Xenon MRI in Pulmonary Hypertension

氙 MRI 在肺动脉高压中的应用

• 批准号: 10204681
• 负责人: Bastiaan Driehuys
• 金额: $ 66.6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10204681
• 关键词: 3-Dimensional; Address; Appointment; Biological Markers; Blood Pressure; Blood Vessels; Blood Volume; Blood capillaries; Blood gas; Cardiac Catheterization Procedures; Cell Proliferation; Cessation of life; Clinic; Clinical; Clinical Research; Defect; Diagnosis; Disease; Disease Progression; Echocardiography; Exposure to; Failure; Fibrosis; Foundations; Future; Gases; Gold; Health; Heart Diseases; Heart failure; Hematological Disease; Histology; Histopathology; Hospitalization; Human; Hypoxia; Inflammation; Knowledge; Lead; Life; Link; Lung; Lung Transplantation; Lung diseases; MRI Scans; Magnetic Resonance Imaging; Maps; Measures; Methods; Mission; Modeling; Monitor; Monocrotaline; Morbidity - disease rate; Outcome; Pathologic; Pathology; Patient Monitoring; Patients; Pattern; Pharmacotherapy; Phenotype; Physiology; Pre-Clinical Model; Process; Public Health; Pulmonary Hypertension; Pulmonary Pathology; Rattus; Research; Savings; Severities; Signal Transduction; Specificity; Spectrum Analysis; Technology; Testing; Time; Transplantation; United States National Institutes of Health; Vascular Diseases; Vascular remodeling; Ventricular; Walking; Xenon; arteriole; base; clinical care; disease diagnosis; follow-up; heart function; hemodynamics; improved; lung imaging; mortality; new technology; non-invasive monitor; noninvasive diagnosis; novel; novel strategies; pre-clinical; prognostic; public health relevance; pulmonary arterial hypertension; response; single-cell RNA sequencing; standard of care

ABSTRACT The diagnosis and follow-up of patients with pulmonary arterial hypertension (PAH) continues to be challenging, with a lack of unambiguous biomarkers that reflect the course of the disease. PAH is characterized by pulmonary vascular remodeling with abnormal cellular proliferation and fibrosis. This leads to an obstructive vasculopathy of the pulmonary arterioles, resulting in pulmonary hypertension (PH) and progressive right heart failure that lead to morbidity and mortality. Hemodynamics and right heart function are commonly used to diagnose disease and monitor progression and response to therapy. However, these readouts are altered in other common heart and lung diseases and their changes are not specific to pulmonary vascular remodeling. This lack of specificity has resulted in critical unmet need for noninvasive approaches for directly monitoring pulmonary vascular remodeling in PAH that could be used to guide treatment in patients, thereby improving their health outcomes. To address this need, we have developed 129Xe magnetic resonance imaging (129Xe MRI) as a method to produce quantitative 3D maps of gas transfer across the pulmonary blood-gas barrier. 129Xe MRI has a distinct PAH signature and can simultaneously measure capillary blood volume and hemodynamic changes associated with pulmonary vascular remodeling. The objective of this project is to associate pathologic pulmonary vascular remodeling in PAH at a cellular and pathological level with specific changes in gas exchange physiology and hemodynamics. We hypothesize that different types of remodeling, such as inflammation, fibrosis and proliferation, result in unique changes in gas exchange physiology and hemodynamics that can be monitored with 129Xe MRI. Our preliminary studies have identified a 129Xe MRI signatures that differentiates PAH from other common heart and lung diseases. This technology is also sensitive to early pulmonary vascular remodeling 1-2 weeks after exposure to monocrotaline (MCT) in a preclinical rat PH model. We will extend these studies and determine our objective via the following specific aims. In Aim 1, we will determine the relationship between pulmonary vascular remodeling and both gas exchange and hemodynamic abnormalities in PAH patients undergoing lung transplant, to correlate lung pathology and cellular identity with defects in 129Xe MRI gas exchange and spectroscopy. In Aim 2, we will determine the sensitivity of different monitoring approaches to early remodeling and response to therapy in the MCT and Sugen-hypoxia preclinical models of PH. In Aim 3, we will determine the ability of 129Xe MRI to longitudinally monitor disease progression in patients. The expected outcomes of this project will be a direct link between pulmonary vascular remodeling and changes in lung physiology, along with a novel, noninvasive biomarker for its monitoring. This proposed research is significant because it will define the mechanistic links between pulmonary vascular remodeling and changes in gas exchange physiology and hemodynamics in PAH. These studies will have an important positive impact because they lay the foundation for a strategy of noninvasive diagnosis and monitoring of PAH activity in the clinic.

摘要 肺动脉高压（PAH）患者的诊断和随访仍然具有挑战性， 缺乏反映疾病进程的明确生物标志物。PAH的特征是肺部 血管重塑伴随异常细胞增殖和纤维化。这导致阻塞性血管病变 肺动脉高压（PH）和进行性右心衰竭， 发病率和死亡率。血流动力学和右心功能通常用于诊断疾病， 监测进展和对治疗的反应。然而，这些读数在其他普通心脏中被改变， 肺部疾病及其改变并不是肺血管重塑所特有的。这种缺乏特异性的情况 导致对直接监测肺血管重塑的非侵入性方法的关键未满足需求 在PAH中，可用于指导患者的治疗，从而改善其健康结局。解决 为了满足这一需求，我们开发了129磁共振成像（129 MRI）作为一种方法， 通过肺血气屏障的气体转移的定量3D图。129例MRI有明显的PAH 特征，并且可以同时测量与以下相关的毛细血管血容量和血液动力学变化： 肺血管重构本项目的目的是将病理性肺血管 PAH在细胞和病理水平的重塑，气体交换生理学的特定变化， 血流动力学我们假设不同类型的重塑，如炎症，纤维化和 增殖，导致气体交换生理学和血液动力学的独特变化， 129次核磁共振我们的初步研究已经确定了一个129碱基的MRI特征，可以区分PAH和其他 常见的心肺疾病。该技术对早期肺血管重构也很敏感1-2 在临床前大鼠PH模型中暴露于野百合碱（MCT）后7周。我们将继续进行这些研究， 通过以下具体目标确定我们的目标。在目标1中，我们将确定 肺动脉高压患者的肺血管重构及气体交换和血流动力学异常 进行肺移植，以将肺病理学和细胞特性与129 μ M MRI气体中的缺陷相关联 交换和光谱学。在目标2中，我们将确定不同监测方法的敏感性， 在MCT和Sugen-缺氧PH临床前模型中的早期重塑和对治疗的反应。在目的3中，我们 将确定129 MRI纵向监测患者疾病进展的能力。预期 该项目的结果将是肺血管重塑和肺组织变化之间的直接联系， 生理学，沿着一种新的，非侵入性的生物标志物，用于其监测。这项研究具有重要意义 因为它将定义肺血管重塑和气体变化之间的机械联系， PAH的交换生理学和血液动力学。这些研究将产生重要的积极影响，因为 它们为临床上PAH活性的非侵入性诊断和监测策略奠定了基础。