Angiogenic Imaging in Pulmonary Arterial Hypertension

PAH is a disease of progressive remodeling and obliteration of the distal pulmonary vasculature. The overexpression of VEGF-A in the pulmonary vasculature of patients with PAH and animal models of disease is thought to reflect a process of disordered angiogenesis that is tightly coupled to disease progression. It is hypothesized that positron emission tomography (PET)-CT scan utilizing \[89Zr\]-bevacizumab, a radioisotope-conjugated humanized monoclonal antibody against VEGF-A, would provide a sensitive and specific molecular imaging modality to detect pulmonary vascular remodeling activity. To test this hypothesis the investigators propose a Phase I/II pilot study to enroll 10 patients with known severe idiopathic or familial PAH, 10 individuals with exercise-associated PAH (EPAH), thought to be a mild and early stage of PAH, and 10 healthy volunteers with no evidence of cardiopulmonary disease. This pilot study will compare standardized uptake values (SUV) for the retention of \[89Zr\]-bevacizumab in the distal pulmonary vasculature in these three populations. The kinetics of equilibration and wash-out of this probe will be assessed with sequential scans at 4 and 7 days following the injection of radionuclide. In patients with PAH or EPAH, repeat scans will be performed 1 year after the initial scan to assess whether changes in clinical status correlate with \[89Zr\]-bevacizumab retention. The ability of these protocols to discriminate between the lungs of healthy individuals versus patients with PAH or EPAH will be evaluated using the measure of peripheral lung tissue probe SUV, corresponding to distal pulmonary vessel uptake, normalized to the proximal aortic SUV, corresponding to the blood pool. These data will be used to define normative values for healthy controls versus PAH patients, and to generate cutoffs in signaling ratios with optimal sensitivity and specificity for disease detection. These normative ranges will be applied to the EPAH cohort to determine if this test retains sensitivity and specificity for a potentially milder, earlier form of PAH. This study is divided into 4 Aims: AIM 1: Test the hypothesis that expression of VEGF-A discerned by \[89Zr\]-bevacizumab imaging is increased in the distal pulmonary vascular bed in PAH patients compared to healthy individuals. AIM 2: Test the hypothesis that expression of VEGF-A discerned by \[89Zr\]-bevacizumab imaging is increased in the distal pulmonary vascular bed in patients with exercise-associated PAH compared to healthy individuals. AIM 3: Ascertain whether or not distal pulmonary vascular uptake of \[89Zr\]-bevacizumab correlates with clinical markers of PAH severity, including 6 minute walk distance, New York Heart Association functional class, right atrial pressure, mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, NT-proBNP, tricuspid annular plane systolic excursion (TAPSE) by echocardiography. AIM 4: Ascertain whether or not changes in distal pulmonary vascular uptake of \[89Zr\]-bevacizumab over 1 year in patients with PAH or EPAH correlates with changes in clinical status based on clinical markers of PAH severity.