Alexandre Bossu

Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog

Aims The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. Methods and results In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500 ms), local unipolar electrograms were recorded before and after administration of dofetilide to determine activation and repolarization times (RTs). Maximal RT differences were calculated in the left ventricle (LV) within adjacent electrodes in different orientations (transmural, vertical, and horizontal) and within a square of four needles (cubic dispersion). Dofetilide induced TdP in five out of eight animals. Right ventricle-LV was similar between inducible and non-inducible dogs at baseline (327 ± 30 vs. 345 ± 17 ms) and after dofetilide administration (525 ± 95 vs. 508 ± 15 ms). All measurements of intraventricular dispersion were not different at baseline, but this changed for horizontal (206 ± 20 vs. 142 ± 34 ms) and cubic dispersion (272 ± 29 vs. 176 ± 48 ms) after dofetilide: significantly higher values in inducible animals. Single ectopic beats and the first TdP beat arose consistently from a subendocardially located electrode terminal with the shortest RT in the region with largest RT differences. Conclusion Chronic complete atrioventricular block dogs susceptible for TdP demonstrate higher RT differences. Torsade de pointes arises from a region with maximal heterogeneity of repolarization suggesting that a minimal gradient is required in order to initiate TdP.

A 2015 focus on preventing drug-induced arrhythmias

ABSTRACT Drug-induced Torsade de Pointes arrhythmia is a life-threatening adverse effect feared by pharmaceutical companies. For the last decade, the cardiac safety guidelines have imposed human ether-a-go-go-related gene channel blockade and prolongation of QT interval as surrogates for proarrhythmic risk propensity of a new chemical entity. Suffering from a lack of specificity, this assessment strategy led to a great amount of false positive outcomes. Therefore, this review will discuss new pharmaceutical strategies: the cardiac safety proposal that recently emerged, the Comprehensive in vitro Proarrhythmia Assay, combining in vitro assays that integrate effects on main cardiac ion channels, with computational models of human ventricular action potential as well as assays using human stem cell-derived cardiomyocytes for an improved prediction of drug’s proarrhythmic liability, alternative pharmacological perspectives as well as the current treatment of drug-induced long QT syndrome.

Short-term variability of repolarization is superior to other repolarization parameters in the evaluation of diverse antiarrhythmic interventions in the chronic atrioventricular block dog

Short-term variability (STV), to quantify beat-to-beat variability of repolarization (BVR), is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed, but also in vulnerable patients with heart failure or drug-induced long QT syndrome. In the CAVB dog model, STV can specifically distinguish between safe and unsafe drugs in proarrhythmic screening. Conversely, this dog model also offers the possibility to evaluate antiarrhythmic strategies in a setting of Torsades de Pointes (TdP) induction with a standard IKr inhibitor. The different antiarrhythmic interventions studied in suppression and prevention of drug-induced TdP in vivo in the CAVB dog model and in vitro in canine ventricular cardiomyocytes are described in this overview. We provide evidence that STV predicts the magnitude of antiarrhythmic effect against TdP better than other repolarization parameters in both suppression and prevention conditions. Moreover, suppression and prevention experiments revealed the same level of antiarrhythmic efficacy, while cellular experiments appear more sensitive in comparison to drug testing in vivo. Together, these observations suggest that STV could be used as a consistent indicator to rank efficacy of antiarrhythmic interventions in a number of conditions.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Abstract: Short-term variability (STV), to quantify beat-to-beat variability of repolarization, is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed but also in vulnerable patients with heart failure or drug-induced long QT syndrome. In the CAVB dog model, STV can specifically distinguish between safe and unsafe drugs in proarrhythmic screening. Conversely, this dog model also offers the possibility to evaluate antiarrhythmic strategies in a setting of Torsades de Pointes (TdP) induction with a standard IKr inhibitor. The different antiarrhythmic interventions studied in suppression and prevention of drug-induced TdP in vivo in the CAVB dog model and in vitro in canine ventricular cardiomyocytes are described in this overview. We provide evidence that STV predicts the magnitude of antiarrhythmic effect against TdP better than other repolarization parameters in both suppression and prevention conditions. Moreover, suppression and prevention experiments revealed the same level of antiarrhythmic efficacy, whereas cellular experiments seem more sensitive in comparison with drug testing in vivo. Together, these observations suggest that STV could be used as a consistent indicator to rank efficacy of antiarrhythmic interventions in a number of conditions.

The inward rectifier current inhibitor PA‐6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models

The density of the inward rectifier current (IK1) increases in atrial fibrillation (AF), shortening effective refractory period and thus promoting atrial re‐entry. The synthetic compound pentamidine analogue 6 (PA‐6) is a selective and potent IK1 inhibitor. We tested PA‐6 for anti‐AF efficacy and potential proarrhythmia, using established models in large animals.

