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资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。先兆子痫影响3-5%的妊娠，并显着有助于孕产妇和新生儿的发病率和死亡率。我们已经产生了一个新的假说，关于先兆子痫的发展，假定两个主要特征独立地促进其发展。一个特征是妊娠前表型，其包括血浆体积减少、交感神经紧张升高、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相关性表明了这一特征。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，以前认为这是妊娠独有的，在妊娠前检查的妇女中。第二个特征是妊娠的生理性体积扩张。我们的理论是，先兆子痫的明显临床表现在妊娠晚期变得明显，这是由于1）由于长期适应低血管内容量（异常孕前表型）而无法耐受的女性的正常体积扩张或2）具有正常孕前表型（即双胞胎，葡萄胎妊娠）的女性的过度体积扩张。在这项研究中，我们提出了3个主要的具体目标，采用详细的全身生理测量妇女，这将支持这种病理生理学观点的发展先兆子痫;第一章我们将证实与高加索人和亚洲人先兆子痫相关的血管紧张素原基因型与未孕人群血浆容量减少有关，这种血浆容量收缩与升高的交感神经紧张，子宫血流量减少和妊娠前血小板活化增加，2）当我们跟踪这些妇女进入妊娠期时，我们将证明; a）妊娠前血浆容量低与妊娠早期交感神经张力升高和子宫血流减少有关（12周）尽管血浆容量扩张相似，但仍易发生异常胎盘形成，和B）孕前血浆容量与平均动脉压的变化间接相关（针对血浆体积膨胀校正）和晚期妊娠中血小板活化程度，3）最后，我们将证明妊娠导致产后血浆容量和动脉顺应性的增加，从而降低未来妊娠中先兆子痫和以后生活中高血压的风险。这是一项前瞻性纵向对照研究，旨在探讨先兆子痫发生的综合病理生理机制。本研究提出了一个新的假设，合成明显矛盾的数据到一个单一的连贯的理论进行评估。