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12. Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model

Author

Medische Fysiologie, Circulatory Health, van Weperen, Valerie Y.H., Dunnink, Albert, Bossu, Alexandre, Beekman, Jet D.M., Meijborg, Veronique M.F., de Bakker, Jacques M.T., Coronel, Ruben, Varkevisser, Rosanne, van der Heyden, Marcel A.G., Vos, Marc A., Medische Fysiologie, Circulatory Health, van Weperen, Valerie Y.H., Dunnink, Albert, Bossu, Alexandre, Beekman, Jet D.M., Meijborg, Veronique M.F., de Bakker, Jacques M.T., Coronel, Ruben, Varkevisser, Rosanne, van der Heyden, Marcel A.G., and Vos, Marc A.

Published
2021

15. Evaluation of a Fully Automatic Measurement of Short-Term Variability of Repolarization on Intracardiac Electrograms in the Chronic Atrioventricular Block Dog

Author

Smoczyńska, Agnieszka, primary, Sprenkeler, David J., additional, Aranda, Alfonso, additional, Beekman, Jet D.M., additional, Bossu, Alexandre, additional, Dunnink, Albert, additional, Wijers, Sofieke C., additional, Stegemann, Berthold, additional, Meine, Mathias, additional, and Vos, Marc A., additional

Published
2020
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18. Evaluation of a Fully Automatic Measurement of Short-Term Variability of Repolarization on Intracardiac Electrograms in the Chronic Atrioventricular Block Dog

Author

Medische Fysiologie, Arts Assistenten Cardiologie, Circulatory Health, Team Medisch, Smoczyńska, Agnieszka, Sprenkeler, David J., Aranda, Alfonso, Beekman, Jet D.M., Bossu, Alexandre, Dunnink, Albert, Wijers, Sofieke C., Stegemann, Berthold, Meine, Mathias, Vos, Marc A., Medische Fysiologie, Arts Assistenten Cardiologie, Circulatory Health, Team Medisch, Smoczyńska, Agnieszka, Sprenkeler, David J., Aranda, Alfonso, Beekman, Jet D.M., Bossu, Alexandre, Dunnink, Albert, Wijers, Sofieke C., Stegemann, Berthold, Meine, Mathias, and Vos, Marc A.

Published
2020

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

Author

Ji, Yuan, Varkevisser, Rosanne, Opacic, Dragan, Bossu, Alexandre, Kuiper, Marion, Beekman, Jet D.M., Yang, Sihyung, Khan, Azinwi Phina, Dobrev, Dobromir, Voigt, Niels, Wang, Michael Zhuo, Verheule, Sander, Vos, Marc A., van der Heyden, Marcel A.G., Fysiologie, RS: CARIM - R2.11 - Experimental atrial fibrillation, and Cardiologie

Subjects
Pharmacology, III DRUGS, Medizin, UP-REGULATION, HUMAN AFRICAN TRYPANOSOMIASIS, POTASSIUM CURRENT, ATRIOVENTRICULAR-BLOCK, cardiovascular system, Journal Article, CARDIAC REPOLARIZATION, TORSADES-DE-POINTES, IONIC MECHANISMS, TRANSMURAL CONDUCTION, CURRENT I-K1
Abstract

BACKGROUND AND PURPOSE The density of the inward rectifier current (I-K1) 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 I-K1 inhibitor. We tested PA-6 for anti-AF efficacy and potential proarrhythmia, using established models in large animals. EXPERIMENTAL APPROACH PA-6 was applied i.v. in anaesthetized goats with rapid pacing-induced AF and anaesthetized dogs with chronic atrio-ventricular (AV) block. Electrophysiological and pharmacological parameters were determined. KEY RESULTS PA-6 (2.5 mg.kg(-1) .10 min(-1)) induced cardioversion to sinus rhythm (SR) in 5/6 goats and prolonged AF cycle length. AF complexity decreased significantly before cardioversion. PA-6 accumulated in cardiac tissue with ratios between skeletal muscle : atrial muscle : ventricular muscle of approximately 1:8:21. In SR dogs, PA-6 peak plasma levels 10 min post infusion were 5.5 +/- 0.9 mu M, PA-6 did not induce significant prolongation of QTc and did not affect heart rate, PQ or QRS duration. In dogs with chronic AV block, PA-6 did not affect QRS but lengthened QTc during the experiment, but not chronically. PA-6 did not induce TdP arrhythmias in nine animals (0/9) in contrast to dofetilide (5/9). PA-6 (200 nM) inhibited I-K1, but not I-K,I-ACh,I- in human isolated atrial cardiomyocytes. CONCLUSION AND IMPLICATIONS PA-6 restored SR in goats with persistent AF and, in dogs with chronic AV block, prolonged QT intervals, without inducing TdP arrhythmias. Our results demonstrate cardiac safety and good anti-AF properties for PA-6.

