Document text
Principal Investigator: Bastiaan Driehuys
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $736,853
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <3-D><3-Dimensional><3D><Active Follow-up><Address><Appointment><Biological Markers><Blood Diseases><Blood Vessels><Blood Volume><Blood capillaries><Blood gas><Cardiac Catheterization><Cardiac Catheterization Procedures><Cardiac Diseases><Cardiac Disorders><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cellular Proliferation><Cessation of life><Clinic><Clinical><Common Rat Strains><Death><Defect><Diagnosis><Disease><Disease Progression><Disorder><Drug Therapy><Early Diagnosis><Echocardiogram><Echocardiography><Exposure to><Fibrosis><Foundations><Future><Gases><Health><Heart Catheterization><Heart Catheterization Procedure><Heart Diseases><Heart failure><Hematologic Diseases><Hematological Disease><Hematological Disorder><Histology><Histopathology><Hospital Admission><Hospitalization><Human><Hypoxia><Hypoxic><Inflammation><Insertion of catheter into heart chamber><Intracellular Communication and Signaling><Knowledge><Life><Link><Lung><Lung Diseases><Lung Grafting><Lung Respiratory System><Lung Transplantation><MR Imaging><MR Tomography><MRI><MRI Scans><MRIs><Magnetic Resonance Imaging><Magnetic Resonance Imaging Scan><Maps><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Methods><Mission><Modeling><Modern Man><Monitor><Monocrotaline><Morbidity><Morbidity - disease rate><NIH><NMR Imaging><NMR Tomography><National Institutes of Health><Nuclear Magnetic Resonance Imaging><Outcome><Oxygen Deficiency><Pathologic><Pathology><Patient Monitoring><Patients><Pattern><Pharmacotherapy><Phenotype><Physiology><Pre-Clinical Model><Preclinical Models><Process><Proliferating><Public Health><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Graft><Pulmonary Hypertension><Pulmonary Pathology><Pulmonary Transplant><Pulmonary Transplantation><Pulmonary imaging><Rat><Rats Mammals><Rattus><Research><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Spectroscopy><Spectrum Analyses><Spectrum Analysis><Technology><Testing><Time><Transplantation><Transthoracic Echocardiography><United States National Institutes of Health><Walking><Xe element><Xenon><Zeugmatography><active followup><arteriole><bio-markers><biologic marker><biological signal transduction><biomarker><blood disorder><blood pressure elevation><capillary><cardiac failure><cardiac function><clinical care><disease diagnosis><disease of the lung><disorder of the lung><drug treatment><early detection><elevated blood pressure><follow up><follow-up><followed up><followup><function of the heart><heart disorder><heart function><heart sonography><hemodynamics><impaired pulmonary vascularization><improved><increase in blood pressure><increased blood pressure><lung disorder><lung imaging><lung pathology><lung scanning><lung transplant><lung vascular disease><lung vascular remodeling><mortality><new approaches><new technology><non-invasive diagnosis><non-invasive diagnostic><non-invasive monitor><noninvasive diagnosis><noninvasive diagnostic><noninvasive monitor><novel><novel approaches><novel strategies><novel strategy><novel technologies><pre-clinical><preclinical><prognostic><public health relevance><pulmonary><pulmonary arterial hypertension><pulmonary artery hypertension><pulmonary vascular disease><pulmonary vascular disorder><pulmonary vascular dysfunction><pulmonary vascular remodeling><pulmonary vasculopathy><response><response to therapy><response to treatment><right heart failure><right sided heart failure><right ventricle failure><right ventricular failure><right ventricular heart failure><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><standard of care><therapeutic response><therapy response><three dimensional><transplant><treatment response><treatment responsiveness><vascular>