title: Myocardial Fibrosis Quantified by Extracellular Volume Is Associated With Subsequent Hospitalization for Heart Failure, Death, or Both Across the Spectrum of Ejection Fraction and Heart Failure Stage.
abstract: BACKGROUND
  Myocardial fibrosis (MF) in noninfarcted myocardium may be an interstitial disease pathway that confers vulnerability to hospitalization for heart failure, death, or both across the spectrum of heart failure and ejection fraction. Hospitalization for heart failure is an epidemic that is difficult to predict and prevent and requires potential therapeutic targets associated with outcomes.
  
  
  RESULTS
  We quantified MF with cardiovascular magnetic resonance extracellular volume fraction (ECV) measures in 1172 consecutive patients without amyloidosis or hypertrophic or stress cardiomyopathy and assessed associations with outcomes using Cox regression. ECV ranged from 16.6% to 47.8%. Over a median of 1.7 years, 111 patients experienced events after cardiovascular magnetic resonance, 55 had hospitalization for heart failure events, and there were 74 deaths. ECV was more strongly associated with outcomes than "nonischemic" MF observed with late gadolinium enhancement, thus ECV quantified MF in multivariable models. Adjusting for age, sex, renal function, myocardial infarction size, ejection fraction, hospitalization status, and heart failure stage, higher ECV was associated with hospitalization for heart failure (hazard ratio 1.77; 95% CI 1.32 to 2.36 for every 5% increase in ECV), death (hazard ratio 1.87 95% CI 1.45 to 2.40) or both (hazard ratio 1.85, 95% CI 1.50 to 2.27). ECV improved classification of persons at risk and improved model discrimination for outcomes (eg, hospitalization for heart failure: continuous net reclassification improvement 0.33, 95% CI 0.05 to 0.66; P=0.02; 0.16, 95% CI 0.01 to 0.33; P=0.02; integrated discrimination improvement 0.037, 95% CI 0.008 to 0.073; P<0.01).
  
  
  CONCLUSIONS
  MF measured by ECV is associated with hospitalization for heart failure, death, or both. MF may represent a principal phenotype of cardiac vulnerability that improves risk stratification. Because MF can be reversible, cells and enzymes regulating collagen could be potential therapeutic targets.
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA (E.B.S., K.M.Z., C.C.H.C., T.C.W.) UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA (E.B.S., K.M.P., K.M.Z., T.C.W.) Clinical and Translational Science Institute, University of Pittsburgh, PA (E.B.S., T.C.W.).
authors.forename: Erik B
authors.initials: EB
authors.lastname: Schelbert
authors.affiliation: UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA (E.B.S., K.M.P., K.M.Z., T.C.W.).
authors.forename: Kayla M
authors.initials: KM
authors.lastname: Piehler
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA (E.B.S., K.M.Z., C.C.H.C., T.C.W.) UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA (E.B.S., K.M.P., K.M.Z., T.C.W.) Department of Medicine, The Ohio State University, Columbus, OH (K.M.Z.).
authors.forename: Karolina M
authors.initials: KM
authors.lastname: Zareba
authors.affiliation: Barts Heart Centre and University College London, London, UK (J.C.M.).
authors.forename: James C
authors.initials: JC
authors.lastname: Moon
authors.affiliation: Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (M.U.).
authors.forename: Martin
authors.initials: M
authors.lastname: Ugander
authors.affiliation: Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany (D.R.M.).
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Messroghli
authors.affiliation: Cardiology Division, University of Minnesota, Minneapolis, MN (U.S.V.).
authors.forename: Uma S
authors.initials: US
authors.lastname: Valeti
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA (E.B.S., K.M.Z., C.C.H.C., T.C.W.) Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA (C.C.H.C.).
authors.forename: Chung-Chou H
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Bioengineering, University of Pittsburgh, PA (S.G.S.).
authors.forename: Sanjeev G
authors.initials: SG
authors.lastname: Shroff
authors.affiliation: Program of Cardiovascular Diseases, Center for Applied Medical Research and University Clinic of Navarra, Pamplona, Spain (J.D.).
authors.forename: Javier
authors.initials: J
authors.lastname: Diez
authors.affiliation: Centre for Imaging Sciences and Biomedical Imaging Institute, University of Manchester, UK (C.A.M., M.S.).
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Centre for Imaging Sciences and Biomedical Imaging Institute, University of Manchester, UK (C.A.M., M.S.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: National Heart, Lung, and Blood Institute, Bethesda, MD (P.K.).
authors.forename: Peter
authors.initials: P
authors.lastname: Kellman
authors.affiliation: Cardiology Division, Stony Brook University, Stony Brook, NY (J.B.).
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA (E.B.S., K.M.Z., C.C.H.C., T.C.W.) UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA (E.B.S., K.M.P., K.M.Z., T.C.W.) Clinical and Translational Science Institute, University of Pittsburgh, PA (E.B.S., T.C.W.).
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wong
mesh_terms: D000328:Adult; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000453:epidemiology* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D016016:Proportional Hazards Models; D012307:Risk Factors; D012720:Severity of Illness Index; D013318:Stroke Volume
keywords: T1 mapping; cardiovascular magnetic resonance; extracellular matrix; extracellular volume fraction; heart failure; myocardial fibrosis