title: Proteomic analysis of coronary sinus serum reveals leucine-rich α2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure.
abstract: BACKGROUND
  Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF.
  
  
  RESULTS
  Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich α2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P≤0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-α (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-βR1 (P<0.001) and α-smooth muscle actin (P=0.025) expression.
  
  
  CONCLUSIONS
  LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, β-blocker therapy, and BNP.
authors.affiliation: School of Medicine and Medical Science, St Vincent's University Hospital and The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Watson
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ledwidge
authors.forename: Dermot
authors.initials: D
authors.lastname: Phelan
authors.forename: Patrick
authors.initials: P
authors.lastname: Collier
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Byrne
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dunn
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: McDonald
authors.forename: John A
authors.initials: JA
authors.lastname: Baugh
mesh_terms: D000199:Actins / Q000032:analysis; D000368:Aged; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D016009:Chi-Square Distribution; D054326:Coronary Sinus; D015150:Echocardiography, Doppler; D015180:Electrophoresis, Gel, Two-Dimensional; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006333:Heart Failure / Q000097:blood* / Q000175:diagnosis / Q000209:etiology; D006801:Humans; D006973:Hypertension / Q000097:blood* / Q000150:complications / Q000175:diagnosis; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D007494:Ireland; D016015:Logistic Models; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009206:Myocardium / Q000737:chemistry; D020097:Natriuretic Peptide, Brain / Q000097:blood; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D040901:Proteomics / Q000379:methods; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D018570:Risk Assessment; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D018487:Ventricular Dysfunction, Left / Q000097:blood* / Q000175:diagnosis / Q000209:etiology
chemical_list: D000199:Actins; D015415:Biomarkers; D006023:Glycoproteins; C508600:IL6 protein, human; D015850:Interleukin-6; C015246:LRG1 protein, human; D018125:Receptors, Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D020097:Natriuretic Peptide, Brain; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I