Xenon MRI in Pulmonary Hypertension

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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.