Search

Ventricular remodelling can make the heart more susceptible to ventricular arrhythmias like torsades de pointes. Understanding the underlying mechanisms of initiation of ventricular arrhythmias and the determining factors for its severity has the potential to uncover new interventions. Beat-to-beat variation of repolarisation, quantified as short-term variability of repolarisation (STV), has been identified as an important factor contributing to arrhythmogenesis. This article provides an overview of experimental data about STV in relation to the initiation of torsades de pointes in a canine model of complete chronic atrioventricular block susceptible to torsades de pointes arrhythmias. Furthermore, it explores STV in relation to the severity of the arrhythmic outcome.

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia treated in clinical practice. Structural remodeling is characterized by atrial enlargement and contributes to the therapeutic resistance in patients with long-standing AF. Purpose To study the atrial arrhythmogenic and echocardiographic consequences induced by volume overload in the complete chronic atrioventricular block (CAVB) dog. Methods Echocardiographic and electrophysiological data was obtained in 14 anaesthetized Mongrel dogs, in acute AV-block (AAVB), after 6 weeks of CAVB (CAVB6) and CAVB10. Left atrial (LA) volume was determined with 2D echocardiography by using the biplane method. An electrocardiogram and monophasic action potentials (MAP) at the right atrial (RA) free wall were recorded. Atrial effective refractory period (AERP) was determined by continuous programmed electrical stimulation (PES) of 20 beats with a cycle length of 400 ms and an extrastimulus with decremental design until refractoriness was reached. A continuous PES protocol of 20 beats with an extrastimulus 5 ms longer than the AERP was applied for 150 seconds to trigger AF. After 5 min without arrhythmias, autonomic neuromodulation was performed by intravenous infusion (IV) of acetylcholine (1,5μg/kg/min to 6,0μg/kg/min) for 20 min followed by prompt IV infusion of isoprenaline (3μg/min) until the atrial heart rate increased by 20 bpm. PES with an extrastimulus was repeated for 150 seconds to induce AF. Results LA volume increased from 13.7±3.2 ml at AAVB to 20.5±5.9 ml* at CAVB6, and 22.7±6.0 ml* at CAVB10 (Fig. 1A). AERP was similar at AAVB, CAVB6, and CAVB10 (115.8±11.9, 117.3±11.7, and 106.8±12.1 ms respectively). Repetitive AF paroxysms of >10 seconds were induced in 1/14 (7%) dogs at AAVB, 1/11 (9%) at CAVB6, and 5/10 (50%)* at CAVB10 (*p Conclusion Sustained atrial dilation forms a substrate for repetitive paroxysms of AF. Neuro-modulation prolongs AF episode duration in susceptible dogs. This animal model can be used to study structural remodeling of the atria and possible therapeutic advances in the management of AF. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen Research

Background The anesthetized, chronic complete atrioventricular block (CAVB) dog model allows reproducible inducibility of Torsade de Pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr-blocker. High rate pacing (HRP) prevents ventricular arrhythmias, but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases prior to ventricular arrhythmias and has been proposed as a marker to guide HRP. Purpose A proof-of-principle study to show STV determined automatically and in real-time by an ICD can guide HRP to prevent imminent ventricular arrhythmias. Methods Eight CAVB dogs were implanted with an ICD (Medtronic, lead in the right ventricular (RV) apex), with software to automatically determine STV online (STV-ICD). STV was determined from the activation recovery interval (ARI) of 31 consecutive beats with the formula: STV = Σ|ARI(n+1) − ARI(n)|/(N*√2). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg i.v. in 5 minutes or until the first TdP). In the first experiment, the individual STV-ICD threshold was determined prior to the first arrhythmic event and programmed into the ICD. In a serial experiment, HRP was initiated automatically once the STV-ICD threshold was reached, by gradually increasing the heart rate to 100 bpm. Occurrence of TdPs was monitored for 10 minutes from the start of dofetilide infusion in both experiments. During HRP, STV was measured offline from RV electrograms (EGM) and left ventricular (LV) monophasic action potential durations (MAPD) (STV-offline). Results During the inducibility experiment, 8/8 dogs had repetitive TdPs and STV-ICD increased from 0.96±0.42 to 2.10±1.26 ms* (*p Conclusion Temporal dispersion of repolarization, quantified as STV, can guide HRP automatically by an ICD to prevent ventricular arrhythmias. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Public Private Partnership

Background The anesthetized, complete chronic atrioventricular block (CAVB) dog model allows reproducible inducibility of torsades de pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr blocker. High-rate pacing (HRP) prevents ventricular arrhythmias but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases before ventricular arrhythmias and has been proposed as a marker to guide HRP. Objective The purpose of this proof-of-principle study was to show that automatically determined STV can guide HRP to prevent imminent ventricular arrhythmias. Methods Eight CAVB dogs were implanted with an implantable cardioverter-defibrillator (ICD) with software to automatically determine STV (STVICD) in real time. During HRP, STV was measured offline from right ventricular (RV) electrograms (EGMs) and left ventricular (LV) monophasic action potential durations (MAPDs) (STVRV,EGM/LV,MAPD). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg intravenously over 5 minutes or until the first TdP). In experiment 1, the individual STVICD threshold before the first arrhythmic event was determined and programmed into the ICD. In experiment 2, HRP with 100 bpm was initiated automatically once the STVICD threshold was reached. Results In experiment 1, 8 of 8 dogs had repetitive TdP, and STVICD increased from 0.96 ± 0.42 ms to 2.10 ± 1.26 ms (P Conclusion STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.

© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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 μM) evoked no afterdepolarizations and significantly shortened action potential duration (APD) at 3 and 10 μM. Istaroxime at 3 μg/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 μg/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 μg/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.

Background and Purpose 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 IKr-blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility. Experimental Approach 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. Key Results 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. Conclusions and Implications In the canine CAVB model, ventricular remodelling and IKr 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.

Background and Purpose Drug interference with normal hERG protein trafficking substantially reduces the channel density in the plasma membrane and thereby poses an arrhythmic threat. The chemical substructures important for hERG trafficking inhibition were investigated using pentamidine as a model drug. Furthermore, the relationship between acute ion channel block and correction of trafficking by dofetilide was studied. Experimental Approach hERG and KIR2.1 trafficking in HEK293 cells was evaluated by Western blot and immunofluorescence microscopy after treatment with pentamidine and six pentamidine analogues, and correction with dofetilide and four dofetilide analogues that displayed different abilities to inhibit IKr. Molecular dynamics simulations were used to address mode, number and type of interactions between hERG and dofetilide analogues. Key Results Structural modifications of pentamidine differentially affected plasma membrane levels of hERG and KIR2.1. Modification of the phenyl ring or substituents directly attached to it had the largest effect, affirming the importance of these chemical residues in ion channel binding. PA-4 had the mildest effects on both ion channels. Dofetilide corrected pentamidine-induced hERG, but not KIR2.1 trafficking defects. Dofetilide analogues that displayed high channel affinity, mediated by pi-pi stacks and hydrophobic interactions, also restored hERG protein levels, whereas analogues with low affinity were ineffective. Conclusions and Implications Drug-induced trafficking defects can be minimized if certain chemical features are avoided or ‘synthesized out’; this could influence the design and development of future drugs. Further analysis of such features in hERG trafficking correctors may facilitate the design of a non-blocking corrector for trafficking defective hERG proteins in both congenital and acquired LQTS.

In the chronic complete atrioventricular (AV) block dog (CAVB) model, both bradycardia and altered ventricular activation due to the uncontrolled idioventricular rhythm contribute to ventricular remodeling and the enhanced susceptibility to Torsade de Pointes (TdP) arrhythmias. We investigated the effect of permanent bradycardic right ventricular apex (RVA) pacing on mechanical and electrical remodeling and TdP. In 23 anesthetized dogs, serial experiments were performed at sinus rhythm (SR), acutely after AV block (AAVB) and 3 weeks of remodeling CAVB at a fixed pacing rate of 60/min. ECG, and left (LV) and right ventricular (RV) monophasic action potentials durations (MAPD) were recorded; activation time (AT) and activation recovery interval (ARI) were determined from ten distinct LV electrograms; interventricular mechanical delay (IVMD) and time-to-peak strain (TTP) of the LV septal and lateral wall (ΔTTP: lateral wall minus septal wall) were obtained echocardiographically. Dofetilide (25 μg/kg/5 min) was infused to study TdP inducibility. In baseline AAVB, in comparison to SR, RVA bradypacing acutely increased QT interval, LV, and RVMAPD. Echocardiographic IVMD and ΔTTP were initially increased, which was partially corrected after 3 weeks of RVA pacing (IVMD: 22 ± 13 vs. 42 ± 11 vs. 31 ± 6 ms; ΔTTP: -2 ± 47 vs. -114 ± 38 vs. -36 ± 22 ms). QT interval (362 ± 23 vs. 373 ± 29 ms), LVMAPD (245 ± 18 vs. 253 ± 22 ms), RVMAPD (226 ± 26 vs. 238 ± 31 ms), and mean LV-ARI (268 ± 5 vs. 267 ± 6 ms) were not significantly changed after 3 weeks of RVA pacing. During AAVB, dofetilide increased mean LV-ARI (381 ± 11 ms) with largest increases in the later activated basal areas (slope AT-ARI: +0.96). In contrast with acute RVA pacing, 3 week pacing increased TdP inducibility (0/13 vs. 11/21) and mean LV-ARI (484 ± 18 ms), while the slope of AT-ARI responded differently on dofetilide (-2.37), with larger APD increases in the early region. The latter was supported at the molecular level: reduced RNA expressions of three repolarization-related ion channel genes in early (KCNQ1, KCNH2, and KCNJ2) versus two in late regions (KNCQ1 and KCNJ2). In conclusion, bradycardic RVA pacing acutely induced LV intra- and interventricular mechanical dyssynchrony, which was partially reversed after 3 weeks of pacing (remodeling). The latter occurred without apparent baseline electrical effects. However, dofetilide clearly unmasked (region-specific) arrhythmic consequences of remodeling.

