Proarrhythmia as a class effect of quinolones: increased dispersion of repolarization and triangulation of action potential predict torsades de pointes.

Milberg P, Hilker E, Ramtin S, Cakir Y, Stypmann J, Engelen MA, Mönnig G, Osada N, Breithardt G, Haverkamp W, Eckardt L

Research article (journal)

Abstract

BACKGROUND: Numerous noncardiovascular drugs prolong repolarization and thereby increase the risk for patients to develop life-threatening tachyarrhythmias of the torsade de pointes (TdP) type. The development of TdP is an individual, patient-specific response to a repolarization-prolonging drug, depending on the repolarization reserve. The aim of the present study was to analyze the underlying mechanisms that discriminate hearts that will develop TdP from hearts that will not develop TdP. We therefore investigated the group of quinolone antibiotics that reduce repolarization reserve via I(Kr) blockade in an intact heart model of proarrhythmia. METHODS AND RESULTS: In 47 Langendorff-perfused, AV-blocked rabbit hearts, ciprofloxacin (n = 10), ofloxacin (n = 14), levofloxacin (n = 10), and moxifloxacin (n = 13) in concentrations from 100 microM to 1,000 microM were infused. Eight monophasic action potentials (MAPs) and an ECG were recorded simultaneously. After incremental pacing at cycle lengths from 900 ms to 300 ms to compare the action potential duration, potassium concentration was lowered to provoke TdP. All antibiotics led to a significant increase in QT interval and MAP duration, and exhibited reverse-use dependence. Eight simultaneously recorded MAPs demonstrated an increase in dispersion of repolarization in the presence of all antibiotics. MAP triangulation (ratio: MAP(90/50)) and fluctuation of consecutive action potentials were increased for all tested drugs at high concentrations. In the presence of low potassium concentration, all quinolones led to TdP: ciprofloxacin, 4 out of 10 (40%); ofloxacin, 3 out of 14 (21%); moxifloxacin, 9 out of 13 (69%); and levofloxacin, 2 out of 10 (20%). Hearts that developed TdP demonstrated a significant greater influence on dispersion of repolarization and on triangulation as compared with hearts without TdP. CONCLUSION: Quinolone antibiotics may be proarrhythmic due to a significant effect on myocardial repolarization. The individual response of a heart to develop TdP in this experimental model is characterized by a greater effect on dispersion of repolarization and on triangulation of action potential as compared with hearts that do not develop TdP.

Details about the publication

JournalJournal of Cardiovascular Electrophysiology
Volume18
Issue6
Page range647-654
StatusPublished
Release year2007
Language in which the publication is writtenEnglish
KeywordsMale; Dose-Response Relationship Drug; Animals; Action Potentials; Torsades de Pointes; Quinolines; Disease Models Animal; Anti-Infective Agents; Electrophysiologic Techniques Cardiac; Ofloxacin; Quinolones; Rabbits; Electrocardiography; Aza Compounds; Heart Conduction System; Ciprofloxacin; Male; Dose-Response Relationship Drug; Animals; Action Potentials; Torsades de Pointes; Quinolines; Disease Models Animal; Anti-Infective Agents; Electrophysiologic Techniques Cardiac; Ofloxacin; Quinolones; Rabbits; Electrocardiography; Aza Compounds; Heart Conduction System; Ciprofloxacin

Authors from the University of Münster

Eckardt, Lars
Department for Cardiovascular Medicine
Engelen, Markus Andreas
Department for Cardiovascular Medicine
Hilker, Ekkehard
Department for Cardiovascular Medicine
Milberg, Peter
Department for Cardiovascular Medicine
Mönnig, Gerold
Department for Cardiovascular Medicine
Ramtin, Shahram
Department for Cardiovascular Medicine
Stypmann, Jörg
Department for Cardiovascular Medicine