Pulmonary Vascular Development in Single Ventricle Heart Disease: A Longitudinal Biomarker Approach

项目摘要/摘要 背景：单心室性心脏病(SVHD)的儿童由于以下原因而有显著的发病率 肺血管发育不足导致的肺血流量不足。用于诊断的选项和 治疗这种病理性肺血管发育仍然有限。内皮素-1(ET1)与精氨酸/一氧化氮 一氧化氮(NO)和色氨酸代谢产物与病理性肺血管发育有关。 我们小组的初步数据显示循环ET1、精氨酸代谢物和色氨酸发生了变化 第二阶段缓解时的代谢物。这些通路异常在第2期和第2期之间持续存在 第三阶段的姑息治疗及其与预后的关系尚未被研究。 假设：SVHD患者ET1水平升高，精氨酸/一氧化氮和色氨酸通路失调 阶段性姑息治疗会破坏肺血管发育，导致肺血流量减少 在关键的生长前期3年，血流、恶化的低氧血症和心肺疾病， 手术后即刻，以及整个童年。 目的：定量测定SVHD患者血清ET1、精氨酸/NO代谢物和色氨酸代谢物浓度 在第二阶段和第三阶段姑息治疗之前和之后，以及丰坦治疗后的受试者 心脏MRI：1)确定生物标记物异常与2期持续性径路之间的关联 阶段3的变化和阶段3的肺血管生长，2)评估生物标记物之间的关联 第三阶段的异常，第三阶段手术的肺血管充分性，以及手术后 并发症，以及3)确定促血管生成代谢特征，改变 3期前后的主-肺侧支负荷及肺动脉血流动力学改变。 方法：对接受阶段性SVHD姑息联合治疗的儿童进行纵向前瞻性队列研究。 一项对老年SVHD患者的横断面研究。 影响：1)首次对SVHD姑息治疗早期的ET1暴露进行纵向研究，以支持未来的发展 ET1作为ET1受体拮抗剂的临床诊断试验和生物标记物指导的临床试验。2)首先 精氨酸/一氧化氮和色氨酸代谢作为病理标志物的综合路径图 冠心病的肺血管发育。3)新陈代谢学方法对AP络脉的认识 疾病的表型和新标记物的识别/潜在的治疗靶点。 职业发展：拟议的研究将使我获得数据、技能、经验和出版物 需要支持我向独立研究的过渡。我将在此基础上再攻读理科硕士学位 临床科学(MSCS)专门针对高级数据分析和临床试验设计。加在一起， 这些发展目标将使我实现成为R01资助的肺科专家的目标 先天性心脏病儿童的血管发育。

Project Summary/Abstract Background: Children with single ventricle heart disease (SVHD) experience significant morbidity due to inadequate pulmonary blood flow from insufficient pulmonary vascular development. Options to diagnose and treat this pathologic pulmonary vascular development remain limited. Endothelin-1 (ET1) and both arginine/nitric oxide (NO) and tryptophan metabolites have been linked to pathologic pulmonary vascular development. Preliminary data from our group demonstrate alterations in circulating ET1, arginine metabolites, and tryptophan metabolites at the time of Stage 2 palliation. Persistence of these pathway abnormalities between Stage 2 and Stage 3 palliation and their association with outcomes have not been studied. Hypothesis: Increased ET1 and dysregulation of the arginine/NO and tryptophan pathways in SVHD patients undergoing staged palliation disrupts pulmonary vascular development, leading to decreased pulmonary blood flow, worsened hypoxemia, and cardiorespiratory morbidities during the critical pre-Stage 3 growth years, the immediate post-operative period, and throughout childhood. Aims: Quantify serum concentrations of ET1, arginine/NO metabolites, and tryptophan metabolites in SVHD subjects immediately prior to and following both Stage 2 and Stage 3 palliation, and at the time of post-Fontan cardiac MRI to: 1) determine the association between biomarker abnormalities at Stage 2, persistent pathway changes at Stage 3, and pulmonary vascular growth by Stage 3, 2) evaluate the association between biomarker abnormalities at Stage 3, pulmonary vascular adequacy for the Stage 3 operation, and post-operative complications, and 3) determine the relationship between a pro-angiogenic metabolic signature, changes in aorto-pulmonary collateral burden, and altered pulmonary arterial flow dynamics before and after Stage 3. Methods: Longitudinal, prospective cohort study in children undergoing staged SVHD palliation combined with a cross-sectional study of older SVHD patients. Impact: 1) First longitudinal study of ET1 exposure early in SVHD palliation to support future development of ET1 as a clinical diagnostic test and biomarker-directed clinical trials of ET1 receptor antagonist. 2) First comprehensive pathway mapping of arginine/NO and tryptophan metabolism as markers of pathologic pulmonary vascular development in CHD. 3) Novel metabolomic approach to understanding AP collateral phenotype and identification of new markers of disease/potential therapeutic targets. Career Development: The proposed study will allow me to gain the data, skills, experience, and publications needed to support my transition to independent research. I will augment this with a Master of Science degree in the Clinical Sciences (MSCS) specifically targeting advanced data analysis and clinical trial design. Combined, these development aims will position me to achieve my goal of becoming an R01 funded expert in pulmonary vascular development in children with congenital heart disease.