PRegnancy OuTcomEs and subclinical Cardiovascular disease sTudy: (PROTECT)

摘要 这项建议的目标是妊娠结局和亚临床心血管疾病研究(PROTECT)， 是为了了解危险因素的轨迹和相互关联的不良妊娠结局的机制 (APOS)和亚临床心血管疾病(CVD)。妊娠高血压疾病，早产， 小于胎龄的APOS是常见的APOS，发病率增加，目前近五分之一的病例并发 美国的怀孕人数。这些APO与心血管疾病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亚型的表现(妊娠期高血压疾病、早产和小儿麻痹 胎龄)，这些APO被认为是相互关联的血管疾病，具有共同的潜在基础 与胎盘发育缺陷有关的病理生理学。导致异常的过程 胎盘形成早在临床表现明显之前就开始了，后来经历过任何一次APO的妇女 亚型(包括和除妊娠高血压疾病外)更有可能(但不是普遍) 以较高的血压水平进入怀孕阶段。因此，目前尚不清楚APO是反映潜在的心血管疾病风险，还是 自身是未来心血管疾病的独立危险因素。此外，经历过这些APO的女性 亚型孕妇在妊娠后5年内发生高血压的风险较高。然而，中国的发展 APO后的高血压和其他传统的心血管危险因素可能只能部分解释这种增加 以后患心血管疾病的风险。来自小规模生物标志物研究的初步数据表明潜在的机制 APOS和CVD可能与炎症和抗血管生成有关。因此，为了阐明 在APOS和CVD之间的途径，关键是从女性的第一次怀孕开始，并将两者结合起来 妊娠内危险因素水平(APOS上游)和孕后纵向随访(下游 APOS)。我们建议利用正在进行的NHLBI资助的未分娩妊娠结局研究： 监测准妈妈心脏健康研究(nuMoM2B-HHS)：一项种族/人种和地理研究 在第一次怀孕期间招募了不同的队列，严格判断怀孕结果，范围广泛 暴露数据和纵向随访。我们将进行颈动脉超声检查，以评估标准和新型 检查已经经历过和没有经历过APOS的女性的成像参数的差异。在目标1中，我们 将量化APO和亚临床心血管疾病之间的关联的强度和方向性，独立于 妊娠早期血压升高。在目标2中，我们将确定APO和APO之间的关系 亚临床脑血管病是由孕后血压介导的。在目标3中，我们将鉴定早期怀孕蛋白质组 与APOS和亚临床心血管疾病相关的通路。完成这些目标将产生新颖和 对亚临床心血管疾病发展轨迹和机制的重要见解，为量身定制的心血管疾病提供信息 预防战略，并为APOS后的妇女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.