, Volume 70, Issue 5, pp 573–603

Minimizing Repolarization-Related Proarrhythmic Risk in Drug Development and Clinical Practice

Review Article


Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a major limitation to the development and use of new drugs. There are different types of drug-induced proarrhythmia, including long-QT syndrome (LQTS), short-QT syndrome and proarrhythmia related to Na+-channel blockade/conduction impairment. By far the most important form of proarrhythmia at present is drug-induced LQTS and its associated characteristic tachyarrhythmia, torsades de pointes (TdP). TdP arises when cellular action potentials (APs) are excessively prolonged, leading to arrhyth-mogenic afterdepolarizations, especially early afterdepolarizations (EADs), which trigger complex re-entry in a substrate involving increased transmural dispersion of repolarization. In vitro screening, increasingly involving high-throughput assays, is used to assess potential candidate molecules and eliminate potentially problematic structures at an early stage of development. The most commonly used screening assays assess drug block of the K+ current carried by human ether-à-go-go (hERG) subunits, corresponding to the rapid delayed-rectifier K+ channel, the overwhelmingly most common target of TdP-inducing drugs. In addition, the effects of drugs on AP duration or the in vivo equivalent, QT interval, are often assessed in animal models. Methods available for repolarization-related proarrhythmic risk assessment include in vitro (Langendorff-perfused rabbit or guinea pig hearts) and in vivo models (such as α-adrenoceptor-stimulated rabbits, rabbits with reduced repolarization reserve due to block of slow delayed-rectifier current, animals with chronic atrioventricular block or animals with cardiac remodelling caused by congestive heart failure). In silico modelling may be helpful for molecular design of non-hERG blocking candidates and for optimization of compound selection (at the molecular and pharmacological profile levels). Finally, clinical evaluation of effects on electrocardiographic intervals (particularly QT) and cardiac rhythm are often needed, both prior to drug approval and after successful introduction on the market (postmarketing surveillance). The successful avoidance of proarrhythmic complications is a shared responsibility of the innovative pharmaceutical industry, regulatory authorities, partners in the clinical drug development phase and practicing physicians. This paper reviews the principal forms of proarrhythmia and the methods that can be used to minimize the risk of proarrhythmia in drug development and clinical practice, with particular emphasis on the most common and problematic form, acquired LQTS.


  1. 1.
    Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics — 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119(3): 480–6PubMedCrossRefGoogle Scholar
  2. 2.
    Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006; 114(10): e385–484PubMedCrossRefGoogle Scholar
  3. 3.
    The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321(6): 406–12CrossRefGoogle Scholar
  4. 4.
    Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction: the SWORD Investigators (Survival With ORal d-Sotalol). Lancet 1996; 348(9019): 7–12PubMedCrossRefGoogle Scholar
  5. 5.
    Frey W. Weitere erfahrungen mit chinidin bei absoluter herzun-regelmäbigkeit. Wien Med Wschr 1918; 55: 849–53Google Scholar
  6. 6.
    Selzer A, Wray HW. Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 1964; 30: 17–26PubMedCrossRefGoogle Scholar
  7. 7.
    Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999; 354(9190): 1625–33PubMedCrossRefGoogle Scholar
  8. 8.
    Dessertenne F. Ventricular tachycardia with 2 variable opposing foci. Arch Mal Coeur Vaiss 1966; 59(2): 263–72PubMedGoogle Scholar
  9. 9.
    Zeltser D, Justo D, Halkin A, et al. Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug. J Am Coll Cardiol 2004; 44(1): 105–8PubMedCrossRefGoogle Scholar
  10. 10.
    Farkas A, Qureshi A, Curtis MJ. Inadequate ischaemia-selectivity limits the antiarrhythmic efficacy of mibefradil during regional ischaemia and reperfusion in the rat isolated perfused heart. Br J Pharmacol 1999; 128(1): 41–50PubMedCrossRefGoogle Scholar
  11. 11.
    Watanabe Y. Effects of calcium and sodium concentrations on atrioventricular conduction: experimental study in rabbit hearts with clinical implications on heart block and slow calcium channel blocking agent usage. Am Heart J 1981; 102(5): 883–91PubMedCrossRefGoogle Scholar
  12. 12.
    Oros A, Beekman JD, Vos MA. The canine model with chronic, complete atrio-ventricular block. Pharmacol Ther 2008; 119(2): 168–78PubMedCrossRefGoogle Scholar
  13. 13.
    Fenichel RR, Malik M, Antzelevitch C, et al. Drug-induced torsades de pointes and implications for drug development. J Cardiovasc Electrophysiol 2004; 15(4): 475–95PubMedCrossRefGoogle Scholar
  14. 14.
    Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications: report on a Policy Conference of the European Society of Cardiology. Cardiovasc Res 2000; 47(2): 219–33PubMedCrossRefGoogle Scholar
  15. 15.
    Carlsson L. The anaesthetised methoxamine-sensitised rabbit model of torsades de pointes. Pharmacol Ther 2008; 119(2): 160–7PubMedCrossRefGoogle Scholar
  16. 16.
    Roden DM, Anderson ME. Proarrhythmia. Handb Exp Pharmacol 2006; (171): 73–97Google Scholar
  17. 17.
    Sarapa N, Britto MR. Challenges of characterizing proar-rhythmic risk due to QTc prolongation induced by non-adjuvant anticancer agents. Expert Opin Drug Saf 2008; 7(3): 305–18PubMedCrossRefGoogle Scholar
  18. 18.
    Thomsen MB, Matz J, Volders PG, et al. Assessing the proarrhythmic potential of drugs: current status of models and surrogate parameters of torsades de pointes arrhythmias. Pharmacol Ther 2006; 112(1): 150–70PubMedCrossRefGoogle Scholar
  19. 19.
    International Conference on Harmonisation; guidance on S7B nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals; availability. Notice. Fed Regist 2005; 70(202): 61133–4Google Scholar
  20. 20.
    International Conference on Harmonisation; guidance on E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs; availability. Notice. Fed Regist 2005; 70(202): 61134–5Google Scholar
  21. 21.
    Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J 1957; 54(1): 59–68PubMedCrossRefGoogle Scholar
  22. 22.
    Romano C, Gemme G, Pongiglione R. Rare cardiac arrhythmias of the pediatric age: I, repetitive paroxysmal tachycardia. Minerva Pediatr 1963; 15: 1155–64PubMedGoogle Scholar
  23. 23.
    Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc 1964; 54: 103–6PubMedGoogle Scholar
  24. 24.
    Roden DM. Cellular basis of drug-induced torsades de pointes. Br J Pharmacol 2008; 154(7): 1502–7PubMedCrossRefGoogle Scholar
  25. 25.
    Shah RR, Hondeghem LM. Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart Rhythm 2005; 2(7): 758–72PubMedCrossRefGoogle Scholar
  26. 26.
    Jackman WM, Friday KJ, Anderson JL, et al. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988; 31(2): 115–72PubMedCrossRefGoogle Scholar
  27. 27.
    Belardinelli L, Antzelevitch C, Vos MA. Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol Sci 2003; 24(12): 619–25PubMedCrossRefGoogle Scholar
  28. 28.
    Sipido KR, Varro A, Eisner D. Sodium calcium exchange as a target for antiarrhythmic therapy. Handb Exp Pharmacol 2006; (171): 73–97Google Scholar
  29. 29.
    Gallacher DJ, Van de Water A, van der Linde H, et al. In vivo mechanisms precipitating torsades de pointes in a canine model of drug-induced long-QT1 syndrome. Cardiovasc Res 2007; 76(2): 247–56PubMedCrossRefGoogle Scholar
  30. 30.
    Ben Caref E, Boutjdir M, Himel HD, et al. Role of sub-endocardial Purkinje network in triggering torsade de pointes arrhythmia in experimental long QT syndrome. Europace 2008; 10(10): 1218–23PubMedCrossRefGoogle Scholar
  31. 31.
    Nattel S, Quantz MA. Pharmacological response of quinidine induced early afterdepolarisations in canine cardiac Purkinje fibres: insights into underlying ionic mechanisms. Cardiovasc Res 1988; 22(11): 808–17PubMedCrossRefGoogle Scholar
  32. 32.
    Tweedie D, O'Gara P, Harding SE, et al. The effect of alterations to action potential duration on beta-adrenoceptor-mediated aftercontractions in human and guinea-pig ventricular myocytes. J Mol Cell Cardiol 1997; 29(5): 1457–67PubMedCrossRefGoogle Scholar
  33. 33.
    Volders PG, Kulcsar A, Vos MA, et al. Similarities between early and delayed afterdepolarizations induced by isoproterenol in canine ventricular myocytes. Cardiovasc Res 1997; 34(2): 348–59PubMedCrossRefGoogle Scholar
  34. 34.
    Mazur A, Roden DM, Anderson ME. Systemic administration of calmodulin antagonist W-7 or protein kinase A inhibitor H-8 prevents torsade de pointes in rabbits. Circulation 1999; 100(24): 2437–42PubMedCrossRefGoogle Scholar
  35. 35.
