title: Automatic Measurement of the Myocardial Interstitium: Synthetic Extracellular Volume Quantification Without Hematocrit Sampling.
abstract: OBJECTIVE
  The authors sought to generate a synthetic extracellular volume fraction (ECV) from the relationship between hematocrit and longitudinal relaxation rate of blood.
  
  
  BACKGROUND
  ECV quantification by cardiac magnetic resonance (CMR) measures diagnostically and prognostically relevant changes in the extracellular space. Current methodologies require blood hematocrit (Hct) measurement-a complication to easy clinical application. We hypothesized that the relationship between Hct and longitudinal relaxation rate of blood (R1 = 1/T1blood) could be calibrated and used to generate a synthetic ECV without Hct that was valid, user-friendly, and prognostic.
  
  
  METHODS
  Proof-of-concept: 427 subjects with a wide range of health and disease were divided into derivation (n = 214) and validation (n = 213) cohorts. Histology cohort: 18 patients with severe aortic stenosis with histology obtained during valve replacement. Outcome cohort: For comparison with external outcome data, we applied synthetic ECV to 1,172 consecutive patients (median follow-up 1.7 years; 74 deaths). All underwent CMR scanning at 1.5-T with ECV calculation from pre- and post-contrast T1 (blood and myocardium) and venous Hct.
  
  
  RESULTS
  Proof-of-concept: In the derivation cohort, native R1blood and Hct showed a linear relationship (R(2) = 0.51; p < 0.001), which was used to create synthetic Hct and ECV. Synthetic ECV correlated well with conventional ECV (R(2) = 0.97; p < 0.001) without bias. These results were maintained in the validation cohort. Histology cohort: Synthetic and conventional ECV both correlated well with collagen volume fraction measured from histology (R(2) = 0.61 and 0.69, both p < 0.001) with no statistical difference (p = 0.70). Outcome cohort: Synthetic ECV related to all-cause mortality (hazard ratio 1.90; 95% confidence interval 1.55 to 2.31; for every 5% increase in ECV). Finally, we engineered a synthetic ECV tool, generating automatic ECV maps during image acquisition.
  
  
  CONCLUSIONS
  Synthetic ECV provides validated noninvasive quantification of the myocardial extracellular space without blood sampling and is associated with cardiovascular outcomes.
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Treibel
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Marianna
authors.initials: M
authors.lastname: Fontana
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology & Geriatric Sciences, Sapienza University, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Maestrini
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Castelletti
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rosmini
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Simpson
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom.
authors.forename: Arthur
authors.initials: A
authors.lastname: Nasis
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Anish N
authors.initials: AN
authors.lastname: Bhuva
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Heerajnarain
authors.initials: H
authors.lastname: Bulluck
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Amna
authors.initials: A
authors.lastname: Abdel-Gadir
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Steven K
authors.initials: SK
authors.lastname: White
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Manisty
authors.affiliation: Siemens Healthcare, Chicago, Illinois.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Spottiswoode
authors.affiliation: UPMC Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wong
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Piechnik
authors.affiliation: National Heart, Lung, and Blood Institute, National Institute for Health, Bethesda, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Kellman
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Robson
authors.affiliation: UPMC Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Erik B
authors.initials: EB
authors.lastname: Schelbert
authors.affiliation: Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom. Electronic address: j.moon@ucl.ac.uk.
authors.forename: James C
authors.initials: JC
authors.lastname: Moon
mesh_terms: D000328:Adult; D000368:Aged; D001331:Automation; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D003094:Collagen / Q000032:analysis; D005110:Extracellular Space; D005260:Female; D006331:Heart Diseases / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006400:Hematocrit; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D016014:Linear Models; D008131:London; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000737:chemistry / Q000473:pathology*; D010414:Pennsylvania; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D013318:Stroke Volume; D016277:Ventricular Function, Left; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003094:Collagen
keywords: ECV; collagen; magnetic resonance imaging; mortality; myocardial fibrosis