Mechanism of Vasopressin-Mediated Placental Vascular Resistance after Fetal Bypas

胎儿绕道术后加压素介导的胎盘血管阻力机制

• 批准号: 7660599
• 负责人: Pirooz Eghtesady
• 金额: $ 22.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660599
• 关键词: Acidosis; Adrenal Glands; Affect; American Heart Association; Birth; Blood Circulation; Blood Vessels; Blood flow; Brain; Bypass; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cardiovascular system; Catheters; Child; Chronic; Clinic; Clinical; Complex; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Deterioration; Development; Disease; Echocardiography; Face; Fetal Distress; Fetal Heart; Fetal Therapies; Fetoplacental Circulation; Fetus; Functional disorder; Gases; Goals; Heart; Heart Diseases; Heart failure; Heel; Hormones; Human; Hypoxia; Infant; Infusion procedures; Intervention; Kidney; Lead; Lesion; Life; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Neonatal; Nitric Oxide Pathway; Operative Surgical Procedures; Organ; Outcome; Pattern; Peripheral; Pharmaceutical Preparations; Pituitary Gland; Placenta; Plasma; Pregnancy; Premature Mortality; Procedures; Reporting; Research; Respiratory physiology; Risk; Sheep; Stress; Stressful Event; Structure; Surgeon; Techniques; Testing; Time; Tissues; Translating; Translations; United States; Uterus; V1 Receptors; Vascular resistance; Vasoconstrictor Agents; Vasopressin Antagonist; Vasopressin Receptor; Vasopressins; base; biological adaptation to stress; clinical application; congenital heart disorder; fetal; fetal cardiac surgery; fetus surgery; hemodynamics; improved; in utero; instrumentation; mortality; novel; postnatal; prenatal stress; prevent; public health relevance; response; tool; vasoconstriction

DESCRIPTION (provided by applicant): Congenital heart disease is the most common of all birth defects, affecting 1 in 100 infants born each year. Many of the complex lesions begin early in fetal life as simple defects that cause abnormal blood flow patterns within the fetal heart, but ultimately result in abnormal development of major cardiac structures. Despite great advances in neonatal cardiac surgery, a child born with congenital heart disease will likely face far greater morbidity and significant risk of premature mortality. Increasingly, these defects can now be identified early in pregnancy (~20 weeks) by fetal echocardiography, allowing consideration of in utero therapy when postnatal outcomes are grim. Certain interventions require in utero open-heart surgery, which in turn necessitates cardiopulmonary bypass support. However, placental dysfunction following fetal bypass remains the primary impediment to clinical translation of fetal cardiac surgery. This placental dysfunction manifests as an increase in placental vascular resistance, deterioration in fetal gas exchange, and redistribution of fetal circulation. Despite continuing efforts since the 1980's, the mechanism(s) leading to increased placental vascular resistance with fetal bypass remain unexplained. As part of our long-term goal to translate fetal cardiac surgery to the clinic, the purpose of this study is to demonstrate that the fetal stress hormone vasopressin is a key mediator and central cause of fetal circulatory dysfunction during, and following fetal cardiac surgery. The stress hormone vasopressin is a potent vasoconstrictor in the fetal/placental circulation capable of increasing placental vascular resistance primarily through its receptors, (V1 & V2) which are present in ovine and human placental tissues. Fetal insults and the highly stressful event of fetal cardiac surgery elicit rapid and profound increases in fetal vasopressin levels, (~100 times baseline). Placental dysfunction following fetal bypass and cardiac surgery share all the classic hallmarks of vasopressin mediated vasoconstriction: increased peripheral vasoconstriction, placental vascular resistance, and centralized fetal circulation, which when uncontrolled, leads to fetal demise. We propose to test the hypothesis that vasopressin mediates the placental and fetal vascular circulatory disturbances seen following fetal bypass using a mid-gestation fetal sheep model. Specific Aim 1 tests the hypothesis that selective V1 vasopressin receptor antagonism prevents increased placental vascular resistance and improves fetal gas exchange with fetal cardiac surgery and bypass. Specific Aim 2 defines the mechanism(s) of vasopressin receptor actions in the placenta that cause increased placental vascular resistance and placental dysfunction with fetal cardiac surgery and fetal bypass. Defining the mechanism by which placental vasopressin receptors respond to fetal bypass will permit reasonable application of available vasopressin antagonist therapy. This novel application may provide the fetal surgeon with a reasonable tool to translate application of fetal cardiac surgery to the clinic or improve fetal outcomes. The results could also translate into the world's first successful human fetal open-heart procedure. PUBLIC HEALTH RELEVANCE: Some of the 40,000 babies born every year in the United States with heart defects have defects so complex or life-threatening that these babies would benefit most from corrective open heart surgery performed when they are still in the womb. However, the ability to perform fetal open-heart surgery depends on providing cardiopulmonary bypass support during surgery without causing harm to the placenta. Using a standard sheep model our study will examine the use of medications that would protect the placenta during fetal open heart surgery. In this way we can perfect our techniques before attempting this procedure in human babies.

