Novel, Non-invasive Multi-spectral, Multi-compartment 129Xe MR Gas-exchange Measurements: MUCXE

超极化129Xe磁共振成像提供了一种同时快速量化肺功能的方法，包括吸入气体在哪里通过呼吸道(通风)以及在哪里发生气体交换-肺泡和肺血管膜之间的界面以及毛细血管中的红细胞摄取(灌流)。这种新的、非侵入性的功能磁共振波谱(MRS)方法是在近30年前的一项基础研究物理学发现的基础上开创的。我的研究重点是发展肺129Xe MRI和MRS的采集和分析方法，以便更详细地从机制上了解：1)肺MRI通气性及其与呼吸道和实质结构的关系；2)肺的气体交换和灌流及其与终末气道和心肺血管结构和形态的关系。我们最近发现了两个推动这项医学物理学研究的发现。首先，我们偶然检测到了5倍的超级增强的129Xe磁共振红细胞信号，这反映了一名无症状的青少年患有先前沉默但严重的先天性心脏病(而不是以前模型中预测的肺动脉重构或肺动脉高压)。第二，我们首次表明，在长途COVID但肺功能正常的人中，129Xe MRI检测到了肺气体交换和/或换气异常。这些MRI表现与劳力性呼吸困难和饱和度降低高度相关，这巩固了肺气体交换和换气异常作为长距离COVID中心的作用。这些意想不到的发现导致了目前关于升级过时基础设施的提议，并将使我们能够提出关于InVivo 129Xe磁共振气体交换测量的生理学意义的重要问题。简而言之，我们建议建立一个生物物理模型，以基于129Xe测量来估计毛细血管体积、血流量、红细胞压积、粘度、血管体积和阻抗。虽然以前的模型忽略了心脏工作负荷对生理变异性的贡献，但我们将模拟不同的工作负荷条件。这项拟议的假设驱动的研究和机制建模依赖于高通量的129Xe极化(硬件和软件)和一套探测心肺对运动输出的影响的心肺测试设备。为了升级临终设备，我们请求为工具提供资金，这些工具将加速我们的研究，实现我们的目标，即解释和验证表现为呼吸困难和运动受限的肺部微小异常。有了这些建议的研究工具和我的实验室的物理研发专业知识，这一目标的实现是可能的。我的实验室目前由两名研究员、六名博士生、一名硕士和荣誉论文学生、三名本科生和两名研究人员组成，所需的基础设施将在我的实验室持续日常运行。

Hyperpolarized 129Xe MRI provides a way to simultaneously and rapidly quantify the function of the lung including where inhaled gas travels through the airways (ventilation) AND where gas-exchange occurs - the interface between the alveolar and pulmonary vascular membranes and uptake into red blood cells (perfusion) in the capillaries. This novel, non-invasive functional MRI and spectroscopy (MRS) method was pioneered on the basis of a basic research physics discovery nearly 30 years ago. My research program focuses on the development of pulmonary 129Xe MRI and MRS acquisition and analysis methods towards a detailed, mechanistic understanding of: 1) pulmonary MRI ventilation and its relationship with airway and parenchyma structure, and, 2) pulmonary gas-exchange and perfusion and their relationship with the structure and morphometry of the terminal airways and cardio-pulmonary vasculature. We recently discovered two findings that are driving this medical physics research. First, we serendipitously detected 5-fold super-enhanced 129Xe MRI red blood cell signal, which reflected previously silent but serious congenital heart disease in an asymptomatic teenager (and not pulmonary artery remodelling or pulmonary hypertension predicted in previous models). Second, we showed for the first time that in people with long-haul COVID but normal pulmonary function, 129Xe MRI detected pulmonary gas-exchange and/or ventilation abnormalities. These MRI findings were highly correlated with exertional dyspnea and desaturation which has cemented the role of pulmonary gas-exchange and ventilation abnormalities as central to long-haul COVID. These unexpected findings led to the current proposal to upgrade obsolete infrastructure and would allow us to ask important questions about the physiologic meaning of invivo 129Xe MRI gas-exchange measurements. Briefly, we propose to develop a biophysical model to estimate capillary volume, blood flow, hematocrit, viscosity, vessel volume, impedance based on 129Xe measurements. Whilst previous models have ignored cardiac workload contributions to physiologic variability, we will model diverse workload conditions. This proposed hypothesis-driven research and mechanistic modelling is dependent on high throughput 129Xe polarization (hardware and software) and a suite of cardiopulmonary testing equipment which probes cardiac and pulmonary influences on exercise output. To upgrade end-of-life equipment, we request funding for tools that will accelerate our research towards our goal of explaining and validating subtle abnormalities in the lung that manifest as dyspnea and exercise limitation. With these proposed research tools and my lab's physics R&D expertise, the accomplishment of this goal is possible. The requested infrastructure will be in continuous daily operation in my lab which currently consists of two fellows, six PhD students, a single MSc and honours thesis student, three undergrads and two staff researchers.