Document Detail

Proarrhythmia as a class effect of quinolones: increased dispersion of repolarization and triangulation of action potential predict torsades de pointes.
MedLine Citation:
PMID:  17388913     Owner:  NLM     Status:  MEDLINE    
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.
Peter Milberg; Ekkehard Hilker; Shahram Ramtin; Yilmaz Cakir; Jörg Stypmann; Markus A Engelen; Gerold Mönnig; Nani Osada; Günter Breithardt; Wilhelm Haverkamp; Lars Eckardt
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Publication Detail:
Type:  In Vitro; Journal Article     Date:  2007-03-28
Journal Detail:
Title:  Journal of cardiovascular electrophysiology     Volume:  18     ISSN:  1540-8167     ISO Abbreviation:  J. Cardiovasc. Electrophysiol.     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-05-24     Completed Date:  2007-08-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9010756     Medline TA:  J Cardiovasc Electrophysiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  647-54     Citation Subset:  IM    
Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology, Münster, Germany.
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MeSH Terms
Action Potentials* / drug effects
Anti-Infective Agents / pharmacology
Aza Compounds / pharmacology
Ciprofloxacin / pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Electrophysiologic Techniques, Cardiac
Heart Conduction System / drug effects,  physiopathology*
Ofloxacin / pharmacology
Quinolines / pharmacology
Quinolones / pharmacology
Torsades de Pointes / chemically induced*,  diagnosis,  physiopathology*
Reg. No./Substance:
0/Anti-Infective Agents; 0/Aza Compounds; 0/Quinolines; 0/Quinolones; 0/moxifloxacin; 82419-36-1/Ofloxacin; 85721-33-1/Ciprofloxacin
Comment In:
J Cardiovasc Electrophysiol. 2007 Jun;18(6):655-7   [PMID:  17488264 ]

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