    Farkas AS, Makra P, Csik N, et al. The role of the Na+/Ca2+ exchanger, I(Na) and I(CaL) in the genesis of dofetilide-induced torsades de pointes in isolated, AV-blocked rabbit hearts. Br J Pharmacol 2009; 156(6): 920–32PubMedCrossRefGoogle Scholar
  36. 36.
    Hamlin RL, Kijtawornrat A. Use of the rabbit with a failing heart to test for torsadogenicity. Pharmacol Ther 2008; 119(2): 179–85PubMedCrossRefGoogle Scholar
  37. 37.
    Zygmunt AC, Goodrow RJ, Antzelevitch C. I(NaCa) contributes to electrical heterogeneity within the canine ventricle. Am J Physiol Heart Circ Physiol 2000; 278(5): H1671–8PubMedGoogle Scholar
  38. 38.
    Milberg P, Pott C, Fink M, et al. Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3. Heart Rhythm 2008; 5(10): 1444–52PubMedCrossRefGoogle Scholar
  39. 39.
    Antzelevitch C. Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes. Europace 2007; 9 Suppl. 4: iv4–15PubMedCrossRefGoogle Scholar
  40. 40.
    Milberg P, Reinsch N, Wasmer K, et al. Transmural dispersion of repolarization as a key factor of arrhythmogenicity in a novel intact heart model of LQT3. Cardiovasc Res 2005; 65(2): 397–404PubMedCrossRefGoogle Scholar
  41. 41.
    Antzelevitch C. Drug-induced spatial dispersion of repolarization. Cardiol J 2008; 15(2): 100–21PubMedGoogle Scholar
  42. 42.
    Chen YJ, Hsieh MH, Chiou CW, et al. Electropharmacologic characteristics of ventricular proarrhythmia induced by ibutilide. J Cardiovasc Pharmacol 1999; 34(2): 237–47PubMedCrossRefGoogle Scholar
  43. 43.
    Haapalahti P, Viitasalo M, Perhonen M, et al. Electro-cardiographic interventricular dispersion of repolarization during autonomic adaptation in LQT1 subtype of long QT syndrome. Scand Cardiovasc J 2008; 42(2): 130–6PubMedCrossRefGoogle Scholar
  44. 44.
    Vos MA, Gorenek B, Verduyn SC, et al. Observations on the onset of torsade de pointes arrhythmias in the acquired long QT syndrome. Cardiovasc Res 2000; 48(3): 421–9PubMedCrossRefGoogle Scholar
  45. 45.
    Hondeghem LM, Carlsson L, Duker G. Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation 2001; 103(15): 2004–13PubMedCrossRefGoogle Scholar
  46. 46.
    Thomsen MB, Verduyn SC, Stengl M, et al. Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs. Circulation 2004; 110(16): 2453–9PubMedCrossRefGoogle Scholar
  47. 47.
    Hondeghem LM. Relative contributions of TRIaD and QT to proarrhythmia. J Cardiovasc Electrophysiol 2007; 18(6): 655–7PubMedCrossRefGoogle Scholar
  48. 48.
    Sicouri S, Glass A, Ferreiro M, et al. Transseptal dispersion of repolarization and its role in the development of torsade de pointes arrhythmias. J Cardiovasc Electrophysiol. Epub 2009 Nov 10Google Scholar
  49. 49.
    Kay GN, Plumb VJ, Arciniegas JG, et al. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol 1983; 2(5): 806–17PubMedCrossRefGoogle Scholar
  50. 50.
    Noda T, Shimizu W, Satomi K, et al. Classification and mechanism of torsade de pointes initiation in patients with congenital long QT syndrome. Eur Heart J 2004; 25(23): 2149–54PubMedCrossRefGoogle Scholar
  51. 51.
    El-Sherif N, Caref EB, Chinushi M, et al. Mechanism of arrhythmogenicity of the short-long cardiac sequence that precedes ventricular tachyarrhythmias in the long QT syndrome. J Am Coll Cardiol 1999; 33(5): 1415–23PubMedCrossRefGoogle Scholar
  52. 52.
    Liu J, Laurita KR. The mechanism of pause-induced torsade de pointes in long QT syndrome. J Cardiovasc Electrophysiol 2005; 16(9): 981–7PubMedCrossRefGoogle Scholar
  53. 53.
    El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol 2003; 18(1): 6–13PubMedCrossRefGoogle Scholar
  54. 54.
    El-Sherif N, Chinushi M, Caref EB, et al. Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long-QT syndrome: detailed analysis of ventricular tridimensional activation patterns. Circulation 1997; 96(12): 4392–9PubMedCrossRefGoogle Scholar
  55. 55.
    Johnson JN, Tester DJ, Perry J, et al. Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. Heart Rhythm 2008; 5(5): 704–9PubMedCrossRefGoogle Scholar
  56. 56.
    Seslar SP, Shepard SM, Berul CI. “Atrial torsades de pointes” in the long QT syndrome. J Interv Card Electrophysiol 2009; 24(2): 95–7PubMedCrossRefGoogle Scholar
  57. 57.
    Kirchhof P, Eckardt L, Franz MR, et al. Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. J Cardiovasc Electrophysiol 2003; 14(10): 1027–33PubMedCrossRefGoogle Scholar
  58. 58.
    Kirchhof P, Eckardt L, Monnig G, et al. A patient with “atrial torsades de pointes”. J Cardiovasc Electrophysiol 2000; 11(7): 806–11PubMedCrossRefGoogle Scholar
  59. 59.
    Stansfeld PJ, Sutcliffe MJ, Mitcheson JS. Molecular mechanisms for drug interactions with hERG that cause long QT syndrome. Expert Opin Drug Metab Toxicol 2006; 2(1): 81–94PubMedCrossRefGoogle Scholar
  60. 60.
    Carlsson L. In vitro and in vivo models for testing arrhy-thmogenesis in drugs. J Intern Med 2006; 259(1): 70–80PubMedCrossRefGoogle Scholar
  61. 61.
    Gintant GA. Preclinical torsades-de-pointes screens: advantages and limitations of surrogate and direct approaches in evaluating proarrhythmic risk. Pharmacol Ther 2008; 119(2): 199–209PubMedCrossRefGoogle Scholar
  62. 62.
    Lawrence CL, Bridgland-Taylor MH, Pollard CE, et al. A rabbit Langendorff heart proarrhythmia model: predictive value for clinical identification of torsades de pointes. Br J Pharmacol 2006; 149(7): 845–60PubMedCrossRefGoogle Scholar
  63. 63.
    Lawrence CL, Pollard CE, Hammond TG, et al. In vitro models of proarrhythmia. Br J Pharmacol 2008; 154(7): 1516–22PubMedCrossRefGoogle Scholar
  64. 64.
    Lewis BH, Antman EM, Graboys TB. Detailed analysis of 24 hour ambulatory electrocardiographic recordings during ventricular fibrillation or torsade de pointes. J Am Coll Cardiol 1983; 2(3): 426–36PubMedCrossRefGoogle Scholar
  65. 65.
    Yan GX, Wu Y, Liu T, et al. Phase 2 early after-depolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome: direct evidence from intracellular recordings in the intact left ventricular wall. Circulation 2001; 103(23): 2851–6PubMedCrossRefGoogle Scholar
  66. 66.
    Hlaing T, DiMino T, Kowey PR, et al. ECG repolarization waves: their genesis and clinical implications. Ann Noninvasive Electrocardiol 2005; 10(2): 211–23PubMedCrossRefGoogle Scholar
  67. 67.
    Armoundas AA, Nanke T, Cohen RJ. Images in cardiovascular medicine: T-wave alternans preceding torsade de pointes ventricular tachycardia. Circulation 2000; 101(21): 2550PubMedCrossRefGoogle Scholar
  68. 68.
    Tomcsanyi J, Somloi M, Fresz T, et al. T-wave alternans and torsade de pointes ventricular tachycardia in a patient with intracerebral hemorrhage. Orv Hetil 2003; 144(42): 2077–9PubMedGoogle Scholar
  69. 69.
    Wegener FT, Ehrlich JR, Hohnloser SH. Amiodarone-associated macroscopic T-wave alternans and torsade de pointes unmasking the inherited long QT syndrome. Europace 2008; 10(1): 112–3PubMedCrossRefGoogle Scholar
  70. 70.
    Cutler MJ, Rosenbaum DS. Risk stratification for sudden cardiac death: is there a clinical role for T wave alternans? Heart Rhythm 2009; 6 (8 Suppl.): S56–61PubMedCrossRefGoogle Scholar
  71. 71.
    Garcia Ede V. T-wave alternans: reviewing the clinical performance, understanding limitations, characterizing methodologies. Ann Noninvasive Electrocardiol 2008; 13(4): 401–20PubMedCrossRefGoogle Scholar
  72. 72.
    Yan GX, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation 1998; 98(18): 1928–36PubMedCrossRefGoogle Scholar
  73. 73.
    Antzelevitch C, Oliva A. Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes. J Intern Med 2006; 259(1): 48–58PubMedCrossRefGoogle Scholar
  74. 74.
    Wu L, Guo D, Li H, et al. Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine. Heart Rhythm 2008; 5(12): 1726–34PubMedCrossRefGoogle Scholar
  75. 75.
    Yamaguchi M, Shimizu M, Ino H, et al. T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin Sci (Lond) 2003; 105(6): 671–6CrossRefGoogle Scholar
  76. 76.
