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Xenon MRI in Pulmonary Hypertension

氙 MRI 在肺动脉高压中的应用

基本信息

批准号：
10415160
负责人：
Bastiaan Driehuys
金额：
$ 76.95万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10415160
关键词：
3-Dimensional Address Appointment Biological Markers 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 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 Walking Xenon arteriole base blood pressure elevation 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 pulmonary vascular disorder pulmonary vascular remodeling response right ventricular failure single-cell RNA sequencing standard of care treatment response

项目摘要

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