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， 由于缺乏反映疾病进程的明确生物标志物。 PAH的特征是肺部 具有异常细胞增殖和纤维化的血管重塑。这导致阻塞性血管病 肺动脉菌的肺动脉高压（pH）和进行性右心力衰竭 发病和死亡率。血液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。但是，这些读数在另一个常见的心中发生了改变， 肺部疾病及其变化不是肺血管重塑的特异性。缺乏特异性 导致对直接监测肺血管重塑的非侵入性方法的严重未满足的需求 在PAH中，可用于指导患者的治疗，从而改善其健康结果。解决 这种需求，我们已经开发了129xE磁共振成像（129xE MRI）作为生产的方法 跨肺气体屏障的定量3D气体转移。 129XE MRI具有独特的PAH 签名并可以同时测量与 肺血管重塑。该项目的目的是关联病理肺血管 在PAH中重塑在细胞和病理水平上，气体交换生理学的特定变化和 血液动力学。我们假设不同类型的重塑，例如炎症，纤维化和 增殖，导致可以监测的气体交换生理和血液动力学的独特变化 具有129xE MRI。我们的初步研究已经确定了一个129XE MRI特征，将PAH与其他 常见的心脏和肺部疾病。该技术也对早期肺血管重塑敏感1-2 在临床前大鼠pH模型中暴露于单蛋白（MCT）后几周。我们将扩展这些研究，并 通过以下特定目标确定我们的目标。在AIM 1中，我们将确定 PAH患者的肺血管重塑以及气体动力学异常 接受肺移植，以将肺病理和细胞身份与129xE MRI气体中的缺陷相关联 交换和光谱法。在AIM 2中，我们将确定不同监视方法的灵敏度 pH的MCT和Sugen催眠临床前模型中的早期重塑和对治疗的反应。在AIM 3中，我们 将确定129XE 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与肺部变化之间的直接联系 生理学，以及一种用于监测的新型无创生物标志物。这项拟议的研究很重要 因为它将定义肺血管重塑与气体变化之间的机械联系 PAH中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 他们为诊所中无创诊断和监测PAH活动的策略奠定了基础。