    Zhang H, Kharche S, Holden AV, et al. Repolarisation and vulnerability to re-entry in the human heart with short QT syndrome arising from KCNQ1 mutation: a simulation study. Prog Biophys Mol Biol 2008; 96(1–3): 112–31PubMedCrossRefGoogle Scholar
  77. 77.
    Letsas KP, Weber R, Astheimer K, et al. Tpeak-Tend interval and Tpeak-Tend/QT ratio as markers of ventricular tachycardia inducibility in subjects with Brugada ECG phenotype. Europace 2010; 12(2): 271–4PubMedCrossRefGoogle Scholar
  78. 78.
    Nemec J, Hejlik JB, Shen WK, et al. Catecholamine-induced T-wave lability in congenital long QT syndrome: a novel phenomenon associated with syncope and cardiac arrest. Mayo Clin Proc 2003; 78(1): 40–50PubMedCrossRefGoogle Scholar
  79. 79.
    Carlsson L, Andersson B, Linhardt G, et al. Assessment of the ion channel-blocking profile of the novel combined ion channel blocker AZD1305 and its proarrhythmic potential versus dofetilide in the methoxamine-sensitized rabbit in vivo. J Cardiovasc Pharmacol 2009; 54(1): 82–9PubMedCrossRefGoogle Scholar
  80. 80.
    Lengyel C, Varro A, Tabori K, et al. Combined pharmacological block of I(Kr) and I(Ks) increases short-term QT interval variability and provokes torsades de pointes. Br J Pharmacol 2007; 151(7): 941–51PubMedCrossRefGoogle Scholar
  81. 81.
    Hinterseer M, Thomsen MB, Beckmann BM, et al. Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: a case control pilot study. Eur Heart J 2008; 29(2): 185–90PubMedCrossRefGoogle Scholar
  82. 82.
    Hinterseer M, Beckmann BM, Thomsen MB, et al. Relation of increased short-term variability of QT interval to congenital long-QT syndrome. Am J Cardiol 2009; 103(9): 1244–8PubMedCrossRefGoogle Scholar
  83. 83.
    van der Linde H, Van de Water A, Loots W, et al. A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anesthetized dogs. J Pharmacol Toxicol Methods 2005; 52(1): 168–77PubMedCrossRefGoogle Scholar
  84. 84.
    Brennan M, Palaniswami M, Kamen P. Do existing measures of Poincare plot geometry reflect nonlinear features of heart rate variability? IEEE Trans Biomed Eng 2001; 48(11): 1342–7PubMedCrossRefGoogle Scholar
  85. 85.
    Perkiomaki JS, Zareba W, Nomura A, et al. Repolarization dynamics in patients with long QT syndrome. J Cardiovasc Electrophysiol 2002; 13(7): 651–6PubMedCrossRefGoogle Scholar
  86. 86.
    Vincze D, Farkas AS, Rudas L, et al. Relevance of anaesthesia for dofetilide-induced torsades de pointes in alpha1-adrenoceptor-stimulated rabbits. Br J Pharmacol 2008; 153(1): 75–89PubMedCrossRefGoogle Scholar
  87. 87.
    Copie X, Le Heuzey JY, Iliou MC, et al. Correlation between time-domain measures of heart rate variability and scatterplots in postinfarction patients. Pacing Clin Electrophysiol 1996; 19(3): 342–7PubMedCrossRefGoogle Scholar
  88. 88.
    Schoenwald RD, Isaacs VE. QT corrected for heart rate: a new approach and its application. Arch Int Pharmacodyn Ther 1974; 211(1): 34–48PubMedGoogle Scholar
  89. 89.
    Berger RD, Kasper EK, Baughman KL, et al. Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation 1997; 96(5): 1557–65PubMedCrossRefGoogle Scholar
  90. 90.
    Bilchick K, Viitasalo M, Oikarinen L, et al. Temporal repolarization lability differences among genotyped patients with the long QT syndrome. Am J Cardiol 2004; 94(10): 1312–6PubMedCrossRefGoogle Scholar
  91. 91.
    Champeroux P, Martel E, Fowler JS, et al. Calculation of QT shift in non clinical safety pharmacology studies. J Pharmacol Toxicol Methods 2009; 59(2): 73–85PubMedCrossRefGoogle Scholar
  92. 92.
    Fossa AA. Assessing QT prolongation in conscious dogs: validation of a beat-to-beat method. Pharmacol Ther 2008; 119(2): 133–40PubMedCrossRefGoogle Scholar
  93. 93.
    Krahn AD, Yee R, Chauhan V, et al. Beta blockers normalize QT hysteresis in long QT syndrome. Am Heart J 2002; 143(3): 528–34PubMedCrossRefGoogle Scholar
  94. 94.
    Van Deuren B, Van Ammel K, Somers Y, et al. The fentanyl/etomidate-anaesthetised beagle (FEAB) dog: a versatile in vivo model in cardiovascular safety research. J Pharmacol Toxicol Methods 2009; 60(1): 11–23PubMedCrossRefGoogle Scholar
  95. 95.
    Bertinieri G, Di Rienzo M, Cavallazzi A, et al. Evaluation of baroreceptor reflex by blood pressure monitoring in unanesthetized cats. Am J Physiol 1988; 254 (2 Pt 2): H377–83PubMedGoogle Scholar
  96. 96.
    Schwartz PJ, Vanoli E, Crotti L, et al. Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome. J Am Coll Cardiol 2008; 51(9): 920–9PubMedCrossRefGoogle Scholar
  97. 97.
    Billman GE, Schwartz PJ, Stone HL. Baroreceptor reflex control of heart rate: a predictor of sudden cardiac death. Circulation 1982; 66(4): 874–80PubMedCrossRefGoogle Scholar
  98. 98.
    Nattel S, Comtois P. Teasing out circadian variability in heart rate turbulence: a new approach to detecting biorhythms underlying cardiac function. Heart Rhythm 2007; 4(3): 301–3PubMedCrossRefGoogle Scholar
  99. 99.
    Guzik P, Schmidt G. A phenomenon of heart-rate turbulence, its evaluation, and prognostic value. Card Electro-physiol Rev 2002; 6(3): 256–61CrossRefGoogle Scholar
  100. 100.
    Grimm W, Schmidt G, Maisch B, et al. Prognostic significance of heart rate turbulence following ventricular premature beats in patients with idiopathic dilated cardiomyopathy. J Cardiovasc Electrophysiol 2003; 14(8): 819–24PubMedCrossRefGoogle Scholar
  101. 101.
    Verrier RL, Antzelevitch C. Autonomic aspects of arrhythmogenesis: the enduring and the new. Curr Opin Cardiol 2004; 19(1): 2–11PubMedCrossRefGoogle Scholar
  102. 102.
    Lombardi F. Clinical implications of present physiological understanding of HRV components. Card Electrophysiol Rev 2002; 6(3): 245–9PubMedCrossRefGoogle Scholar
  103. 103.
    Pierre B, Babuty D, Poret P, et al. Abnormal nocturnal heart rate variability and QT dynamics in patients with Brugada syndrome. Pacing Clin Electrophysiol 2007; 30 Suppl. 1: S188–91PubMedCrossRefGoogle Scholar
  104. 104.
    Perkiomaki JS, Zareba W, Couderc JP, et al. Heart rate variability in patients with congenital long QT syndrome. Ann Noninvasive Electrocardiol 2001; 6(4): 298–304PubMedCrossRefGoogle Scholar
  105. 105.
    Shimizu W, Antzelevitch C. Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J Am Coll Cardiol 2000; 35(3): 778–86PubMedCrossRefGoogle Scholar
  106. 106.
    Michael G, Kane KA, Coker SJ. Adrenaline reveals the torsadogenic effect of combined blockade of potassium channels in anaesthetized guinea pigs. Br J Pharmacol 2008; 154(7): 1414–26PubMedCrossRefGoogle Scholar
  107. 107.
    Ring CL, Idriss SF, Neu WK. Variability of action potential duration in pharmacologically induced long QT syndrome type 1. Conf Proc IEEE Eng Med Biol Soc 2009; 1: 4520–2Google Scholar
  108. 108.
    Seebohm G, Pusch M, Chen J, et al. Pharmacological activation of normal and arrhythmia-associated mutant KCNQ1 potassium channels. Circ Res 2003; 93(10): 941–7PubMedCrossRefGoogle Scholar
  109. 109.
    Nissen JD, Diness JG, Diness TG, et al. Pharmacologically induced long QT type 2 can be rescued by activation of IKs with benzodiazepine R-L3 in isolated guinea pig cardiomyocytes. J Cardiovasc Pharmacol 2009; 54(2): 169–77PubMedCrossRefGoogle Scholar
  110. 110.
    Farkas AS, Acsai K, Toth A, et al. Importance of extra-cardiac alpha1-adrenoceptor stimulation in assisting dofetilide to induce torsade de pointes in rabbit hearts. Eur J Pharmacol 2006; 537(1–3): 118–25PubMedCrossRefGoogle Scholar
  111. 111.
    Farkas A, Dempster J, Coker SJ. Importance of vagally mediated bradycardia for the induction of torsade de pointes in an in vivo model. Br J Pharmacol 2008; 154(5): 958–70PubMedCrossRefGoogle Scholar
  112. 112.
