Dofetilide-induced Torsade De Pointes Research Articles

Evaluation of a Fully Automatic Measurement of Short-Term Variability of Repolarization on Intracardiac Electrograms in the Chronic Atrioventricular Block Dog

Background: Short-term variability (STV) of repolarization of the monophasic action potential duration (MAPD) or activation recovery interval (ARI) on the intracardiac electrogram (EGM) increases abruptly prior to the occurrence of ventricular arrhythmias in the chronic AV-block (CAVB) dog model. Therefore, this parameter might be suitable for continuous monitoring of imminent arrhythmias using the EGM stored on an implanted device. However, 24/7 monitoring would require automatic STVARI measurement by the device.Objective: To evaluate a newly developed automatic measurement of STVARI for prediction of dofetilide-induced torsade de pointes (TdP) arrhythmias in the CAVB-dog.Methods: Two retrospective analyses were done on data from recently performed dog experiments. (1) In seven anesthetized CAVB-dogs, the new automatic STVARI method was compared with the gold standard STVMAPD at baseline and after dofetilide administration (0.025 mg/kg in 5 min). (2) The predictive value of the automatic method was compared to currently used STVARI methods, i.e., slope method and fiducial segment averaging (FSA) method, in 11 inducible (≥3 TdP arrhythmias) and 10 non-inducible CAVB-dogs.Results: (1) The automatic measurement of STVARI had good correlation with STVMAPD (r2 = 0.89; p < 0.001). Bland-Altman analysis showed a small bias of 0.06 ms with limits of agreement between −0.63 and 0.76 ms. (2) STVARI of all three methods was significantly different between inducible and non-inducible dogs after dofetilide. The automatic method showed the highest predictive performance with an area under the ROC-curve of 0.93, compared to 0.85 and 0.87 of the slope and FSA methods, respectively. With a threshold of STV set at 1.69 ms, STVARI measured with the automatic method had a sensitivity of 0.91 and specificity of 0.90 in differentiating inducible from non-inducible subjects.Conclusion: We developed a fully-automatic method for measurement of STVARI on the intracardiac EGM that can accurately predict the occurrence of ventricular arrhythmias in the CAVB-dog. Future integration of this method into implantable devices could provide the opportunity for 24/7 monitoring of arrhythmic risk.

An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog.

Introduction: In the chronic AV-block (CAVB) dog model, structural, contractile, and electrical remodeling occur, which predispose the heart to dofetilide-induced Torsade de Pointes (TdP) arrhythmias. Previous studies found a relation between electrical remodeling and inducibility of TdP, while structural remodeling is not a prerequisite for arrhythmogenesis. In this study, we prospectively assessed the relation between in vivo markers of contractile remodeling and TdP inducibility.Methods: In 18 anesthetized dogs, the maximal first derivative of left ventricular pressure (LV dP/dtmax) was assessed at acute AV-block (AAVB) and after 2 weeks of chronic AV-block (CAVB2). Using pacing protocols, three markers of contractile remodeling, i.e., force-frequency relationship (FFR), mechanical restitution (MR), and post-extrasystolic potentiation (PESP) were determined. Infusion of dofetilide (0.025 mg/kg in 5 min) was used to test for TdP inducibility.Results: After infusion of dofetilide, 1/18 dogs and 12/18 were susceptible to TdP-arrhythmias at AAVB and CAVB2, respectively (p = 0.001). The inducible dogs at CAVB2 showed augmented contractility at a CL of 1200 ms (2354 ± 168 mmHg/s in inducible dogs versus 1091 ± 59 mmHg/s in non-inducible dogs, p < 0.001) with a negative FFR, while the non-inducible dogs retained their positive FFR. The time constant (TC) of the MR curve was significantly higher in the inducible dogs (158 ± 7 ms versus 97 ± 8 ms, p < 0.0001). Furthermore, a linear correlation was found between a weighted score of the number and severity of arrhythmias and contractile parameters, i.e., contractility at CL of 1200 ms (r = 0.73, p = 0.002), the slope of the FFR (r = -0.58, p = 0.01) and the TC of MR (r = 0.66, p = 0.003). Thus, more severe arrhythmias were seen in dogs with the most pronounced contractile remodeling.Conclusion: Contractile remodeling is concomitantly observed with susceptibility to dofetilide-induced TdP-arrhythmias. The inducible dogs show augmented contractile remodeling compared to non-inducible dogs, as seen by a negative FFR, higher maximal response of MR and PESP and slowed MR kinetics. These altered contractility parameters could reflect disrupted Ca2+ handling and Ca2+-overload, which predispose the heart to delayed- and early afterdepolarizations that could trigger TdP-arrhythmias.

