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Introduction

Unfortunately, the vast majority of antiarrhythmicdrugs (AADs) aggravate heart rhythm disturbances (in3 – 15 % of cases); this phenomenon is known asproarrhythmia, or drug-induced arrhythmogenesis [1].It occurs most often when an AAD increases the fre-quency and/or duration of the tachyarrhythmicepisodes it is intended to suppress, but the AAD mayalso induce a life-threatening ventricular arrhythmia(VT/VF) by activating a previously dormant arrhyth-mic substrate, or by creating a de novo arrhythmogenicmechanism [2]. In recent years, those non-cardiovas-cular drugs capable of inducing ventricular tach-yarrhythmias and sudden arrhythmic cardiac death(SACD) even in subjects with a structurally intactheart [3,4] have become of increasing interest to us.We also refer to a "proarrhythmic effect" if deteriora-tion of a tachyarrhythmia is induced by an implantable

antiarrhythmia device (pacemaker, ICD), either aloneor in conjunction with an AAD [5,6].

Antiarrhythmic and Non-cardiovascular Drugs

At the present time, specifically characterized proar-rhythmia syndromes can be distinguished from theunderlying mechanisms, the clinical features, and thenecessary therapeutic measures [1]. The proarrhythmiceffect of AADs of the Vaughan Williams-HarrisonClass I, which exclusively block (I/B) or predominant-ly block (I/C) the sarcolemmal sodium channels (INa),can be attributed to the use-dependent slowing ofimpulse conduction and facilitation of reentry [7]. Theproarrhythmic potential of these drugs is usually mani-fested in the form of incessant or sustained monomor-phic ventricular tachycardia (SMVT), accompanied by

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Ventricular Proarrhythmias Induced by Antiarrhythmic Drugs,Non-Cardiovascular Agents, and Implantable Antiarrhythmia Devices

T. FAZEKASSzeged University Medical School, Albert Szent-Györgyi Health Sciences Center, Szeged, Hungary

G. LISZKAIBékés County Kálmán Pándy Hospital, Intensive Care Unit, Gyula, Hungary

Summary

The authors briefly survey the electrophysiological mechanism and clinical spectrum of the aggravation of ven-tricular arrhythmias provoked by antiarrhythmic drugs, non-cardiovascular agents, and implantable cardioverter-defibrillators. The main aspects of the recognition, the differential diagnosis, and the treatments are discussed. Itis emphasized that prevention of drug-induced arrhythmogenesis necessitates a fundamental understanding of therisk factors of proarrhythmias and of the clinical pharmacological properties of the drugs that are intended to beused, including proarrhythmic drug interactions. An account is presented of those drugs prescribed in non-arrhyth-mic states which may lead to ventricular fibrillation / ventricular tachycardia and out-of-hospital cardiac arrest.The proarrhythmic phenomena that may be observed in recipients of implantable cardioverter-defibrillators arediscussed, as are the undesirable interactions between devices and antiarrhythmic drugs in such patients.

Key Words

Ventricular proarrhythmias, antiarrhythmics, non-antiarrhythmic drugs, implantable cardioverter-defibrillator

