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

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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.