Jurren M. van Opstal

Increased Short-Term Variability of Repolarization Predicts d-Sotalol–Induced Torsades de Pointes in Dogs

Background—Identification of patients at risk for drug-induced torsades de pointes arrhythmia (TdP) is difficult. Increased temporal lability of repolarization has been suggested as being valuable to predict proarrhythmia. The predictive value of different repolarization parameters, including beat-to-beat variability of repolarization (BVR), was compared in this serial investigation in dogs with chronic AV block. Methods and Results—In anesthetized dogs with electrically remodeled hearts, the dose-dependent difference in drug-induced TdP (d-sotalol, 2 and 4 mg/kg IV over 5 minutes, 25% and 75% TdP, respectively) could not be accounted for by prolongation of QTc (410±37 to 475±60 versus 415±47 to 484±52 ms, respectively). BVR was quantified by Poincaré plots at baseline and immediately before onset of d-sotalol–induced extrasystolic activity. TdP occurrence was associated with an increase in short-term variability (STV) of the left ventricular monophasic action potential duration (3.5±1.5 to 5.5±1.6 versus 3.0±0.7 to 8.6±3.8 ms, respectively), which was reversible when TdP was abolished by IK,ATP activation. The absence of TdP despite QTc prolongation after chronic amiodarone treatment could also be explained by an unchanged STV. In experiments with isolated ventricular myocytes, STV increased after IKr block and was highest in cells that subsequently showed early afterdepolarizations. Conclusions—Proarrhythmia is not related to differences in prolongation of repolarization but corresponds to BVR, here quantified as STV of the left ventricle. STV could be a new parameter to predict drug-induced TdP in patients.

Probing the Contribution of IKs to Canine Ventricular Repolarization: Key Role for β-Adrenergic Receptor Stimulation

Background—In large mammals and humans, the contribution of IKs to ventricular repolarization is still incompletely understood. Methods and Results—In vivo and cellular electrophysiological experiments were conducted to study IKs in canine ventricular repolarization. In conscious dogs, administration of the selective IKs blocker HMR 1556 (3, 10, or 30 mg/kg PO) caused substantial dose-dependent QT prolongations with broad-based T waves. In isolated ventricular myocytes under baseline conditions, however, IKs block (chromanols HMR 1556 and 293B) did not significantly prolong action potential duration (APD) at fast or slow steady-state pacing rates. This was because of the limited activation of IKs in the voltage and time domains of the AP, although at seconds-long depolarizations, the current was substantial. Isoproterenol increased and accelerated IKs activation to promote APD95 shortening. This shortening was importantly reversed by HMR 1556 and 293B. Quantitatively similar effects were obtained in ventricular-tissue preparations. Finally, when cellular repolarization was impaired by IKr block, IKs block exaggerated repolarization instability with further prolongation of APD. Conclusions—Ventricular repolarization in conscious dogs is importantly dependent on IKs. IKs function becomes prominent during &bgr;-adrenergic receptor stimulation, when it promotes AP shortening by increased activation, and during IKr block, when it limits repolarization instability by time-dependent activation. Unstimulated IKs does not contribute to cellular APD at baseline. These data highlight the importance of the synergism between an intact basal IKs and the sympathetic nervous system in vivo.

Hybrid thoracoscopic surgical and transvenous catheter ablation of atrial fibrillation.

OBJECTIVES The purpose of this study was to evaluate the feasibility, safety, and clinical outcomes up to 1 year in patients undergoing combined simultaneous thoracoscopic surgical and transvenous catheter atrial fibrillation (AF) ablation. BACKGROUND The combination of the transvenous endocardial approach with the thoracoscopic epicardial approach in a single AF ablation procedure overcomes the limitations of both techniques and should result in better outcomes. METHODS A cohort of 26 consecutive patients with AF who underwent hybrid thoracoscopic surgical and transvenous catheter ablation were followed, with follow-up of up to 1 year. RESULTS Twenty-six patients (42% with persistent AF) underwent successful hybrid procedures. There were no complications. The mean follow-up period was 470 ± 154 days. In 23% of the patients, the epicardial lesions were not transmural, and endocardial touch-up was necessary. One-year success, defined according to the Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac Arrhythmia Society consensus statement for the catheter and surgical ablation of AF, was 93% for patients with paroxysmal AF and 90% for patients with persistent AF. Two patients underwent catheter ablation for recurrent AF or left atrial flutter after the hybrid procedure. CONCLUSIONS A combined transvenous endocardial and thoracoscopic epicardial ablation procedure for AF is feasible and safe, with a single-procedure success rate of 83% at 1 year.

