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Plays an Important Role in Drug-Induced Cardiac Arrhythmias: Beyond QT-Prolongation and Torsades De Pointes (Tdps)

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Plays an Important Role in Drug-Induced Cardiac Arrhythmias: Beyond QT-Prolongation and Torsades De Pointes (Tdps) Journal of Pharmacological and Toxicological Methods 68 (2013) 250–259 Contents lists available at ScienceDirect Journal of Pharmacological and Toxicological Methods journal homepage: www.elsevier.com/locate/jpharmtox Original article A new biomarker – index of Cardiac Electrophysiological Balance (iCEB) – plays an important role in drug-induced cardiac arrhythmias: beyond QT-prolongation and Torsades de Pointes (TdPs) Hua Rong Lu a,⁎, Gan-Xin Yan b, David J. Gallacher a a Janssen Research and Development, Janssen Pharmaceutica NV, Belgium b Main Line Health Heart Center and Lankenau Institute for Medical Research, Wynnewood, PA, USA article info abstract Article history: Introduction: In the present study, we investigated whether a new biomarker – index of cardiac electro- Received 9 November 2012 physiological balance (iCEB=QT/QRS) – could predict drug-induced cardiac arrhythmias (CAs), including ven- Accepted 5 January 2013 tricular tachycardia/ventricular fibrillation (VT/VF) and Torsades de Pointes (TdPs). Methods: The rabbit left ventricular arterially-perfused-wedge was used to investigate whether the simple iCEB measured from the Keywords: ECG is reflective of the more difficult measurement of λ (effective refractory period×conduction velocity) iCEB (index of Cardiac Electrophysiological for predicting CAs induced by a number of drugs. Results: Dofetilide concentration-dependently increased Balance) iCEB and λ, predicting potential risk of drug-induced incidence of early afterdepolarizations (EADs) starting Drug-induced arrhythmias μ μ μ μ QRS at 0.01 M. Digoxin (1 and 5 M), encainide (5 and 20 M) and propoxyphene (10 and 100 M) markedly re- QT duced both iCEB and λ, predicting their ability to induce non-TdP-like VT/VF. At 10 μM, both NS1643 and VT/VF: ventricular tachycardia/fibrillation levcromakalim significantly decreased λ and iCEB, which was preceded with presence of non-TdP-like VT/VF. TdPs: Torsades de Pointes Isoprenaline (0.05 to 0.5 μM) significantly reduced both λ and iCEB, which was associated with a high incidence of non-TdP-like VT/VF in most preparations. Other biomarkers (i.e. transmural dispersion of T-wave and insta- bility of the QT interval) predicted only dofetilide-induced long QT and EADs, but did not predict drug-induced risk of non-TdP-like VT/VF. Discussion: Our data from 7 reference drugs of known pro-arrhythmic effects sug- gests that 1) this non-invasive iCEB predicts potential risk of drug-induced CAs beyond long QT and TdP; 2) iCEB is more useful than the current biomarkers (i.e. transmural dispersion and instability) in predicting poten- tial risks for drug-induced non-TdP-like VT/VF. © 2013 Elsevier Inc. All rights reserved. 1. Introduction use of a broad range of cardiovascular and non-cardiovascular drugs (Cubeddu, 2003; Pugsley, Authier, & Curtis, 2008; Shah, 2004). Cur- Drug-induced QT prolongation and the appearance of Torsade de rent and past established regulatory guidelines (CPMP/986/96 points Pointes (TdP) are recognized as a potential risk associated with the to consider document, 1997 and ICH S7B, 2005) recommend the con- duct of preclinical studies both in vivo and in vitro to detect drug- induced QT-interval prolongation and arrhythmogenic potential. The preclinical guidance was followed more recently by the ICH E14 rec- Abbreviations: BCL, Basic cycle lengths; CAST, Cardiac Arrhythmia Suppression ommendation for conducting thorough QT (TQT) investigations in Trial; CPMP, committee for proprietary medicinal products; CV, conduction velocity; early clinical trials (2005). Drug-induced long QT and its risk for TdP DMSO, dimethyl sulphoxide; EAD, early afterdepolarization; ECG, electrocardiogram; are now well known, because in recent years, extensive progress has λ, lambda; ERP, effective refractory period; E14, ICH Harmonized Tripartite Guideline E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Poten- been made in studying the congenital long QT syndromes (Roden, tial for Non-Antiarrhythmic Drugs; hERG, human ether-à-go-go-related gene; ICH, The 2004), and also different screening strategies for detecting drug- International Conference on Harmonisation of Technical Requirements for Registration induced TdP have been evaluated following the release of CPMP/ of Pharmaceuticals for Human Use; iCEB, index of Cardiac Electrophysiological Balance; 986/96 in 1997. I , the rapidly activating delayed rectifier potassium current; I , the slowly activating Kr Ks However, cardiovascular safety in general is still the major cause of component of delayed rectifier potassium current; INa, sodium current; MAP, mono- phasic