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

单心室心脏病的肺血管发育：纵向生物标志物方法

• 批准号: 10591167
• 负责人: Benjamin S Frank
• 金额: $ 18.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591167
• 关键词: 4D MRI; Acceleration; Affect; Amino Acids; Arginine; Biological Markers; Blood Vessels; Blood flow; Bronchitis; Cell Proliferation; Cessation of life; Child; Childhood; Chronic; Cirrhosis; Clinical; Clinical Sciences; Clinical Trials; Clinical Trials Design; Common Ventricle; Cross-Sectional Studies; Data; Data Analyses; Development; Diagnosis; Diagnostic tests; Disease; Disease Marker; Drainage procedure; Endothelin A Receptor; Endothelin-1; Ensure; Evaluation; Failure; Family; Fontan Procedure; Funding; Future; Glutamates; Glutamine; Goals; Growth; Health; Heart; Hypoxemia; Impairment; Intervention; Length of Stay; Link; Liquid substance; Longitudinal Studies; Lung; Magnetic Resonance Imaging; Maps; Master of Science; Measures; Metabolic; Metabolic Pathway; Methods; Monitor; Morbidity - disease rate; Nitric Oxide; Operative Surgical Procedures; Outcome; Oxygen; Pathologic; Pathway interactions; Patients; Perioperative; Phenotype; Pleural; Pleural effusion disorder; Population; Positioning Attribute; Postoperative Complications; Postoperative Period; Prospective, cohort study; Protein-Losing Enteropathies; Publications; Pulmonary Valve Insufficiency; Pulmonary Vascular Resistance; Pulmonary artery structure; Pump; Readiness; Research; Research Design; Risk; Serology; Serum; Severities; Single ventricle congenital heart disease; Smooth Muscle Myocytes; Testing; Time; Tryptophan; Tryptophan Metabolism Pathway; Vasoconstrictor Agents; Vasodilator Agents; antagonist; cardiac magnetic resonance imaging; career development; clinical diagnostics; congenital heart disorder; constriction; design; diagnostic biomarker; experience; improved; indexing; innovation; interest; metabolomics; new therapeutic target; novel; novel marker; operation; palliation; protein biomarkers; pulmonary vascular disorder; skills; small molecule; therapeutic target; timeline

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.

项目概要/摘要 背景：患有单心室心脏病（SVHD）的儿童由于以下原因而发病率显着 肺血管发育不足导致肺血流量不足。诊断和选项 治疗这种病理性肺血管的发育仍然有限。内皮素-1 (ET1) 和精氨酸/硝酸 氧化氮（NO）和色氨酸代谢物与病理性肺血管发育有关。 我们小组的初步数据表明循环 ET1、精氨酸代谢物和色氨酸发生变化 第二阶段姑息治疗时的代谢产物。这些途径异常在第 2 阶段和第 2 阶段之间持续存在 第三阶段姑息治疗及其与结果的关联尚未研究。 假设：SVHD 患者 ET1 增加以及精氨酸/NO 和色氨酸途径失调 分阶段姑息治疗会扰乱肺血管发育，导致肺血减少 在关键的前 3 生长年中，血流量增加、低氧血症恶化和心肺疾病 术后即刻以及整个童年时期。 目的：量化 SVHD 中 ET1、精氨酸/NO 代谢物和色氨酸代谢物的血清浓度 受试者在第二阶段和第三阶段姑息治疗之前和之后，以及在 Fontan 后的时间 心脏 MRI 用于：1) 确定第 2 阶段（持续途径）生物标志物异常之间的关联 第 3 阶段的变化和第 3 阶段的肺血管生长，2) 评估生物标志物之间的关联 第 3 阶段的异常、第 3 阶段手术的肺血管充足性以及术后 并发症，以及 3) 确定促血管生成代谢特征、血管生成变化之间的关系 主肺侧支负荷，以及第 3 阶段前后肺动脉血流动力学的改变。 方法：对接受阶段性 SVHD 姑息治疗联合治疗的儿童进行纵向、前瞻性队列研究 一项针对老年 SVHD 患者的横断面研究。 影响：1) 第一项关于 SVHD 姑息治疗早期 ET1 暴露的纵向研究，以支持未来的发展 ET1作为ET1受体拮抗剂的临床诊断测试和生物标志物导向的临床试验。 2）第一 精氨酸/NO 和色氨酸代谢作为病理标志物的综合通路图谱 CHD 中的肺血管发育。 3) 理解 AP 抵押品的新代谢组学方法 表型和疾病/潜在治疗靶点的新标志物的鉴定。 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。我将通过理学硕士学位来增强这一点 临床科学 (MSCS) 专门针对高级数据分析和临床试验设计。综合起来， 这些发展目标将使我能够实现成为 R01 资助的肺病专家的目标 先天性心脏病儿童的血管发育。