title: In silico cardiac risk assessment in patients with long QT syndrome: type 1: clinical predictability of cardiac models.
abstract: OBJECTIVE
  The study was designed to assess the ability of computer-simulated electrocardiography parameters to predict clinical outcomes and to risk-stratify patients with long QT syndrome type 1 (LQT1).
  
  
  BACKGROUND
  Although attempts have been made to correlate mutation-specific ion channel dysfunction with patient phenotype in long QT syndrome, these have been largely unsuccessful. Systems-level computational models can be used to predict consequences of complex changes in channel function to the overall heart rhythm.
  
  
  METHODS
  A total of 633 LQT1-genotyped subjects with 34 mutations from multinational long QT syndrome registries were studied. Cellular electrophysiology function was determined for the mutations and introduced in a 1-dimensional transmural electrocardiography computer model. The mutation effect on transmural repolarization was determined for each mutation and related to the risk for cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) among patients.
  
  
  RESULTS
  Multivariate analysis showed that mutation-specific transmural repolarization prolongation (TRP) was associated with an increased risk for cardiac events (35% per 10-ms increment [p < 0.0001]; ≥upper quartile hazard ratio: 2.80 [p < 0.0001]) and life-threatening events (aborted cardiac arrest/sudden cardiac death: 27% per 10-ms increment [p = 0.03]; ≥upper quartile hazard ratio: 2.24 [p = 0.002]) independently of patients' individual QT interval corrected for heart rate (QTc). Subgroup analysis showed that among patients with mild to moderate QTc duration (<500 ms), the risk associated with TRP was maintained (36% per 10 ms [p < 0.0001]), whereas the patient's individual QTc was not associated with a significant risk increase after adjustment for TRP.
  
  
  CONCLUSIONS
  These findings suggest that simulated repolarization can be used to predict clinical outcomes and to improve risk stratification in patients with LQT1, with a more pronounced effect among patients with a lower-range QTc, in whom a patient's individual QTc may provide less incremental prognostic information.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hoefen
authors.forename: Matthias
authors.initials: M
authors.lastname: Reumann
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldenberg
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Jin
authors.initials: J
authors.lastname: O-Uchi
authors.forename: Yiping
authors.initials: Y
authors.lastname: Gu
authors.forename: Scott
authors.initials: S
authors.lastname: McNitt
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
authors.forename: Christian
authors.initials: C
authors.lastname: Jons
authors.forename: Jorgen K
authors.initials: JK
authors.lastname: Kanters
authors.forename: Pyotr G
authors.initials: PG
authors.lastname: Platonov
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: John Jeremy
authors.initials: JJ
authors.lastname: Rice
authors.forename: Coeli M
authors.initials: CM
authors.lastname: Lopes
mesh_terms: D000293:Adolescent; D000328:Adult; D003198:Computer Simulation; D004247:DNA / Q000032:analysis; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006339:Heart Rate / Q000235:genetics*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D008955:Models, Cardiovascular; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D029597:Romano-Ward Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D051657:KCNQ1 Potassium Channel; D004247:DNA