Electrophysiologic parameters and predisposing factors in the generation of drug-induced Torsade de Pointes arrhythmias

When a new (cardiovascular) drug shows signs of QT interval prolongation on the ECG (delay in repolarization time), the regulatory agencies demand screening of its possible proarrhythmic potential before approving it for clinical practice. In this review, identified predisposing factors have been related to specific electrophysiological parameters, allowing quantification of their contribution to Torsade de Pointes arrhythmias. In addition, arrhythmogenic mechanisms involved in the initiation and perpetuation of drug-induced Torsade de Pointes are discussed.

Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias

Torsade de Pointes arrhythmias are a feared proarrhythmic effect of (antiarrhythmic) drugs. In dogs with chronic complete AV-block bradycardia-induced volume overload leads to electrical remodeling, which includes increased susceptibility to drug-induced Torsade de Pointes arrhythmias. The IKr channel blocker, dofetilide (Tikosyn, 0.025 mg/kg/5 min), and the less specific ion channel blocker, azimilide (5 mg/kg/5 min), were compared in nine anesthetized dogs at 4 and 6 weeks of AV-block in a randomized cross-over design. Dosages were based on our own dose-dependence studies and on anti-arrhythmic dosages reported in the literature. Monophasic action potential catheters were placed endocardially in both the left and right ventricle to measure action potential duration, visualize early afterdepolarizations, and to assess interventricular dispersion of repolarization (i.e. left ventricular monophasic action potential duration (at 100%) minus right ventricular monophasic action potential duration (at 100%). Cycle length of idioventricular rhythm, QT-time and the occurrence of drug-induced Torsade de Pointes arrhythmias were determined using the surface electrocardiogram (ECG). Before drug administration, the electrophysiological parameters were identical at 4 and 6 weeks. Both azimilide and dofetilide increased monophasic action potential duration, cycle length of idioventricular rhythm, and QT-time. Dissimilar lengthening of left ventricular and right ventricular monophasic action potential duration increased the interventricular dispersion significantly from 55 to 110 ms for both drugs. All dogs had early afterdepolarizations, while, in the majority, ectopic ventricular beats developed (dofetilide 8/9 and azimilide 7/9). Torsade de Pointes arrhythmias incidence was comparable for dofetilide (6/9) and azimilide (5/9). In conclusion, azimilide and dofetilide show similar electrophysiological and proarrhythmic effects in our canine model with a high incidence of Torsade de Pointes arrhythmias.

Sudden cardiac death in dogs with remodeled hearts is associated with larger beat–to–beat variability of repolarization

AbstractIncreased proarrhythmia in dogs with chronic AV block (AVB) has been explained by ventricular remodeling causing a decrease in repolarization reserve. Beat–to–beat variability of repolarization (BVR) has been suggested to reflect repolarization reserve, in which high variability represents diminished reserve and larger propensity for repolarization–dependent ventricular arrhythmia. A subset of chronic AVB dogs (10%) suffers sudden cardiac death (SCD). With the assumption that repolarization defects constitute a potentially lethal proarrhythmic substrate, we hypothesized that BVR in SCD dogs are larger than in matched control chronic AVB dogs.From a population of 200 chronic AVB dogs, initially two groups were chosen retrospectively: 8 dogs that died suddenly (SCD) and 8 control dogs. Control dogs had a longer lifespan after AVB (10 to 18 weeks) than SCD dogs (5 to 10 weeks). All dogs had undergone electrophysiological testing under anesthesia where ECG, left and right ventricular endocardial monophasic action potentials (MAP) were recorded. BVR was assessed from 30 consecutive beats, illustrated by Poincaré plots and was the only parameter discriminating between SCD and control group. All other electrophysiological parameters (RR, QT and MAP durations) were comparable for the two groups. Extending the number of animals and groups confirmed a larger BVR in the SCD group (SCD: 5.1 ± 2.7; n = 11 versus control: 2.5 ± 0.4 ms; n = 61; P < 0.05) and showed reverse–use dependence of BVR. In comparison, dogs with acute AVB had low variability (1.3 ± 0.3 ms; n = 9; P < 0.05 versus chronic AVB).Cardiac electrical remodeling after AVB is associated with an increase in beat–to–beat variability of repolarization. Chronic AVB dogs displaying further elevated variability of repolarization are prone to arrhythmia–related SCD.

