Short‐term variability in <scp>QT</scp> interval and ventricular arrhythmias induced by dofetilide are dependent on high‐frequency autonomic oscillations

Champéroux, Pascal; Thireau, Jérôme; Judé, Sébastien; Laigot-Barbé, C; Maurin, Anne; Sola, Marie Laure; Fowler, John; Richard, Serge; Guennec, J.-Y. Le

doi:10.1111/bph.13093

Cited by 17 publications

(23 citation statements)

References 41 publications

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“…The increased propensity for torsade de pointes upon dofetilide treatment could be partially accounted for by the increased beat‐to‐beat APD (and QT interval) variability, which fully complies with the TRIaD concept (see Section for discussion).…”

Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 56%

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

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In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K channel (dofetilide).

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Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 56%

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

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“…Alternatively, the autonomic nervous system has been reported to play a critical role in ventricular arrhythmia liability of drugs, causing QT prolongation through abnormalities in the restoration of the QT/RR relationship (Fossa, ). In a recent study, we showed that the autonomic high‐frequency (HF) oscillations in the amplitude of heart rate (HR) play a major role in beat‐to‐beat variability of ventricular repolarisation (BVR) and are one of the mechanisms responsible for dofetilide‐induced TdP (Champeroux et al , ). These HF oscillations result from alternate sequences of parasympathetic activation and deactivation occurring within a very short period of a few seconds (Pagani et al , ).…”

Section: Introductionmentioning

confidence: 99%

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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“…This is why the hERG assay is a regulatory test in drug development17. However, all drugs blocking the hERG channel are not systematically associated with TdP, suggesting that I KR blockade and QT prolongation are insufficient to trigger TdP18. However, the fact that some I KR inhibitors are torsadogenic has slowed the development of promising new drugs1920.…”

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confidence: 99%

Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?

Guennec¹,

Thireau²,

Ouillé³

et al. 2016

Sci Rep

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Safety pharmacology aims to predict rare side effects of new drugs. We explored whether rare pro-arrhythmic effects could be linked to the variability of the effects of these drugs on ion currents and whether taking into consideration this variability in computational models could help to better detect and predict cardiac side effects. For this purpose, we evaluated how intra- and inter-individual variability influences the effect of hERG inhibition on both the action potential duration and the occurrence of arrhythmias. Using two computer simulation models of human action potentials (endocardial and Purkinje cells), we analyzed the contribution of two biological parameters on the pro-arrhythmic effects of several hERG channel blockers: (i) spermine concentration, which varies with metabolic status, and (ii) L-type calcium conductance, which varies due to single nucleotide polymorphisms or mutations. By varying these parameters, we were able to induce arrhythmias in 1 out of 16 simulations although conventional modeling methods to detect pro-arrhythmic molecules failed. On the basis of our results, taking into consideration only 2 parameters subjected to intra- and inter-individual variability, we propose that in silico computer modeling may help to better define the risks of new drug candidates at early stages of pre-clinical development.

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Short‐term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high‐frequency autonomic oscillations

Cited by 17 publications

References 41 publications

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

The high frequency relationship: implications for torsadogenic hERG blockers

Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?

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