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presence of the mid-myocardial M-cell layer and to thereverse use-dependent increase in the dispersion ofrefractoriness [10]. In addition to removing the drug,therapy usually consists in intravenous administrationof potassium and magnesium, and/or temporary trans-venous pacing at a rate > 80 – 90 beats/min [11], butother APD-shortening drugs may also be effective, e.g.,the slowly inactivating Na+-current-blocking mexile-tine (Figure 1) [12], or the ATP-dependent potassiumchannel opener nicorandil [9]. It has been experimen-tally demonstrated that certain AADs, which inhibit therapidly activating delayed rectifier potassium current(IKr) with high potency, and the slow L-type Ca2+-cur-rent (ICa-L) with somewhat lower potency (e.g.,H 342/52 or BRL-32872), are capable of prolongingAPD without provoking either EADs or torsades depointes VT [13]. On the other hand, those IK-blockingcompounds that prolong phase 2 (plateau) repolariza-tion without APD triangulation, instability, and reverseuse-dependence, exert a significant antiarrhythmiceffect without "torsadogenic" activity [14]. It is note-worthy that the specific (dofetilide, almokalant) andnon-selective (quinidine, sotalol, ibutilide) blockers ofIKr that is mainly responsible for the terminal (phase 3)repolarization are able to induce not only torsades depointes, but also monomorphic VT (Figures 2 and 3)[15]; the ECG morphology of the ventricular arrhyth-mia is therefore of limited diagnostic value. Of theAADs that are currently used, oral amiodarone (withClass I/B and II and III and IV properties) has the low-est (< 2 %) proarrhythmic activity and can be adminis-tered safely even in patients with CHF [16]. It is almostcertain that not even a combined IKr and IKs-block(azimilide, GLG-V-13, bepridil, indapamide,mibefradil) per se abolishes "torsadogenic" side-effectsof AADs [9,17,18]. The longest-known, drug-acquiredarrhythmia is ventricular bigeminy and monomorphicor bidirectional VT induced by digitalis glycosides,which can be attributed to tachycardia-dependentdelayed afterdepolarizations (DAD) due to sarcoplas-matic reticular Ca2+-overload [1]. The proarrhythmicactivity of β-receptor blockers and heart rate loweringCa2+-antagonists (verapamil, diltiazem, gallopamil) isbased on depression of sinoatrial (SA) impulse forma-tion and atrioventricular (AV) conduction, and accord-ingly it appears in the form of sinus arrest, pronouncedbradycardia or advanced AV block [1].The CAST studies have clearly revealed that, if ananatomical substrate (e.g., post-MI scar) is present,

a wide QRS complex [2]. The use-dependent blockadeof the fast Na+-channels (INa) may be responsible forthe clinical observation, that VT occurring in the pres-ence of I/C AADs (flecainide, propafenone, mori-cizine) often commences in response to sinus tachy-cardia, e.g., exercise stress test [2]. The view is nowwidely accepted that, in post-MI patients, the addi-tive negative dromotropic effect of acute ischemia andNa+-channel blockers is responsible for the reentry-facilitation and the increased mortality observed in thecourse of randomized, controlled trials (RCTs), e.g.,CAST I – II [8]. With regard to the generally slow VTinduced by Na+-channel-blocking AADs, the mostimportant therapy is to withdraw the drug, but addi-tional possibilities include overdrive suppression and(if there is not a volume overload) the intravenousadministration of NaHCO3 or Na-lactate [1]. The Class I/A and Class III AADs, which block cardiacpotassium channels, and which lengthen the duration ofaction potentials (APD) and the QT interval, generallyinduce bradycardia/pause-dependent polymorphic VT(torsades de pointes) [4,9]. This arrhythmia is initiatedby early afterdepolarizations (EAD) arising in thePurkinje cells with inherently long APDs, and is main-tained by transmural reentry that can be ascribed to the

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Figure 1. Transmembrane action potentials recorded fromcanine Purkinje fibers by the conventional microelectrodetechnique. Erythromycin (200 mg/l) induced early afterde-polarizations (EADs) at an average stimulation cycle lengthof 2344 ± 310 ms in all experiments (n = 9). The addition ofmexiletine (10 µmol/l) markedly shortened the duration ofthe action potential, and the abolition of EADs was observed[12].

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life-threatening, AAD-related ventricular tachyarrhyth-mias can occur not only in the first few weeks of phar-macotherapy (early proarrhythmia), but also muchlater (late proarrhythmia) [8]. Interim modification ofthe CAST-II protocol (allowing inclusion of post-MIpatients with an LVEF of less than 40 %) shed light onthe fact that one of the most important factors predis-posing a patient to proarrhythmia is impaired systolicleft ventricular function [8]. As regards the torsades depointes VT developing on the basis of a lengthenedventricular repolarization, the most significant risk fac-tors are hypopotassemia/hypomagnesiemia, bradycar-dia, female gender, prolonged (> 460 ms) pretherapeu-tic QTc interval, and the interactive presence of anoth-er drug which lengthens the QT interval [4,9]. It istempting to speculate that the decrease in the risk ofSACD observed in some subgroups of large-scaleCHF-RCTs (RALES, SOLVD) may be attributed to the"anti-torsades" action of the potassium-saving diuretic

