title: Enhanced sensitivity to drug-induced QT interval lengthening in patients with heart failure due to left ventricular systolic dysfunction.
abstract: Patients with heart failure (HF) are at increased risk for drug-induced torsades de pointes (TdP) due to unknown mechanisms. Our objective was to determine if sensitivity to drug-induced QT interval lengthening is enhanced in patients with HF. In this multicenter, prospective study, 15 patients with atrial fibrillation or flutter requiring conversion to sinus rhythm were enrolled: 6 patients with New York Heart Association class II to III HF (mean ejection fraction [EF], 30% ± 9%), and 9 controls (mean EF, 53% ± 6%). Patients received ibutilide 1 mg intravenously. Blood samples and 12-lead electrocardiograms were obtained prior to and during 48 hours postinfusion. Serum ibutilide concentrations at 50% maximum effect on Fridericia-corrected QT (QT(F)) intervals (EC(50)) were determined, and areas under the effect (QT(F) interval vs time) curves (AUECs) were calculated. Ibutilide concentration-QT(F) relationships were best described by a sigmoidal E(max) model with a hypothetical effect compartment. Median [interquartile range] AUEC from 0 to 4 hours was larger in the HF group than in controls (1.86 [1.86-1.93] vs 1.82 [1.81-1.84] s·h; P = .04). Median EC(50) was lower in the HF group (0.48 [0.46-0.49] vs 1.85 [1.10-3.23] μg/L; P = .008). Sensitivity to drug-induced QT interval lengthening is enhanced in patients with systolic HF, which may contribute to the increased risk of drug-induced TdP.
authors: Department of Pharmacy Practice, College of Pharmacy, Purdue University, W7555 Myers Building, WHS, 1001 West 10th Street, Indianapolis, IN 46202, USA. jtisdale@iupui.edu
authors: James E
authors: JE
authors: Tisdale
authors: Brian R
authors: BR
authors: Overholser
authors: Heather A
authors: HA
authors: Wroblewski
authors: Kevin M
authors: KM
authors: Sowinski
authors: Kwadwo
authors: K
authors: Amankwa
authors: Steven
authors: S
authors: Borzak
authors: Joanna R
authors: JR
authors: Kingery
authors: Rita
authors: R
authors: Coram
authors: Douglas P
authors: DP
authors: Zipes
authors: David A
authors: DA
authors: Flockhart
authors: Richard J
authors: RJ
authors: Kovacs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006333:Heart Failure / Q000209:etiology* / Q000503:physiopathology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D018487:Ventricular Dysfunction, Left / Q000150:complications* / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D013449:Sulfonamides; C067192:ibutilide