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Background: In the chronic atrioventricular block (CAVB) dog model, beat-to-beat variation of repolarization in the left ventricle (LV) quantified as short-term variability of the left monophasic action potential duration (STVLVMAPD) increases abruptly upon challenge with a proarrhythmic drug. This increase occurs before the first ectopic beat (EB), specifically in subjects who demonstrate subsequent repetitive torsades de pointes arrhythmias (TdP).Objective: The purpose of this study was to demonstrate that STV is feasible to monitor arrhythmic risk through use of the intracardiac electrogram (EGM) derived from the right ventricular (RV) lead from pacemakers or implantable cardioverter-defibrillators.Methods: In 30 anaesthetized, inducible (≥3 TdP) CAVB dogs, STV between LV and RV monophasic action potential duration (STVLVMAPD and STVRVMAPD) was compared. In prospectively enrolled CAVB dogs, STV of the activation-recovery interval (ARI) derived from the RV EGM (STVRVARI) was measured before and after a challenge with dofetilide under anesthesia (2a; n = 10) and cisapride under awake conditions (2b; n = 8).Results: Both STVLVMAPD and STVRVMAPD increased before the first EB (1.29 ± 0.58 ms to 3.05 ± 1.70 ms and 1.11 ± 0.53 ms to 2.18 ± 1.43 ms, respectively; P = 0.001). STVRVARI increased from 2.82 ± 0.33 ms to 3.77 ± 0.69 ms (P = .001). Inducible subjects (4/8) showed an increase in STVRVARI from 2.65 ± 0.55 ms to 3.45 ± 0.33 ms (in the first hour; P = .02) and 4.20 ± 1.33 ms (before the first EB; P = .04).Conclusion: Behavior of STV from the RV and LV is comparable. STVRVARI increases significantly before the occurrence of an arrhythmia in awake and anaesthetized conditions. This finding can be integrated into devices to monitor arrhythmic risk. [ABSTRACT FROM AUTHOR]

Background: Pacing at higher rates is known to suppress torsade de pointes (TdP) arrhythmias. Nevertheless, exact application and mechanism need further clarification. In the anesthetized canine chronic atrioventricular block model, ventricular remodeling is responsible for a high and reproducible incidence of TdP upon a challenge with dofetilide.Objective: We used this model to investigate by what mechanism accelerated pacing averts TdP and what repolarization parameter could be used to guide temporary accelerated pacing (TAP).Methods: Ten dogs with repetitive TdP after administration of dofetilide when paced at 60 beats/min were selected. In a serial experiment, TAP was initiated at 100 beats/min after the first ectopic beat. Electrocardiogram and right and left ventricular (LV) monophasic action potential durations (MAPDs) were recorded. In a subset, vertical dispersion was determined with a duodecapolar catheter. Temporal dispersion was quantified as short-term variability (STV). Arrhythmias were quantified with the arrhythmia score.Results: The increase in repolarization parameters observed after administration of dofetilide was counteracted by TAP (eg, LV MAPD from 381 ± 94 ms back to 310 ± 17 ms; P < .05). Temporal dispersion (STVLVMAPD) increased from 0.69 ± 0.37 to 2.59 ± 0.96 ms (P < .05) after administration of dofetilide and back to 1.15 ± 0.54 ms (P < .05) with TAP. This was accompanied by suppression of recurrent TdP in 7 of 10 dogs (P < .05) and a trend toward reduction in vertical (spatial) dispersion from 56 ± 25 to 31 ± 4 ms (P = .06). In those dogs, seconds after capture of TAP, almost all ectopy disappeared, causing a decrease in arrhythmia score from 21 ± 12 to 4 ± 3 (P < .05).Conclusion: TAP is effective in averting TdP by decreasing spatial and temporal measures of repolarization. Increase in temporal dispersion (STV) can guide TAP. [ABSTRACT FROM AUTHOR]