agent aldactone. The d-sotalol sensitivity of the ven-tricular myocardium is likewise enhanced by cardiachypertrophy and electrical remodeling accompanied bydownregulation of potassium channels (IK, Ito) and by aprolongation of ventricular APDs [10]. Accordingly,certain authors currently consider biventricular hyper-trophy to be a potential risk factor for drug-acquiredtorsades de pointes VT/VF. In November 2000, Woosley and Franz established theInternational Registry of Drug-Induced Arrhythmias(ULR: http://www.qtdrugs.org), an electronic forum touniversally register drug-induced arrhythmias and uni-formly process the clinical data. This includes casereports provoked by AADs and non-CV drugs whichlengthen QT. Although these drugs are prescribed fornon-arrhythmic conditions, even in a therapeutic dosethey display a considerable selective IKr (HERG)-blocking activity [3,4]. They include certain macro-lides (erythromycin, clarithromycin, spiramycine) and

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Figure 2. Ibutilide (0.025 mg per kg body weight)-induced non-sustained monomorphic ventricular tachycardia in a dog withchronic complete AV block. ECG limb leads (I, II, aVR) and intracardiac monophasic action potentials were recorded by theelectrode-catheter technique from the right (RV-MAP) and left ventricle (LV-MAP). LV-MAP shows EAD-formation (indicat-ed by an arrow) [15].

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and domperidone display concentration-dependentinhibition of the IKr [19,20]. Therefore, the possibilityexists that sooner or later case reports will announcethat, in the presence of some predisposing factor, thesedrugs induce torsades de pointes VT and/or SACD.Recently, in a female patient with advanced structuralheart disease (CHD and severe mitral valve prolapse),we observed the QTc-interval-prolonging and pro-fibrillatory effects of vinpocetine, a vasodilator that iswidely utilized to treat diseases involving chronic cere-bral hypoperfusion [21]. It has long been known thatrapid intravenous injection of vinpocetine can provokelife-threatening ventricular arrhythmias (VT/VF), butin our case VF developed just after the administrationof a slow drip infusion (40 mg vinpocetine dissolved in500 ml physiological saline infusion); this indicates

fluoroquinolone antibiotics (sparfloxacin, grepa-floxacin), some antimalarial agents (chloroquine, halo-fantrine), 2nd generation non-sedating antihistamines(astemizole, terfenadine, loratadine), certain gastroin-testinal (GI) prokinetics (cisapride, domperidone), tri-azole-skeleton antimycotics (ketokonazole, flukona-zole, itrakonazole) and a significant number of psy-chotropic drugs (phenothiazines, butyrophenons, tri-and tetracyclic antidepressants, pimozide, Li, chloral-hydrate) [2,4,9]. Similar to cocaine, various tricyclicantidepressants (TCAs), e.g., imipramine or amitripty-line, block not only IKr, but also INa. Based on thisinformation, it is readily understandable why a TCAoverdose causes torsades de pointes VT in one patientand monomorphic VT with a broad QRS complex inanother patient. Under in vitro conditions, sildenafil

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Figure 3. Ibutilide-induced (0.05 mg per kg body weight) non-sustained torsades de pointes ventricular tachycardia in a dogwith chronic complete AV block. ECG limb leads (I, II, aVR) and intracardiac monophasic action potentials recorded by theelectrode-catheter technique from the right (RV-MAP) and left ventricle (LV-MAP). Early afterdepolarizations (EAD) andEAD-induced ventricular extrasystoles are marked with arrows and asterisks [15].

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that, in the presence of an enhanced susceptibility toarrhythmia, VT/VF may occur even when this cautiousmode of administration is employed [21].