Published
2017

20. 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

Author

Medische Fysiologie, Team Onderzoek, Circulatory Health, Planningssecretariaat HCK, Team Medisch, Wijers, Sofieke C., Sprenkeler, David J., Bossu, Alexandre, Dunnink, Albert, Beekman, Jet D.M., Varkevisser, Rosanne, Hernández, Alfonso Aranda, Meine, Mathias, Vos, Marc A., Medische Fysiologie, Team Onderzoek, Circulatory Health, Planningssecretariaat HCK, Team Medisch, Wijers, Sofieke C., Sprenkeler, David J., Bossu, Alexandre, Dunnink, Albert, Beekman, Jet D.M., Varkevisser, Rosanne, Hernández, Alfonso Aranda, Meine, Mathias, and Vos, Marc A.

Published
2018

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

Author

Medische Fysiologie, Circulatory Health, Team Onderzoek, Cardiologie Arts-onderzoekers, Dunnink, Albert, Stams, Thom R G, Bossu, Alexandre, Meijborg, Veronique M F, Beekman, Jet D.M., Wijers, Sofieke C., De Bakker, Jacques M.T., Vos, Marc A., Medische Fysiologie, Circulatory Health, Team Onderzoek, Cardiologie Arts-onderzoekers, Dunnink, Albert, Stams, Thom R G, Bossu, Alexandre, Meijborg, Veronique M F, Beekman, Jet D.M., Wijers, Sofieke C., De Bakker, Jacques M.T., and Vos, Marc A.

Published
2017

23. Short-Lasting Episodes of Torsade de Pointes in the Chronic Atrioventricular Block Dog Model Have a Focal Mechanism, While Longer-Lasting Episodes Are Maintained by Re-Entry

Author

Medische Fysiologie, UMC Utrecht, Circulatory Health, Vandersickel, Nele, Bossu, Alexandre, De Neve, Jan, Dunnink, Albert, Meijborg, Veronique M F, van der Heyden, Marcel A.G., Beekman, Jet D.M., De Bakker, Jacques M.T., Vos, Marc A., Panfilov, Alexander V, Medische Fysiologie, UMC Utrecht, Circulatory Health, Vandersickel, Nele, Bossu, Alexandre, De Neve, Jan, Dunnink, Albert, Meijborg, Veronique M F, van der Heyden, Marcel A.G., Beekman, Jet D.M., De Bakker, Jacques M.T., Vos, Marc A., and Panfilov, Alexander V

Published
2017

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

Author

Medische Fysiologie, Circulatory Health, Ji, Yuan, Varkevisser, Rosanne, Opacic, Dragan, Bossu, Alexandre, Kuiper, Marion, Beekman, Jet D.M., Yang, Sihyung, Khan, Azinwi Phina, Dobrev, Dobromir, Voigt, Niels, Wang, Michael Zhuo, Verheule, Sander, Vos, Marc A., van der Heyden, Marcel A.G., Medische Fysiologie, Circulatory Health, Ji, Yuan, Varkevisser, Rosanne, Opacic, Dragan, Bossu, Alexandre, Kuiper, Marion, Beekman, Jet D.M., Yang, Sihyung, Khan, Azinwi Phina, Dobrev, Dobromir, Voigt, Niels, Wang, Michael Zhuo, Verheule, Sander, Vos, Marc A., and van der Heyden, Marcel A.G.