描述（由申请人提供）：先天性心脏病是所有出生缺陷中最常见的，每年每100名婴儿中就有1名受到影响。许多复杂的病变开始在胎儿生命的早期，作为简单的缺陷，导致胎儿心脏内的异常血流模式，但最终导致主要心脏结构的异常发育。尽管新生儿心脏手术取得了很大进展，但出生时患有先天性心脏病的儿童可能会面临更高的发病率和过早死亡的重大风险。越来越多地，这些缺陷现在可以确定在怀孕早期（约20周）的胎儿超声心动图，允许考虑在子宫内治疗时，产后结果是严峻的。某些干预措施需要在子宫内进行心脏直视手术，这反过来又需要心肺转流支持。然而，胎盘功能障碍后，胎儿旁路仍然是主要的障碍，胎儿心脏手术的临床翻译。这种胎盘功能障碍表现为胎盘血管阻力增加、胎儿气体交换恶化和胎儿循环重新分布。尽管自20世纪80年代以来一直在努力，但导致胎儿旁路胎盘血管阻力增加的机制仍然无法解释。作为我们将胎儿心脏手术转化为临床的长期目标的一部分，本研究的目的是证明胎儿应激激素血管加压素是胎儿心脏手术期间和之后胎儿循环功能障碍的关键介质和中心原因。应激激素加压素是胎儿/胎盘循环中的有效血管收缩剂，能够主要通过其受体（V1和V2）增加胎盘血管阻力，所述受体存在于绵羊和人胎盘组织中。胎儿损伤和胎儿心脏手术的高度应激事件引起胎儿血管加压素水平快速而显著的增加（约为基线的100倍）。胎儿搭桥术和心脏手术后的胎盘功能障碍具有加压素介导的血管收缩的所有经典特征：外周血管收缩增加、胎盘血管阻力和集中的胎儿循环，当不受控制时，导致胎儿死亡。我们建议使用妊娠中期胎羊模型来检验这一假设，即加压素介导了胎儿旁路术后胎盘和胎儿血管循环障碍。特异性目的1检验选择性V1加压素受体拮抗剂通过胎儿心脏手术和搭桥术预防胎盘血管阻力增加并改善胎儿气体交换的假设。具体目标2定义了胎盘中血管加压素受体作用的机制，该机制导致胎儿心脏手术和胎儿搭桥术时胎盘血管阻力增加和胎盘功能障碍。明确胎盘血管加压素受体对胎儿转流反应的机制将允许合理应用现有的血管加压素拮抗剂治疗。这一新的应用可以为胎儿外科医生提供一个合理的工具，将胎儿心脏手术的应用转化为临床或改善胎儿结局。这一结果也可能转化为世界上第一个成功的人类胎儿心脏直视手术。公共卫生相关性：在美国，每年有4万名患有心脏缺陷的婴儿出生，其中一些婴儿的缺陷非常复杂或危及生命，这些婴儿在子宫内进行心脏直视手术时受益最大。然而，进行胎儿心脏直视手术的能力取决于在手术期间提供心肺转流支持而不对胎盘造成伤害。使用标准绵羊模型，我们的研究将检查在胎儿心脏直视手术中保护胎盘的药物的使用。通过这种方式，我们可以完善我们的技术，然后再尝试在人类婴儿身上进行这种手术。