Prepregnancy Phenotype & Predisposition to Pre-eclampsia

描述（由申请人提供）：先兆子痫影响3-5%的妊娠，对孕产妇和新生儿的发病率和死亡率有重要影响。我们已经产生了一个关于先兆子痫发展的新假设，假设两个主要特征独立地促进了其发展。其中一个特征是孕前表型，包括血浆量减少，交感神经张力升高，心室血流减少和血小板活化增强。血管紧张素原（TT235）的特定遗传多态性与子痫前期风险增加有关，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特征有关，在怀孕前检查的妇女中，以前认为子痫是妊娠独有的。第二个特点是妊娠期生理性容积扩张。我们的理论认为，子痫前期的明显临床表现在妊娠后期变得明显，可能是以下两种情况的结果：1)由于慢性适应血管内体积低（异常孕前表型）而无法耐受的正常体积扩张；2)正常孕前表型（如双胞胎、磨牙妊娠）的女性体积过度扩张。在这项资助中，我们建议检查3个主要的具体目标，采用详细的女性全身生理测量，这将支持这种病理生理学观点的先兆子痫的发展；1)我们将证实与白种人和亚洲人子痫前期相关的血管紧张素原基因型与无妊娠人群血浆容量减少有关，并且这种血浆容量收缩与妊娠前交感神经张力升高、子宫血流量减少和血小板活化升高有关。2)随着我们对这些妇女的随访，我们将证明；a)低孕前血浆容量与妊娠早期（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，但易导致胎盘异常；b)孕前血浆容量与妊娠晚期平均动脉压（经血浆容量扩张校正）变化和血小板活化程度间接相关。我们将证明妊娠导致产后血浆容量和动脉顺应性的增加，从而降低未来妊娠发生子痫前期和以后生活中高血压的风险。这将是一项对照前瞻性纵向研究，检查子痫前期发展的综合病理生理机制。本研究提出评估一个新的假设，综合明显矛盾的数据成一个单一的连贯的理论。

DESCRIPTION (provided by applicant): 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 utenne blood flow and enhanced platelet activation. This feature has been suggested by the association of a specific genetic polymorphism of angiotensinogen (TT235) 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 Iowering 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.