The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs

The electromechanical window (EMW), the interval between the end of the T-wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the I(Kr) -blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility. Our 11 year database of experiments of CAVB in dogs under general anaesthesia was reviewed and experiments included if ECG and LVP were recorded simultaneously at spontaneous rhythm. In total, 89 experiments in 44 dogs were appropriate and were analysed. During normally conducted sinus rhythm or acute atrioventricular block, EMW was positive. During CAVB, EMW was decreased to negative values. Dofetilide further reduced EMW before inducing repetitive TdP in 82% of the experiments. However, subclassification into inducible and non-inducible dogs revealed no difference in EMW. Analysis of the components of EMW revealed that the observed changes in EMW were solely caused by QT prolongation. In the canine CAVB model, ventricular remodelling and I(Kr) block by dofetilide are associated with negative EMW values, but this reflects QT prolongation, and implies that the EMW lacks specificity to predict dofetilide-induced TdP.

Dofetilide induced torsade de pointes: Mechanism, risk factors and management strategies

Dofetilide is an effective antiarrhythmic agent for conversion of atrial fibrillation and atrial flutter as well as maintenance of sinus rhythm in appropriately selected patients. However, as with other antiarrhythmic agents, proarrhythmia is a known adverse effect. The risk of dofetilide induced torsade de pointes (Tdp) is low when used with strict dosing criteria guided by renal function, QT interval and concomitant drug therapy. Benefit from dofetilide use must be individualized and weighed against the side effects and the role of other available treatment options. In this review, we discuss the underlying mechanism, risk factors and precautionary measures to avoid dofetilide induced QT prolongation and ventricular tachycardia/Tdp. We suggest a scheme for the management of QT prolongation, ventricular arrhythmia and Tdp as well.

Relevance of calmodulin/CaMKII activation for arrhythmogenesis in the AV block dog

The calcium-dependent signaling molecules calcineurin and calcium/calmodulin-dependent protein kinase II (CaMKII) both have been linked to decompensated hypertrophy and arrhythmias. CaMKII is also believed to be involved in acute modulation of ion channels. The purpose of this study was to determine the role of calcineurin and CaMKII in a dog model of compensated hypertrophy and a long QT phenotype. AV block was created in dogs to induce ventricular remodeling, including enhanced susceptibility to dofetilide-induced torsades de pointes arrhythmias. Dogs were treated with cyclosporin A for 3 weeks, which reduced calcineurin activity, as determined by mRNA expression levels of regulator of calcineurin 1 exon 4, but which was unable to prevent structural, contractile, or electrical remodeling and arrhythmias. Biopsies were taken before and at 2 or 9 weeks after AV block. Western blots were performed against phosphorylated and total CaMKII, phospholamban, Akt, and histone deacetylase 4 (HDAC4). Chronic AV block showed an increase in Akt, CaMKII and phospholamban phosphorylation levels, but HDAC4 phosphorylation remained unaltered. Dofetilide induced torsades de pointes in vivo and early afterdepolarizations in cardiomyocytes, and increased [Ca(2+)](i) and CaMKII autophosphorylation. Both W-7 and KN-93 treatment counteracted this. The calcineurin pathway seems not to be involved in long-term cardiac remodeling of the chronic AV block dog. Although CaMKII is chronically activated, this does not translate to HDAC4 phosphorylation. However, acute CaMKII overactivation is able to initiate arrhythmias based on triggered activity.