    Yamauchi S, Yamaki M, Watanabe T, et al. Restitution properties and occurrence of ventricular arrhythmia in LQT2 type of long QT syndrome. J Cardiovasc Electrophysiol 2002; 13(9): 910–4PubMedCrossRefGoogle Scholar
  113. 113.
    Hansen RS, Diness TG, Christ T, et al. Activation of human ether-a-go-go-related gene potassium channels by the diphenylurea 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643). Mol Pharmacol 2006; 69(1): 266–77PubMedGoogle Scholar
  114. 114.
    Hansen RS, Diness TG, Christ T, et al. Biophysical characterization of the new human ether-a-go-go-related gene channel opener NS3623 [N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl)urea]. Mol Pharmacol 2006; 70(4): 1319–29PubMedCrossRefGoogle Scholar
  115. 115.
    Grunnet M, Hansen RS, Olesen SP. hERG1 channel activators: a new anti-arrhythmic principle. Prog Biophys Mol Biol 2008; 98(2–3): 347–62PubMedCrossRefGoogle Scholar
  116. 116.
    Yap YG, Behr ER, Camm AJ. Drug-induced Brugada syndrome. Europace 2009; 11(8): 989–94PubMedCrossRefGoogle Scholar
  117. 117.
    Veltmann C, Wolpert C, Sacher F, et al. Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges. Europace 2009; 11(10): 1345–52PubMedCrossRefGoogle Scholar
  118. 118.
    Stokoe KS, Balasubramaniam R, Goddard CA, et al. Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/-murine hearts modelling the Brugada syndrome. J Physiol 2007; 581 (Pt 1): 255–75PubMedCrossRefGoogle Scholar
  119. 119.
    Michael G, Dempster J, Kane KA, et al. Potentiation of E-4031-induced torsade de pointes by HMR1556 or ATX-II is not predicted by action potential short-term variability or triangulation. Br J Pharmacol 2007; 152(8): 1215–27PubMedCrossRefGoogle Scholar
  120. 120.
    Milberg P, Reinsch N, Osada N, et al. Verapamil prevents torsade de pointes by reduction of transmural dispersion of repolarization and suppression of early after-depolarizations in an intact heart model of LQT3. Basic Res Cardiol 2005; 100(4): 365–71PubMedCrossRefGoogle Scholar
  121. 121.
    Patel C, Antzelevitch C. Pharmacological approach to the treatment of long and short QT syndromes. Pharmacol Ther 2008; 118(1): 138–51PubMedCrossRefGoogle Scholar
  122. 122.
    Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115(4): 442–9PubMedCrossRefGoogle Scholar
  123. 123.
    Sicouri S, Timothy KW, Zygmunt AC, et al. Cellular basis for the electrocardiographic and arrhythmic manifestations of Timothy syndrome: effects of ranolazine. Heart Rhythm 2007; 4(5): 638–47PubMedCrossRefGoogle Scholar
  124. 124.
    Cheng HC, Incardona J. Models of torsades de pointes: effects of FPL64176, DPI201106, dofetilide, and chromanol 293B in isolated rabbit and guinea pig hearts. J Pharmacol Toxicol Methods 2009; 60(2): 174–84PubMedCrossRefGoogle Scholar
  125. 125.
    Chaudhry GM, Haffajee CI. Antiarrhythmic agents and proarrhythmia. Crit Care Med 2000; 28 (10 Suppl.): N158–64PubMedCrossRefGoogle Scholar
  126. 126.
    Remme CA, Verkerk AO, Nuyens D, et al. Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD. Circulation 2006; 114(24): 2584–94PubMedCrossRefGoogle Scholar
  127. 127.
    Remme CA, Wilde AA, Bezzina CR. Cardiac sodium channel overlap syndromes: different faces of SCN5A mutations. Trends Cardiovasc Med 2008; 18(3): 78–87PubMedCrossRefGoogle Scholar
  128. 128.
    Postema PG, Van den Berg M, Van Tintelen JP, et al. Founder mutations in the Netherlands: SCN5a 1795insD, the first described arrhythmia overlap syndrome and one of the largest and best characterised families worldwide. Neth Heart J 2009; 17(11): 422–8PubMedCrossRefGoogle Scholar
  129. 129.
    Algra A, Tijssen JG, Roelandt JR, et al. QT interval variables from 24 hour electrocardiography and the two year risk of sudden death. Br Heart J 1993; 70(1): 43–8PubMedCrossRefGoogle Scholar
  130. 130.
    Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology 2000; 94(2): 99–102PubMedCrossRefGoogle Scholar
  131. 131.
    Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004; 109(20): 2394–7PubMedCrossRefGoogle Scholar
  132. 132.
    Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004; 109(1): 30–5PubMedCrossRefGoogle Scholar
  133. 133.
    Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 2005; 96(7): 800–7PubMedCrossRefGoogle Scholar
  134. 134.
    Shah RR. Drug-induced QT interval shortening: potential harbinger of proarrhythmia and regulatory perspectives. Br J Pharmacol 2010; 159(1): 58–69PubMedCrossRefGoogle Scholar
  135. 135.
    Kang J, Chen XL, Wang H, et al. Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. Mol Pharmacol 2005; 67(3): 827–36PubMedCrossRefGoogle Scholar
  136. 136.
    Zhou J, Augelli-Szafran CE, Bradley JA, et al. Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their invitroantiarrhythmic activity. Mol Pharmacol 2005; 68(3): 876–84PubMedGoogle Scholar
  137. 137.
    Pugsley MK, Hancox JC, Curtis MJ. Perception of validity of clinical and preclinical methods for assessment of torsades de pointes liability. Pharmacol Ther 2008; 119(2): 115–7PubMedCrossRefGoogle Scholar
  138. 138.
    Abi-Gerges N, Small BG, Lawrence CL, et al. Evidence for gender differences in electrophysiological properties of canine Purkinje fibres. Br J Pharmacol 2004; 142(8): 1255–64PubMedCrossRefGoogle Scholar
  139. 139.
    Wang D, Patel C, Cui C, et al. Preclinical assessment of drug-induced proarrhythmias: role of the arterially perfused rabbit left ventricular wedge preparation. Pharmacol Ther 2008; 119(2): 141–51PubMedCrossRefGoogle Scholar
  140. 140.
    Tomaselli GF, Rose J. Molecular aspects of arrhythmias associated with cardiomyopathies. Curr Opin Cardiol 2000; 15(3): 202–8PubMedCrossRefGoogle Scholar
  141. 141.
    Vos MA, van Opstal JM, Leunissen JD, et al. Electro-physiologic parameters and predisposing factors in the generation of drug-induced torsade de pointes arrhythmias. Pharmacol Ther 2001; 92(2–3): 109–22PubMedCrossRefGoogle Scholar
  142. 142.
    Dhein S, Perlitz F, Mohr FW. An invitromodel for assessment of drug-induced torsade de pointes arrhythmia: effects of haloperidol and dofetilide on potential duration, repolarization inhomogeneities, and torsade de pointes arrhythmia. Naunyn Schmiedebergs Arch Pharmacol 2008; 378(6): 631–44PubMedCrossRefGoogle Scholar
  143. 143.
    Carlsson L, Almgren O, Duker G. QTU-prolongation and torsades de pointes induced by putative class III antiarrhythmic agents in the rabbit: etiology and interventions. J Cardiovasc Pharmacol 1990; 16(2): 276–85PubMedCrossRefGoogle Scholar
  144. 144.
    Vos MA, Verduyn SC, Gorgels AP, et al. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation 1995; 91(3): 864–72PubMedCrossRefGoogle Scholar
  145. 145.
    Toyoshima S, Kanno A, Kitayama T, et al. QT PRODACT: invivoQT assay in the conscious dog for assessing the potential for QT interval prolongation by human pharmaceuticals. J Pharmacol Sci 2005; 99(5): 459–71PubMedCrossRefGoogle Scholar
  146. 146.
    Ando K, Hombo T, Kanno A, et al. QT PRODACT: invivoQT assay with a conscious monkey for assessment of the potential for drug-induced QT interval prolongation. J Pharmacol Sci 2005; 99(5): 487–500PubMedCrossRefGoogle Scholar
  147. 147.
    Lindgren S, Bass AS, Briscoe R, et al. Benchmarking safety pharmacology regulatory packages and best practice. J Pharmacol Toxicol Methods 2008; 58(2): 99–109PubMedCrossRefGoogle Scholar
  148. 148.
    Bass AS, Darpo B, Breidenbach A, et al. International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes. Br J Pharmacol 2008; 154(7): 1491–501PubMedCrossRefGoogle Scholar
  149. 149.
    Aronov AM. Predictive in silico modeling for hERG channel blockers. Drug Discov Today 2005; 10(2): 149–55PubMedCrossRefGoogle Scholar
  150. 150.
    Kleber AG, Rudy Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev 2004; 84(2): 431–88PubMedCrossRefGoogle Scholar
  151. 151.
    Arrigoni C, Crivori P. Assessment of QT liabilities in drug development. Cell Biol Toxicol 2007; 23(1): 1–13PubMedCrossRefGoogle Scholar
  152. 152.
