive exposure data, and longitudinal follow-up. We will perform carotid artery ultrasound to assess standard and novel imaging parameters to examine differences in women who have and have not experienced APOs. In Aim 1, we will quantify the strength and directionality of associations between APOs and subclinical CVD, independent of BP in early pregnancy. In Aim 2, we will determine the extent to which the relationship between APOs and subclinical CVD is mediated by post-pregnancy BP. In Aim 3, we will identify early pregnancy proteomic pathways that are associated with APOs and subclinical CVD. Completion of these aims will yield novel and significant insights into the trajectory and mechanisms of development of subclinical CVD, inform tailored CVD prevention strategies, and advance discovery of new therapeutic targets for women following APOs.