Biomarkers and endogenous determinants of dofetilide-induced torsades de pointes in α 1-adrenoceptor-stimulated, anaesthetized rabbits

Attila S. Farkas, L. Rudas, Péter Makra, Norbert Csík, I. Leprán, T. Forster, M. Csanády, J. Papp, A. Varró, A. Farkas

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Abstract

BACKGROUND AND PURPOSE: Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug-induced TdP. EXPERIMENTAL APPROACH: We studied dofetilide-induced TdP in pentobarbital-anaesthetized, phenylephrine-sensitized rabbits, seeking biomarkers that discriminated between the animals that experienced TdP ('TdP+' animals) and those that did not ('TdP+' animals). As novel variables, the beat-to-beat variability and instability of ECG intervals were measured at preset times, irrespective of whether or not hearts were in stable sinus rhythm ('absolute' variability and instability). Autonomic activity was also determined. KEY RESULTS: Dofetilide delayed repolarization and induced arrhythmias prior to TdP. The variability of the coupling interval and shape of arrhythmic beats before TdP were significantly greater in the 'TdP+' group than in the 'TdP-' group. Accordingly, the 'absolute' variability and instability of the ECG intervals were significantly elevated in the 'TdP+' group. Phenylephrine increased significantly the up-baroreflex sensitivity in the 'TdP+' group before dofetilide administration. CONCLUSIONS AND IMPLICATIONS: 'Preceding' arrhythmias have characteristics that permit prediction of TdP occurrence: the more chaotic the ventricular rhythm, the greater the probability of TdP initiation. This suggests that complexity of the arrhythmic beats may play an important mechanistic role in TdP genesis. The electrical instability quantified by the novel 'absolute' variability and instability parameters correlates with the probability of TdP occurrence. Baroreflex may contribute to TdP genesis in vivo.

Original languageEnglish
Pages (from-to)1477-1495
Number of pages19
JournalBritish Journal of Pharmacology
Volume161
Issue number7
DOIs
Publication statusPublished - Dec 2010

Fingerprint

Torsades de Pointes
Adrenergic Receptors
Biomarkers
Rabbits
dofetilide
Baroreflex
Phenylephrine
Cardiac Arrhythmias
Electrocardiography

Keywords

  • α -adrenoceptor stimulation
  • Absolute beat-to-beat variability and instability
  • Anaesthetized rabbit
  • Baroreflex
  • Biomarkers
  • Coupling interval
  • Dofetilide
  • Phenylephrine
  • Preceding arrhythmias
  • Torsades de pointes

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{fe50e48ec78d41d1a27c7463762f5830,
title = "Biomarkers and endogenous determinants of dofetilide-induced torsades de pointes in α 1-adrenoceptor-stimulated, anaesthetized rabbits",
abstract = "BACKGROUND AND PURPOSE: Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug-induced TdP. EXPERIMENTAL APPROACH: We studied dofetilide-induced TdP in pentobarbital-anaesthetized, phenylephrine-sensitized rabbits, seeking biomarkers that discriminated between the animals that experienced TdP ('TdP+' animals) and those that did not ('TdP+' animals). As novel variables, the beat-to-beat variability and instability of ECG intervals were measured at preset times, irrespective of whether or not hearts were in stable sinus rhythm ('absolute' variability and instability). Autonomic activity was also determined. KEY RESULTS: Dofetilide delayed repolarization and induced arrhythmias prior to TdP. The variability of the coupling interval and shape of arrhythmic beats before TdP were significantly greater in the 'TdP+' group than in the 'TdP-' group. Accordingly, the 'absolute' variability and instability of the ECG intervals were significantly elevated in the 'TdP+' group. Phenylephrine increased significantly the up-baroreflex sensitivity in the 'TdP+' group before dofetilide administration. CONCLUSIONS AND IMPLICATIONS: 'Preceding' arrhythmias have characteristics that permit prediction of TdP occurrence: the more chaotic the ventricular rhythm, the greater the probability of TdP initiation. This suggests that complexity of the arrhythmic beats may play an important mechanistic role in TdP genesis. The electrical instability quantified by the novel 'absolute' variability and instability parameters correlates with the probability of TdP occurrence. Baroreflex may contribute to TdP genesis in vivo.",
keywords = "α -adrenoceptor stimulation, Absolute beat-to-beat variability and instability, Anaesthetized rabbit, Baroreflex, Biomarkers, Coupling interval, Dofetilide, Phenylephrine, Preceding arrhythmias, Torsades de pointes",
author = "Farkas, {Attila S.} and L. Rudas and P{\'e}ter Makra and Norbert Cs{\'i}k and I. Lepr{\'a}n and T. Forster and M. Csan{\'a}dy and J. Papp and A. Varr{\'o} and A. Farkas",
year = "2010",
month = "12",
doi = "10.1111/j.1476-5381.2010.00965.x",
language = "English",
volume = "161",
pages = "1477--1495",
journal = "British Journal of Pharmacology",
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publisher = "Wiley-Blackwell",
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TY - JOUR