    Bender A, Scheiber J, Glick M, et al. Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure. Chem Med Chem 2007; 2(6): 861–73PubMedGoogle Scholar
  153. 153.
    Grandi E, Pasqualini FS, Pes C, et al. Theoretical investigation of action potential duration dependence on extracellular Ca2+ in human cardiomyocytes. J Mol Cell Cardiol 2009; 46(3): 332–42PubMedCrossRefGoogle Scholar
  154. 154.
    Vecchietti S, Grandi E, Severi S, et al. In silico assessment of Y1795C and Y1795H SCN5A mutations: implication for inherited arrhythmogenic syndromes. Am J Physiol Heart Circ Physiol 2007; 292(1): H56–65PubMedCrossRefGoogle Scholar
  155. 155.
    Roden DM. Taking the “idio” out of “idiosyncratic”: predicting torsades de pointes. Pacing Clin Electrophysiol 1998; 21(5): 1029–34PubMedCrossRefGoogle Scholar
  156. 156.
    Hancox JC, McPate MJ, El Harchi A, et al. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol Ther 2008; 119(2): 118–32PubMedCrossRefGoogle Scholar
  157. 157.
    Nattel S, Duker G, Carlsson L. Model systems for the discovery and development of antiarrhythmic drugs. Prog Biophys Mol Biol 2008; 98(2–3): 328–39PubMedCrossRefGoogle Scholar
  158. 158.
    Kirsch GE, Trepakova ES, Brimecombe JC, et al. Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern. J Pharmacol Toxicol Methods 2004; 50(2): 93–101PubMedCrossRefGoogle Scholar
  159. 159.
    Yao JA, Du X, Lu D, et al. Estimation of potency of HERG channel blockers: impact of voltage protocol and temperature. J Pharmacol Toxicol Methods 2005; 52(1): 146–53PubMedCrossRefGoogle Scholar
  160. 160.
    Sanguinetti MC, Jiang C, Curran ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995; 81(2): 299–307PubMedCrossRefGoogle Scholar
  161. 161.
    Yang T, Snyders DJ, Roden DM. Rapid inactivation determines the rectification and [K+]o dependence of the rapid component of the delayed rectifier K+ current in cardiac cells. Circ Res 1997; 80(6): 782–9PubMedCrossRefGoogle Scholar
  162. 162.
    Stork D, Timin EN, Berjukow S, et al. State dependent dissociation of HERG channel inhibitors. Br J Pharmacol 2007; 151(8): 1368–76PubMedCrossRefGoogle Scholar
  163. 163.
    Yang T, Snyders D, Roden DM. Drug block of I(kr): model systems and relevance to human arrhythmias. J Cardiovasc Pharmacol 2001; 38(5): 737–44PubMedCrossRefGoogle Scholar
  164. 164.
    Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electro-physiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 2004; 110(8): 904–10PubMedCrossRefGoogle Scholar
  165. 165.
    Schram G, Zhang L, Derakhchan K, et al. Ranolazine: ionchannel-blocking actions and invivoelectrophysiological effects. Br J Pharmacol 2004; 142(8): 1300–8PubMedCrossRefGoogle Scholar
  166. 166.
    Cavero I, Mestre M, Guillon JM, et al. Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias. Expert Opin Pharmacother 2000; 1(5): 947–73PubMedCrossRefGoogle Scholar
  167. 167.
    Redfern WS, Carlsson L, Davis AS, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 2003; 58(1): 32–45PubMedCrossRefGoogle Scholar
  168. 168.
    Ficker E, Dennis AT, Wang L, et al. Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG. Circ Res 2003; 92(12): e87–100PubMedCrossRefGoogle Scholar
  169. 169.
    Unnikrishnan D, Dutcher JP, Varshneya N, et al. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001; 97(5): 1514–6PubMedCrossRefGoogle Scholar
  170. 170.
    Wang L, Wible BA, Wan X, et al. Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. J Pharmacol Exp Ther 2007; 320(2): 525–34PubMedCrossRefGoogle Scholar
  171. 171.
    Wible BA, Hawryluk P, Ficker E, et al. HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk. J Pharmacol Toxicol Methods 2005; 52(1): 136–45PubMedCrossRefGoogle Scholar
  172. 172.
    Rezazadeh S, Hesketh JC, Fedida D. Rb+ flux through hERG channels affects the potency of channel blocking drugs: correlation with data obtained using a high-throughput Rb+ efflux assay. J Biomol Screen 2004; 9(7): 588–97PubMedCrossRefGoogle Scholar
  173. 173.
    Chaudhary KW, O'Neal JM, Mo ZL, et al. Evaluation of the rubidium efflux assay for preclinical identification of HERG blockade. Assay Drug Dev Technol 2006; 4(1): 73–82PubMedCrossRefGoogle Scholar
  174. 174.
    Titus SA, Beacham D, Shahane SA, et al. A new homogeneous high-throughput screening assay for profiling compound activity on the human ether-a-go-go-related gene channel. Anal Biochem 2009; 394(1): 30–8PubMedCrossRefGoogle Scholar
  175. 175.
    Meyer T, Sartipy P, Blind F, et al. New cell models and assays in cardiac safety profiling. Expert Opin Drug Metab Toxicol 2007; 3(4): 507–17PubMedCrossRefGoogle Scholar
  176. 176.
    Lu HR, Vlaminckx E, Hermans AN, et al. Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B guidelines. Br J Pharmacol 2008; 154(7): 1427–38PubMedCrossRefGoogle Scholar
  177. 177.
    Hosaka Y, Iwata M, Kamiya N, et al. Mutational analysis of block and facilitation of HERG current by a class III anti-arrhythmic agent, nifekalant. Channels (Austin) 2007; 1(3): 198–208Google Scholar
  178. 178.
    Jo SH, Hong HK, Chong SH, et al. Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652. Eur J Pharmacol 2008; 592(1–3): 19–25PubMedCrossRefGoogle Scholar
  179. 179.
    Kamiya K, Niwa R, Morishima M, et al. Molecular determinants of hERG channel block by terfenadine and cisapride. J Pharmacol Sci 2008; 108(3): 301–7PubMedCrossRefGoogle Scholar
  180. 180.
    Shah RR. Drug-induced QT interval prolongation: regulatory guidance and perspectives on hERG channel studies. Novartis Found Symp 2005; 266: 251–80; discussion 80-5PubMedCrossRefGoogle Scholar
  181. 181.
    Witchel HJ. The hERG potassium channel as a therapeutic target. Expert Opin Ther Targets 2007; 11(3): 321–36PubMedCrossRefGoogle Scholar
  182. 182.
    Martin RL, McDermott JS, Salmen HJ, et al. The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block. J Cardiovasc Pharmacol 2004; 43(3): 369–79PubMedCrossRefGoogle Scholar
  183. 183.
    Limberis JT, McDermott JS, Salmen HJ, et al. The effects of plasma proteins on delayed repolarization invitrowith cisapride, risperidone, and D,L-sotalol. J Pharmacol Toxicol Methods 2007; 56(1): 11–7PubMedCrossRefGoogle Scholar
  184. 184.
    Hanson LA, Bass AS, Gintant G, et al. ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation. J Pharmacol Toxicol Methods 2006; 54(2): 116–29PubMedCrossRefGoogle Scholar
  185. 185.
    Lu HR, Vlaminckx E, Van de Water A, et al. In-vitro experimental models for the risk assessment of antibiotic-induced QT prolongation. Eur J Pharmacol 2006; 553(1–3): 229–39PubMedCrossRefGoogle Scholar
  186. 186.
    Hayashi S, Kii Y, Tabo M, et al. QT PRODACT: a multi-site study of invitroaction potential assays on 21 compounds in isolated guinea-pig papillary muscles. J Pharmacol Sci 2005; 99(5): 423–37PubMedCrossRefGoogle Scholar
  187. 187.
    Kii Y, Hayashi S, Tabo M, et al. QT PRODACT: evaluation of the potential of compounds to cause QT interval prolongation by action potential assays using guinea-pig papillary muscles. J Pharmacol Sci 2005; 99(5): 449–57PubMedCrossRefGoogle Scholar
  188. 188.
    Yan GX, Shimizu W, Antzelevitch C. Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations. Circulation 1998; 98(18): 1921–7PubMedCrossRefGoogle Scholar
  189. 189.
    Poelzing S. Are electrophysiologically distinct M-cells a characteristic of the wedge preparation? Heart Rhythm 2009; 6(7): 1035–7PubMedCrossRefGoogle Scholar
  190. 190.
    Voss F, Opthof T, Marker J, et al. There is no transmural heterogeneity in an index of action potential duration in the canine left ventricle. Heart Rhythm 2009; 6(7): 1028–34PubMedCrossRefGoogle Scholar
  191. 191.
    Opthof T, Coronel R, Wilms-Schopman FJ, et al. Dispersion of repolarization in canine ventricle and the electro-cardiographic T wave: Tp-e interval does not reflect transmural dispersion. Heart Rhythm 2007; 4(3): 341–8PubMedCrossRefGoogle Scholar
  192. 192.
