Background: Acute pulmonary embolism (PE) can cause a sudden rise in pulmonary artery (PA) pressure and right ventricular dysfunction (RVD), which can lead to circulatory collapse and death. Increased PA pressure and RVD results from mechanical obstruction by thrombus, but also pulmonary artery (PA) vasoconstriction. We have developed a validated porcine model of acute PE and found that, after experimental induction of PE with RVD, supplemental oxygen rapidly and reproducibly reduces PA pressure by 50%. However, it is not known how supplemental oxygen reduces PA pressure and RVD, nor is it known whether the underlying mechanisms also apply to human patients. We hypothesize that oxygen affects RVD primarily by relieving hypoxic pulmonary vasoconstriction and reducing PA pressure, and that this process is metabolically driven. To study this hypothesis, we designed a mechanistic trial of supplemental oxygen in patients with acute PE and a correlated study of PE in pigs. Setting: This study will be performed in the Massachusetts General Hospital Emergency Department (MGH ED), Harvard Medical School (HMS), and Aarhus University, Denmark. Patients with acute PE will be enrolled in the MGH ED by experienced clinical researchers with expertise in PE and bedside echocardiography. At Aarhus University an experienced team of cardiologists and anesthesiologists will perform experiments on our porcine model of PE with RVD. Metabolomics will be performed by Metabolon and analyses will be performed at HMS. Research Plan: In the MGH ED, we will perform a randomized, crossover trial of 80 human subjects with acute PE, evidence of RVD, and no baseline hypoxemia. Patients will be randomized to breathe room air or 60% supplemental oxygen via facemask. Therapy will be alternated at T=15, T=30, T=45 minutes, and then maintained for 180 minutes. After each change and at 180 minutes, we will: 1) perform echocardiograms and calculate specific measurements to identify the mechanisms by which supplemental oxygen changes PA pressure and RV function and, 2) draw blood for agnostic metabolomic analyses and to test our a priori hypotheses that the regulation of diacylglycerols, triacylglycerols, PC plasmalogens, TCA-cycle intermediates, acyl carnitines, and breakdown products of branched-chain amino acids change with supplemental oxygen. At Aarhus University, we will experimentally induce PE with RVD in 24 pigs. As in our human experiment, we will measure PA pressure, RV function, and circulating metabolites. We will also assess changes in pulmonary perfusion and cardiac metabolism associated with supplemental oxygen using dual-energy computed tomography and hyperpolarized MRI. Relevance to Public Health: PE causes >100,000 annual deaths and is the third most common cause of cardiovascular mortality in the U.S.. This project will decipher the underlying molecular and pathogenic changes induced by supplemental oxygen in PE. Our study design is innovative, based on strong preclinical data, and our results may identify therapeutic targets for future clinical trials.

Project Narrative: This study will enroll patients diagnosed with pulmonary embolism (blood clots in the lung) in the emergency department and treat them with either supplemental oxygen or normal room air. The purpose of the study is to determine how supplemental oxygen affects the pulmonary artery, right ventricle, and metabolic processes in patients with these blood clots. We will also perform experiments in pigs with pulmonary emboli to determine how treatment with supplemental oxygen affects the flow of blood through the lungs and cardiac metabolism.