Effects of K201 on repolarization and arrhythmogenesis in anesthetized chronic atrioventricular block dogs susceptible to dofetilide-induced torsade de pointes

The novel antiarrhythmic drug K201 (4‐[3-{1-(4‐benzyl)piperidinyl}propionyl]‐7‐methoxy‐2,3,4,5‐tetrahydro‐1,4‐benzothiazepine monohydrochloride) is currently in development for treatment of atrial fibrillation. K201 not only controls intracellular calcium release by the ryanodine receptors, but also possesses a ventricular action that might predispose to torsade de pointes arrhythmias. The anti- and proarrhythmic effects of K201 were investigated in the anesthetized canine chronic atrioventricular block model. Two doses of K201 (0.1 and 0.3 mg/kg/2 min followed by 0.01 and 0.03 mg/kg/30 min i.v.) were tested in 4 serial experiments in dogs with normally conducted sinus rhythm (n = 10) and in torsade de pointes-susceptible dogs with chronic atrioventricular block. Susceptibility was assessed with dofetilide (0.025 mg/kg/5 min i.v.). Beat-to-beat variability of repolarization was quantified as short-term variability of left ventricular monophasic action potential duration. In dogs with normally conducted sinus rhythm, both doses of K201 prolonged ventricular repolarization whereas only the higher dose prolonged atrial repolarization. At chronic atrioventricular block, dofetilide induced torsade de pointes in 9 of 10 dogs. K201 did neither suppress nor prevent dofetilide-induced torsade de pointes. K201 dose-dependently prolonged ventricular repolarization. In contrary to the lower dose, the higher dose did increase beat-to-beat variability of repolarization (from 1.2 ± 0.3 to 2.9 ± 0.8 ms, P < 0.05) and resulted in spontaneous, repetitive torsade de pointes arrhythmias in 1 of 7 dogs; Programmed electrical stimulation resulted in torsade de pointes in 2 more dogs. In conclusion, both doses of K201 showed a class III effect. No relevant antiarrhythmic effects against dofetilide-induced torsade de pointes were seen. Only at the higher dose a proarrhythmic signal was observed.

Ventricular remodelling is a prerequisite for the induction of dofetilide-induced torsade de pointes arrhythmias in the anaesthetized, complete atrio-ventricular-block dog

A number of predisposing factors have been suggested to be contributing to drug-induced torsade de pointes (TdP) arrhythmias: short-long-short (SLS) sequence, bradycardia, timing of drug administration, anaesthesia, ventricular remodelling, and altered ventricular activation due to ventricular ectopic beats (SLS) or idioventricular rhythm (IVR). Chronic atrio-ventricular (AV)-block (CAVB) dogs are susceptible to dofetilide-induced TdP. In 32 anaesthetized animals, the relevance of ventricular remodelling for TdP susceptibility was studied by dofetilide [0.025 mg/kg/5 min intravenously (iv)] during bradycardia in the presence (CAVB, n= 18) or absence [acute atrio-ventricular block (AVB), n= 32] of ventricular remodelling. In sub-protocols, the possible pro-arrhythmic effects of timing of dofetilide administration: prior to (n= 11), or after creation of AVB (n= 9) and relevance of SLS pacing (n= 17) was investigated during IVR. Dofetilide was also given after AVB when the activation of the ventricles was normal: pacing (1000 ms) from the high septum (n= 7) or abnormal but fixed from the left ventricular apex (n= 5). Torsade de pointes inducibility was defined as reproducible (≥ 3 times) occurrence. In acute AV block (AAVB), dofetilide did not induce TdP spontaneously (0 of 32), whereas TdP was seen in 10 out of 18 serially tested dogs in CAVB (P< 0.001). The other factors: timing of dofetilide (0 of 11 vs. 0 of 9), SLS pacing (0 of 17 vs. 1 of 17), or ventricular activation (0 of 7 vs. 0 of 5) did not increase TdP susceptibility. Beat-to-beat variability of repolarization increased after ventricular remodelling and was highest prior to TdP induction. In AAVB dogs, TdP is not spontaneously seen, whereas it is present in CAVB. This implies that ventricular remodelling is a prerequisite for TdP induction in this model.

