title: Objective criteria for septal fibrosis in non-ischemic dilated cardiomyopathy: validation for the prediction of future cardiovascular events.
abstract: BACKGROUND
  Expert subjective reporting of mid-wall septal fibrosis on late gadolinium enhancement (LGE) images has been shown to predict major cardiovascular outcomes in patients with non-ischemic dilated cardiomyopathy (NIDCM). This study aims to establish objective criteria for non-experts to report clinically relevant septal fibrosis and compare its performance by such readers versus experts for the prediction of cardiovascular events.
  
  
  METHODS
  LGE cardiovascular magnetic resonance (CMR) was performed in 118 consecutive patients with NIDCM (mean age 57 ± 14, 42 % female) and the presence of septal fibrosis scored by expert readers. CMR-naive readers performed signal threshold-based LGE quantification by referencing mean values of remote tissue and applying these to a pre-defined anatomic region to measure septal fibrosis. All patients were followed for the primary composite outcome of cardiac mortality or appropriate implantable cardioverter-defibrillator (ICD) therapy.
  
  
  RESULTS
  The mean LVEF was 32 ± 12 %. At a median follow-up of 1.9 years, 20 patients (17 %) experienced a primary composite outcome. Expert visual scoring identified 55 patients with septal fibrosis. Non-expert septal fibrosis quantification was highly reproducible and identified mean septal fibrosis burden for three measured thresholds as follows; 5SD: 2.9 ± 3.6 %, 3SD: 6.9 ± 6.3 %, and 2SD: 11.1 ± 7.5 % of the left ventricular (LV) mass, respectively. By ROC analysis, optimal thresholds for prediction of the primary outcome were; 5SD: 2.74 % (HR 8.7, p < 0.001), 3SD: 6.63 % (HR 5.7, p = 0.001) and 2SD: 10.15 % (HR 6.1, p = 0.001). By comparison, expert visual scoring provided a HR of 5.3 (p = 0.001). In adjusted analysis, objective quantification by a novice reader (>5SD threshold) was the strongest independent predictor of the primary outcome (HR 8.7) and provided improved risk reclassification beyond LVEF alone (NRI 0.54, 95 % CI 0.16-0.92, p = 0.005).
  
  
  CONCLUSIONS
  Novice readers were able to achieve superior risk prediction for future cardiovascular events versus experts using objective criteria for septal fibrosis in patients with NIDCM. Patients with a septal fibrosis burden >2.74 % of the LV mass (>5SD threshold) were at a 9-fold higher risk of cardiac death or appropriate ICD therapy versus those not meeting this criteria. As such, this study validates reproducible criteria applicable to all levels of expertise to identify NIDCM patients at high risk of future cardiovascular events.
authors.affiliation: Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute of Alberta, University of Calgary, #0700, SSB, Foothills Medical Centre, 1403-29th St. NW, Calgary, AB, T2N2T9, Canada.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mikami
authors.affiliation: Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute of Alberta, University of Calgary, #0700, SSB, Foothills Medical Centre, 1403-29th St. NW, Calgary, AB, T2N2T9, Canada.
authors.forename: Aidan
authors.initials: A
authors.lastname: Cornhill
authors.affiliation: Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute of Alberta, University of Calgary, #0700, SSB, Foothills Medical Centre, 1403-29th St. NW, Calgary, AB, T2N2T9, Canada.|Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Canada.|Department of Diagnostic Imaging, University of Calgary, Calgary, Canada.
authors.forename: Bobak
authors.initials: B
authors.lastname: Heydari
authors.affiliation: Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute of Alberta, University of Calgary, #0700, SSB, Foothills Medical Centre, 1403-29th St. NW, Calgary, AB, T2N2T9, Canada.
authors.forename: Sebastien X
authors.initials: SX
authors.lastname: Joncas
authors.affiliation: Department of Medicine, Western University, London, ON, Canada.
authors.forename: Fahad
authors.initials: F
authors.lastname: Almehmadi
authors.affiliation: Department of Medicine, Western University, London, ON, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Zahrani
authors.affiliation: Department of Medicine, Western University, London, ON, Canada.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Bokhari
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Stirrat
authors.affiliation: Department of Medicine, Western University, London, ON, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Yee
authors.affiliation: Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute of Alberta, University of Calgary, #0700, SSB, Foothills Medical Centre, 1403-29th St. NW, Calgary, AB, T2N2T9, Canada.|Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Canada.|Department of Diagnostic Imaging, University of Calgary, Calgary, Canada.
authors.forename: Naeem
authors.initials: N
authors.lastname: Merchant
authors.affiliation: Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute of Alberta, University of Calgary, #0700, SSB, Foothills Medical Centre, 1403-29th St. NW, Calgary, AB, T2N2T9, Canada.|Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Canada.|Department of Diagnostic Imaging, University of Calgary, Calgary, Canada.
authors.forename: Carmen P
authors.initials: CP
authors.lastname: Lydell
authors.affiliation: Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute of Alberta, University of Calgary, #0700, SSB, Foothills Medical Centre, 1403-29th St. NW, Calgary, AB, T2N2T9, Canada.|Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Canada.|Department of Diagnostic Imaging, University of Calgary, Calgary, Canada.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Howarth
authors.affiliation: Stephenson Cardiac Imaging Centre, Libin Cardiovascular Institute of Alberta, University of Calgary, #0700, SSB, Foothills Medical Centre, 1403-29th St. NW, Calgary, AB, T2N2T9, Canada. jawhit@ucalgary.ca.|Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Canada. jawhit@ucalgary.ca.|Department of Diagnostic Imaging, University of Calgary, Calgary, Canada. jawhit@ucalgary.ca.
authors.forename: James A
authors.initials: JA
authors.lastname: White
mesh_terms: D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002983:Clinical Competence; D003287:Contrast Media / Q000008:administration & dosage; D017147:Defibrillators, Implantable; D018450:Disease Progression; D018572:Disease-Free Survival; D004554:Electric Countershock / Q000295:instrumentation; D005240:Feasibility Studies; D005260:Female; D005355:Fibrosis; D006346:Heart Septum / Q000000981:diagnostic imaging* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D015588:Observer Variation; D009942:Organometallic Compounds / Q000008:administration & dosage; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012042:Registries; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; C090600:gadobutrol
keywords: Cardiovascular magnetic resonance; Dilated cardiomyopathy; Fibrosis; Prognosis