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CARDIOVASCULAR
Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, California (L.W., J.C.S., L.B.); and Department of Medicine, University of Florida, Gainesville, Florida (Y.S.)
Received August 30, 2005; accepted October 14, 2005.
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Abstract |
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; Belardinelli et al., 2003). Prolongation of the QT interval of the electrocardiogram (ECG) is poorly correlated with the propensity of a drug to cause TdP (Antzelevitch, 2004). Many factors, including beat-to-beat variability of repolarization and transmural dispersion of ventricular repolarization, are important indirect determinants of the proarrhythmic effects of drugs (Belardinelli et al., 2003). Physiological (e.g., female gender) and pathophysiological (e.g., bradycardia, electrolyte disturbances, drug interactions, heritable ion channelopathies, and history of long-QT syndrome) situations have been associated with an increased risk for arrhythmias during treatment with drugs that prolong the QT interval (Zeltser et al., 2003).
Assessment of the potential risk of proarrhythmic activity during therapy with drugs that prolong the QT interval is important but difficult because the incidence of arrhythmias during the use of most of these drugs is very low (Haverkamp et al., 2000; Roden and Temple, 2005). Better preclinical assays are needed to identify drugs with the potential to cause TdP (Shryock et al., 2004). Drug-induced reduction of net repolarizing current (i.e., "repolarization reserve") during the plateau of the ventricular action potential is a mechanism of arrhythmic activity. This reduction of repolarizing current is due most commonly to a decrease of IKr (Roden, 1998; Biliczki et al., 2002). An abnormal increase of "late openings" of sodium channels (INaL) due either to heritable SCN5A mutations or to organic heart disease (e.g., heart failure) is also associated with a decrease of repolarization reserve and an increased susceptibility to TdP (Bennett et al., 1995; Makita et al., 2002; Splawski et al., 2002). Further-more, an increase of INaL causes increases of intracellular sodium content and sodium extrusion/calcium entry via the sodium-calcium exchanger and may lead to intracellular calcium overload. Therefore, we hypothesized that a small augmentation of INaL would potentiate and unmask the proarrhythmic effects of QT-prolonging drugs, including drugs that have a very low risk of causing ventricular tachycardia (VT). The methodology of this study was to evaluate the facilitation by ATX-II (an enhancer of INaL) of the proarrhythmic effects of QT-prolonging drugs in the female rabbit isolated, perfused heart. The female rabbit heart was chosen for its high sensitivity to human ether-a-go-go-related gene (i.e., IKr) channel blockade and its relatively low repolarization reserve (Joshi et al., 2004).
The drugs selected for evaluation in this study were cisapride, quinidine, ziprasidone, moxifloxacin, pentobarbital, and ranolazine. These drugs have different pharmacological activities but share an effect to inhibit IKr. The risk of proarrhythmic activity associated with the clinical use of each drug, however, is quite different. Cisapride (Propulsid), a motility enhancer that can be used to treat patients with gastroesophageal reflux disease, and quinidine, a class Ia antiarrhythmic agent, have been shown to prolong the QT interval and to trigger TdP (Roden et al., 1986; Wysowski and Bacsanyi, 1996; Walker et al., 1999; Levy et al., 2001). Cisa-pride is a potent (IC50 = 7 nM) IKr blocker (Walker et al., 1999). Its use has been associated with QT prolongation, TdP, and cardiac arrest, and it has been withdrawn from use by the Food and Drug Administration. Quinidine reduces INa, IKr, and other ionic currents. Quinidine is reported to cause TdP in 2.8 to 8.8% of treated patients (Haverkamp et al., 2000). Reported cases of TdP caused by antimicrobial quinolones such as moxifloxacin could be as low as 0.3 to 27 in 10 million prescriptions (Frothingham, 2005). Moxifloxacin (Avelox) has been reported to cause QT prolongation, but its use has been very rarely associated with TdP in humans (Noel et al., 2003). Ziprasidone (Geodon) is an antipsychotic agent that has been reported to prolong the QT interval and cause arrhythmias, but the risk of arrhythmic activity associated with its use is likely to be very low (Haddad and Anderson, 2002). Pentobarbital, a barbiturate, and ranolazine, an antianginal agent, have been shown to prolong the QT interval without causing TdP in cardiac preparations from laboratory animals or in clinical use (Shimizu et al., 1999; Song et al., 2004; Wu et al., 2004). Therefore, in this study, we consider cisapride and quinidine as drugs with documented risk of TdP, moxifloxacin and ziprasidone as drugs with possible risk, and pentobarbital as a drug with no risk for causing TdP.