Biomarkers and endogenous determinants of dofetilide-induced torsades de pointes in α(1) -adrenoceptor-stimulated, anaesthetized rabbits.

Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug-induced TdP. We studied dofetilide-induced TdP in pentobarbital-anaesthetized, phenylephrine-sensitized rabbits, seeking biomarkers that discriminated between the animals that experienced TdP ('TdP+' animals) and those that did not ('TdP-' animals). As novel variables, the beat-to-beat variability and instability of ECG intervals were measured at preset times, irrespective of whether or not hearts were in stable sinus rhythm ('absolute' variability and instability). Autonomic activity was also determined. Dofetilide delayed repolarization and induced arrhythmias prior to TdP. The variability of the coupling interval and shape of arrhythmic beats before TdP were significantly greater in the 'TdP+' group than in the 'TdP-' group. Accordingly, the 'absolute' variability and instability of the ECG intervals were significantly elevated in the 'TdP+' group. Phenylephrine increased significantly the up-baroreflex sensitivity in the 'TdP+' group before dofetilide administration. 'Preceding' arrhythmias have characteristics that permit prediction of TdP occurrence: the more chaotic the ventricular rhythm, the greater the probability of TdP initiation. This suggests that complexity of the arrhythmic beats may play an important mechanistic role in TdP genesis. The electrical instability quantified by the novel 'absolute' variability and instability parameters correlates with the probability of TdP occurrence. Baroreflex may contribute to TdP genesis in vivo.

Anesthesia and Arrhythmogenesis in the Chronic Atrioventricular Block Dog Model

Drug-induced torsade de pointes (TdP) arrhythmias can readily be induced in anesthetized dogs with remodeled hearts [chronic complete atrioventricular block (CAVB) dogs]. Similar studies in conscious CAVB dogs reveal lower TdP incidences. Regulations forced us to reconsider our anesthetic regimen, which consist of pentobarbital followed by halothane (P + H). We investigated the relevance of anesthesia for this enhanced susceptibility (part 1) and compared 3 anesthetic regimens (part 2). Part 1-Ten CAVB dogs paced from the high septum at 1000 milliseconds were challenged with dofetilide (25 microg x kg(-1) x 5 min(-1)) twice: once under anesthesia and once awake. Anesthesia consisted of P + H (n = 5) and thiopental maintained by isoflurane (T + I). Part 2-In CAVB dogs (n = 6) with spontaneous idioventricular rhythm, the electrophysiological and arrhythmogenic consequences of different anesthetic regimens (P + H, T + I, and P + I) were serially compared. Part 1-In paced dogs, dofetilide-induced TdP was higher under anesthetized than in conscious circumstances, with the more severe outcome seen after T + I as compared with P + H or control (2x): 5/5, 2/5, 0/5, and 0/5, respectively; P < 0.05. Part 2-Electrophysiologically, T accelerated idioventricular rhythm, increased QTc, and transiently induced polymorphic ventricular tachycardias in 2 of 6 dogs. This was not seen after P. At 120 minutes (end of the preparation), QTc increase was highest after T + I, intermediate with P + I, and the smallest after P + H. Dofetilide in combination with T + I induced the most severe arrhythmogenic outcome. Thiopental anesthesia causes arrhythmias sec, whereas anesthesia in general predisposes for drug-induced TdP in the CAVB dog. In combination with dofetilide, T + I has a more arrhythmic outcome than P + I or P + H.

Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

QT prolongation may increase the risk of torsades de pointes (TdP). Early afterdepolarizations (EADs) and transmural dispersion of repolarization have been known to serve as physiological substrates and predictors for TdP. Abnormal Ca(2+) cycling is the proximate cause of EADs, and Ca(2+) cycling is abnormal in heart failure (HF). However, the mechanisms for drug-induced TdP in HF are poorly understood. The purpose of this study was to search for torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPD) and TdP in rabbits with HF. Rabbits with HF were pretreated with propranolol followed by test articles before continuous infusion of dofetilide to induce TdP. In the control hearts, VPD and TdP were induced in all rabbits and the onsets of VPD and TdP were 3.6 +/- 1.3 minutes and 10.3 +/- 1.4 minutes, respectively. Dofetilide lengthened RR, QT and QTc. Verapamil, ryanodine and H-8 significantly delayed onset of VPD (P < 0.05) and suppressed TdP (P < 0.01). KB-R7943, W-7, and KN-93 accelerated onset of TdP. Blockades of L-type Ca(2+) channel, ryanodine channel, and protein kinase A prevent dofetilide-induced TdP, suggesting roles for intracellular Ca(2+) overload and Ca(2+) signaling pathways in drug-induced TdP.

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

AZD1305 is a novel antiarrhythmic agent under clinical evaluation for management of atrial fibrillation. This study assessed its ion channel-blocking potency by the whole cell patch-clamp technique in vitro and its proarrhythmic liability in anesthetized methoxamine-sensitized rabbits in comparison with dofetilide. AZD1305 predominantly blocked the hERG, the L-type calcium and the hNav1.5 currents in a concentration-dependent manner. In vivo AZD1305 increased the QT interval (from 145 +/- 8 to 196 +/- 18 ms, P < 0.01) without inducing ventricular extrasystoles or torsades de pointes (TdP). In contrast, dofetilide prolonged the QT interval from 161 +/- 3 to 256 +/- 15 ms (P < 0.001) and caused TdP in 12/17 rabbits (P < 0.01 vs. AZD1305). During AZD1305 and dofetilide infusion, the QTend-peak interval maximally increased by 14 +/- 4 and 30 +/- 6 ms (P < 0.05 vs. AZD1305) and the beat-by-beat QT interval variability (quantified as the short-term variability, STV) changed from 2 +/- 0.8 to 2 +/- 0.3 ms (NS) and from 2 +/- 0.2 to 12 +/- 1.1 ms (P < 0.001), respectively. Following dofetilide-induced TdP, 6 rabbits each were injected with saline or AZD1305. In contrast to saline, AZD1305 abbreviated the QT interval (from 275 +/- 25 to 216 +/- 9 ms, P < 0.05), reduced the STV to 1 +/- 0.1 ms (P < 0.001) and suppressed TdP in all 6 rabbits (P < 0.01 vs. saline). In conclusion, AZD1305 can be characterised as a combined ion channel blocker that delays repolarization without increasing beat-by-beat variability of repolarization (BVR) or inducing TdP whereas selective IKr blockade by dofetilide prolongs the QT interval and eventually increases BVR resulting in TdP.

Enhanced efficacy with MgSO4 due to an additive, alternative, or dual mode of action?

