Early Detection of Changes in Pulmonary Gas Exchange by Hyperpolarized Xe MRI

项目摘要/摘要 呼吸困难(呼吸急促)是寻求医疗服务的最常见原因之一。它有一个 患病率与慢性疼痛不相上下，占急诊室就诊人数的10%。呼吸困难的治疗包括 广泛的诊断检测，成本高，诊断时间慢。呼吸困难的负担将进一步 随着更多的患者出现慢性冠状病毒感染的症状，这一数字也在增加。129Xe磁共振提供了一个有希望的解决方案 其全面、非侵入性、快速的肺功能成像。通过它的溶解性和组织- 依赖化学位移，129Xe探针从远端空气空间通过肺组织扩散转移 间质(膜)到毛细血管红细胞(RBC)；这提供了驱动因素的3D分解 气体交换。然而，为了充分评估呼吸困难，我们必须解决肺动脉高压(PH)和 缺氧。我们通过量化心源性红细胞信号振荡来做到这一点，这可以区分治疗前和治疗后 毛细血管PH和利用~(129)Xe-RBC化学位移检测毛细血管血氧。而是为了 结合这些强大的129Xe-RBC生物标志物，我们必须知道它们是如何影响血红蛋白的 肺泡氧分压及其对肺血管流量变化的反应。我们的长期目标是 开发一个5分钟的、全面的、129Xe的MRI/MRS检查，显示所有可治疗的呼吸困难的特征。我们带来了 开创性研究的记录，先进的获取、重建和分析方法，以及 经验丰富的临床医生合作调查员，可以接触到必要的患者群体并进行比较 临床评估。这次更新的目标是展示改变这三个方面的干预措施 与129Xe-RBC相关的生物标志物--RBC转移、心源性振荡和化学位移。我们的中央 假设是通过使用适当的患者群体和精心选择的干预措施，每一个 这些129Xe-RBC标志物可以被修改，以巩固我们对它们的理解，用于临床决策 制作。这项拟议研究的基本原理是将这些生物标志物推进到多中心临床试验中。 以扩大FDA对129Xe通风磁共振成像的预期批准。这项工作与美国国立卫生研究院的 通过发展和加快生物医药技术的应用来改善健康。我们将追求三个目标 具体目标：1)建立并验证129Xe核磁共振的血红蛋白校正；2)确定氧气的影响 在129Xe MRI/MRS指标上的应用；3)测量急慢性治疗的纵向变化 肺栓塞。完成这些目标将1)建立对红细胞相关的129Xe的理解 生物标志物，2)它们对治疗的反应，以及3)为氧气治疗的更广泛的研究奠定了基础。建议数 方法是创新的，因为它使用了新的技术、患者群体和干预措施来揭示 呼吸困难的生理驱动因素。它意义重大，因为它将使单个5分钟129Xe的开发成为可能 MRI/MRS检查，可以有效地评估呼吸困难的多种可能原因。

Project Summary/Abstract Dyspnea (shortness of breath) is among the most common reasons for seeking medical attention. It has a prevalence rivaling chronic pain and accounts for 10% of emergency room visits. Dyspnea workups involve extensive diagnostic testing, with high cost, and a slow time to diagnosis. The burden of dyspnea will further increase as more patients present with symptoms from long COVID. 129Xe MRI provides a promising solution with its comprehensive, non-invasive, and rapid imaging of lung function. Enabled by its solubility and tissue- dependent chemical shift, 129Xe probes diffusive transfer from the distal airspaces through the pulmonary interstitium (membrane) to the capillary red blood cells (RBCs); this provides a 3D decomposition of the drivers of gas exchange. However, to fully evaluate dyspnea, we must address pulmonary hypertension (PH) and hypoxia. We do this by quantifying cardiogenic RBC signal oscillations, which can differentiate pre- and post- capillary PH and exploiting the 129Xe-RBC chemical shift to interrogate mean capillary blood oxygenation. But to incorporate these powerful 129Xe-RBC biomarkers, we must know how they are affected hemoglobin, changing alveolar oxygen tension and how they respond to changes in pulmonary vascular flow. Our long-term goal is to develop a 5-min, comprehensive, 129Xe MRI/MRS exam that reveals all the treatable traits of dyspnea. We bring a track-record of pioneering studies, advanced acquisition, reconstruction and analysis methods, and experienced clinician co-investigators who can access the necessary patient populations and comparative clinical assessments. The objective of this renewal is to demonstrate interventions that change each of the three 129Xe-RBC related biomarkers – RBC transfer, cardiogenic oscillations, and chemical shift. Our central hypothesis is that by employing appropriate patient populations and carefully selected interventions, each of these 129Xe-RBC markers can be modified in a way that solidifies our understanding of them for clinical decision making. The rationale for the proposed research is to advance these biomarkers into multi-center clinical trials to expand upon anticipated FDA approval for 129Xe ventilation MRI. This work is relevant to the NIH Mission of improving health by developing and accelerating the application of biomedical technologies. We will pursue three Specific Aims: 1) Establish and validate a hemoglobin correction for 129Xe MRI, 2) determine the effect of oxygen administration on 129Xe MRI/MRS Metrics, and 3) measure longitudinal therapeutic change in acute and chronic pulmonary embolism. Completion of these aims will 1) establish understanding of the RBC-associated 129Xe biomarkers, 2) how they respond to therapy, and 3) set the stage for broader studies of O2 therapy. The proposed approach is innovative because it uses novel technologies, patient groups and interventions to uncover the physiological drivers of dyspnea. It is significant because it will enable development of a single 5-minute 129Xe MRI/MRS exam that can efficiently assess the multiple possible etiologies of breathlessness.