Pharmacological safety evaluation of (pro) drugs includes cardiac safety assessment of proarrhythmic liability in healthy tissue with emphasis on the rapid component of the delayed rectifier (IKr). The lack of (1) an arrhythmic end point, (2) tests in remodeled, predisposed tissue, and (3) testing chronic drug influence on channel trafficking impairs on the drawn conclusions of these assays regarding drug safety. Moreover, the currently used human ether-à-go-go-related gene assays, action potential duration, prolongation in multicellular preparations, or the QT interval have significant shortcomings in their prediction of an increased risk for drug-induced torsades de pointes arrhythmia. In this review, it will be proposed that beat-to-beat variability of repolarization quantified as short-term variability can (1) discriminate between safe and unsafe drugs even under predisposed and highly arrhythmogenic conditions despite accompanying QT prolongation and (2) identify the individual at risk for subsequent arrhythmic events. [Copyright &y& Elsevier]

Abstract: Proarrhythmic susceptibility to drug-induced Torsades de Pointes is restricted to individuals with a predisposed phenotype characterized by a reduced repolarization reserve. Additional factors are often involved in a further impairment of repolarization, possibly culminating with dangerous ventricular polymorphic tachyarrhythmias. Drugs that block repolarizing currents represent such an additional hit. The dog model with chronic, complete atrio-ventricular block has been used frequently for proarrhythmic drug screening. The ventricular remodeling seen after ablation of the AV node enhances the susceptibility for repolarization-dependent arrhythmias. In this review, we 1) describe the cellular and molecular basis of ventricular remodeling, 2) validate the CAVB dog as a drug screening model and 3) introduce a new surrogate predictive proarrhythmic parameter: beat-to-beat variability of repolarization. [Copyright &y& Elsevier]

Background: The novel compound AVE0118 has been shown to prevent and terminate persistent atrial fibrillation. AVE0118 blocks IKur, IKAch, and Ito, 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. Objectives: 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). Methods: 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). Results: At 0.55 ± 0.10 μg/mL (fast infusion at 10 minutes), AVE0118 did not increase ventricular repolarization or induce TdP; however, right atrial MAPD50 and MAPD90 were significantly increased by 26% ± 9% and 10% ± 5%, respectively (P <.05 vs baseline). At 1.9 ± 0.5 μg/mL and 6.1 ± 1.2 μg/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. Conclusion: 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. [Copyright &y& Elsevier]

Background: 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. Objective: 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. Methods: 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). Results: 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 [Ca2+]i and CaMKII autophosphorylation. Both W-7 and KN-93 treatment counteracted this. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated whether ranolazine reduces dofetilide-induced torsades de pointes (TdP) in a model of long QT syndrome with down-regulated K+ currents due to hypertrophic remodeling in the dog with chronic atrioventricular block (cAVB). Background: Ranolazine inhibits the late Na+ current (INaL) and is effective against arrhythmias in long QT3 syndromes despite its blocking properties of the rapid component of delayed rectifying potassium current. Methods: Ranolazine was administered to cAVB dogs before or after TdP induction with dofetilide and electrophysiological parameters were determined including beat-to-beat variability of repolarization (BVR). In single ventricular myocytes, effects of ranolazine were studied on INaL, action potential duration, and dofetilide-induced BVR and early afterdepolarizations. Results: After dofetilide, ranolazine reduced the number of TdP episodes from 10 ± 3 to 3 ± 1 (p < 0.05) and partially reversed the increase of BVR with no abbreviation of the dofetilide-induced QT prolongation. Likewise, pre-treatment with ranolazine, or using lidocaine as a specific Na+ channel blocker, attenuated TdP, but failed to prevent dofetilide-induced increases in QT, BVR, and ectopic activity. In cAVB myocytes, ranolazine suppressed dofetilide-induced early afterdepolarizations in 25% of cells at 5 μmol/l, in 75% at 10 μmol/l, and in 100% at 15 μmol/l. At 5 μmol/l, ranolazine blocked 26 ± 3% of tetrodotoxin-sensitive INaL, and 49 ± 3% at 15 μmol/l. Despite a 54% reduction of INaL amplitude in cAVB compared with control cells, INaL inhibition by 5 μmol/l tetrodotoxin equally shortened relative action potential duration and completely abolished dofetilide-induced early afterdepolarizations. Conclusions: Despite down-regulation of INaL in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR. [Copyright &y& Elsevier]