Selective late sodium current inhibitor GS‐458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia

Enhanced late sodium current (late INa) in heart failure and long QT syndrome type 3 is proarrhythmic. This study investigated the antiarrhythmic effect and mode of action of the selective and potent late INa inhibitor GS‐458967 (GS967) against Torsades de Pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog.

Beat-to-beat variations in activation recovery interval derived from the right ventricular electrogram can monitor arrhythmic risk under anesthetic and awake conditions in the canine chronic atrioventricular block model

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.

Istaroxime, a positive inotropic agent devoid of proarrhythmic properties in sensitive chronic atrioventricular block dogs

Graphical abstract Figure. No Caption available. &NA; Current inotropic agents in heart failure therapy associate with low benefit and significant adverse effects, including ventricular arrhythmias. Istaroxime, a novel Na+/K+‐transporting ATPase inhibitor, also stimulates SERCA2a activity, which would confer improved inotropic and lusitropic properties with less proarrhythmic effects. We investigated hemodynamic, electrophysiological and potential proarrhythmic and antiarrhythmic effects of istaroxime in control and chronic atrioventricular block (CAVB) dogs sensitive to drug‐induced Torsades de Pointes arrhythmias (TdP). In isolated normal canine ventricular cardiomyocytes, istaroxime (0.3–10 &mgr;M) evoked no afterdepolarizations and significantly shortened action potential duration (APD) at 3 and 10 &mgr;M. Istaroxime at 3 &mgr;g/kg/min significantly increased left ventricular (LV) contractility (dP/dt+) and relaxation (dP/dt−) respectively by 81 and 94% in anesthetized control dogs (n = 6) and by 61 and 49% in anesthetized CAVB dogs (n = 7) sensitive to dofetilide‐induced TdP. While istaroxime induced no ventricular arrhythmias in control conditions, only single ectopic beats occurred in 2/7 CAVB dogs, which were preceded by increase of short‐term variability of repolarization (STV) and T wave alternans in LV unipolar electrograms. Istaroxime pre‐treatment (3 &mgr;g/kg/min for 60 min) did not alleviate dofetilide‐induced increase in repolarization and STV, and mildly reduced incidence of TdP from 6/6 to 4/6 CAVB dogs. In six CAVB dogs with dofetilide‐induced TdP, administration of istaroxime (90 &mgr;g/kg/5 min) suppressed arrhythmic episodes in two animals. Taken together, inotropic and lusitropic properties of istaroxime in CAVB dogs were devoid of significant proarrhythmic effects in sensitive CAVB dogs, and istaroxime provides a moderate antiarrhythmic efficacy in prevention and suppression of dofetilide‐induced TdP.

Efficacy of pentamidine analogue 6 in dogs with chronic atrial fibrillation

Background The inward rectifier inhibitor pentamidine analogue 6 (PA‐6) is effective in cardioversion of goats with persistent rapid pacing induced atrial fibrillation (AF) and is not proarrhythmic in dogs with experimental chronic 3rd‐degree AV block. Efficacy and safety in the clinical setting are unknown. Hypothesis That PA‐6 would be effective in converting AF to sinus rhythm (SR) in dogs with naturally occurring AF, without the presence of overt adverse effects. Animals Ten client‐owned large and giant breed dogs. Methods Animals with persistent or permanent AF were recruited for our prospective study. PA‐6 was administered IV as a bolus of 2.5 mg/kg 10 min−1 followed by a maintenance infusion of 0.04 mg/kg min−1 for a maximum of 50 minutes in conscious dogs. Standard 6 lead limb ECG was recorded during the infusion. Visible and audible signs of adverse effects were scored during the entire procedure. Results PA‐6 did not induce changes in QRS duration (54.7 ± 4.6 versus 56.7 ± 6.1 ms, P = .42), QTc interval (241.1 ± 19.5 versus 258.7 ± 19.8 ms, P = .061) or RR interval (363.4 ± 84.6 versus 440.8 ± 96.3 ms, P = .072) at the end of the bolus. No cardioversion to SR was observed in any dog. Three dogs displayed no adverse effects. Five dogs had premature ventricular depolarizations during PA‐6 infusion on the ECG. Respiratory distress with laryngeal stridor, subtle muscle twitching, and mild generalized muscular weakness were noncardiac adverse effects observed in 5 dogs. Adverse effects resolved spontaneously. Conclusions and Clinical importance Chronic naturally occurring AF in large and giant breed dogs could not be cardioverted to SR by PA‐6.

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.