    Di Diego JM, Belardinelli L, Antzelevitch C. Cisapride-induced transmural dispersion of repolarization and torsade de pointes in the canine left ventricular wedge preparation during epicardial stimulation. Circulation 2003; 108(8): 1027–33PubMedCrossRefGoogle Scholar
  193. 193.
    Wu L, Rajamani S, Li H, et al. Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na(+) current in the heart. Am J Physiol Heart Circ Physiol 2009; 297(3): H1048–57PubMedCrossRefGoogle Scholar
  194. 194.
    Extramiana F, Antzelevitch C. Amplified transmural dispersion of repolarization as the basis for arrhythmogenesis in a canine ventricular-wedge model of short-QT syndrome. Circulation 2004; 110(24): 3661–6PubMedCrossRefGoogle Scholar
  195. 195.
    Patel C, Antzelevitch C. Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome. Heart Rhythm 2008; 5(4): 585–90PubMedCrossRefGoogle Scholar
  196. 196.
    Calloe K, Cordeiro JM, Di Diego JM, et al. A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome. Cardiovasc Res 2009; 81(4): 686–94PubMedCrossRefGoogle Scholar
  197. 197.
    Morita H, Zipes DP, Fukushima-Kusano K, et al. Repolarization heterogeneity in the right ventricular outflow tract: correlation with ventricular arrhythmias in Brugada patients and in an invitrocanine Brugada model. Heart Rhythm 2008; 5(5): 725–33PubMedCrossRefGoogle Scholar
  198. 198.
    Joshi A, Dimino T, Vohra Y, et al. Preclinical strategies to assess QT liability and torsadogenic potential of new drugs: the role of experimental models. J Electrocardiol 2004; 37 Suppl.: 7–14PubMedCrossRefGoogle Scholar
  199. 199.
    Liu T, Brown BS, Wu Y, et al. Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias. Heart Rhythm 2006; 3(8): 948–56PubMedCrossRefGoogle Scholar
  200. 200.
    Chen X, Cordes JS, Bradley JA, et al. Use of arterially perfused rabbit ventricular wedge in predicting arrhythmogenic potentials of drugs. J Pharmacol Toxicol Methods 2006; 54(3): 261–72PubMedCrossRefGoogle Scholar
  201. 201.
    Valentin JP, Hoffmann P, De Clerck F, et al. Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs. J Pharmacol Toxicol Methods 2004; 49(3): 171–81PubMedCrossRefGoogle Scholar
  202. 202.
    Hondeghem LM, Lu HR, van Rossem K, et al. Detection of proarrhythmia in the female rabbit heart: blinded validation. J Cardiovasc Electrophysiol 2003; 14(3): 287–94PubMedCrossRefGoogle Scholar
  203. 203.
    Guo L, Dong Z, Guthrie H. Validation of a guinea pig Langendorff heart model for assessing potential cardiovascular liability of drug candidates. J Pharmacol Toxicol Methods 2009; 60(2): 833–43CrossRefGoogle Scholar
  204. 204.
    Hondeghem LM, Hoffmann P. Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: importance of triangulation, reverse use dependence, and instability. J Cardiovasc Pharmacol 2003; 41(1): 14–24PubMedCrossRefGoogle Scholar
  205. 205.
    Dumotier BM, Deurinck M, Yang Y, et al. Relevance of invitroSCREENIT results for drug-induced QT interval prolongation invivo:a database review and analysis. Pharmacol Ther 2008; 119(2): 152–9PubMedCrossRefGoogle Scholar
  206. 206.
    Hondeghem LM. Use and abuse of QT and TRIaD in cardiac safety research: importance of study design and conduct. Eur J Pharmacol 2008; 584(1): 1–9PubMedCrossRefGoogle Scholar
  207. 207.
    Zabel M, Hohnloser SH, Behrens S, et al. Electro-physiologic features of torsades de pointes: insights from a new isolated rabbit heart model. J Cardiovasc Electrophysiol 1997; 8(10): 1148–58PubMedCrossRefGoogle Scholar
  208. 208.
    Johna R, Mertens H, Haverkamp W, et al. Clofilium in the isolated perfused rabbit heart: a new model to study proarrhythmia induced by class III antiarrhythmic drugs. Basic Res Cardiol 1998; 93(2): 127–35PubMedCrossRefGoogle Scholar
  209. 209.
    Milberg P, Hilker E, Ramtin S, et al. Proarrhythmia as a class effect of quinolones: increased dispersion of repolarization and triangulation of action potential predict torsades de pointes. J Cardiovasc Electrophysiol 2007; 18(6): 647–54PubMedCrossRefGoogle Scholar
  210. 210.
    Lu HR, Vlaminckx E, Van de Water A, et al. In-vitro experimental models for the risk assessment of antibiotic-induced QT prolongation. Eur J Pharmacol 2007; 577(1–3): 222–32PubMedCrossRefGoogle Scholar
  211. 211.
    Gray RA, Jalife J, Panfilov A, et al. Nonstationary vortexlike reentrant activity as a mechanism of polymorphic ventricular tachycardia in the isolated rabbit heart. Circulation 1995; 91(9): 2454–69PubMedCrossRefGoogle Scholar
  212. 212.
    Shimizu W, Antzelevitch C. Effects of a K(+) channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in LQT1, LQT2, and LQT3 models of the long-QT syndrome. Circulation 2000; 102(6): 706–12PubMedCrossRefGoogle Scholar
  213. 213.
    Farkas A, Lepran I, Papp JG. Comparison of the antiarrhythmic and the proarrhythmic effect of almokalant in anaesthetised rabbits. Eur J Pharmacol 1998; 346(2–3): 245–53PubMedCrossRefGoogle Scholar
  214. 214.
    Farkas A, Coker SJ. Limited induction of torsade de pointes by terikalant and erythromycin in an invivo model. Eur J Pharmacol 2002; 449(1–2): 143–53PubMedCrossRefGoogle Scholar
  215. 215.
    Farkas A, Coker SJ. Prevention of clofilium-induced torsade de pointes by prostaglandin E2 does not involve ATP-dependent K+ channels. Eur J Pharmacol 2003; 472(3): 189–96PubMedCrossRefGoogle Scholar
  216. 216.
    Fedida D, Braun AP, Giles WR. Alpha1-adrenoceptors reduce background K+ current in rabbit ventricular myocytes. J Physiol 1991; 441: 673–84PubMedGoogle Scholar
  217. 217.
    Fedida D, Braun AP, Giles WR. Alpha1-adrenoceptors in myocardium: functional aspects and transmembrane signaling mechanisms. Physiol Rev 1993; 73(2): 469–87PubMedGoogle Scholar
  218. 218.
    Fedida D, Shimoni Y, Giles WR. Alpha-adrenergic modulation of the transient outward current in rabbit atrial myocytes. J Physiol 1990; 423: 257–77PubMedGoogle Scholar
  219. 219.
    Terzic A, Puceat M, Vassort G, et al. Cardiac alpha1-adrenoceptors: an overview. Pharmacol Rev 1993; 45(2): 147–75PubMedGoogle Scholar
  220. 220.
    Steinberg SF, Kaplan LM, Inouye T, et al. Alpha-1 adrenergic stimulation of 1,4,5-inositol trisphosphate formation in ventricular myocytes. J Pharmacol Exp Ther 1989; 250(3): 1141–8PubMedGoogle Scholar
  221. 221.
    Carlsson L, Drews L, Duker G. Rhythm anomalies related to delayed repolarization invivo:influence of sarcolemmal Ca++ entry and intracellular Ca++ overload. J Pharmacol Exp Ther 1996; 279(1): 231–9PubMedGoogle Scholar
  222. 222.
    Wang WQ, Robertson C, Dhalla AK, et al. Anti-torsadogenic effects of (+/−)-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine) (ranolazine) in anesthetized rabbits. J Pharmacol Exp Ther 2008; 325(3): 875–81PubMedCrossRefGoogle Scholar
  223. 223.
    Farkas A, Batey AJ, Coker SJ. How to measure electro-cardiographic QT interval in the anaesthetized rabbit. J Pharmacol Toxicol Methods 2004; 50(3): 175–85PubMedCrossRefGoogle Scholar
  224. 224.
    Farkas A, Lepran I, Papp JG. Proarrhythmic effects of intravenous quinidine, amiodarone, D-sotalol, and almokalant in the anesthetized rabbit model of torsade de pointes. J Cardiovasc Pharmacol 2002; 39(2): 287–97PubMedCrossRefGoogle Scholar
  225. 225.
    Lu HR, Remeysen P, De Clerck F. Nonselective I(Kr)-blockers do not induce torsades de pointes in the anesthetized rabbit during alpha1-adrenoceptor stimulation. J Cardiovasc Pharmacol 2000; 36(6): 728–36PubMedCrossRefGoogle Scholar
  226. 226.
    Provan G, Stanton A, Sutton A, et al. Development of a surgical approach for telemetering guinea pigs as a model for screening QT interval effects. J Pharmacol Toxicol Methods 2005; 52(2): 223–8PubMedCrossRefGoogle Scholar
  227. 227.
    Chaves AA, Keller WJ, O’sullivan S, et al. Cardiovascular monkey telemetry: sensitivity to detect QT interval prolongation. J Pharmacol Toxicol Methods 2006; 54(2): 150–8PubMedCrossRefGoogle Scholar
  228. 228.