Objectives: We investigated whether increasing or decreasing beat-to-beat variability of repolarization (BVR) would change drug-induced proarrhythmic outcome accordingly. Background: Increased variability of repolarization has been suggested as a prelude to proarrhythmic circumstances in experimental and clinical situations. Methods: The non-cardiovascular, I Kr-blocking drug sertindole was administered to anesthetized dogs with chronic atrioventricular block. Three interventions were used to prevent or suppress sertindole-induced torsades de pointes (TdP). Results: Supratherapeutic doses of sertindole (1.0 mg/kg intravenously) induced TdP in 10 of 13 dogs whereas 0.2 mg/kg induced no TdP, despite increases in QT intervals by both doses. The BVR, quantified as short-term variability (STV) from Poincaré plots, was the only parameter that predicted TdP outcome (1.0 mg/kg sertindole: 2.3 ± 0.7 ms to 5.1 ± 2.1 ms, p < 0.05; 0.2 mg/kg sertindole: 2.3 ± 0.8 ms to 3.2 ± 1.1 ms, p= NS). Interventions: 1) KCl, intravenous, reduced the incidence of sertindole-induced TdP from 6 of 7 to 1 of 7 dogs (p<0.05) and prevented sertindole-related increase of STV: 3.0 ± 1.1 ms vs. 4.5 ± 1.3 ms (p < 0.05); 2) levcromakalim (I K,ATP activator) reduced sertindole-induced TdP and decreased STV from 4.9 ± 2.1 ms to 2.6 ± 0.9 ms (p < 0.05); 3) steady-state ventricular pacing (60 beats/min) abolished sertindole-induced TdP and decreased STV from 4.9 ± 1.5 to 3.2 ± 1.0 (p < 0.05). Torsades de pointes reappeared upon return to non-paced idioventricular rhythm. None of the 3 interventions reduced the sertindole-induced prolonged QT interval. Conclusions: Proarrhythmic intervention is related to an increase in BVR, whereas antiarrhythmic treatment is associated with a decrease in BVR. The BVR is superior to QT interval prolongation in the prediction and prevention of drug-induced TdP in this experimental model. [Copyright &y& Elsevier]

Objectives: This study was designed to analyze the relevance of ventricular activation patterns for ventricular electrical remodeling after atrioventricular (AV) block in dogs. Background: Bradycardia is thought to be the main contributor to ventricular electrical remodeling after complete AV block. However, an altered ventricular activation pattern or AV dyssynchrony may also contribute. Methods: For 4 weeks, AV block dogs were either paced from the high-ventricular septum near the His bundle at lowest captured rate (n = 9, high-septal pacing [HSP]) or kept at idioventricular rate without controlled activation (n = 14, chronic AV block [CAVB]). Multiple electrocardiographic and electrophysiological parameters were measured under anesthesia at 0 and 4 weeks. Proarrhythmia was tested at 4 weeks by IKr block (25 μg/kg dofetilide intravenous). Results: At 0 weeks, the 2 groups were comparable, whereas after 4 weeks of similar bradycardia, QT duration at unpaced conditions had increased from 300 ± 5 to 395 ± 18 ms in CAVB (+32 ± 6%) and from 307 ± 8 ms to 357 ± 11 ms in HSP (+17 ± 4%; p < 0.05). Frequency dependency of repolarization was less steep in HSP compared to CAVB dogs after 4 weeks remodeling. Beat-to-beat variability of repolarization, a proarrhythmic parameter, increased only in CAVB from 0 to 4 weeks. Torsades de pointes arrhythmias were induced at 4 weeks in 44% HSP versus 78% CAVB dogs (p = 0.17). Cumulative duration of arrhythmias per inducible dog was 87 ± 36 s in CAVB and 30 ± 21 s in HSP (p < 0.05). Conclusions: High-septal pacing reduces the magnitude of ventricular electrical remodeling and proarrhythmia in AV block dogs, suggesting a larger role for altered ventricular activation pattern in the generation of ventricular electrical remodeling than previously assumed. [Copyright &y& Elsevier]