Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts.

British Journal of Pharmacology (2008) 154, 1528–1537 & 2008 Nature Publishing Group All rights reserved 0007– 1188/08 $30.00 www.brjpharmacol.org REVIEW Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts A Sugiyama Department of Pharmacology, Yamanashi Research Center of Clinical Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan As an increasing number of non-cardiac drugs have been reported to cause QT interval prolongation and torsades de pointes (TdP), we extensively studied the utility of atrioventricular (AV) block animals as a model to predict their torsadogenic action in human. The present review highlights such in vivo proarrhythmia models. In the case of the canine model, test substances were administered p.o. at conscious state 44 weeks after the induction of AV block, with subsequent Holter ECG monitoring to evaluate drug effects. Control AV block dogs (no pharmacological treatment) survive for several years without TdP attack. For pharmacologically treated dogs, drugs were identified as high, low or no risk. High-risk drugs induced TdP at 1–3 times the therapeutic dose. Low-risk drugs did not induce TdP at this dose range, but induced it at higher doses. No-risk drugs never induced TdP at any dose tested. Electrophysiological, anatomical histological and biochemical adaptations against persistent bradycardia-induced chronic heart failure were observed in AV block dogs. Recently, we have developed another highly sensitive proarrhythmia model using a chronic AV block cynomolgus monkey, which possesses essentially the same pathophysiological adaptations and drug responses as those demonstrated in the canine model. As a common remodelling process leading to a diminished repolarization reserve may present in patients who experience drug-induced TdP and in the AV block animals, the in vivo proarrhythmia models described in this review may be useful for predicting the risk of pharmacologically induced TdP in humans. British Journal of Pharmacology (2008) 154, 1528–1537; doi:10.1038/bjp.2008.240; published online 16 June 2008 Keywords: chronic atrioventricular block; QT interval prolongation; torsades de pointes; ECG; repolarization reserve Abbreviations: AV, atrioventricular; ERP, effective refractory period; MAP, monophasic action potential; IKr, a rapid component of delayed rectifier K þ currents; TdP, torsades de pointes An increasing number of non-cardiac drugs have been reported to delay cardiac repolarization process through inhibition of a rapid component of delayed rectifier K þ currents (IKr) in the heart, occasionally causing torsades de pointes (TdP) in some patients, although these drugs did not show pronounced QT interval prolongation during the preclinical animal experiments or clinical studies (Roden, 2005; Thomsen et al., 2006b). This issue has been identified as a serious public health problem, which attracted attention from the clinicians, pharmaceutical companies as well as drug regulatory authorities. In this article, we focus on (1) in vivo mechanism(s) of the drug-induced QT interval prolon- Correspondence: Dr A Sugiyama, Department of Pharmacology, Yamanashi Research Center of Clinical Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan. E-mail: Received 27 February 2008; revised 6 May 2008; accepted 20 May 2008; published online 16 June 2008 gation, leading to the onset of TdP, (2) utility and limitation of current animal models in predicting the risk of pharmacologically induced TdP in humans and (3) comparison of these animal models with existing in vitro and in vivo proarrhythmia models. Onset mechanisms of TdP QT interval prolongation by drugs that can inhibit IKr usually delays phase 3 repolarization, leading to increased electrical vulnerability of the ventricles. This can include spatial dispersion of repolarization (Volders et al., 1998; Vos et al., 1998; Sugiyama and Hashimoto, 2002; Sugiyama et al., 2002a; Belardinelli et al., 2003), as shown in Figure 1. Also, QT interval prolongation by IKr blockers often complicates temporal dispersion of repolarization, leading to the onset of early afterdepolarizations and R on T type premature ventricular contractions, which trigger TdP in the presence of proarrhythmic substrates (Volders et al., 1998; Vos et al., In vivo proarrhythmia models A Sugiyama Figure 1 Onset mechanisms of TdP. 1529 2004a; Sugiyama and Hashimoto, 1998; Usui et al., 1998; Satoh et al., 1999, 2000a–c, 2004, 2005; Chiba et al., 2000, 2004a, b; Shiina et al., 2000; Takahara et al., 2000, 2003a, b, 2004a, 2005b; Yoneyama et al., 2002; Yoshida et al., 2002a). On the other hand, both high-risk human patients and chronic atrioventricular (AV) block animals have limited repolarization reserve and elevated inward calcium current; thus, they are most susceptible to drug-induced QT interval prolongation and subsequent TdP (Chiba et al., 2000, 2004a; Sugiyama et al., 2002c, 2003; Yoshida et al., 2002b; Satoh et al., 2004; Takahara et al., 2004b, 2006c). In other words, most of the drugs with IKr-blocking activity do not show pronounced QT interval prolongation in a patient with normal repolarization reserve. Utility and limitation of the halothane-anaesthetized canine model Figure 2 Typical tracing of drug-induced torsades de pointes (TdP) in patients taking antidepressant sulpiride. Significant QT interval prolongation would provide the increase of electrical vulnerability (substrate) and induce the R on T type premature ventricular contraction (PVC, trigger), leading to an onset of TdP. 1998; Sugiyama and Hashimoto, 2002; Sugiyama et al., 2002a; Belardinelli et al., 2003). As depicted in Figure 2, QT interval prolongation can provide proarrhythmic substrates and triggers in the heart, leading to the onset of TdP. This concept explains the difference between drug-induced QT interval prolongation and the onset of TdP; namely, QT interval prolongation is never lethal in and of itself, but TdP can be lethal. Role of reduced repolarization reserve in the onset of drug-induced QT interval prolongation Excessive QT interval prolongation by IKr blockers is thought to occur only in patients with reduced repolarization reserve (Roden, 2005). To better understand the concept of repolarization reserve, we evaluated the ability of the animal models and human data for predicting the onset of drug-induced QT interval prolongation. As summarized in Figure 3, conscious animal models usually have more repolarization reserve than healthy human volunteers, which may make the models less sensitive for detecting drug-induced QT interval prolongation (Sugiyama and Hashimoto, 2002; Sakaguchi et al., 2005; Takahara et al., 2005a, b, 2006b; Chiba et al., 2006). The extent of repolarization is (...truncated)