Download Editorial to PBMB_2016_7_Hondeghem-Final

Editorial to PBMB_2016_7
"Disturbances of Cardiac Wavelength and Repolarization Precede Torsade de Pointes and
Ventricular Fibrillation In Langendorff Perfused Rabbit hearts" by Luc Hondeghem
It is difficult to make predictions, especially about the future:* thoughts about forecasting
cardiotoxicity of pharmacological interventions
Katja E. Odening1,2,3 MD; Peter Kohl2,3,4 MD PhD
Department of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen,
Medical Center – University of Freiburg, Germany;
2
Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg – Bad
Krozingen, Medical Center – University of Freiburg, Germany
3
Faculty of Medicine, University of Freiburg, Germany
4
Cardiac Biophysics and Systems Biology, National Heart and Lung Institute, London, UK
1
* a quote, variably attributed to Mark Twain, Niels Bohr, Robert Storm Petersen, Yogi Berra, and others.
Reliable preclinical safety testing of new compounds in general, and assessment of potential
pro-arrhythmic properties in particular, are of the utmost importance yet loaded with challenges.
To date no single electrical surrogate parameter in patients, and no single cellular, tissue or
whole animal model, including computer simulations, enables reliable clinical risk prediction
[Haverkamp et al. 2000; Mirams et al. 2012]. Therefore, potential new drugs are evaluated by a
combined integrative approach, using several preclinical test systems [ICH S7B safety guideline
2005], in a bid that focusses to a large extent on the avoidance of false-negative risk prediction.
This comes at significant cost to the drug industry: the development of a drug takes more than
10 years, out of those that enter clinical trials only 12 % turn into an approved (revenue
generating) medicine, and if one divides the overall R&D investment by the number of drugs
that make it to market, this is now in the order of USD 2.5 billion [Pharma-2015]. This highlights
the importance of predicative pre-clinical assessment of lead compounds.
Cardiac safety pharmacology has been dominated, perhaps overly so, by concerns about
delayed repolarization as a cause of Torsade de Pointes (TdP), a potentially lethal ventricular
tachycardia. This is an exceedingly rare event, and may occur as infrequently as once in every
10 000 patient-years of exposure to a compound [Yap et al. 2003]. However, due to the
potentially lethal character of this arrhythmia, indications of ‘torsadogenicity’ generally preclude
marketing. Preclinical measurement of drug-induced prolongation of action potential duration
(APD) or of QT interval duration in the ECG as surrogate markers have not achieved a sufficient
sensitivity for reliable prediction of pro-arrhythmic effects of drugs [Hondeghem et al. 2001;
Milberg et al. 2002]. Therefore, additional parameters, such as triangulation of action potential
shape (APD90-30) indicating slowing of phase-3-repolarization [Hondeghem et al. 2001], reverserate dependence [Hondeghem and Hoffmann 2003], ventricular rate adaptation [Green et al.
2011], spatial APD dispersion [Antzelevitch 2008], and temporal beat-to-beat APD/QT variability
[Jacobsen et al. 2011] have been proposed to increase the performance of ex vivo whole heart
assays for the detection of drug-induced pro-arrhythmia.
In this issue, Luc Hondeghem, who pioneered the TRIaD score (disturbance of Triangulation,
Reverse use dependence, Instability of repolarization, Dispersion of repolarization) for
combined assessment of various factors indicative of increased pro-arrhythmia [Hondeghem et
al., 2001], provides further evidence that a combination of various electrical markers
outperforms any single parameter [Hondeghem PBMB 2016]. He adds another aspect to the
pro-arrhythmia score (-TRIaD) – cardiac wavelength that is determined by conduction velocity
and effective refractory period – to further enhance prediction of drug-induced TdP and
illustrates its utility in isolated rabbit heart models.
This is in keeping with current safety pharmaceutical guidelines, according to which all novel
candidate drugs have to be screened for HERG/IKr-blocking properties and potential proarrhythmia in a combined, integrative ex vivo and in vivo approach at an early stage of drug
development [ICH S7B safety guideline 2005]. The rabbit is one of the more suitable preclinical
model species for investigation of drug-induced pro-arrhythmia [Valentin et al. 2004], since it
demonstrates similarities to human (patho-) physiology in ion currents determining cardiac
electrical characteristics, action potential properties, intracellular ion concentrations, cardiac
responses to drugs and ischemia, and regional contractile and diastolic behaviour [Galinanes
and Hearse 1990; Nerbonne 2000; Panfilov 2006; Jung et al. 2012].
Human subjects that appear particularly prone to drug-induced QT prolongation and TdP may
harbour an increased susceptibility due to single nucleotide polymorphisms or rare variants in
genes related to the so-called long QT syndrome (LQT), including KCNQ1, KCNH2, SCN5A,
KCNE1, KCNE2, KCNJ2, KCNJ5, and AKAP9 [Yang et al. 2002; Kannankeril et al. 2005;
Weeke et al. 2014]. The sensitivity to detect pro-arrhythmia and the capability to translate
experimental findings into clinical practice may therefore be further enhanced if pre-clinical
testing on rabbit hearts utilized models harbouring the above risk factors. Indeed, rabbit models
with a similarly impaired repolarization reserve – such as drug-induced LQT or transgenic
rabbits models of LQT1, LQT2, or LQT5 – may outperform wild-type rabbit hearts in the
detection of drug-related pro-arrhythmia [Odening et al. 2008, Ziupa et al. 2014, Major et al.
2016].
The utility of experimental and computational models of the rabbit heart for cardiovascular
research will be the focus of a forthcoming special issue of this journal that will appear in
autumn of 2016. Themed to address non-murine (lagomorph) heart models, it will include
papers on (patho-) physiological research into rabbit cardiac structure and electro-mechanical
function, including novel insight from transgenic rabbit models, and highlight important insights
gained with these model systems from ion channel function to integrated modelling, covering
themes from arteriosclerosis to arrhythmogenesis.
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