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: 7780332
• 负责人: Pirooz Eghtesady
• 金额: $ 18.75万
• 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/7780332
• 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，每年影响出生婴儿的百分之一。许多复杂的病变在胎儿生命早期就开始作为简单的缺陷，导致胎儿心脏内血流模式异常，但最终导致主要心脏结构发育异常。尽管新生儿心脏手术取得了巨大进步，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显着风险。现在，这些缺陷越来越多地可以在怀孕早期（约 20 周）通过胎儿超声心动图来识别，从而在产后结局严峻时考虑宫内治疗。某些干预措施需要进行子宫内心脏直视手术，这反过来又需要体外循环支持。然而，胎儿搭桥术后的胎盘功能障碍仍然是胎儿心脏手术临床转化的主要障碍。这种胎盘功能障碍表现为胎盘血管阻力增加、胎儿气体交换恶化以及胎儿循环重新分配。尽管自 20 世纪 80 年代以来不断进行努力，但导致胎儿搭桥术导致胎盘血管阻力增加的机制仍不清楚。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主要原因。应激激素加压素是胎儿/胎盘循环中的有效血管收缩剂，能够主要通过羊和人胎盘组织中存在的受体（V1 和 V2）增加胎盘血管阻力。胎儿侮辱和胎儿心脏手术的高压力事件会引起胎儿加压素水平快速而显着的升高（约基线的 100 倍）。胎儿搭桥手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胎儿循环，如果不加控制，会导致胎儿死亡。我们建议使用妊娠中期胎羊模型来检验加压素介导胎儿搭桥后观察到的胎盘和胎儿血管循环障碍的假设。具体目标 1 检验了以下假设：选择性 V1 加压素受体拮抗剂可防止胎盘血管阻力增加，并通过胎儿心脏手术和搭桥改善胎儿气体交换。具体目标 2 定义了胎盘中加压素受体作用的机制，该机制导致胎盘血管阻力增加和胎盘功能障碍（胎儿心脏手术和胎儿搭桥术）。明确胎盘加压素受体对胎儿旁路反应的机制将允许合理应用现有的加压素拮抗剂疗法。这种新颖的应用可以为胎儿外科医生提供合理的工具，将胎儿心脏手术的应用转化为临床或改善胎儿的结局。研究结果还可能转化为世界上首例成功的人类胎儿心脏直视手术。公共健康相关性：美国每年出生的 40,000 名患有心脏缺陷的婴儿中，有一些缺陷非常复杂或危及生命，因此这些婴儿在子宫内时就可以从进行的矫正性心脏直视手术中获益最多。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旁路支持而不对胎盘造成伤害。我们的研究将使用标准绵羊模型来检查在胎儿心脏直视手术期间保护胎盘的药物的使用情况。通过这种方式，我们可以在对人类婴儿尝试此手术之前完善我们的技术。