title: Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia.
abstract: Pulmonary hypertension (PH) commonly develops in thalassaemia syndromes, but is poorly characterized. The goal of this study was to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassaemia at risk for PH. A case-control study of thalassaemia patients at high versus low PH-risk was performed. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including Doppler-echocardiography, 6-min-walk-test, Borg Dyspnoea Score, New York Heart Association functional class, cardiac magnetic resonance imaging (MRI), chest-computerized tomography, pulmonary function testing and laboratory analyses targeting mechanisms of coagulation, inflammation, haemolysis, adhesion and the arginine-nitric oxide pathway. Twenty-seven thalassaemia patients were evaluated, 14 with an elevated tricuspid-regurgitant-jet-velocity (TRV) ≥ 2·5 m/s. Patients with increased TRV had a higher frequency of splenectomy, and significantly larger right atrial size, left atrial volume and left septal-wall thickness on echocardiography and/or MRI, with elevated biomarkers of abnormal coagulation, lactate dehydrogenase (LDH) levels and arginase concentration, and lower arginine-bioavailability compared to low-risk patients. Arginase concentration correlated significantly to several echocardiography/MRI parameters of cardiovascular function in addition to global-arginine-bioavailability and biomarkers of haemolytic rate, including LDH, haemoglobin and bilirubin. Thalassaemia patients with a TRV ≥ 2·5 m/s have additional echocardiography and cardiac-MRI parameters suggestive of right and left-sided cardiac dysfunction. In addition, low arginine bioavailability may contribute to cardiopulmonary dysfunction in β-thalassaemia.
authors.affiliation: Department of Pediatrics, Division of Emergency Medicine, Emory University School of Medicine, Emory Children's Centre for Cystic Fibrosis and Airways Disease Research, Atlanta, GA, USA.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Morris
authors.affiliation: New England Research Institutes Watertown, Watertown, MA, USA.
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: The Pulmonary Centre, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Klings
authors.affiliation: Children's Hospital of Los Angeles, Los Angeles, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wood
authors.affiliation: University College London, London, UK.
authors.forename: John B
authors.initials: JB
authors.lastname: Porter
authors.affiliation: New England Research Institutes Watertown, Watertown, MA, USA.
authors.forename: Felicia
authors.initials: F
authors.lastname: Trachtenberg
authors.affiliation: Hematology/Oncology, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Sweeters
authors.affiliation: Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Olivieri
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Kwiatkowski
authors.affiliation: New England Research Institutes Watertown, Watertown, MA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Virzi
authors.affiliation: Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hassell
authors.affiliation: American University of Beirut, Beirut, Lebanon.
authors.forename: Ali
authors.initials: A
authors.lastname: Taher
authors.affiliation: Children's Hospital Boston, Boston, MA, USA.
authors.forename: Ellis J
authors.initials: EJ
authors.lastname: Neufeld
authors.affiliation: Haematology, Oncology & Stem Cell Transplant, Children's Memorial Hospital, Chicago, IL, USA.
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Thompson
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Larkin
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: Jung H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Hematology/Oncology, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.
authors.forename: Elliott P
authors.initials: EP
authors.lastname: Vichinsky
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: Frans A
authors.initials: FA
authors.lastname: Kuypers
mesh_terms: D000328:Adult; D001119:Arginase / Q000097:blood / Q000378:metabolism; D001120:Arginine / Q000378:metabolism*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D015150:Echocardiography, Doppler; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D013789:Thalassemia / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism*; D055815:Young Adult
chemical_list: D001120:Arginine; D001119:Arginase
keywords: arginase; global arginine bioavailability ratio; haemolysis; pulmonary hypertension; β-thalassaemia