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Materials and Methods |
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2.5 h. Monophasic Action Potential (MAP) and ECG Recording. MAP and ECG electrodes were used to record left ventricular MAPs and bipolar ECGs, respectively. Pressure-contact Ag-AgCl MAP electrodes were placed on the epicardial ventricular free wall below the level of the atrial-ventricular valve at the base of the left ventricle. The duration of the MAP at 100% repolarization was observed and monitored with an on-screen caliper. MAP profiles were analyzed by computer to determine the duration of the MAP at the level at which repolarization is 90% completed (MAPD90). MAPs, ECGs, and CPP signals were digitized in real time and displayed on a computer monitor. Steady-state responses to drug(s) are reported in this study.
Beat-to-Beat Variability of MAPD90. Values of MAPD90 for 30 consecutive beats were used for calculation of the beat-to-beat variability of ventricular repolarization (BVR). As a measure of BVR, the mean orthogonal distance on the Poincaré plot from the diagonal to each point was determined using the following equation: 
(Thomsen et al., 2004).
Measurements of Transmembrane Potential and INaL from Rabbit Ventricular Myocytes. To measure the effect of ATX-II on myocyte INaL, single myocytes were isolated by collagenase digestion of rabbit hearts as described by Song et al. (2004) for guinea pig hearts with the following modifications: hearts were perfused at a rate of 16 ml/min; the activity of collagenase used for digestion was 240 U/ml; and the volume of collagenase-containing solution was 70 ml, and it was recirculated through the heart for a period of 40 min. Transmembrane voltages and currents were recorded from quiescent myocytes using borosilicate glass capillary microelectrodes (1-3 M
resistance when filled) in a whole-cell patch-clamp configuration. An Axopatch-200 amplifier, a DigiData-1200A interface, and a computer with pCLAMP8 software (Molecular Devices, Sunnyvale, CA) were used to amplify, store, and analyze the recorded signals. For recording of late I+Na, K and Ca2+ were omitted from both the bath Tyrode's solution and the microelectrode solution to reduce contamination of INa by K+ and Ca2+ currents. Recording microelectrodes were filled with 120 mmol/l Cs-aspartate, 20 mmol/l CsCl, 1 mmol/l MgSO4, 4 mmol/l Na2ATP, 0.1 mmol/l Na3GTP, 1 mmol/l EGTA, and 10 mmol/l HEPES, pH 7.2. Myocytes were voltage-clamped at a holding potential of -90 mV. The electrode capacitance, whole-cell capacitance, and series resistance were maximally compensated. The liquid junction potential was measured and nulled using the pCLAMP program. To elicit INa, a 300-ms depolarizing pulse to -20 mV was applied at a frequency of 0.16 Hz. The magnitude of late INa was determined by integration of the area (nA x ms = nC) of the current over the last 50 ms of the -20-mV clamp pulse, using the integration (area) feature of the pCLAMP program.
Determination of Concentration-Response Relationships for Effects of Drugs in the Absence and Presence of 1 nM ATX-II in Rabbit Isolated, Perfused (Method of Langendorff) Hearts. Rabbit hearts were exposed to increasing concentrations of cisapride (10-600 nM), quinidine (0.1-30 µM), ziprasidone (0.1-10 µM), and moxifloxacin (0.1-100 µM) in a cumulative manner, allowing 7 to 15 min between increases in drug concentration to facilitate the recording of a steady-state, maximal effect. All hearts were paced at a rate of 1 Hz throughout the experimental procedure. Drug effects (concentration-response relationships) were measured in the absence and presence of ATX-II. After recording of drug responses in the absence of ATX-II, a heart was perfused with K-H solution containing 1 nM ATX-II for 20 min, and drug administration was repeated in the continued presence of ATX-II.
Determination of Proarrhythmic and Antiarrhythmic Activities of QT-Prolonging Drugs in the Absence and Presence of ATX-II. Ventricular arrhythmic activity, including ectopic ventricular beats (EVBs), early after-depolarizations (EADs), and VT, was monitored continuously during drug treatment of the isolated heart. Postdrug control values of MAPD were obtained when drug washout was completed. An EVB was defined as a spontaneous beat occurring earlier than the next paced beat. VT was defined as a sequence of three or more consecutive spontaneous ventricular de-polarizations at a rate exceeding the pacing rate. An EAD was defined as the positive depolarization during phase 2 and/or 3 of an MAP signal.
Determination of Pause-Triggered Ventricular Arrhythmia. Pause-triggered EVBs, EADs, and VT in the absence (control) and presence of drugs (ATX-II and ATX-II + moxifloxacin) were induced by a 3-s pause in ventricular electrical stimulation. This was repeated three times in the presence of each concentration of test drug. Pause-triggered EADs and ventricular arrhythmias were defined as EADs, EVBs, or VT that occurred within the first three beats after ventricular pacing was resumed.
