Potassium channels and uteroplacental vessels function in pregnant long QT type 1 women

项目总结 长QT间期综合征(LQTS)是一种心脏通道病，易发生室性心律失常和 心脏骤停。1型LQTS(LQT1)是由KCNQ1或KCNE1基因突变引起的，KCNQ1或KCNE1编码电压- 门控K+(Kv7.1)通道和辅助亚基。携带致病Kv7.1变异的母亲显示 与一般人群相比，胎儿生长受限和妊娠丢失的发生率更高。KV7频道 已被证明有助于人类胎盘血管的扩张，而胎盘血管对维持 妊娠期间子宫胎盘灌流。KV7在胎盘绒毛膜板动脉中的表达减少 妊娠并发症，如先兆子痫。然而，Kv7.1在血管扩张反应中的作用 正常或复杂妊娠期间的母体阻力血管(即子宫肌层动脉)尚未 已澄清。我们实验室在健康和妊娠期子宫肌层动脉的血管反应性方面有丰富的经验。 并发症。我们的初步数据显示，依赖Kv7.1的绒毛膜板状动脉的血管扩张是 与健康对照组相比，一些LQT1患者的LQT1降低。因此，我们假设受损的功能 和/或Kv7.1在子宫肌层和/或胎盘动脉的表达是不良妊娠结局的基础 在LQT1患者中观察到。为了验证这一假设，我们提出了两个综合的科学目标。在AIM 1，我们将研究Kv7.1通道在分离的子宫肌层和绒毛膜板动脉中的血管扩张作用。 剖宫产后有LQT1或正常妊娠的妇女。我们将通过电线评估体外血管扩张 肌电图像术。我们还将评估KV7及其辅助蛋白在子宫肌层和子宫肌层中的表达和定位。 胎盘组织。目的2将确定临床超声指标子宫胎盘血流是否可以预测 LQT1期妇女胎盘功能不全。我们将使用三维能量超声来评估子宫动脉的血流 3个不同胎龄(14、20和34周)的胎盘血管形成指数 LQT1女性。我们将把这些测量与胎儿和新生儿的生物测量以及妊娠结局联系起来。 从科学上讲，拟议的工作对于提高我们对 在LQT1妇女中观察到胎儿生长减少和不良妊娠结局。我们提议的项目还包括 具有潜在的重要临床意义；尤其是，我们的研究结果可能确定新的治疗方法。 预防这些妊娠并发症的目标和诊断方法。

PROJECT SUMMARY Long QT syndrome (LQTS) is a cardiac channelopathy that predispose individuals to ventricular arrhythmias and cardiac arrest. Type 1 LQTS (LQT1) is caused by mutations in KCNQ1 or KCNE1, genes that encode for voltage- gated K+ (Kv7.1) channels and auxiliary subunits, respectively. Mothers with pathogenic Kv7.1 variants show higher prevalence of fetal growth restriction and pregnancy loss compared to general population. Kv7 channels have been shown to contribute to the vasodilation of human placental vessels, which are important in maintaining uteroplacental perfusion during pregnancy. Kv7 expression in placental chorionic plate arteries is reduced in pregnancy complications such as preeclampsia. However, the role of Kv7.1 in vasodilatory responses in maternal resistance vessels (i.e., myometrial arteries) during normal or complicated pregnancies has not been elucidated. Our lab has extensive experience in vasoreactivity of myometrial arteries in healthy and pregnancy complications. Our preliminary data show that Kv7.1-dependent vasodilation of chorionic plate arteries is reduced in some LQT1 patients compared with healthy controls. Thus, we hypothesize that impaired function and/or expression of Kv7.1 in myometrial and/or placental arteries underlies the adverse pregnancy outcomes observed in LQT1 patients. To test this hypothesis, we propose to conduct two integrated scientific aims. In Aim 1, we will address the vasodilatory role of Kv7.1 channels in myometrial and chorionic plate arteries isolated from women with LQT1 or normal pregnancies after delivery by C-section. We will assess vasodilation in vitro via wire myography. We will also evaluate the Kv7 and ancillary proteins expression and localization in myometrial and placental tissue. Aim 2 will determine whether clinical ultrasound indices of uteroplacental blood flow can predict placental insufficiency in LQT1 women. We will use 3-D power ultrasound to assess uterine artery blood flow and placental vascularization indices at three different gestational ages (14, 20 and 34 weeks) in control and LQT1 women. We will correlate these measurements with fetal and neonatal biometry and pregnancy outcomes. Scientifically, the work proposed is vital to improving our understanding of the mechanisms underlying the reduced fetal growth and adverse pregnancy outcomes observed in LQT1 women. Our proposed project also has potentially important clinical implications; in particular, our study outcomes may identify novel therapeutic targets and diagnostic approaches to prevent these pregnancy complications.