Published
2017

25. Electrophysiological measurements that can explain and guide temporary accelerated pacing to avert (re)occurrence of torsade de pointes arrhythmias in the canine chronic atrioventricular block model

Author

Medische Fysiologie, Team Onderzoek, Circulatory Health, Researchbureau DHL, Team Medisch, Wijers, Sofieke C., Bossu, Alexandre, Dunnink, Albert, Beekman, Jet D.M., Varkevisser, Rosanne, Aranda Hernández, Alfonso, Meine, Mathias, Vos, Marc A., Medische Fysiologie, Team Onderzoek, Circulatory Health, Researchbureau DHL, Team Medisch, Wijers, Sofieke C., Bossu, Alexandre, Dunnink, Albert, Beekman, Jet D.M., Varkevisser, Rosanne, Aranda Hernández, Alfonso, Meine, Mathias, and Vos, Marc A.

Published
2017

34. Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation

Author

Thomsen, Morten B., Oros, Avram, Schoenmakers, Marieke, van Opstal, Jurren M., Maas, Joep N., Beekman, Jet D.M., and Vos, Marc A.

Subjects
LONG QT syndrome, ARRHYTHMIA, LABORATORY dogs, BRADYCARDIA, VENTRICULAR remodeling
Abstract

Abstract: Objective: Acquired long-QT syndrome in combination with increased beat-to-beat variability of repolarisation duration (BVR) is associated with lethal torsades de pointes arrhythmias (TdP) in dogs with remodelled heart after atrioventricular block (AVB). We evaluated the relative contributions of bradycardia and ventricular remodelling to proarrhythmic BVR with and without pharmacological I Kr block in order to identify the individual at risk. Methods: Three groups of dogs were used: sinus rhythm dogs (n =12), dogs with acute AVB (n =8), and dogs with >3 weeks chronic AVB (n =27). Under anaesthesia, ECG and monophasic action potential duration (MAPD) were measured. Local BVR was quantified as short-term variability from 30 consecutive left ventricular MAPD (STV=∑|Dni − Dn+1 |/[30×√2]). All dogs received dofetilide iv. Results: The slower ventricular rate acutely after AVB affected neither QTc nor STV (288±18 to 293±38 ms and 0.7±0.1 to 0.7±0.1 ms, respectively; P =NS for both), whereas ventricular remodelling increased both (to 376±46 and 2.3±0.6 ms, respectively; P<0.05 for both). Neither dogs in sinus rhythm nor acute AVB showed any TdP, whereas dofetilide induced TdP in 74% of the chronic-AVB dogs. Dofetilide increased the QTc interval in all groups (19–24%; P <0.05 for all groups), whereas STV was elevated in chronic-AVB dogs only (to 4.2±1.5 ms; P <0.05) and further confined to inducible chronic-AVB dogs (5.0±0.8 versus 1.9±0.4 ms for resistant dogs; P <0.05). Variability of the idioventricular rate was increased directly after AVB and did not influence BVR. Conclusions: Under drug-free circumstances, a persistent high BVR in chronic-AVB dogs is remodelling dependent rather than a direct consequence of bradycardia acutely after AVB. Variability of this slower rate does not influence BVR. Dofetilide causes a transient increase in BVR only in proarrhythmic dogs. Thus, BVR may aid the identification of the TdP-susceptible patient. [Copyright &y& Elsevier]

Published
2007
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35. Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Author

Thomsen, Morten B., Volders, Paul G.A., Stengl, Milan, Späatjens, Roel L.H.M.G., Beekman, Jet D.M., Bischoff, Ulrike, Kall, Morten A., Frederiksen, Kristen, Matz, Jørgen, and Vos, Marc A.

Abstract

Inhibition of the potassium current IKrand QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of IHERGover other ion currents. For IHERG, the IC50value was 64 ± 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3were blocked in the micromolar range. In canine ventricular myocytes, the IC50value for IKrinhibition by sertindole was 107 ± 21 nM. Action potentials in these cells prolonged in a reverse rate- and concentration-dependent manner at 10 to 300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0-2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30-157 nM), QTcwas prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB). TdP was not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0 to 2.0 mg/kg sertindole (plasma concentrations 0.5-3.1 μM), QTcprolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.

