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Principal Investigator: CHRISTOPHER KABRHEL
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $568,519
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <1,2-diacylglycerol><Accident and Emergency department><Acute><Address><Affect><Air><American><Angiogram><Angiography><Biometrics><Biometry><Biostatistics><Blinded><Blood><Blood Clotting><Blood Reticuloendothelial System><Blood Sample><Blood coagulation><Blood flow><Blood specimen><Body Tissues><Branched-Chain Amino Acids><Breathing><CAT scan><CT X Ray><CT Xray><CT imaging><CT scan><Cardiac Output><Cardiology><Cardiopulmonary><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Carnitine><Categories><Catheters><Causality><Cessation of life><Chest><Circulatory Collapse><Citric Acid Cycle><Clinical><Clinical Trials><Collaborations><Computed Tomography><Correlation Studies><Cross-Over Trials><Crossover Trials><Data><Death><Denmark><Diacylglycerols><Diagnosis><Diglycerides><Dilatation><Dilatation - action><ED patient><ER patient><Echocardiogram><Echocardiography><Embolism><Embolus><Emergency Department><Emergency Department patient><Emergency Room patient><Emergency room><Enrollment><Etiology><Experimental Designs><Experimental Models><Failure><Family suidae><Fellowship><Financial cost><Future><General Hospitals><Heart><Heart Vascular><History><Human><Hypoxemia><Hypoxia><Hypoxic><Image><Incidence><Intermediary Metabolism><Interventricular Septum><Investigators><Knowledge><Krebs Cycle><Label><Left Ventricles><Left ventricular structure><Lung><Lung Respiratory System><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Massachusetts><Measurement><Measures><Mechanics><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Methodology><Modern Man><Molecular><Myocardial><Myocardial perfusion><NMR Imaging><NMR Tomography><Nuclear Magnetic Resonance Imaging><O element><O2 element><Obstruction><Oxygen><Oxygen Deficiency><Pathogenicity><Patients><Perfusion><Physiology><Pigs><Plasmalogens><Position><Positioning Attribute><Process><Public Health><Publishing><Pulmonary Artery><Pulmonary Embolism><Pulmonary Hypertension><Pulmonary artery structure><Pyruvate><Randomized><Recording of previous events><Regulation><Reproducibility><Research><Research Design><Research Personnel><Researchers><Respiratory Aspiration><Respiratory Inspiration><Right Ventricles><Right Ventricular Dysfunction><Right heart dysfunction><Right ventricle dysfunction><Right ventricular structure><Right-sided heart dysfunction><Risk><Series><Shock><Societies><Statistical Correlation><Study Type><Suidae><Swine><Syndrome><TCA cycle><Testing><Thorace><Thoracic><Thorax><Thrombus><Time><Tissues><Tomodensitometry><Training><Transthoracic Echocardiography><Triacylglycerol><Tricarboxylic Acid Cycle><Triglycerides><United States><Universities><Up-Regulation><Upregulation><Ventricular septum><Work><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><Zeugmatography><angiographic imaging><branched amino acids><cardiac metabolism><catscan><causation><circulatory shock><circulatory system><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><design><designing><diacylglycerol><diglyceride><disease causation><enroll><experience><experiment><experimental research><experimental study><experiments><face mask><heart metabolism><heart output><heart sonography><histories><human subject><hypoxemic><imaging><improved><innovate><innovation><innovative><inspiration><lung artery blood pressure><lung hypoxia><lung vasoconstriction><mechanic><mechanical><medical college><medical schools><metabolism measurement><metabolomics><metabonomics><monetary cost><mortality><multi-modality><multimodality><non-contrast CT><noncontrast CT><noncontrast computed tomography><participant enrollment><patient enrollment><phrases><pig model><piglet model><porcine><porcine model><pre-clinical><preclinical><pressure in pulmonary arteries><pulmonary><pulmonary arterial blood pressure><pulmonary arterial pressure><pulmonary artery pressure><pulmonary artery systolic pressure><pulmonary hypoxia><pulmonary vascular constriction><pulmonary vasoconstriction><randomisation><randomization><randomly assigned><recruit><school of medicine><shocks><study design><suid><supplemental oxygen><swine model><therapeutic target><vascular constriction><vasoconstriction>