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

Dunnink, Albert; Opstal, Jurren M. van; Oosterhoff, Peter; Winckels, Stephan K.G.; Beekman, Jet D.M.; Nagel, Roel van der; Verduyn, S. Cora; Vos, Marc A.

doi:10.1093/europace/eur311

Cited by 27 publications

(14 citation statements)

References 27 publications

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“…Noteworthy signs of slowed conduction associated with premature ventricular beats have also been recorded in this latter model of TdP (Figures S14–S16). Dofetilide did not produce TdP in healthy beagle dogs, in accordance with the fact that this species requires ventricular remodelling (such as chronic atrioventricular block) as a prerequisite for TdP induction (Dunnink et al , ). This mechanism responsible for these transient sequences of sympathetic activation and increased HR during HF oscillations is triggered even under conditions of mild QT prolongation, because an increase in HR HF oscillations was found with all the torsadogenic agents tested under conditions of moderate QT prolongation.…”

Section: Discussionmentioning

confidence: 52%

The high frequency relationship: implications for torsadogenic hERG blockers

Champéroux¹,

Guennec

Judé³

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEVentricular arrhythmias induced by human ether-a-go-go related gene (hERG; K v 11.1 channel) blockers are a consequence of alterations in ventricular repolarisation in association with high-frequency (HF) oscillations, which act as a primary trigger; the autonomic nervous system plays a modulatory role. In the present study, we investigated the role of β 1 -adrenoceptors in the HF relationship between magnitude of heart rate and QT interval changes within discrete 10 s intervals (sorted into 5 bpm heart rate increments) and its implications for torsadogenic hERG blockers. EXPERIMENTAL APPROACHThe HF relationship was studied under conditions of autonomic blockade with atenolol (β 1 -adrenoceptor blocker) in the absence or presence of five hERG blockers in beagle dogs. In total, the effects of 14 hERG blockers on the HF relationship were investigated. KEY RESULTSAll the torsadogenic hERG blockers tested caused a vertical shift in the HF relationship, while hERG blockers associated with a low risk of Torsades de Pointes did not cause any vertical shift. Atenolol completely prevented the effects four torsadogenic agents (quinidine, thioridazine, risperidone and terfenadine) on the HF relationship, but only partially reduced those of dofetilide, leading to the characterization of two types of torsadogenic agent. CONCLUSIONS AND IMPLICATIONSAnalysis of the vertical shift in the HF relationship demonstrated that signs of transient sympathetic activation during HF oscillations in the presence of torsadogenic hERG blockers are mediated by β 1 -adrenoceptors. We suggest the HF relationship as a new biomarker for assessing Torsades de pointes liability, with potential implications in both preclinical studies and the clinic. AbbreviationsAPD, action potential duration; BBB, bundle branch block; BVR, beat-to-beat variability of ventricular repolarisation; HF, high frequency; HR, heart rate; STV QT , short term QT interval variability; TdP, Torsades de Pointes BJP British Journal of Pharmacology

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Section: Discussionmentioning

confidence: 52%

The high frequency relationship: implications for torsadogenic hERG blockers

Champéroux¹,

Guennec

Judé³

et al. 2016

British J Pharmacology

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“…This investigation studied the effects of acute bradycardia and may be less clinically relevant than animal models of chronic bradycardia where considerable tissue remodeling occurs (20,58,59). The study focused on the epicardium and did not investigate SCR from different regions of the ventricles.…”

Section: Discussionmentioning

confidence: 99%

Bradycardia alters Ca²⁺dynamics enhancing dispersion of repolarization and arrhythmia risk

Kim

Němec

Papp

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Kim JJ, Němec J, Papp R, Strongin R, Abramson JJ, Salama G. Bradycardia alters Ca 2ϩ dynamics enhancing dispersion of repolarization and arrhythmia risk. Am J Physiol Heart Circ Physiol 304: H848 -H860, 2013. First published January 11, 2013; doi:10.1152/ajpheart.00787.2012.-Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca 2ϩ transients and APs were measured optically from Langendorff rabbit hearts at high (150 ϫ 150 m 2 ) or low (1.5 ϫ 1.5 cm 2 ) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR ϭ 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant f¡s ϭ 48 Ϯ 9.2 s) and caused a secondary Ca 2ϩ release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 Ϯ 9.7 ms after the Ca 2ϩ transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca 2ϩ release events leading to subcellular Ca 2ϩ waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation (P Ͻ 0.01, n ϭ 5), enhanced DOR (r ϭ 0.9277 Ϯ 0.03, n ϭ 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening (P Ͻ 0.05, n ϭ 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)propan-1-one (K201; 1 M), suppressed SCR and reduced APD at the base, thereby reducing DOR (P Ͻ 0.02, n ϭ 5). Ventricular ectopy induced by bradycardia (n ϭ 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca 2ϩ channel protein (Cav1.2␣), Na ϩ -Ca 2ϩ exchange (NCX1), voltage-gated Na ϩ channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca 2ϩ ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations. action potential adaptation; arrhythmia; bradycardia; optical mapping; secondary Ca 2ϩ release BRADYCARDIA, DEFINED AS heart rate (HR) Ͻ 60 beats/min in adult humans (12), is usually a normal adaptive response to conditions of low metabolic demand, such as rest and sleep. Bradycardia due to pathological conditions, e.g., sick sinus syndrome, atrioventricular (AV) nodal disease, or conduction system disease, is common in clinical practice and frequently causes symptoms because of inappropriately low cardiac output. Less frequently, profound bradycardia, usuall...

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“…Heart rate corrected QT values were calculated using the formula especially developed for this particular animal model: QT C = QT ‒ 0.175(RR ‒ 300) . Endocardial LV monophasic action potential durations were measured semi‐automatically with a custom made Matlab application (Mathworks, Natick, USA) at 80% repolarization (LVMAP80) . Beat‐to‐beat variability of repolarization (BVR) was quantified as short‐term variability (STV) from LVMAPD80 of at least 30 consecutive beats as described previously .…”

Section: Methodsmentioning

confidence: 99%

AV‐Block and Conduction Slowing Prevail Over TdP Arrhythmias in the Methoxamine‐Sensitized Pro‐Arrhythmic Rabbit Model

Varkevisser

Vos

Beekman

et al. 2014

Cardiovasc electrophysiol

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

Abstract: 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.

Cited by 27 publications

References 27 publications

The high frequency relationship: implications for torsadogenic hERG blockers

The high frequency relationship: implications for torsadogenic hERG blockers

Bradycardia alters Ca²⁺dynamics enhancing dispersion of repolarization and arrhythmia risk

AV‐Block and Conduction Slowing Prevail Over TdP Arrhythmias in the Methoxamine‐Sensitized Pro‐Arrhythmic Rabbit Model

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

Abstract: 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.

Cited by 27 publications

References 27 publications

The high frequency relationship: implications for torsadogenic hERG blockers

The high frequency relationship: implications for torsadogenic hERG blockers

Bradycardia alters Ca2+dynamics enhancing dispersion of repolarization and arrhythmia risk

AV‐Block and Conduction Slowing Prevail Over TdP Arrhythmias in the Methoxamine‐Sensitized Pro‐Arrhythmic Rabbit Model

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Bradycardia alters Ca²⁺dynamics enhancing dispersion of repolarization and arrhythmia risk