Published
2003
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39. Calcium release near l-type calcium channels promotes beat-to-beat variability in ventricular myocytes from the chronic AV block dog

Author

Antoons, Gudrun, Johnson, Daniel M., Dries, Eef, Santiago, Demetrio J., Ozdemir, Semir, Lenaerts, Ilse, Beekman, Jet D.M., Houtman, Marien J.C., Sipido, Karin R., Vos, Marc A., Antoons, Gudrun, Johnson, Daniel M., Dries, Eef, Santiago, Demetrio J., Ozdemir, Semir, Lenaerts, Ilse, Beekman, Jet D.M., Houtman, Marien J.C., Sipido, Karin R., and Vos, Marc A.

Abstract

Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca2 + handling. This remodeling process also leads to increased BVR. We aimed to determine the role that (local) Ca2 + handling plays in BVR. In isolated LV myocytes an exponential relationship was observed between BVR magnitude and action potential duration (APD) at baseline. Inhibition of Ca2 + release from sarcoplasmic reticulum (SR) with thapsigargin resulted in a reduction of [Ca2 +]i, and of both BVR and APD. Increasing ICaL in the presence of thapsigargin restored APD but BVR remained low. In contrast, increasing ICaL with preserved Ca2 + release increased both APD and BVR. Inhibition of Ca2 + release with caffeine, as with thapsigargin, reduced BVR despite maintained APD. Simultaneous inhibition of Na+/Ca2 + exchange and ICaL decreased APD and BVR to similar degrees, whilst increasing diastolic Ca2 +. Buffering of Ca2 + transients with BAPTA reduced BVR for a given APD to a greater extent than buffering with EGTA, suggesting subsarcolemmal Ca2 + transients modulated BVR to a larger extent than the cytosolic Ca2 + transient. In conclusion, BVR in hypertrophied dog myocytes, at any APD, is strongly dependent on SR Ca2 + release, which may act through modulation of the l-type Ca2 + current in a subsarcolemmal microdomain.

40. Calcium release near l-type calcium channels promotes beat-to-beat variability in ventricular myocytes from the chronic AV block dog

Author

Antoons, Gudrun, Johnson, Daniel M., Dries, Eef, Santiago, Demetrio J., Ozdemir, Semir, Lenaerts, Ilse, Beekman, Jet D.M., Houtman, Marien J.C., Sipido, Karin R., Vos, Marc A., Antoons, Gudrun, Johnson, Daniel M., Dries, Eef, Santiago, Demetrio J., Ozdemir, Semir, Lenaerts, Ilse, Beekman, Jet D.M., Houtman, Marien J.C., Sipido, Karin R., and Vos, Marc A.

Abstract

Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca2 + handling. This remodeling process also leads to increased BVR. We aimed to determine the role that (local) Ca2 + handling plays in BVR. In isolated LV myocytes an exponential relationship was observed between BVR magnitude and action potential duration (APD) at baseline. Inhibition of Ca2 + release from sarcoplasmic reticulum (SR) with thapsigargin resulted in a reduction of [Ca2 +]i, and of both BVR and APD. Increasing ICaL in the presence of thapsigargin restored APD but BVR remained low. In contrast, increasing ICaL with preserved Ca2 + release increased both APD and BVR. Inhibition of Ca2 + release with caffeine, as with thapsigargin, reduced BVR despite maintained APD. Simultaneous inhibition of Na+/Ca2 + exchange and ICaL decreased APD and BVR to similar degrees, whilst increasing diastolic Ca2 +. Buffering of Ca2 + transients with BAPTA reduced BVR for a given APD to a greater extent than buffering with EGTA, suggesting subsarcolemmal Ca2 + transients modulated BVR to a larger extent than the cytosolic Ca2 + transient. In conclusion, BVR in hypertrophied dog myocytes, at any APD, is strongly dependent on SR Ca2 + release, which may act through modulation of the l-type Ca2 + current in a subsarcolemmal microdomain.

42. Late Na+ Current Inhibition by Ranolazine Reduces Torsades de Pointes in the Chronic Atrioventricular Block Dog Model

Author

Antoons, Gudrun, Oros, Avram, Beekman, Jet D.M., Engelen, Markus A., Houtman, Marien J.C., Belardinelli, Luiz, Stengl, Milan, and Vos, Marc A.

Subjects
*LONG QT syndrome, *DOFETILIDE, *CARDIAC hypertrophy, *LABORATORY dogs, *ANIMAL disease models, *ARRHYTHMIA, *TETRODOTOXIN, *SODIUM channels
Abstract

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]

Published
2010
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