title: Identification of Transthyretin Cardiac Amyloidosis Using Serum Retinol-Binding Protein 4 and a Clinical Prediction Model.
abstract: Transthyretin cardiac amyloidosis (ATTR) is an underrecognized cause of heart failure (HF) in older individuals, owing in part to difficulty in diagnosis. ATTR can result from substitution of valine for isoleucine at codon 122 of the transthyretin (TTR) gene (V122I), present in 3.43% of African American individuals.
  
  
  
  To examine whether serum retinol-binding protein 4 (RBP4), an endogenous TTR ligand, could be used as a diagnostic test for ATTR V122I amyloidosis.
  
  
  
  In this combined prospective and retrospective cohort study performed at a tertiary care referral center, 50 African American patients 60 years or older with nonamyloid HF and cardiac wall thickening prospectively genotyped from September 1, 2014, through December 31, 2015, and a comparator cohort of 25 patients with biopsy-proven ATTR V122I amyloidosis recruited from September 1, 2009, through November 31, 2014, comprised the development cohort. Twenty-seven African American patients and 9 patients with ATTR V122I amyloidosis comprised the validation cohort.
  
  
  
  Circulating RBP4, TTR, B-type natriuretic peptide (BNP), and troponin I (TnI) concentrations and electrocardiographic, echocardiographic, and clinical characteristics were assessed in all patients. Receiver operating characteristic (ROC) analysis was performed to identify optimal thresholds for ATTR V122I amyloidosis identification. A clinical prediction rule was developed using penalized logistic regression, evaluated using ROC analysis and validated in an independent cohort of cases and controls.
  
  
  
  Age, sex, and BNP and TnI concentrations were similar between the 25 patients with ATTR V122I amyloidosis (mean [SD] age, 72.2 [7.4] years; 18 male [72%]) and the 50 controls (mean [SD] age, 69.2 [5.7] years; 31 male [62%]). Serum RBP4 concentration was lower in patients with ATTR V122I amyloidosis compared with nonamyloid controls (31.5 vs 49.4 µg/mL, P < .001), and the difference persisted after controlling for potential confounding variables. Left ventricular ejection fraction was lower in patients with ATTR V122I amyloidosis (mean [SD], 40% [14%] vs 57% [14%], P < .001), whereas interventricular septal diameter was higher (mean [SD], 16 [3] vs 14 [2] mm, P < .001). The ROC analysis identified RBP4 as a sensitive identifier of ATTR V122I amyloidosis (area under the curve [AUC] = 0.78; 95% CI, 0.67-0.88). A clinical prediction algorithm composed of RBP4, TTR, left ventricular ejection fraction, interventricular septal diameter, mean limb lead QRS voltage, and grade 3 diastolic dysfunction yielded excellent discriminatory capacity for ATTR V122I amyloidosis (AUC = 0.97; 95% CI, 0.93-1.00), whereas a 4-parameter model, including RBP4 concentration, retained excellent discrimination (AUC = 0.92; 95% CI, 0.86-0.99). The models maintained excellent discrimination in the validation cohort.
  
  
  
  A prediction model using circulating RBP4 concentration and readily available clinical parameters accurately discriminated ATTR V122I amyloidosis from nonamyloid HF in a case-matched cohort. This clinical algorithm may be useful for identification of ATTR V122I amyloidosis in elderly African American patients with HF.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
authors.forename: Marios
authors.initials: M
authors.lastname: Arvanitis
authors.affiliation: Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts3Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
authors.forename: Clarissa M
authors.initials: CM
authors.lastname: Koch
authors.affiliation: Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
authors.forename: Gloria G
authors.initials: GG
authors.lastname: Chan
authors.affiliation: Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
authors.forename: Celia
authors.initials: C
authors.lastname: Torres-Arancivia
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Michael P
authors.initials: MP
authors.lastname: LaValley
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts2Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts5Hematology/Oncology Section, Medical Service, Veterans Affairs Boston Healthcare System, Boston, Massachusetts.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Jacobson
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts2Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
authors.forename: John L
authors.initials: JL
authors.lastname: Berk
authors.affiliation: Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts3Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
authors.forename: Lawreen H
authors.initials: LH
authors.lastname: Connors
authors.affiliation: Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts6Section of Cardiovascular Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts.
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Ruberg
mesh_terms: D001741:Black or African American; D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000097:blood* / Q000175:diagnosis / Q000208:ethnology; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D009202:Cardiomyopathies / Q000097:blood* / Q000175:diagnosis / Q000208:ethnology; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies; D012372:ROC Curve; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism*; D016277:Ventricular Function, Left
chemical_list: D015415:Biomarkers; D011228:Prealbumin; C101326:RBP4 protein, human; D054839:Retinol-Binding Proteins, Plasma; C000630214:TTR protein, human; D004247:DNA