Statistical Analysis. Data are reported as means ± S.E.M. Concentration-response curves were analyzed using Prism Version 3.0 (GraphPad Software Inc., San Diego, CA). To compare values of measurements obtained from the same heart before and after a drug treatment, repeated measures one-way analysis of variance was used, and Student-Newman-Keuls test was applied to determine which pairs of group means were significantly different. Paired and nonpaired Student t tests were used to determine the significance of a difference between two means before (as control) and after drug treatment in same or different hearts, respectively. A significant difference between two group means was defined as P < 0.05.
Source of Drugs. Ranolazine was synthesized at CV Therapeutics. Cisapride was purchased from Research Diagnostics (Flanders, NJ), quinidine and dimethyl sulfoxide were purchased from Sigma-Aldrich (St. Louis, MO), moxifloxacin hydrochloride was purchased from Alchemie (Plantsville, CT), and ziprasidone was purchased from Apin Chemicals (Oxon, UK). ATX-II from Anemonia sulcata was purchased from Alomone Labs (Jerusalem, Israel).
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Ranolazine (0.1-100 µM, n = 7) prolonged MAPD90 by up to 52 ± 6 ms (Fig. 3A, P < 0.001). However, when hearts were pretreated with 1 nM ATX-II, the prolongation of MAPD90 by ranolazine was only 31 ± 4 ms (n = 6, P < 0.05), and when hearts were pretreated with 2 nM ATX-II, MAPD90 was decreased by ranolazine (Fig. 3A). Pentobarbital (10-300 µM, n = 7) prolonged MAPD90 by 21 ± 5 ms from 185 ± 6 to 205 ± 8 ms (P < 0.001, Fig. 3B). The increases of MAPD90 caused by 1 nM ATX-II and by pentobarbital were additive (Fig. 3B).
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Proarrhythmic Effects of Cisapride, Quinidine, Ziprasidone, and Moxifloxacin in the Absence and Presence of 1 nM ATX-II. Cisapride, quinidine, ziprasidone, and moxifloxacin caused arrhythmic activity (VT) in female isolated rabbit hearts (Figs. 2, 4, 5, and 6). In the absence of ATX-II, cisapride (600 nM, n = 5) caused VT in all hearts (Fig. 2). Cisapride (300 nM) caused VT in only four of six hearts. In the presence of 1 nM ATX-II, however, the effective concentration of cisapride to cause VT was reduced, such that 30 nM cisapride caused EVBs, EADs, and VT in six of six hearts (Fig. 2). Quinidine (1 µM) alone caused EVBs and nonsustained VT in one of six hearts. In contrast, in the presence of 1 nM ATX-II, quinidine (1 µM) caused EVBs, EADs, and VT in seven of seven hearts (Fig. 2). The effects of ziprasidone and moxifloxacin to cause VT were also enhanced in the presence of 1 nM ATX-II (Fig. 2). In contrast, ranolazine (0.1-100 µM) and pentobarbital (10-300 µM) both prolonged MAPD90 but caused no arrhythmic activity in either the absence or presence of ATX-II (Fig. 3). The concentrations of ziprasidone to induce VT were approximately 10-fold lower in the presence than in the absence of ATX-II (Figs. 4 and 5). Moxifloxacin at a concentration of 1 µM did not cause either VT or pause-triggered arrhythmic activity (Figs. 6 and 7). When administered at concentrations as high as 60 to 100 µM (Figs. 2D and 6B), moxifloxacin caused VT in only three of eight hearts. However, in the presence of 1 to 3 nM ATX-II, moxifloxacin (1-3 µM) prolonged MAPD90 and caused VT in 12 of 13 hearts studied (Figs. 2D and 6D). ATX-II (3 nM) alone prolonged MAPD90 by 28 ± 8% from 177 ± 5 to 225 ± 15 ms but caused neither EADs nor VT (Fig. 6C). ATX-II (3 nM) and moxifloxacin (1 µM) together caused spontaneous and paused-triggered EADs, EVBs, and polymorphic VT in seven of seven hearts studied (Figs. 6D and 7C).