Pharmacological conversion of atrial fibrillation–atrial flutter (AF–AFl) is still an important therapeutic modality in daily patient care. Frequently used drugs are the class III anti-arrhythmics dofetilide, sotalol, and ibutilide. By blocking (specific) potassium currents, they will prolong the duration of the action potential (APD) providing less space for re-entry to manoeuvre. Their effectiveness is still not optimal and is also hampered by their pro-arrhythmic risk due to dose-dependent lengthening of the (ventricular) repolarization times. Their use is therefore restricted, including hospitalizations when therapy is started, as was the case in this single site (Hartford Hospital) retrospective investigation (2000–08) about the effectiveness of dofetilide to acutely convert AF–AFl.1 To protect their patients for dofetilide-induced torsade de pointes (TdP) arrhythmias, some ( n = 50) from the 160 eligible patients with AF–AFl received adjunctive magnesium sulfate (Mg). The evaluation demonstrated that a single or repeated bolus of Mg (mean ± 3 g MgSO4) did not only protect for drug-induced adverse effects (0/50 vs. 1/110 TdP occurrences), but also improved the efficacy of dofetilide to suppress/prevent AF–AFl: 38% without vs. 50% with Mg, P < 0.05. This important improvement with this combination (doubling of the odds), which was recently also shown for ibutilide and Mg by … *Corresponding author. Tel: +31 30 2538900, Fax: +31 30 2539036, Email: m.a.vos{at}umcutrecht.nl

The role of the Na+/Ca2+ exchanger, INa and ICaL in the genesis of dofetilide‐induced torsades de pointes in isolated, AV‐blocked rabbit hearts

The Na+/Ca2+ exchanger (NCX) may contribute to triggered activity and transmural dispersion of repolarization, which are substrates of torsades de pointes (TdP) type arrhythmias. This study examined the effects of selective inhibition of the NCX by SEA0400 on the occurrence of dofetilide-induced TdP. Effects of SEA0400 (1 micromol x L(-1)) on dofetilide-induced TdP was studied in isolated, Langendorff-perfused, atrioventricular (AV)-blocked rabbit hearts. To verify the relevance of the model, lidocaine (30 micromol x L(-1)) and verapamil (750 nmol x L(-1)) were also tested against dofetilide-induced TdP. Acute AV block caused a chaotic idioventricular rhythm and strikingly increased beat-to-beat variability of the RR and QT intervals. SEA0400 exaggerated the dofetilide-induced increase in the heart rate-corrected QT interval (QTc) and did not reduce the incidence of dofetilide-induced TdP [100% in the SEA0400 + dofetilide group vs. 75% in the dofetilide (100 nmol x L(-1)) control]. In the second set of experiments, verapamil further increased the dofetilide-induced QTc prolongation and neither verapamil nor lidocaine reduced the dofetilide-induced increase in the beat-to-beat variability of the QT interval. However, lidocaine decreased and verapamil prevented the development of dofetilide-induced TdP as compared with the dofetilide control (TdP incidence: 13%, 0% and 88% respectively). Na+/Ca2+ exchanger does not contribute to dofetilide-induced TdP, whereas Na+ and Ca2+ channel activity is involved in TdP genesis in isolated, AV-blocked rabbit hearts. Neither QTc prolongation nor an increase in the beat-to-beat variability of the QT interval is a sufficient prerequisite of TdP genesis in rabbit hearts.

Ultrafast sodium channel block by dietary fish oil prevents dofetilide-induced ventricular arrhythmias in rabbit hearts

Several epidemiologic and clinical studies show that following myocardial infarction, dietary supplements of omega-3 polyunsaturated fatty acids (omega3FA) reduce sudden death. Animal data show that omega3FA have antiarrhythmic properties, but their mechanisms of action require further elucidation. The effects of omega3FA supplementation were studied in female rabbits to analyze whether their antiarrhythmic effects are due to a reduction of triangulation, reverse use-dependence, instability, and dispersion (TRIaD) of the cardiac action potential (TRIaD as a measure of proarrhythmic effects). In Langendorff-perfused hearts challenged by a selective rapidly activating delayed rectifier potassium current inhibitor that has been shown to exhibit proarrhythmic effects (dofetilide; 1 to 100 nM), omega3FA pretreatment (30 days; n=6) prolonged the plateau phase of the monophasic action potential; did not slow the terminal fast repolarization; reduced the dofetilide-induced prolongation of the action potential duration; reduced dofetilide-induced triangulation; and reduced dofetilide-induced reverse use-dependence, instability of repolarization, and dispersion. Dofetilide reduced excitability in omega3FA-pretreated hearts but not in control hearts. Whereas torsades de pointes (TdP) were observed in five out of six in control hearts, none were observed in omega3FA-pretreated hearts. Docosahexaenoic acid (DHA) inhibited the sodium current with ultrafast kinetics. Dietary omega3FA supplementation markedly reduced dofetilide-induced TRIaD and abolished dofetilide-induced TdP. Ultrafast sodium channel block by DHA may account for the antiarrhythmic protection of the dietary supplements of omega3FA against dofetilide-induced proarrhythmia observed in this animal model.

