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

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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.