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BVR of Ventricular Repolarization Caused by Drugs in the Absence and Presence of ATX-II. Short-term BVR was measured during a control (no drug) period, in the presence of ATX-II or drug alone, and in the presence of drug + 1 nM ATX-II (Fig. 8). ATX-II (1 and 3 nM; n = 26 and 6, respectively), quinidine (1 µM; n = 6), moxifloxacin (1 µM; n = 6), and ziprasidone (1 µM; n = 6) significantly increased the BVR (P < 0.05 and 0.01, respectively). The increases of BVR caused by quinidine (1 µM), moxifloxacin (1 µM), and ziprasidone (1 µM) were significantly greater (P < 0.01) in the presence than in the absence of 1 nM ATX-II (Fig. 8). For example, cisapride (Cisa, 30 nM) alone did not increase BVR (n = 5, P > 0.05 compared with control; Fig. 8A) but significantly increased BVR in the presence of ATX-II (n = 6, P < 0.01, Fig. 8B) and caused TdP. Although both ranolazine (0.1-100 µM) and pentobarbital (10-300 µM) prolonged MAPD90, neither drug increased BVR in either the absence (Fig. 8A) or presence (Fig. 8B) of 1 nM ATX-II.
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Discussion |
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; Haddad and Anderson, 2002; Belardinelli et al., 2003; Joshi et al., 2004). However, the incidence of TdP caused by drugs that prolong the QT interval does not correlate with the extent of QT prolongation by the same drugs (Haverkamp et al., 2000; Belardinelli et al., 2003). Thus, QT interval prolongation is not an adequate indicator of the drug-induced risk of TdP, and the rare occurrence of TdP makes the direct assessment of risk difficult. The size of clinical trials is insufficient to detect a very rare incident of TdP. The present study shows that the female rabbit heart exposed to ATX-II is a very sensitive model for detection of proarrhythmic effects of QT-prolonging drugs. ATX-II increases INaL and thereby decreases the net repolarizing current. This model can differentiate QT-prolonging drugs with proarrhythmic activity at clinically relevant drug concentrations from QT-prolonging drugs without such activity. The proarrhythmic activities of IKr blockers whose use is associated with moderate-to-high (cisapride, quinidine), very low (moxifloxacin, ziprasidone), or no (e.g., pentobarbital) risk of causing TdP were distinguished. The data obtained with this model should be considered informative of the potential of a drug to induce proarrhythmic activity only under the tested condition of reduced repolarization reserve. Results of drug screening in this model are not intended to be used to predict the risk/benefit ratio of use of drugs in general clinical practice.
The reported therapeutic concentrations of cisapride, quinidine, ziprasidone, and moxifloxacin are 0.085 to 0.134, 2.55 to 10.2, 0.18 to 0.59, and 1.3 to 10.7 µM, respectively (Hatlebakk and Berstad, 1996; Stass et al., 1998; Campbell and Williams, 2001; Miceli et al., 2005). At these respective concentrations, cisapride, quinidine, and moxifloxacin caused significant MAPD prolongation, EADs, frequent ventricular premature beats, and polymorphic VTs in the rabbit heart exposed to 1 nM ATX-II. Ziprasidone caused VT only at concentrations (i.e., 
0.3 µM) that are equal to or exceed the therapeutic range of drug concentrations. Therapeutic concentrations of ranolazine and pentobarbital are 1 to 10 and 4 to 20 µM, respectively (Hart AP et al., 1997; Chaitman et al., 2004b). At these (and higher) concentrations, neither drug caused arrhythmic activity in either the absence or presence of ATX-II.
The finding that ATX-II increases proarrhythmic actions of cisapride, quinidine, moxifloxacin, and ziprasidone suggests that these drugs may be unsafe in patients in which late INa is increased due to heritable (i.e., SCN5A) or acquired channelopathies. INaL is reported to be increased in myocytes from both canine and human failing hearts, in myocytes exposed to oxygen free radicals, in postmyocardial infarction "remodeled" myocytes, and in hypoxic and ischemic hearts (Ward and Giles, 1997; Undrovinas et al., 2002; Valdivia et al., 2005). The increase in INaL causes a decrease in repolarization reserve and may cause cytosolic calcium overload. Reduced repolarization reserve has been used to explain the increased proarrhythmic risk of QT-prolonging drugs in animal and human hearts (Roden, 1998). An increase of INa,L and a decrease of IKr both reduce repolarization reserve. Thus, the effects of cisapride, moxifloxacin, and ziprasidone to increase MAPD in the presence of ATX-II in the present study can be explained as the result of two actions, both of which decrease repolarization reserve. Our results are consistent with the finding (Song et al., 2004) that ATX-II and blockers of IK have synergistic actions to increase the duration of the action potential of guinea pig ventricular myocytes. Our results are also consistent with the report that veratridine, an inhibitor of sodium channel inactivation, caused EADs, TdP, and increased transmural dispersion of repolarization in Langendorff-perfused rabbit hearts (Milberg et al., 2005). Although the increase of late INa caused by ATX-II may not accurately mimic the many other conditions that predispose to drug-induced VT, inasmuch as the effect of these conditions to cause VT depends on a reduction of repolarization reserve, that effect may be reproduced by exposure of the heart to ATX-II.