action potential; TdPs, Torsades de Pointes; TDR, maximal transmural disper- drug attrition in early drug development and of drug withdrawal from sion of repolarization; Tp-Te, T wave peak-Twave end (measurement of transmural the market (Laverty et al., 2011). In some cases, the identification of dispersion); VF, ventricular fibrillation; VT, ventricular tachycardia. cardiovascular risks is neither detected in earlier clinical trials nor ⁎ Corresponding author at: Safety Pharmacology Research, Translational Sciences, deemed to be biologically or clinically significant until the new medi- Janssen Research and Development, Janssen Pharmaceutica NV, Belgium, B-2340 Beerse,Belgium.Tel.:+3214602215;fax:+3214605839. cines are given to large patient populations for a long period on the E-mail address: [email protected] (H.R. Lu). market (Psaty & Furberg, 2007; Laverty et al., 2011; Redfern et al., 1056-8719/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.vascn.2013.01.003 H.R. Lu et al. / Journal of Pharmacological and Toxicological Methods 68 (2013) 250–259 251 2010; Redfern & Valentin, 2011). These cardiovascular risks can lead In the present study, we used seven reference drugs, which are to limitations in the use of the medicine, or to drug withdrawal, and known to induce different types of cardiac effects and arrhythmias, can be caused not only by drug-induced long QT and TdP, but also by in order to investigate whether: 1). iCEB (ratio of QT/QRS) generally other factors (Heist & Ruskin, 2010; Shah, 2010). With the exception reflects the classic λ (ERPxCV); 2). iCEB can be used as a simple, of patients with genetic hERG defects, little is known about the impli- cost-effective, new and easily measured non-invasive biomarker to cations of QT-shortening caused by drugs (Lu, Hermans, & Gallacher, predict drug-induced cardiac arrhythmias beyond TdP, and 3). this 2012; Shah, 2010) or slowing of cardiac conduction time (widening new biomarker (iCEB) is better than the currently-used biomarkers of QRS) (Gintant, Gallacher, & Pugsley, 2011; Harmer, Valentin, & [i.e. transmural dispersion of T wave (Anttonen, Vaananen, Junttila, Pollard, 2011; Lu et al., 2010; Madias, 2008). The Cardiac Arrhythmia Huikuri, & Viitasalo, 2008; Antzelevitch et al., 2007; Liu et al., 2006; Suppression Trial (CAST, 1989)showedthatflecainide and encainide Sicouri, Moro, Litovsky, Elizari, & Antzelevitch, 1997; Yan & [Class Ic antiarrhythmic, sodium current (INa) blocking agents] were asso- Antzelevitch, 1999) and instability or variability of the QT interval ciated with an increased incidence of sudden cardiac death in (Jacobson, Carlsson, & Duke, 2011; Thomsen et al., 2004; Van der post-infarction patients (Sellers & DiMacro, 1984; Echt et al., 1991). Linde et al., 2005)] in the isolated arterially perfused rabbit ventric- Some published papers show that there are large numbers of drugs ular wedge preparation. which block INa current and could have the propensity to induce cardiac arrhythmias (Gintant et al., 2011; Harmer et al., 2011; Lu et al., 2010). Moreover, some drugs that shorten the QT-interval could also have the 2. Methods potential to induce non-TdP-like VT/VF (VT: ventricular tachycardia; VF: ventricular fibrillation) (Lu et al., 2008). Since it is difficult to capture QT 2.1. Arterially perfused rabbit left ventricular wedge preparations shortening in the setting of the associated fatal arrhythmia (VF), due to lack of 24 h holter monitoring data, and to capture a slowing down of The use of animals in this study was approved by the Institutional conduction associated with non-TdP-like VT/VF, details concerning Animal Care and Use Committee (IACUC) at the Lankenau Institute for drug-induced short QT interval and slowing of conduction are limited. Medical Research. Indeed, the present ICH S7B guideline (Food and Drug Administration, The methods used for surgical preparation, isolation, perfusion, HHS, 2005) does not specifically address the potential for drug- and recording of transmembrane activity from the arterially perfused induced slowing of conduction (QRS widening), acquired short QT, ventricular wedge preparation from male and female rabbits (New and their potential for the development of fatal arrhythmias. Therefore, Zealand white weighing 2.5 to 3 kg), as well as the viability and elec- the currently-applied biomarkers (e.g. instability of QT and transmural trical stability of the preparation, have been described in previous dispersion of repolarization-T wave: TDR) may not be adequate to studies (Yan et al., 2001, Yan, Shimizu, & Antzelevitch, 1998; Liu et detect all types of drug-induced cardiac arrhythmias. al., 2006). Briefly, rabbits were anti-coagulated with heparin and Therefore, in the present study, we would like to introduce a new and anesthetized by intramuscular injection of xylazine (5 mg/kg) and in- non-invasive
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