Atrial-specific drug AVE0118 is free of torsades de pointes in anesthetized dogs with chronic complete atrioventricular block

The novel compound AVE0118 has been shown to prevent and terminate persistent atrial fibrillation. AVE0118 blocks I(Kur), I(KAch), and I(to), leading to prolongation of atrial repolarization with no change in ventricular repolarization. This finding suggests that AVE0118 may be devoid of proarrhythmic side effects. Experimentally, AVE0118 has been antiarrhythmic against some specific ventricular arrhythmias. The purpose of this study was to investigate the proarrhythmic and antiarrhythmic effects of AVE0118 in anesthetized dogs with chronic complete AV block, known for a high proclivity for torsades de pointes (TdP). AVE0118 was administered intravenously as a fast infusion (0.5 mg/kg/5 min) and a slow infusion (3 or 10 mg/kg/60 min). Dofetilide was given to induce TdP. ECG and monophasic action potentials were recorded. Short-term beat-to-beat variability (STV) of the left ventricular monophasic action potential duration (MAPD) was calculated. We examined whether AVE0118 (1) caused ventricular proarrhythmia (both infusions), (2) prevented dofetilide-induced TdP (slow infusion + dofetilide after 30 minutes), and (3) abolished TdP (fast infusion). At 0.55 +/- 0.10 microg/mL (fast infusion at 10 minutes), AVE0118 did not increase ventricular repolarization or induce TdP; however, right atrial MAPD(50) and MAPD(90) were significantly increased by 26% +/- 9% and 10% +/- 5%, respectively (P <.05 vs baseline). At 1.9 +/- 0.5 microg/mL and 6.1 +/- 1.2 microg/mL (30 minutes of 3 or 10 mg/kg/h), AVE0118 did not induce TdP (0/6 and 0/4) nor prevent dofetilide-induced TdP (6/6 and 2/2). Dofetilide significantly increased all repolarization parameters, including STV from 2.1 +/- 0.4 ms to 4.6 +/- 1.8 ms (P <.05 vs baseline), which were not changed by AVE0118 (to 2.1 +/- 0.3 ms after 30 minutes). Rapid infusion of AVE0118 did not suppress dofetilide-induced TdP. In the anesthetized chronic complete AV block dog, the atrial-specific drug AVE0118 is free of TdP and has no antiarrhythmic properties against dofetilide-induced torsades de pointes.

Basal vagal nerve activity does not predict susceptibility to dofetilide-induced torsade de pointes in anaesthetized rabbits

Proarrhythmic activity of repolarisation prolonging drugs can be enhanced by vagal nerve mediated bradycardia. This study examined whether baseline vagal nerve activity measured indirectly by baroreflex sensitivity (BRS) and heart rate variability (HRV) correlates with the subsequent occurrence of dofetilide-induced torsade de pointes ventricular tachycardia in Na-pentobarbital anaesthetized rabbits. After a 10 min baseline interval, which was used to calculate baseline HRV and BRS values, α1-adrenoceptor agonist phenylephrine (15 μg/kg/min, for 35 min) and dofetilide (0.02 mg/kg/h, for 30 min) were infused intravenously to each animal.