Enhanced sensitivity to drug-induced QT interval lengthening in patients with heart failure due to left ventricular systolic dysfunction

James E. Tisdale, Brian R. Overholser, Heather A. Wroblewski, Kevin M. Sowinski, Kwadwo Amankwa, Steven Borzak, Joanna R. Kingery, Rita Coram, Douglas P. Zipes, David A. Flockhart, Richard J. Kovacs

Research output: Contribution to journalArticle

11 Scopus citations

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 (QTF) intervals (EC50) were determined, and areas under the effect (QTF interval vs time) curves (AUECs) were calculated. Ibutilide concentration-QTF relationships were best described by a sigmoidal Emax 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.

Original languageEnglish (US)
Pages (from-to)1296-1305
Number of pages10
JournalJournal of clinical pharmacology
Volume52
Issue number9
DOIs
StatePublished - Sep 2012

Keywords

  • Arrhythmias
  • heart failure
  • pharmacodynamics
  • QT interval
  • torsades de pointes

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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    Tisdale, J. E., Overholser, B. R., Wroblewski, H. A., Sowinski, K. M., Amankwa, K., Borzak, S., Kingery, J. R., Coram, R., Zipes, D. P., Flockhart, D. A., & Kovacs, R. J. (2012). Enhanced sensitivity to drug-induced QT interval lengthening in patients with heart failure due to left ventricular systolic dysfunction. Journal of clinical pharmacology, 52(9), 1296-1305. https://doi.org/10.1177/0091270011416939