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.

抽象的 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 的特点是肺 血管重塑伴有异常细胞增殖和纤维化。这会导致阻塞性血管病变 肺小动脉的损伤，导致肺动脉高压（PH）和进行性右心衰竭，从而导致 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和 监测进展和对治疗的反应。然而，这些读数在其他普通心脏和 肺部疾病及其变化并不特定于肺血管重塑。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迫切需求未得到满足 在 PAH 中，可用于指导患者的治疗，从而改善他们的健康结果。致地址 针对这一需求，我们开发了129Xe磁共振成像（129Xe MRI）作为一种方法来产生 穿过肺血气屏障的气体传输的定量 3D 图。 129Xe MRI 具有明显的 PAH 特征并可以同时测量毛细血管血容量和血流动力学变化 肺血管重塑。该项目的目的是将病理性肺血管与 PAH 在细胞和病理水平上进行重塑，并伴有气体交换生理学的特定变化和 血流动力学。我们假设不同类型的重塑，例如炎症、纤维化和 增殖，导致可监测的气体交换生理学和血流动力学的独特变化 129Xe MRI。我们的初步研究已经确定了 129Xe MRI 特征，可以将 PAH 与其他疾病区分开来。 常见的心脏和肺部疾病。该技术对早期肺血管重塑也很敏感1-2 在临床前大鼠 PH 模型中暴露于野百合碱 (MCT) 几周后。我们将扩展这些研究并 通过以下具体目标来确定我们的目标。在目标 1 中，我们将确定之间的关系 PAH 患者的肺血管重塑以及气体交换和血流动力学异常 进行肺移植，将肺病理学和细胞特性与 129Xe MRI 气体缺陷相关联 交换和光谱学。在目标 2 中，我们将确定不同监测方法对 PH 的 MCT 和 Sugen 缺氧临床前模型中的早期重塑和治疗反应。在目标 3 中，我们 将确定 129Xe MRI 纵向监测患者疾病进展的能力。预期的 该项目的成果将是肺血管重塑和肺功能变化之间的直接联系 生理学，以及用于监测的新型非侵入性生物标志物。这项拟议的研究意义重大 因为它将定义肺血管重塑和气体变化之间的机制联系 PAH 的交换生理学和血流动力学。这些研究将产生重要的积极影响，因为 它们为临床中 PAH 活动的无创诊断和监测策略奠定了基础。