    Chaves AA, Zingaro GJ, Yordy MA, et al. A highly sensitive canine telemetry model for detection of QT interval prolongation: studies with moxifloxacin, haloperidol and MK-499. J Pharmacol Toxicol Methods 2007; 56(2): 103–14PubMedCrossRefGoogle Scholar
  229. 229.
    van der Linde HJ, Van Deuren B, Teisman A, et al. The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction. Br J Pharmacol 2008; 154(7): 1474–81PubMedCrossRefGoogle Scholar
  230. 230.
    Han W, Chartier D, Li D, et al. Ionic remodeling of cardiac Purkinje cells by congestive heart failure. Circulation 2001; 104(17): 2095–100PubMedCrossRefGoogle Scholar
  231. 231.
    Nabauer M, Kaab S. Potassium channel down-regulation in heart failure. Cardiovasc Res 1998; 37(2): 324–34PubMedCrossRefGoogle Scholar
  232. 232.
    Tsuji Y, Zicha S, Qi XY, et al. Potassium channel subunit remodeling in rabbits exposed to long-term bradycardia or tachycardia: discrete arrhythmogenic consequences related to differential delayed-rectifier changes. Circulation 2006; 113(3): 345–55PubMedCrossRefGoogle Scholar
  233. 233.
    Li X, Huang CX, Jiang H, et al. The beta-adrenergic blocker carvedilol restores L-type calcium current in a myocardial infarction model of rabbit. Chin Med J (Engl) 2005; 118(5): 377–82Google Scholar
  234. 234.
    Varro A, Papp JG. Low penetrance, subclinical congenital LQTS: concealed LQTS or silent LQTS? Cardiovasc Res 2006; 70(3): 404–6PubMedCrossRefGoogle Scholar
  235. 235.
    Schlotthauer K, Bers DM. Sarcoplasmic reticulum Ca(2+) release causes myocyte depolarization: underlying mechanism and threshold for triggered action potentials. Circ Res 2000; 87(9): 774–80PubMedCrossRefGoogle Scholar
  236. 236.
    Volders PG, Sipido KR, Vos MA, et al. Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation 1998; 98(11): 1136–47PubMedCrossRefGoogle Scholar
  237. 237.
    Volders PG, Sipido KR, Vos MA, et al. Downregulation of delayed rectifier K(+) currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes. Circulation 1999; 100(24): 2455–61PubMedCrossRefGoogle Scholar
  238. 238.
    Tsuji Y, Opthof T, Yasui K, et al. Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block. Circulation 2002; 106(15): 2012–8PubMedCrossRefGoogle Scholar
  239. 239.
    Vos MA, de Groot SH, Verduyn SC, et al. Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation 1998; 98(11): 1125–35PubMedCrossRefGoogle Scholar
  240. 240.
    de Groot SH, Schoenmakers M, Molenschot MM, et al. Contractile adaptations preserving cardiac output predispose the hypertrophied canine heart to delayed afterdepolarization-dependent ventricular arrhythmias. Circulation 2000; 102(17): 2145–51PubMedCrossRefGoogle Scholar
  241. 241.
    Donker DW, Volders PG, Arts T, et al. End-diastolic myofiber stress and ejection strain increase with ventricular volume overload: serial in-vivo analyses in dogs with complete atrioventricular block. Basic Res Cardiol 2005; 100(4): 372–82PubMedCrossRefGoogle Scholar
  242. 242.
    Schoenmakers M, Ramakers C, van Opstal JM, et al. Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog. Cardiovasc Res 2003; 59(2): 351–9PubMedCrossRefGoogle Scholar
  243. 243.
    Sipido KR, Volders PG, de Groot SH, et al. Enhanced Ca(2+) release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis. Circulation 2000; 102(17): 2137–44PubMedCrossRefGoogle Scholar
  244. 244.
    Nattel S, Wang ZG, Matthews C. Direct electrophysiological actions of pentobarbital at concentrations achieved during general anesthesia. Am J Physiol 1990; 259 (6 Pt 2): H1743–51PubMedGoogle Scholar
  245. 245.
    Stadnicka A, Bosnjak ZJ, Kampine JP, et al. Modulation of cardiac inward rectifier K(+)current by halothane and isoflurane. Anesth Analg 2000; 90(4): 824–33PubMedCrossRefGoogle Scholar
  246. 246.
    Bachmann A, Mueller S, Kopp K, et al. Inhibition of cardiac potassium currents by pentobarbital. Naunyn Schmiedebergs Arch Pharmacol 2002; 365(1): 29–37PubMedCrossRefGoogle Scholar
  247. 247.
    Qi XY, Yeh YH, Chartier D, et al. The calcium/calmodulin/kinase system and arrhythmogenic after-depolarizations in bradycardia-related acquired long QT syndrome. Circulation Arrhythmia Electrophysiol 2009; 2(3): 295–304CrossRefGoogle Scholar
  248. 248.
    Satoh Y, Sugiyama A, Takahara A, et al. A novel monkey proarrhythmia model that can predict the drug-induced torsades de pointes in clinical practice [abstract]. J Pharmacol Sci 2006; 100 Suppl. I: 223Google Scholar
  249. 249.
    Sugiyama A. Sensitive and reliable proarrhythmia invivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts. Br J Pharmacol 2008; 154(7): 1528–37PubMedCrossRefGoogle Scholar
  250. 250.
    Hashimoto K. Torsades de pointes liability inter-model comparisons: the experience of the QT PRODACT initiative. Pharmacol Ther 2008; 119(2): 195–8PubMedCrossRefGoogle Scholar
  251. 251.
    Kijtawornrat A, Nishijima Y, Roche BM, et al. Use of a failing rabbit heart as a model to predict torsadogenicity. Toxicol Sci 2006; 93(1): 205–12PubMedCrossRefGoogle Scholar
  252. 252.
    Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J 1975; 89(1): 45–50PubMedCrossRefGoogle Scholar
  253. 253.
    Surawicz B, Fisch C. Cardiac alternans: diverse mechanisms and clinical manifestations. J Am Coll Cardiol 1992; 20(2): 483–99PubMedCrossRefGoogle Scholar
  254. 254.
    Zareba W, Moss AJ, le Cessie S, et al. T wave alternans in idiopathic long QT syndrome. J Am Coll Cardiol 1994; 23(7): 1541–6PubMedCrossRefGoogle Scholar
  255. 255.
    Houltz B, Darpo B, Edvardsson N, et al. Electrocardiographic and clinical predictors of torsades de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: a prospective study. Pacing Clin Electrophysiol 1998; 21(5): 1044–57PubMedCrossRefGoogle Scholar
  256. 256.
    Brockmeier K, Aslan I, Hilbel T, et al. T-wave alternans in LQTS: repolarization-rate dynamics from digital 12-lead Holter data. J Electrocardiol 2001; 34 Suppl.: 93–6PubMedCrossRefGoogle Scholar
  257. 257.
    Shimizu W, Antzelevitch C. Cellular and ionic basis for T-wave alternans under long-QT conditions. Circulation 1999; 99(11): 1499–507PubMedCrossRefGoogle Scholar
  258. 258.
    Schmitt J, Baumann S, Klingenheben T, et al. Assessment of microvolt T-wave alternans in high-risk patients with the congenital long-QT syndrome. Ann Noninvasive Electrocardiol 2009; 14(4): 340–5PubMedCrossRefGoogle Scholar
  259. 259.
    Berger RD. QT variability. J Electrocardiol 2003; 36 Suppl.: 83–7PubMedCrossRefGoogle Scholar
  260. 260.
    Mine T, Shimizu H, Hiromoto K, et al. Beat-to-beat QT interval variability is primarily affected by the autonomic nervous system. Ann Noninvasive Electrocardiol 2008; 13(3): 228–33PubMedCrossRefGoogle Scholar
  261. 261.
    Iwasa A, Hwa M, Hassankhani A, et al. Abnormal heart rate turbulence predicts the initiation of ventricular arrhythmias. Pacing Clin Electrophysiol 2005; 28(11): 1189–97PubMedCrossRefGoogle Scholar
  262. 262.
    Watanabe MA. Heart rate turbulence slope reduction in imminent ventricular tachyarrhythmia and its implications. J Cardiovasc Electrophysiol 2006; 17(7): 735–40PubMedCrossRefGoogle Scholar
  263. 263.
    Bass AS, Darpo B, Valentin JP, et al. Moving towards better predictors of drug-induced torsades de pointes. Br J Pharmacol 2008; 154(7): 1550–3PubMedCrossRefGoogle Scholar
  264. 264.
    Bauman JL, Bauernfeind RA, Hoff JV, et al. Torsade de pointes due to quinidine: observations in 31 patients. Am Heart J 1984; 107(3): 425–30PubMedCrossRefGoogle Scholar
  265. 265.
    Chan AS, Isbister GK, Kirkpatrick CM, et al. Assessing risk of a prolonged QT interval: a survey of emergency physicians. Int J Emerg Med 2008; 1(1): 35–41PubMedCrossRefGoogle Scholar
  266. 266.
