Rabbit models as tools for preclinical cardiac electrophysiological safety testing: Importance of repolarization reserve

Research output: Article

8 Citations (Scopus)

Abstract

It is essential to more reliably assess the pro-arrhythmic liability of compounds in development. Current guidelines for pre-clinical and clinical testing of drug candidates advocate the use of healthy animals/tissues and healthy individuals and focus on the test compound's ability to block the hERG current and prolong cardiac ventricular repolarization. Also, pre-clinical safety tests utilize several species commonly used in cardiac electrophysiological studies. In this review, important species differences in cardiac ventricular repolarizing ion currents are considered, followed by the discussion on electrical remodeling associated with chronic cardiovascular diseases that leads to altered ion channel and transporter expression and densities in pathological settings. We argue that the choice of species strongly influences experimental outcome and extrapolation of results to human clinical settings. We suggest that based on cardiac cellular electrophysiology, the rabbit is a useful species for pharmacological pro-arrhythmic investigations. In addition to healthy animals and tissues, the use of animal models (e.g. those with impaired repolarization reserve) is suggested that more closely resemble subsets of patients exhibiting increased vulnerability towards the development of ventricular arrhythmias and sudden cardiac death.

Original languageEnglish
JournalProgress in Biophysics and Molecular Biology
DOIs
Publication statusAccepted/In press - jan. 26 2016

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Cardiac Electrophysiology
Atrial Remodeling
Rabbits
Safety
Sudden Cardiac Death
Ion Channels
Cardiac Arrhythmias
Chronic Disease
Cardiovascular Diseases
Animal Models
Pharmacology
Guidelines
Ions
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics

Cite this

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title = "Rabbit models as tools for preclinical cardiac electrophysiological safety testing: Importance of repolarization reserve",
abstract = "It is essential to more reliably assess the pro-arrhythmic liability of compounds in development. Current guidelines for pre-clinical and clinical testing of drug candidates advocate the use of healthy animals/tissues and healthy individuals and focus on the test compound's ability to block the hERG current and prolong cardiac ventricular repolarization. Also, pre-clinical safety tests utilize several species commonly used in cardiac electrophysiological studies. In this review, important species differences in cardiac ventricular repolarizing ion currents are considered, followed by the discussion on electrical remodeling associated with chronic cardiovascular diseases that leads to altered ion channel and transporter expression and densities in pathological settings. We argue that the choice of species strongly influences experimental outcome and extrapolation of results to human clinical settings. We suggest that based on cardiac cellular electrophysiology, the rabbit is a useful species for pharmacological pro-arrhythmic investigations. In addition to healthy animals and tissues, the use of animal models (e.g. those with impaired repolarization reserve) is suggested that more closely resemble subsets of patients exhibiting increased vulnerability towards the development of ventricular arrhythmias and sudden cardiac death.",
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AU - Baczkó, I.

AU - Jost, N.

AU - Virág, L.

AU - Bösze, Z.

AU - Varró, A.

PY - 2016/1/26

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N2 - It is essential to more reliably assess the pro-arrhythmic liability of compounds in development. Current guidelines for pre-clinical and clinical testing of drug candidates advocate the use of healthy animals/tissues and healthy individuals and focus on the test compound's ability to block the hERG current and prolong cardiac ventricular repolarization. Also, pre-clinical safety tests utilize several species commonly used in cardiac electrophysiological studies. In this review, important species differences in cardiac ventricular repolarizing ion currents are considered, followed by the discussion on electrical remodeling associated with chronic cardiovascular diseases that leads to altered ion channel and transporter expression and densities in pathological settings. We argue that the choice of species strongly influences experimental outcome and extrapolation of results to human clinical settings. We suggest that based on cardiac cellular electrophysiology, the rabbit is a useful species for pharmacological pro-arrhythmic investigations. In addition to healthy animals and tissues, the use of animal models (e.g. those with impaired repolarization reserve) is suggested that more closely resemble subsets of patients exhibiting increased vulnerability towards the development of ventricular arrhythmias and sudden cardiac death.

AB - It is essential to more reliably assess the pro-arrhythmic liability of compounds in development. Current guidelines for pre-clinical and clinical testing of drug candidates advocate the use of healthy animals/tissues and healthy individuals and focus on the test compound's ability to block the hERG current and prolong cardiac ventricular repolarization. Also, pre-clinical safety tests utilize several species commonly used in cardiac electrophysiological studies. In this review, important species differences in cardiac ventricular repolarizing ion currents are considered, followed by the discussion on electrical remodeling associated with chronic cardiovascular diseases that leads to altered ion channel and transporter expression and densities in pathological settings. We argue that the choice of species strongly influences experimental outcome and extrapolation of results to human clinical settings. We suggest that based on cardiac cellular electrophysiology, the rabbit is a useful species for pharmacological pro-arrhythmic investigations. In addition to healthy animals and tissues, the use of animal models (e.g. those with impaired repolarization reserve) is suggested that more closely resemble subsets of patients exhibiting increased vulnerability towards the development of ventricular arrhythmias and sudden cardiac death.

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