S. Cora Verduyn

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.

Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired torsade de pointes arrhythmias: a comparison between almokalant and d-sotalol using the dog as its own control.

OBJECTIVES We sought to further elucidate the role of early afterdepolarizations (EADs) and interventricular dispersion of repolarization (deltaAPD) in the genesis of acquired torsade de pointes (TdP) arrhythmias. BACKGROUND Administration of class III agents can be associated with TdP. We developed a dog model in which TdP can be reproducibly induced by pacing after d-sotalol. This model shows reproducible results over weeks. METHODS In 14 anesthetized dogs with chronic complete atrioventricular block, two separate experiments were performed in which d-sotalol (2 mg/kg body weight) or almokalant (0.12 mg/kg) was administered. Monophasic action potentials were simultaneously recorded from the endocardium of the right and left ventricle to register EADs and to measure the action potential duration (APD). DeltaAPD was defined as the APD of the left ventricle minus that of the right ventricle. RESULTS Baseline conditions were identical in the serially performed experiments. The cycle length and QT time increased by 16% and 26% after d-sotalol and by 15% and 31% after almokalant, respectively. After both drugs the action potential of the left ventricle prolonged more than that of the right ventricle, thereby increasing deltaAPD (almokalant [mean +/- SD]: 110 +/- 60 ms; d-sotalol: 80 +/- 45 ms, p < 0.05). The incidence of EADs (18 of 22 vs. 11 of 24, p < 0.05) and single ectopic beats (EBs) (1.5 +/- 2 vs. 24 +/- 32, p < 0.01) was more frequently observed after almokalant than after d-sotalol. Moreover, multiple EBs only occurred after almokalant. These beats interfered with the basic rhythm, leading to dynamic changes in left ventricular APD and to additional increases in deltaAPD. Spontaneous TdP was observed in 9 of 14 dogs after almokalant and could be increased to 12 of 14 with programmed electrical stimulation. After d-sotalol, TdP could only be induced by programmed electrical stimulation (5 of 14, p < 0.05). CONCLUSIONS In the same dog, almokalant induced more delay in repolarization, more EADs, multiple EBs and more ventricular inhomogeneity in APD than d-sotalol. These changes were related to a higher incidence of TdP and thereby confirm a strong association of the occurrence of EADs, multiple EBs and deltaAPD in the genesis of TdP. These findings also show the possible value of our model for evaluating the proarrhythmic potential of different drugs.

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.

Observations on the onset of Torsade de Pointes arrhythmias in the acquired long QT syndrome

OBJECTIVE Premature ectopic beats may create a specific sequence of events (e.g. short-long-short) preceding Torsade de Pointes arrhythmias (TdP) in the long QT syndrome. The relevance of this sequence for the initiation of TdP is not clear. In our dog model of TdP, interventricular dispersion (DeltaAPD=left-right ventricular monophasic action potential duration: APD) is associated with TdP, therefore we tested the hypothesis that the ectopic beats contributes to DeltaAPD. METHODS In 17 anaesthetized dogs with chronic AV-block, which showed spontaneous TdP after class III medication, APD was analyzed to 1. quantitate the alterations due to (multiple) ectopic beats on the left and right APD (measured with endocardial catheters) and 2. compare the DeltaAPD prior to the occurrence of premature beats (steady state) in dogs with non-sudden onset of TdP (n=10) and sudden onset TdP (n=7). Three phases were distinguished: phase 1: steady state beats prior to ectopic beats, phase II: the beat(s) belonging to the dynamic phase, and phase III: the beat causing TdP. Because the coupling interval of premature beats in this condition often falls within the APD, the DeltaAPD(50) was validated as an alternative for the previously applied DeltaAPD(100) (r=0.51, P<0.01). RESULTS In steady state (phase I) DeltaAPD(50) is longer in the sudden onset TdP (130+/-35 ms) as in the non-sudden onset TdP (65+/-40 ms). In the non-sudden TdP group the dynamic phase II contribute to the heterogeneity in APD, i.e. LV-APD increases more than RV-APD leading to a DeltaAPD(50) increase to 130+/-100 ms (P<0.01) just preceding TdP (phase III). CONCLUSION The synergism between ectopic beats (short-long-short sequence) and DeltaAPD create the circumstances for TdP initiation.

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.