title: The role of asymmetric dimethylarginine alone and in combination with N-terminal pro-B-type natriuretic peptide as a screening biomarker for systemic sclerosis-related pulmonary arterial hypertension: a case control study.
abstract: OBJECTIVE
  Asymmetric dimethylarginine (ADMA) is a novel biomarker of endothelial cell dysfunction. In this proof of concept study, we sought to evaluate the role of ADMA as a screening biomarker for incident systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH).
  
  
  METHODS
  ADMA levels were measured using high performance liquid chromatography in 15 consecutive treatment-naive patients with newly-diagnosed SSc-PAH and compared with 30 SSc-controls without PAH. Logistic regression models were used to evaluate the independent association of ADMA with PAH. The optimal cut-point of ADMA for SSc-PAH screening was determined. NT-proBNP levels were previously measured in the same patients and the optimal cut-point of NT-proBNP of ≥210ng/mL was coupled with the optimal cut-point of ADMA to create a screening model that combined the two biomarkers.
  
  
  RESULTS
  The PAH group had significantly higher mean ADMA levels than the control group (0.76±0.14 μM versus 0.59±0.07 μM; p<0.0001). ADMA levels remained significantly associated with PAH after the adjustment for specific disease characteristics, cardiovascular risk factors and other SSc-related vascular complications (all p<0.01). An ADMA level ≥0.7 μM had a sensitivity of 86.7%, specificity of 90.0% and AUC of 0.86 for diagnosing PAH. A screening model that combined an NT-proBNP ≥210ng/mL and/ or ADMA ≥0.7 ng/mL resulted in a sensitivity of 100% and specificity of 90% for the detection of SSc-PAH.
  
  
  CONCLUSIONS
  In this small study, use of ADMA in combination with NT-proBNP produced excellent sensitivity and specificity for the non-invasive identification of SSc-PAH. The role of ADMA as a screening biomarker for SSc-PAH merits further evaluation.
authors.affiliation: Department of Medicine; Department of Rheumatology, St. Vincent's Hospital Melbourne, Fitzroy; Department of Rheumatology, Liverpool Hospital, Liverpool; and School of Medicine, University of Western Sydney, Penrith, Australia.
authors.forename: Vivek
authors.initials: V
authors.lastname: Thakkar
authors.affiliation: Department of Medicine, St. Vincent's Hospital Melbourne, Fitzroy, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Stevens
authors.affiliation: Department of Cardiology, St Vincent's Hospital Melbourne, Fitzroy, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Prior
authors.affiliation: Department of Rheumatology, St. Vincent's Hospital Melbourne, Fitzroy, Australia.
authors.forename: Candice
authors.initials: C
authors.lastname: Rabusa
authors.affiliation: Department of Rheumatology, Monash Medical Centre, Clayton, Australia.
authors.forename: Joanne
authors.initials: J
authors.lastname: Sahhar
authors.affiliation: Department of Rheumatology, Flinders Medical Centre, Bedford Park, Australia.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Walker
authors.affiliation: Department of Rheumatology, Royal Perth Hospital, Perth, Australia.
authors.forename: Janet
authors.initials: J
authors.lastname: Roddy
authors.affiliation: Rheumatology Department, The Queen Elizabeth Hospital, Woodville South, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Lester
authors.affiliation: Rheumatology Department, The Queen Elizabeth Hospital, Woodville South, Australia.
authors.forename: Maureen
authors.initials: M
authors.lastname: Rischmueller
authors.affiliation: Department of Rheumatology, The Menzies Institute, Hobart, Australia.
authors.forename: Jane
authors.initials: J
authors.lastname: Zochling
authors.affiliation: Rheumatology Research Unit, Department of Medicine, University of Queensland, Maroochydore, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Nash
authors.affiliation: The University of Notre Dame, Fremantle, Australia.
authors.forename: Eli
authors.initials: E
authors.lastname: Gabbay
authors.affiliation: Institute of Rheumatology and Orthopaedics, Royal Prince Alfred Hospital, Camperdown, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Youssef
authors.affiliation: Royal Adelaide Hospital, North Terrace; and Discipline of Medicine, University of Adelaide, Australia.
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Proudman
authors.affiliation: Department of Medicine; and Department of Rheumatology, St. Vincent's Hospital Melbourne, Fitzroy, Australia. m.nikpour@unimelb.edu.au.
authors.forename: Mandana
authors.initials: M
authors.lastname: Nikpour
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D062186:Arterial Pressure; D001315:Australia; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D011651:Pulmonary Artery / Q000503:physiopathology*; D012372:ROC Curve; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000097:blood / Q000150:complications* / Q000175:diagnosis
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; C018524:N,N-dimethylarginine; D001120:Arginine