MitoQによる妊娠高血圧腎症における血管機能改善 (MAVEN)

Preeclampsia (PreE) impacts ~10% of pregnancies and has severe outcomes both during and after pregnancy. It is a leading cause of pregnancy-related deaths and has long term cardiovascular consequences for maternal and child health. Despite advances in the understanding of preeclampsia over the past 50 years, the underlying unifying mechanism causing preeclampsia remains elusive. This critical gap not only encompasses lack of understanding of the pathophysiology, but it also includes a lack of therapeutics for prevention or treatment. Success in this study could translate into a clinical trial that could finally offer a treatment for PreE.

The investigators have recently demonstrated that endothelial function in the human placental microcirculation is impacted by excess reactive oxygen and nitrogen species (ROS, RNS) from the mitochondria (MT), which in preeclampsia, impairs vasodilation. Excess ROS causes decreased nitric oxide (NO) bioavailability, increased lipid peroxidation, uncoupled eNOS, peroxynitrite, and exacerbates MT dysfunction and MT DNA damage via alterations in NO. Microvascular function can be improved by mechanisms that rebalance the oxidative stress response. The investigators have shown that MitoTempol, a MT antioxidant, improves vasodilation. Moreover, the investigators have shown that a major part of the cycle of excessive oxidative stress is caused by MT DNA damage and subsequent activation of toll like receptor 9 (TLR9), and that inhibiting TLR9 prevents this dysfunction. The finding that MT antioxidants given ex-vivo can reverse placental vascular damage after delivery gives promise that treatment of patients during pregnancy could restore vasodilation and allow for safer prolongation of pregnancy.

MitoQ (Mitoquinol Mesylate) is a nutritional supplement, and mitochondrial antioxidant. MitoQ has been extensively studied pre- clinically in cell-culture, and pregnant mouse, rat, and sheep models of PreE or oxidative stress and demonstrated beneficial fetal results. It has been used in clinical trials for heart failure, hepatitis C, Parkinson's, and multiple sclerosis with doses from 10mg to 80mg per day.

Overall Hypothesis: The investigators hypothesize that MitoQ (Mitoquinol Mesylate)-treated preeclampsia and/or gHTN patients will have improved brachial artery flow-mediated dilation (FMD) and laser Doppler flowmetry assessments of the cutaneous microvasculature, and that placental endothelial function in micro-vessels and placental pathology will be improved in treated patients. To demonstrate this, the investigators will enroll two pilot human cohorts- one of admitted patients with preeclampsia with severe features who will either continue standard in-patient clinical care or be supplemented daily with MitoQ (Mitoquinol Mesylate) and a second outpatient cohort of patients with preeclampsia without severe features or gHTN who will received standard outpatient care or be supplemented daily with MitoQ

Aim: Test whether with MitoQ (Mitoquinol Mesylate) treatment in gHTN/preeclamptic patients improves endothelial function Hypothesis: MitoQ (Mitoquinol Mesylate)-treated patients will have improved brachial artery FMD and laser Doppler flowmetry assessments of the cutaneous microvasculature and placental endothelial function in micro-vessels and placental pathology will be improved in treated patients.