T1 - Biomarkers and endogenous determinants of dofetilide-induced torsades de pointes in α 1-adrenoceptor-stimulated, anaesthetized rabbits

AU - Farkas, Attila S.

AU - Rudas, L.

AU - Makra, Péter

AU - Csík, Norbert

AU - Leprán, I.

AU - Forster, T.

AU - Csanády, M.

AU - Papp, J.

AU - Varró, A.

AU - Farkas, A.

PY - 2010/12

Y1 - 2010/12

N2 - BACKGROUND AND PURPOSE: Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug-induced TdP. EXPERIMENTAL APPROACH: We studied dofetilide-induced TdP in pentobarbital-anaesthetized, phenylephrine-sensitized rabbits, seeking biomarkers that discriminated between the animals that experienced TdP ('TdP+' animals) and those that did not ('TdP+' animals). As novel variables, the beat-to-beat variability and instability of ECG intervals were measured at preset times, irrespective of whether or not hearts were in stable sinus rhythm ('absolute' variability and instability). Autonomic activity was also determined. KEY RESULTS: Dofetilide delayed repolarization and induced arrhythmias prior to TdP. The variability of the coupling interval and shape of arrhythmic beats before TdP were significantly greater in the 'TdP+' group than in the 'TdP-' group. Accordingly, the 'absolute' variability and instability of the ECG intervals were significantly elevated in the 'TdP+' group. Phenylephrine increased significantly the up-baroreflex sensitivity in the 'TdP+' group before dofetilide administration. CONCLUSIONS AND IMPLICATIONS: 'Preceding' arrhythmias have characteristics that permit prediction of TdP occurrence: the more chaotic the ventricular rhythm, the greater the probability of TdP initiation. This suggests that complexity of the arrhythmic beats may play an important mechanistic role in TdP genesis. The electrical instability quantified by the novel 'absolute' variability and instability parameters correlates with the probability of TdP occurrence. Baroreflex may contribute to TdP genesis in vivo.

AB - BACKGROUND AND PURPOSE: Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug-induced TdP. EXPERIMENTAL APPROACH: We studied dofetilide-induced TdP in pentobarbital-anaesthetized, phenylephrine-sensitized rabbits, seeking biomarkers that discriminated between the animals that experienced TdP ('TdP+' animals) and those that did not ('TdP+' animals). As novel variables, the beat-to-beat variability and instability of ECG intervals were measured at preset times, irrespective of whether or not hearts were in stable sinus rhythm ('absolute' variability and instability). Autonomic activity was also determined. KEY RESULTS: Dofetilide delayed repolarization and induced arrhythmias prior to TdP. The variability of the coupling interval and shape of arrhythmic beats before TdP were significantly greater in the 'TdP+' group than in the 'TdP-' group. Accordingly, the 'absolute' variability and instability of the ECG intervals were significantly elevated in the 'TdP+' group. Phenylephrine increased significantly the up-baroreflex sensitivity in the 'TdP+' group before dofetilide administration. CONCLUSIONS AND IMPLICATIONS: 'Preceding' arrhythmias have characteristics that permit prediction of TdP occurrence: the more chaotic the ventricular rhythm, the greater the probability of TdP initiation. This suggests that complexity of the arrhythmic beats may play an important mechanistic role in TdP genesis. The electrical instability quantified by the novel 'absolute' variability and instability parameters correlates with the probability of TdP occurrence. Baroreflex may contribute to TdP genesis in vivo.

KW - α -adrenoceptor stimulation

KW - Absolute beat-to-beat variability and instability

KW - Anaesthetized rabbit

KW - Baroreflex

KW - Biomarkers

KW - Coupling interval

KW - Dofetilide

KW - Phenylephrine

KW - Preceding arrhythmias

KW - Torsades de pointes

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U2 - 10.1111/j.1476-5381.2010.00965.x

DO - 10.1111/j.1476-5381.2010.00965.x

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SP - 1477

EP - 1495

JO - British Journal of Pharmacology

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