PREDISPOSITION TO DEVELOP PREECLAMPSIA

发生先兆子痫的倾向

• 批准号: 7378576
• 负责人: IRA MARK BERNSTEIN
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-09 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378576
• 关键词: blood; eclampsia; phenotype; plasma; platelet activation; preeclampsia; pregnancy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Preeclampsia affects 3-5% of pregnancies and contributes significantly to maternal and neonatal morbidity and mortality. We have generated a novel hypothesis regarding the development of pre-eclampsia that postulates that two primary features contribute independently to its development. One feature is a pre-pregnancy phenotype that includes reduced plasma volume, elevated sympathetic tone, reduced uterine blood flow and enhanced platelet activation. This feature has been suggested by the association of a specific genetic polymorphism of angiotensinogen (TT 235) with an increased risk for pre-eclampsia. This polymorphism has been linked in our preliminary data to key pathophysiologic features of pre-eclampsia, previously thought to be exclusive to pregnancy, in women who are examined prior to pregnancy. The second feature is the physiologic volume expansion of pregnancy. We have theorized that the overt clinical manifestations of pre-eclampsia become apparent in late pregnancy as a result of either 1) a normal volume expansion in women unable to tolerate it due to a chronic adaptation to low intravascular volume (abnormal prepregnancy phenotype) or 2) an excessive volume expansion in women with a normal prepregnancy phenotype (i.e. twins, molar pregnancies). In this grant we propose to examine 3 primary specific aims, employing detailed whole body physiologic measurements in women, that will support this pathophysiologic view of the development of preeclampsia; 1) We will confirm that the angiotensinogen genotype that has been linked to preeclampsia in Caucasians and Asians is associated with reduced plasma volume in a nulligravid population and that this plasma volume constriction is associated with elevated sympathetic tone, reduced uterine blood flow and heightened platelet activation prior to pregnancy, 2) As we follow these women into pregnancy we will demonstrate; a) that low prepregnancy plasma volume is associated with elevated sympathetic tone and reduced uterine blood flow in early pregnancy (12 weeks) predisposing to abnormal placentation despite similar plasma volume expansion, and b) that prepregnancy plasma volume is indirectly related to both the change in mean arterial pressure (corrected for plasma volume expansion) and degree of platelet activation in the third trimester, 3) Finally, we will demonstrate that pregnancy results in an increase in both post-puerperal plasma volume and arterial compliance lowering the risk for both preeclampsia in future pregnancies and hypertension in later life. This will be a controlled prospective longitudinal study examining an integrated pathophysiologic mechanism underlying the development of preeclampsia. This study proposes to evaluate a novel hypothesis that synthesizes apparently contradictory data into a single coherent theory.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。先兆子痫影响 3-5% 的妊娠，并显着增加孕产妇和新生儿的发病率和死亡率。我们提出了一个关于先兆子痫发生的新假说，该假说假设两个主要特征独立地促进了先兆子痫的发生。其中一个特征是孕前表型，包括血浆容量减少、交感神经张力升高、子宫血流量减少和血小板活化增强。血管紧张素原 (TT 235) 的特定遗传多态性与先兆子痫风险增加的关联表明了这一特征。在我们的初步数据中，这种多态性与先兆子痫的关键病理生理学特征有关，以前认为先兆子痫是妊娠前检查的女性所独有的。第二个特点是妊娠的生理体积扩张。我们推测，先兆子痫的明显临床表现在妊娠晚期变得明显，原因如下：1）女性因长期适应低血管内容量（异常孕前表型）而无法耐受正常的容量扩张，或2 ）具有正常孕前表型（即双胞胎、葡萄胎妊娠）的女性体积过度膨胀。在这笔赠款中，我们建议研究 3 个主要具体目标，对女性进行详细的全身生理测量，这将支持先兆子痫发展的病理生理学观点； 1) 我们将确认与白人和亚洲人先兆子痫相关的血管紧张素原基因型与未怀孕人群血浆容量减少有关，并且这种血浆容量收缩与交感神经张力升高、子宫血流量减少和血小板活化增强有关怀孕前，2）当我们跟踪这些妇女怀孕时，我们将证明； a) 孕前血浆容量低与妊娠早期（12 周）交感神经张力升高和子宫血流量减少有关，尽管血浆容量扩张相似，但容易导致胎盘异常；b) 孕前血浆容量与妊娠早期（12 周）的交感神经张力升高和子宫血流量减少相关妊娠晚期的平均动脉压（根据血浆容量扩张进行校正）和血小板活化程度，3) 最后，我们将证明怀孕会导致产后血浆容量和动脉顺应性增加降低未来怀孕时患先兆子痫和晚年患高血压的风险。这将是一项对照前瞻性纵向研究，检查先兆子痫发展的综合病理生理机制。这项研究旨在评估一种新颖的假设，该假设将明显矛盾的数据综合成一个单一的连贯理论。