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

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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.