Editorial to PBMB 2016 7

Editorial to PBMB_2016_7

"Disturbances of Cardiac Wavelength and Repolarization Precede Torsade de Pointes and Ventricular Fibrillation InLangendorff 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

1Department of Cardiology and Angiology I, University Heart CenterFreiburg – Bad Krozingen, Medical Center – University of Freiburg, Germany;

2Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg– Bad Krozingen, Medical Center – University of Freiburg, Germany

3Faculty of Medicine, University of Freiburg, Germany

4Cardiac Biophysics and Systems Biology, National Heart and Lung Institute, London, UK

* a quote, variably attributed to Mark Twain, Niels Bohr, Robert Storm Petersen, Yogi Berra, and others.

Reliable preclinical safety testingof 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 parameterin 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 combinedintegrative 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 delayedrepolarization as a cause of Torsade de Pointes (TdP), a potentially lethal ventricular tachycardia. This is an exceedingly rare event, and may occur as infrequentlyas 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 markershave 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], reverse-rate 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 beenproposedto increase the performance of ex vivowhole 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 acombination of various electrical markers outperforms any single parameter [Hondeghem PBMB 2016]. He adds another aspectto the pro-arrhythmia score (-TRIaD) – cardiac wavelength that is determined by conduction velocity and effective refractory period– to further enhance prediction ofdrug-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 bescreened for HERG/IKr-blocking properties and potential pro-arrhythmia in a combined, integrativeex vivo and in vivoapproach atan early stage of drug development [ICH S7B safety guideline 2005]. The rabbit is one of the more suitable preclinical modelspeciesfor 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 appearparticularly prone to drug-induced QT prolongation and TdPmay 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 enhancedif 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 specialissue of this journal that will appear in autumn of 2016. Themed to addressnon-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 functionto integrated modelling, covering themes from arteriosclerosis to arrhythmogenesis.

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