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Proarrhythmia as a Class Effect of Quinolones: Increased Dispersion of Repolarization and Triangulation of Action Potential Predict Torsades de Pointes PETER MILBERG, M.D.,∗ EKKEHARD HILKER, M.D.,∗ SHAHRAM RAMTIN, M.D.,∗ ¨ YILMAZ CAKIR, M.D.,∗ JORG STYPMANN, M.D.,∗ ,† MARKUS A. ENGELEN, M.D.,∗ ¨ ¨ GEROLD MONNIG, M.D.,∗ NANI OSADA, PH.D., M.D.,‡ GUNTER BREITHARDT, M.D., ∗ F.E.S.C., F.A.C.C., WILHELM HAVERKAMP, M.D., F.E.S.C.,§ and LARS ECKARDT, MD∗ From the ∗ Hospital of the Westf¨alische Wilhelms-University, Department of Cardiology and Angiology, M¨unster, Germany; †Interdisciplinary Centre for Clinical Research, Central Project Group (ZPG 4a), Westf¨alische Wilhelms-University, M¨unster, Germany; ‡Department of Medical Informatics and Biomathematics, University of M¨unster, Germany; §Department of Cardiology, Campus Virchow Clinic, Charit´e – University Medicine Berlin, Germany
Predictors of Proarrhythmia in Quinolones. 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 µM to 1,000 µM 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. (J Cardiovasc Electrophysiol, Vol. 18, pp. 647-654, June 2007) quinolones, predictors of proarrhythmia, class effect, repolarization reserve Introduction The number of noncardiovascular drugs that are associated with QT prolongation and have a proarrhythmic potential is rising continuously. Among noncardiovascular drugs that prolong repolarization and may have serious torsadogenic side effects, quinolones are widely prescribed. They are one of the largest classes of antimicrobial agents used worldwide and have a broad gram negative antimicrobial spectrum. They demonstrate an excellent tissue penetration and are used with Address for correspondence: Peter Milberg, M.D., Medizinische Klinik und Poliklinik C, - Kardiologie und Angiologie -, Universit¨atsklinikum M¨unster, Albert-Schweitzer Str. 33, D-48149 M¨unster. Fax: (+49) 251-834 9943; E-mail:
[email protected] Manuscript received 31 August 2006; Revised manuscript received 23 January 2007; Accepted for publication 24 January 2007. doi: 10.1111/j.1540-8167.2007.00793.x
increasing frequency in severe nosocomial acquired pneumonias, infections of the gastrointestinal and urinary tract, and soft tissue infections. They have bactericidal activity by forming ternary complexes between DNA and type II and type IV topoisomerases.1 The activity of newer substances is extended towards gram-positive bacteria.2 In a postmarketing analysis, the Food and Drug Administration (FDA) reported a prolongation of repolarization due to quinolone antibiotics.3 Moreover, an increase of action potential duration due to block of action potential-repolarizing currents was demonstrated.4 Although the occurrence of proarrhythmia after administration of quinolones is a rare adverse event,3 in several case reports, torsade de pointes (TdP),5-8 a polymorphic ventricular tachycardia that can lead to sudden cardiac death, was reported. Drug-induced TdP remains an important problem, especially in combination with concomitant risk factors such as bradycardia,9 hypokalemia,10 comedication with other QT-prolonging agents,11 accumulation due to liver or renal failure,10 inhibition of cytochrome P450 drug
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metabolism,12 female gender,6 or congenital long QT syndrome. The significance of “acquired QT-syndrome” is underlined by withdrawal of grepafloxacin13 from clinical use and limitation in application of sparfloxacin14 because of torsadogenic side effects.9,15 The development of TdP is an individual, patient-specific response to a repolarization prolonging drug depending on the “so-called” repolarization reserve. As it is still unpredictable which heart develops TdP in the presence of an identical proarrhythmic milieu, the aim of the present study was to analyze the underlying mechanisms that discriminate hearts with TdP from hearts without TdP. Ciprofloxacin, ofloxacin, levofloxacin, and moxifloxacin, belonging to the same group of drugs, seem to be suitable to investigate and to discriminate the established predictors of proarrhythmia in a previously developed animal model of TdP.16-18 Methods All experimental protocols were approved by the local animal care committee and conformed with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 852-3, revised 1996). Preparation of Hearts for Perfusion The method of preparing the hearts has previously been described in detail.19,20 Male New Zealand white rabbits (n = 47) weighing 2.5–3.0 kg were anaesthetized with sodium thiopental (200–300 mg i.v.). After midsternal incision and opening of the pericardium, the complete hearts were removed and immediately placed in an ice-cold KrebsHenseleit solution (composition in mM: CaCl 2 1.80, KCl 4.70, KH 2 PO 4 1.18, MgSO 4 0.83, NaCl 118, NaHCO 3 24.88, Na-pyruvate 2.0, and D-glucose 5.55). The aorta was cannulated, the pulmonary artery was incised, and the spontaneously beating hearts were perfused via the aorta and the coronary arteries at constant flow (52 ml/min) with warm (36.8 to 37.2◦ C) Krebs-Henseleit solution. Perfusion pressure was kept stable at 100 mmHg. The hearts were placed in a heated, solution-filled tissue bath. After cannulation, the hearts were given 10 minutes to stabilize. The perfusate was equilibrated with 95% O 2 and 5% CO 2 (pH 7.35; 37◦ C). The cannulated and perfused hearts were attached to a vertical Langendorff apparatus (Hugo Sachs Elektronic, Medical Research Instrumentation, March-Hugstetten, Germany). A deflated latex balloon was inserted into the left ventricle and connected to a pressure transducer to control hemodynamic stability. The atrioventricular (AV) node was ablated under ECG-control by surgical tweezers to slow the intrinsic heart rate. This resulted in complete AV-dissociation with a ventricular escape rate below 60 beats/minute. Electrocardiographic and Electrophysiologic Measurements A volume-conducted ECG was recorded by complete immersion of the heart into a bath of Krebs-Henseleit solution that had been thermally equilibrated with the myocardial perfusate. Signals from a simulated “Einthoven” configuration were amplified by a standard ECG amplifier (filter settings: 0.1–300 Hz). Monophasic action potential (MAP) recordings and stimulation were accomplished simultaneously, us-
ing contact MAP pacing catheters (EP Technologies, Mountain View, CA, USA). The MAP electrograms were amplified and filtered (low pass 0.1 Hz, high pass 300 Hz). MAPs were analyzed, using a software specifically designed by Franz et al.,21 permitting precise definition of the amplitude and duration of the digitized signals. The recordings were considered reproducible and, therefore, acceptable for analysis only if they had a stable baseline amplitude with a variation of