Implantable Cardioverter-Defibrillators

The results of RCTs have led to ICDs becoming thetreatment of choice for patients at high risk of devel-oping life-threatening ventricular tachyarrhythmias(sustained VT/VF) [22]. Theoretically, ICDs are capa-ble of terminating not only native VT/VF (that is notsuppressed by the AAD), but also drug-inducedarrhythmia [6,23]. Additionally, even modern devicesmay give rise to aggravation of VT, which (thoughrarely) can increase morbidity associated with ICDtherapy [5]. The causes of ICD-induced proarrhythmiainclude the following: suboptimal programming, adevice malfunction (algorithm error, oversensing,mechanical malfunction), a drug-device interaction ofa proarrhythmic nature, and external electromagneticinterference [5,22]. However, in all probability, thereare also patients in whom the background involves thedetrimental influence of autonomic modulating fac-tors and the change of an arrhythmia substrate. Along-known complication of treatment of SMVT withantitachycardia (overdrive) pacing (ATP) is accelera-tion of the VT and its degeneration into VF [5,22]. Insome cases, the (non-synchronized) shock providedby ICDs may precipitate atrial fibrillation (AFib) oratrial flutter; in the case of a rapid ventricularresponse, the device may react to this with a second,inappropriate shock. The ICD may also provide inap-propriate antitachycardia therapy (possibly provokingrapid VT/VF) because it is unable to distinguish thenative SVT or AFib from the VT [5]. Since AFib andother supraventricular tachyarrhythmias are relativelyfrequent in ICD recipients, the latest-generation dual-chamber (AV) devices provide treatment for thesearrhythmias too [24]. The rare cause of inappropriateantitachycardia therapy may also be the oversensingof physiologic, non-QRS signals [22]. Asynchronousventricular pacing with the aim of preventing post-defibrillation bradyarrhythmias may similarly beproarrhythmic [5]. Forty to seventy percent of ICDrecipients also receive antiarrhythmic pharmacothera-py with the intention of preventing the recurrentdevice discharges and/or the supraventricular tach-yarrhythmias, and in some of these cases there may bea proarrhythmic device-drug interaction [6]. The con-

comitant use of ICDs and AADs may cause increasesin the defibrillation threshold (DFT) and in the VTcycle length below the detection cut-off rate [6,22]. Ingeneral, Na+-channel blocker AADs (such as lidocaineor mexiletine) tend to raise the DFT, whereas drugsthat block repolarizing potassium currents (such assotalol, dofetilide or ibutilide) lower it [22,25].Advances in ICD technology have reduced the impor-tance of adverse drug effects. Nonetheless, one agent,chronic oral amiodarone, still demands special atten-tion, for it could raise DFT to a clinically relevantdegree [22]. The I/C AADs could increase pacingthresholds at rapid stimulation rates, leading to loss ofcapturing [22]. The same substances may cause amarked use-dependent QRS widening at elevatedheart rates, and this may lead to rhythm misclassifica-tion and inappropriate shocks in patients whose ICDsuse electrogram width or electrogram templateenhancements. A stand-alone implantable atrial defib-rillator (Metrix System, InControl, USA) does notinduce ventricular arrhythmia; nevertheless, its pro-duction has been suspended: the development ofsophisticated, multifunction, dual-chamber devices isincreasingly coming into the limelight, as they aresuitable for the treatment of atrial and ventriculartachyarrhythmias and bradyarrhythmias alike [22,24].Further clinical observations are clearly necessary inorder to establish, whether these latest-generationICDs have a proarrhythmic potential.

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[16] Sweeney MO. Sudden death in heart failure associated withreduced left ventricular function: Substrates, mechanisms, andevidence-based management. PACE. 2001; 24: 1002-1022.

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ContactT. Fazekas, MD, DSc, FESCSzeged University Medical SchoolAlbert Szent-Györgyi Health Sciences CenterBatthyány St 31.H-6722 SzegedHungaryTelephone: +36 62 451 039Fax: +36 62 451 039E-mail: fat@in1st.szote.u-szeged.hu