title: Heterogeneity in lung (18)FDG uptake in pulmonary arterial hypertension: potential of dynamic (18)FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling, characterized by dysregulated growth of pulmonary vascular cells and inflammation. A prevailing view is that abnormal cellular metabolism, notably aerobic glycolysis that increases glucose demand, underlies the pathogenesis of PAH. Increased lung glucose uptake has been reported in animal models. Few data exist from patients with PAH.
  
  
  RESULTS
  Dynamic positron emission tomography imaging with fluorine-18-labeled 2-fluoro-2-deoxyglucose ((18)FDG) ligand with kinetic analysis demonstrated increased mean lung parenchymal uptake in 20 patients with PAH, 18 with idiopathic PAH (IPAH) (FDG score: 3.27±1.22), and 2 patients with connective tissue disease (5.07 and 7.11) compared with controls (2.02±0.71; P<0.05). Further compartment analysis confirmed increased lung glucose metabolism in IPAH. Lung (18)FDG uptake and metabolism varied within the IPAH population and within the lungs of individual patients, consistent with the recognized heterogeneity of vascular pathology in this disease. The monocrotaline rat PAH model also showed increased lung (18)FDG uptake, which was reduced along with improvements in vascular pathology after treatment with dicholoroacetate and 2 tyrosine kinase inhibitors, imatinib and sunitinib. Hyperproliferative pulmonary vascular fibroblasts isolated from IPAH patients exhibited upregulated glycolytic gene expression, along with increased cellular (18)FDG uptake; both were reduced by dicholoroacetate and imatinib.
  
  
  CONCLUSIONS
  Some patients with IPAH exhibit increased lung (18)FDG uptake. (18)FDG positron emission tomography imaging is a tool to investigate the molecular pathology of PAH and its response to treatment.
authors.affiliation: Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Hammersmith Hospital, London, UK (L.Z., A.A., L.W., O.D., J.C., E.C., H.J., G.B., M.R.W.); Department of Nuclear Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (W.F.); Max-Planck Institute for Heart and Lung Research and University of Giessen and Marburg Lung Center, German Center for Lung Research, Bad Nauheim, Germany (S.D., S.S.P.); Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK (G.T., Q.N., E.O.A.); Department of Histopathology, Imperial College London, UK (M.A.E.-B.); National Heart and Lung Institute, Imperial College London, and National Pulmonary Hypertension Service, Department of Cardiology, Hammersmith Hospital, London, UK (L.S.H., J.S.R.G.); Biological Imaging Centre, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK (W.G.); and Center for Diagnosis and Management of Pulmonary Vascular Diseases, Department of Cardiology, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (J.H.).
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.forename: Ali
authors.initials: A
authors.lastname: Ashek
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.forename: Swati
authors.initials: S
authors.lastname: Dabral
authors.forename: Olivier
authors.initials: O
authors.lastname: Dubois
authors.forename: John
authors.initials: J
authors.lastname: Cupitt
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cotroneo
authors.forename: Hazel
authors.initials: H
authors.lastname: Jones
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Tomasi
authors.forename: Quang-De
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
authors.forename: Mona A
authors.initials: MA
authors.lastname: El-Bahrawy
authors.forename: Gareth
authors.initials: G
authors.lastname: Barnes
authors.forename: Luke S
authors.initials: LS
authors.lastname: Howard
authors.forename: J Simon R
authors.initials: JS
authors.lastname: Gibbs
authors.forename: Willy
authors.initials: W
authors.lastname: Gsell
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: He
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use; D002455:Cell Division; D003999:Dichloroacetic Acid / Q000627:therapeutic use; D004195:Disease Models, Animal; D016903:Drug Monitoring; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D020869:Gene Expression Profiling; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use; D008168:Lung / Q000000981:diagnostic imaging* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016686:Monocrotaline / Q000633:toxicity; D010879:Piperazines / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077210:Sunitinib; D055815:Young Adult
chemical_list: D001549:Benzamides; D005462:Fluorine Radioisotopes; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D016686:Monocrotaline; D000068877:Imatinib Mesylate; D003999:Dichloroacetic Acid; D000077210:Sunitinib
keywords: biomarkers; glucose metabolism; hypertension, pulmonary; imaging