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


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.


CONCLUSIONS
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.
Milberg
Peter
P
Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology, Münster, Germany. milbergp@uni-muenster.de
Hilker
Ekkehard
E
Ramtin
Shahram
S
Cakir
Yilmaz
Y
Stypmann
Jörg
J
Engelen
Markus A
MA
Mönnig
Gerold
G
Osada
Nani
N
Breithardt
Günter
G
Haverkamp
Wilhelm
W
Eckardt
Lars
L
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001372:Aza Compounds / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D024841:Fluoroquinolones; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D064704:Levofloxacin; D008297:Male; D000077266:Moxifloxacin; D015242:Ofloxacin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology*
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D015363:Quinolones; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D000077266:Moxifloxacin