title: T-wave morphology abnormalities in benign, potent, and arrhythmogenic I(kr) inhibition.
abstract: BACKGROUND
  There is a consensus on the limited value of the QTc interval prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited long QT syndrome (LQTS) patients.
  
  
  OBJECTIVE
  We investigated the interest of repolarization morphology in the acquired and the inherited LQTS.
  
  
  METHODS
  We analyzed 2 retrospective electrocardiographic (ECG) datasets from healthy on/off moxifloxacin and from genotyped KCNH2 patients. We measured QT, RR, and T-peak to T-end intervals, early repolarization duration (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 from 143 LQT2 carriers and 150 noncarrier family members were analyzed.
  
  
  RESULTS
  In the moxifloxacin model, ERD was associated with the presence of the drug (odds ratio = 1.15 per ms increase, confidence interval 1.04 to 1.26, P = .0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (odds ratio = 0.38 per 1.5 μV/ms decrease, confidence interval 0.23 to 0.64, P = .0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2.
  
  
  CONCLUSIONS
  These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface electrocardiogram are specific. Future research should investigate whether this phenomenon is linked to different level/form of loss functions of Ikr channels, and whether they could result in different arrhythmogenic mechanisms.
authors.affiliation: Heart Research Follow-Up Program, Cardiology Department, University of Rochester Medical Center, Rochester, New York, USA. jean-philippe.couderc@thew-project.org
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Couderc
authors.forename: Xiajuan
authors.initials: X
authors.lastname: Xia
authors.forename: Derick R
authors.initials: DR
authors.lastname: Peterson
authors.forename: Scott
authors.initials: S
authors.lastname: McNitt
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhao
authors.forename: Slava
authors.initials: S
authors.lastname: Polonsky
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects; D001372:Aza Compounds / Q000009:adverse effects; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D024841:Fluoroquinolones; D005500:Follow-Up Studies; D005838:Genotype; D006321:Heart / Q000187:drug effects; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D000077266:Moxifloxacin; D009154:Mutation; D011804:Quinolines / Q000009:adverse effects; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C000606913:KCNH2 protein, human; D011804:Quinolines; D004247:DNA; D000077266:Moxifloxacin