Item does not contain fulltext BACKGROUND: In the canine complete AV block (AVB) model with bradycardia, inducibility of drug-induced torsades de pointes (TdP) is usually the primary outcome parameter, whereas short-term variability (STV) of the left ventricular monophasic action potential duration (LV MAPD) is used as primary surrogate parameter. The dichotomous parameter inducibility is cumbersome because it requires >/=3 TdP episodes and does not take into account (multiple) ectopic beats or severity of TdP episodes. In this study, we introduce arrhythmia score (AS) and T25, using dofetilide (D) to improve quantification of repolarization reserve. METHODS: Experiments performed under general anesthesia in unremodeled, acute AVB dogs (aAVB, n = 13) and 3 groups of AVB dogs with chronic bradycardia but differences in remodeling due to alterations in chronic activation pattern were analyzed: spontaneous idioventricular rhythm (IVR, n = 19), more physiologic high-septal pacing (HSP, n = 10), and right ventricular apex pacing (RVA, n = 8). AS was calculated as 1 + mean number of beats of the 3 most severe arrhythmias after D (0.025 mg/kg/5 min), with scores of 50, 75, and 100, for 1, 2, and >/=3 cardioversions, respectively. T25 was defined as the time required to obtain 25-ms increase of LV MAPD after D. RESULTS: For groups aAVB, IVR, HSP and RVA, TdP inducibility was 0%, 74% (P

Drug interference with normal hERG protein trafficking substantially reduces the channel density in the plasma membrane and thereby poses an arrhythmic threat. The chemical substructures important for hERG trafficking inhibition were investigated using pentamidine as a model drug. Furthermore, the relationship between acute ion channel block and correction of trafficking by dofetilide was studied.hERG and K(IR)2.1 trafficking in HEK293 cells was evaluated by Western blot and immunofluorescence microscopy after treatment with pentamidine and six pentamidine analogues, and correction with dofetilide and four dofetilide analogues that displayed different abilities to inhibit IKr . Molecular dynamics simulations were used to address mode, number and type of interactions between hERG and dofetilide analogues.Structural modifications of pentamidine differentially affected plasma membrane levels of hERG and K(IR)2.1. Modification of the phenyl ring or substituents directly attached to it had the largest effect, affirming the importance of these chemical residues in ion channel binding. PA-4 had the mildest effects on both ion channels. Dofetilide corrected pentamidine-induced hERG, but not K(IR)2.1 trafficking defects. Dofetilide analogues that displayed high channel affinity, mediated by pi-pi stacks and hydrophobic interactions, also restored hERG protein levels, whereas analogues with low affinity were ineffective.Drug-induced trafficking defects can be minimized if certain chemical features are avoided or 'synthesized out'; this could influence the design and development of future drugs. Further analysis of such features in hERG trafficking correctors may facilitate the design of a non-blocking corrector for trafficking defective hERG proteins in both congenital and acquired LQTS.

Background The chronic atrioventricular (AV) block (CAVB) dog has enhanced susceptibility for drug-induced torsades de pointes arrhythmias. This risk can be estimated using beat-to-beat variability of repolarization, quantified as short term variability (STV) of action potential duration (STV–APD in ms) in vivo or in vitro . Under pathophysiologic conditions, APD prolongation increases STV. Most proarrhythmic drugs increase STV more (up) than APD (rightward), whereas flunarizine, with robust antiarrhythmic properties, has been shown to decrease baseline STV more (down) than APD (leftward) both in vivo and in vitro . The purpose of this study was to assess the stabilizing effect of selective inhibition of late Na + current (I NaL ) by GS-458967 (GS967) and tetrodotoxin (TTX) on the STV–APD relationship. In addition, the effect of ranolazine (RAN), a multiple ion channel blocker, which also inhibits I NaL , and dofetilide, an I Kr blocker, were investigated. Methods Isolated CAVB myocytes were stimulated at 0.5 Hz and exposed to RAN (15 μM), GS967 (0.1, 0.3, 1 μM), TTX (5 μM), and dofetilide (1 μM). Results As expected, dofetilide appeared more up and rightward on the STV-APD (Figure) and caused early afterdepolarizations (4/6). The results of GS967 and TTX showed the opposite effect (down and leftward). This effect was greater than that of flunarizine, whereas RAN had minimal effect. Conclusions The appearance of GS967 and TTX, by blocking I NaL , indicates strong AP-stabilizing properties.