An increase of BVR has also been used to predict proarrhythmic activity of QT-prolonging drugs (Hondeghem and Hoffmann, 2003; Thomsen et al., 2004). The results of the present study indicate that the changes in BVR caused by drugs in the absence and presence of an INaL enhancer are consistent with the effects of the same drugs to cause VT in the presence of ATX-II.
Ranolazine and pentobarbital were found in this study to prolong the MAPD, consistent with previous reports (Wu et al., 2004). Ranolazine did not cause arrhythmic activity in either the absence or presence of ATX-II, and in the presence of 2 nM ATX-II, ranolazine actually decreased MAPD90. Pentobarbital did not cause arrhythmic activity in the absence or presence of ATX-II, but its effect and that of ATX-II to increase MAPD90 were additive. Neither ranolazine nor pentobarbital increased BVR in the absence or presence of ATX-II. In contrast, cisapride, quinidine, moxifloxacin, and ziprasi-done each increased BVR in the presence of 1 nM ATX-II. An increase of BVR was reported to predict drug-induced TdP in dog (Thomsen et al., 2005).
Our results with both pentobarbital and ranolazine confirm the opinion that QT prolongation per se is not a good predictor of TdP because both drugs prolong the QT interval but are not reported to cause TdP (Shimizu et, 1999; Zhou et al., 2002; Chaitman et al., 2004a,b). Furthermore, equal prolongations of MAPD90 in the present study were not associated with equal propensities for arrhythmic activity. Prolongations of MAPD90 of 60 ms caused by either quinidine or moxifloxacin in the absence of ATX-II were not associated with VT, whereas 60-ms prolongations of MAPD90 caused by either drug in the presence of ATX-II were associated with the occurrence of VT in all hearts (Fig. 2). The mechanisms underling the proarrhythmic activities of drugs include increases of MAPD, transmural dispersion of repolarization, beat-to-beat variability of action potential duration, triangulation, and induction of EADs (Belardinelli et al., 2003; Hondeghem et al., 2003; Antzelevitch et al., 2004; Thomsen et al., 2005). For the pure IKr blockers cisapride, moxifloxacin, and ziprasidone, drug effects to increase MAPD prolongation and to induce arrhythmic activity were synergistically increased by ATX-II. However, the effects of quinidine, ranolazine, and pentobarbital to increase MAPD and to cause arrhythmic activity were not directly related, and the effects of ranolazine and pentobarbital were not potentiated by ATX-II. Quinidine, ranolazine, and pentobarbital are "blockers" of more than one ion current. Ranolazine inhibits both IKr and INaL. Reductions of IKr and INaL have opposite actions on action potential duration. In the absence of ATX-II, the inhibition of IKr predominated and ranolazine increased MAPD90; in the presence of 2 nM ATX-II, the inhibition of INaL by ranolazine predominated over its action to inhibit IKr, and ranolazine shortened MAPD. This may explain the findings that ranolazine did not cause arrhythmias in either the presence or absence of ATX-II and reversed the ventricular arrhythmic activity caused by moxifloxacin, quinidine, cisapride, and ziprasidone (this manuscript; Song et al., 2004; Wu et al., 2004).
In conclusion, the results of assays of effects of six QT-prolonging drugs on MAPD90 and arrhythmic activity in the female rabbit isolated, perfused heart exposed to a low concentration of ATX-II (an enhancer of late INa) appear to correlate with the known risks for each drug to cause TdP in patients. Therefore, this preparation can be useful in preclinical studies to predict the risk that a drug candidate will cause TdP when late INa is increased. Assays with this preparation are able to detect the proarrhythmic potential of drugs that are known to have a very low proclivity to cause TdP.
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Footnotes |
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ABBREVIATIONS: TdP, torsades de pointes; ECG, electrocardiogram; VT, ventricular tachycardia; ATX-II, sea anemone toxin; ranolazine, (±)-N-(2,6-dimethylphenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine; K-H, Krebs-Henseleit; CPP, coronary perfusion pressure; MAP, monophasic action potential; MAPD, monophasic action potential duration; BVR, beat-to-beat variability of repolarization of MAPD90; EVB, ectopic ventricular beat; EAD, early after depolarization; LV, left ventricular.
Address correspondence to: Lin Wu, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: lin.wu{at}cvt.com
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, frequent ectopic ventricular beats or polymorphic ventricular tachycardias occurred in the presence of drug at the concentration indicated.