The JT-area indicates dispersion of repolarization in dogs with atrioventricular block.

AbstractHeterogeneity in cardiac repolarization (ΔAPD) is known to be arrhythmic. In the dog model of chronic complete AV-block and acquired long QT syndrome, an increase in ΔMAPD (defined as left ventricular monophasic action potential duration (MAPD) minus right ventricular MAPD) is often associated with changes in T-wave morphology. The purpose of this study was to correlate known changes in ΔMAPD with the planimetric total area of the T-wave on the surface ECG (J∫T,mV · ms). Methods: The relationship between ΔMAPD and total area of the T-wave (i.e., JT-area) was assessed in four different protocols with different types of dispersion: (1) class III drugs followed by levcromakalim (n = 7), (2) LAD coronary artery occlusion and reperfusion (n = 6), (3) dronedarone i.v., an amiodarone like agent (n = 5) and (4) steady state pacing at cycle lengths of 1000 ms and 500 ms (n = 5). Results: Class III drugs increased ΔMAPD (55 ± 40 ms to 120 ± 50 ms#, P < 0.05), which was correlated (r = 0.74, P < 0.001) with JT-area (50 ± 40 mV · ms to 95 ± 35 mV · ms#). Ischemia increased both ΔMAPD (30 ± 25 ms to 90 ± 40 ms#) and JT-area (60 ± 55 mV · ms to 75 ± 50 mV · ms#). Both levcromakalim and reperfusion reversed these conditions. Dronedarone had no effect on ΔMAPD or on JT-area while a faster frequency reduced both ΔMAPD and JT-area. Conclusion: Changes in dispersion of ventricular repolarization are reflected by alterations in JT-area. This non-invasive parameter may therefore be used to indicate changes in heterogeneity in ventricular repolarization.

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

INTRODUCTION 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. METHODS AND RESULTS 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. CONCLUSION 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.

Assessment of the pro-arrhythmic potential of anti-arrhythmic drugs: an experimental approach.

Pro-arrhythmic activity is a feared side effect of almost all antiarrhythmic drugs. One of these proarrhythmic events is the occurrence of Torsade de Pointes arrhythmias (TdP), a polymorphic tachycardia that may develop after use of drugs that prolong ventricular repolarization. To study the mechanisms behind TdP and to screen for pro-arrhythmogenic activity, animal models have been developed during the past 20 years both in vivo as well as in vitro. This review will provide the characteristics of two of these models and compare their results using clinically relevant drugs: the methoxamine-sensitized anesthetized rabbit, and the anesthetized chronic complete atrioventricular block (CAVB) dog.

A Completely Subcutaneous Implantable Cardioverter Defibrillator in a Patient With Situs Inversus Totalis

A 42-year-old male with a known situs inversus totalis was resuscitated because of ventricular fibrillation. The coronary angiogram showed no abnormalities. An echocardiogram demonstrated apart from the known dextrocardia of the heart a moderate mitral insufficiency but no evidence for an infarcted area. The laboratory results showed only mildly elevated enzymes. Neurological recovery of the patient was unremarkable. An MR scan was not successful because of claustrophobia of the patient. As implantation of transvenous leads in situs inversus can be (1) technically challenging as situs inversus is frequently associated with anomalous venous return, (2) the patient was young, and (3) no pacing indication was present, we opted for a completely subcutaneous implantable cardioverter defibrillator (S-ICD, Cameron Health Inc., San Clemente, CA, USA) that was placed on the right side of the thorax (Fig. 1). Defibrillation of 50 Hz induced ventricular fibrillation during the procedure was successfully performed by the S-ICD.