    Batchvarov VN, Ghuran A, Smetana P, et al. QT-RR relationship in healthy subjects exhibits substantial inter-subject variability and high intrasubject stability. Am J Physiol Heart Circ Physiol 2002; 282(6): H2356–63PubMedGoogle Scholar
  267. 267.
    Malik M, Camm AJ. Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. Drug Saf 2001; 24(5): 323–51PubMedCrossRefGoogle Scholar
  268. 268.
    Hodges M. Rate correction of the QT interval. Card Electrophysiol Rev 1997; 1(3): 360–3CrossRefGoogle Scholar
  269. 269.
    Smetana P, Batchvarov V, Hnatkova K, et al. Circadian rhythm of the corrected QT interval: impact of different heart rate correction models. Pacing Clin Electrophysiol 2003 Jan; 26 (1 Pt 2): 383–6PubMedCrossRefGoogle Scholar
  270. 270.
    Camm AJ. Clinical trial design to evaluate the effects of drugs on cardiac repolarization: current state of the art. Heart Rhythm 2005; 2 (2 Suppl.): S23–9PubMedCrossRefGoogle Scholar
  271. 271.
    Letsas KP, Efremidis M, Kounas SP, et al. Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. Clin Res Cardiol 2009; 98(4): 208–12PubMedCrossRefGoogle Scholar
  272. 272.
    Shah RR. If a drug deemed ‘safe’ in nonclinical tests subsequently prolongs QT in phase 1 studies, how can its sponsor convince regulators to allow development to proceed? Pharmacol Ther 2008; 119(2): 215–21PubMedCrossRefGoogle Scholar
  273. 273.
    Jonker DM, Kenna LA, Leishman D, et al. A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data. Clin Pharmacol Ther 2005; 77(6): 572–82PubMedCrossRefGoogle Scholar
  274. 274.
    Piccini JP, Whellan DJ, Berridge BR, et al. Current challenges in the evaluation of cardiac safety during drug development: translational medicine meets the Critical Path Initiative. Am Heart J 2009; 158(3): 317–26PubMedCrossRefGoogle Scholar
  275. 275.
    Heist EK, Ruskin JN. Drug-induced proarrhythmia and use of QTc-prolonging agents: clues for clinicians. Heart Rhythm 2005; 2 (2 Suppl.): S1–8PubMedCrossRefGoogle Scholar
  276. 276.
    Makita N, Horie M, Nakamura T, et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 2002; 106(10): 1269–74PubMedCrossRefGoogle Scholar
  277. 277.
    Itoh H, Sakaguchi T, Ding WG, et al. Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome. Circ Arrhythm Electrophysiol 2009; 2(5): 511–23PubMedCrossRefGoogle Scholar
  278. 278.
    Astrom-Lilja C, Odeberg JM, Ekman E, et al. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. Pharmacoepidemiol Drug Saf 2008; 17(6): 587–92PubMedCrossRefGoogle Scholar
  279. 279.
    Peters RW, Gold MR. The influence of gender on arrhythmias. Cardiol Rev 2004; 12(2): 97–105PubMedCrossRefGoogle Scholar
  280. 280.
    Schrickel JW, Schwab JO, Yang A, et al. “Torsade de pointes” in patients with structural heart disease and atrial fibrillation treated with amiodarone, beta-blockers, and digitalis. Pacing Clin Electrophysiol 2006; 29(4): 363–6PubMedCrossRefGoogle Scholar
  281. 281.
    Di Cori A, Gemignani C, Bini R, et al. “Torsade de pointes” in a patient with variant angina. Ital Heart J 2004; 5(7): 554–8PubMedGoogle Scholar
  282. 282.
    Kozhevnikov DO, Yamamoto K, Robotis D, et al. Electrophysiological mechanism of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmias: tridimensional mapping of activation and recovery patterns. Circulation 2002; 105(9): 1128–34PubMedCrossRefGoogle Scholar
  283. 283.
    Pedersen HS, Elming H, Seibaek M, et al. Risk factors and predictors of torsade de pointes ventricular tachycardia in patients with left ventricular systolic dysfunction receiving dofetilide. Am J Cardiol 2007; 100(5): 876–80PubMedCrossRefGoogle Scholar
  284. 284.
    Elming H, Brendorp B, Kober L, et al. QTc interval in the assessment of cardiac risk. Card Electrophysiol Rev 2002; 6(3): 289–94PubMedCrossRefGoogle Scholar
  285. 285.
    Samuelov-Kinori L, Kinori M, Kogan Y, et al. Takotsubo cardiomyopathy and QT interval prolongation: who are the patients at risk for torsades de pointes? J Electrocardiol 2009 Jul–Aug; 42(4): 353–7PubMedCrossRefGoogle Scholar
  286. 286.
    Choy AM, Darbar D, Dell'Orto S, et al. Exaggerated QT prolongation after cardioversion of atrial fibrillation. J Am Coll Cardiol 1999; 34(2): 396–401PubMedCrossRefGoogle Scholar
  287. 287.
    Koster RW, Wellens HJ. Quinidine-induced ventricular flutter and fibrillation without digitalis therapy. Am J Cardiol 1976; 38(4): 519–23PubMedCrossRefGoogle Scholar
  288. 288.
    Badorff C, Zeiher AM, Hohnloser SH. Torsade de pointes tachycardia as a rare manifestation of acute enteroviral myocarditis. Heart 2001; 86(5): 489–90PubMedCrossRefGoogle Scholar
  289. 289.
    Sani IM, Solomon DS, Imhogene OA, et al. QT dispersion in adult hypertensives. J Natl Med Assoc 2006; 98(4): 631–6PubMedGoogle Scholar
  290. 290.
    McLean A, Sceats G. Torsade de pointes associated with thyrotoxicosis. Intern Med J 2003; 33(4): 207–8PubMedCrossRefGoogle Scholar
  291. 291.
    Kearney P, Reardon M, O'Hare J. Primary hyperparathyroidism presenting as torsades de pointes. Br Heart J 1993; 70(5): 473PubMedCrossRefGoogle Scholar
  292. 292.
    Shimizu K, Miura Y, Meguro Y, et al. QT prolongation with torsade de pointes in pheochromocytoma. Am Heart J 1992; 124(1): 235–9PubMedCrossRefGoogle Scholar
  293. 293.
    Sade E, Oto A, Oner Z, et al. Adrenal adenoma presenting with torsade de pointes: a case report. Angiology 2002; 53(4): 471–4PubMedCrossRefGoogle Scholar
  294. 294.
    Danenberg HD, Hasin Y. Polymorphic ventricular tachycardia and repolarization abnormalities accompanying intracerebral hemorrhage. Circulation 2000; 101(6): E81PubMedCrossRefGoogle Scholar
  295. 295.
    Alehan D, Ceviz N, Celiker A. Torsade de pointes associated with encephalitis. Turk J Pediatr 1999; 41(3): 395–8PubMedGoogle Scholar
  296. 296.
    Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008; 51(24): 2291–300PubMedCrossRefGoogle Scholar
  297. 297.
    Trejbal K, Mitro P. ECG changes in alcoholic intoxication. Vnitr Lek 2008; 54(4): 410–4PubMedGoogle Scholar
  298. 298.
    Anand S, Singh S, Nahar Saikia U, et al. Cardiac abnormalities in acute organophosphate poisoning. Clin Toxicol (Phila) 2009; 47(3): 230–5CrossRefGoogle Scholar
  299. 299.
    De Ponti F, Poluzzi E, Cavalli A, et al. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf 2002; 25(4): 263–86PubMedCrossRefGoogle Scholar
  300. 300.
    Di Micoli A, Zambruni A, Bracci E, et al. “Torsade de pointes” during amiodarone infusion in a cirrhotic woman with a prolonged QT interval. Dig Liver Dis 2009; 41(7): 535–8PubMedCrossRefGoogle Scholar
  301. 301.
    Schattner A, Gindin J, Geltner D. Fatal torsade de pointes following jaundice in a patient treated with disopyramide. Postgrad Med J 1989; 65(763): 333–4PubMedCrossRefGoogle Scholar
  302. 302.
    Reiffel JA, Appel G. Importance of QT interval determination and renal function assessment during antiarrhythmic drug therapy. J Cardiovasc Pharmacol Ther 2001; 6(2): 111–9PubMedCrossRefGoogle Scholar
  303. 303.
    Rottlaender D, Hoppe UC. Risks of non-prescription medication. Clobutinol cough syrup as a recent example. Dtsch Med Wochenschr 2008; 133(4): 144–6Google Scholar
  304. 304.
    Piccirillo G, Magri D, Matera S, et al. Effects of pink grapefruit juice on QT variability in patients with dilated or hypertensive cardiomyopathy and in healthy subjects. Transl Res 2008; 151(5): 267–72PubMedCrossRefGoogle Scholar
  305. 305.
    Schrickel J, Bielik H, Yang A, et al. Amiodarone-associated “torsade de pointes”: relevance of concomitant cardiovascular medication in a patient with atrial fibrillation and structural heart disease. Z Kardiol 2003; 92(10): 889–92PubMedCrossRefGoogle Scholar
  306. 306.
    Singh BN, Gaarder TD, Kanegae T, et al. Liquid protein diets and torsade de pointes. JAMA 1978; 240(2): 115–9PubMedCrossRefGoogle Scholar
  307. 307.
    Chen IC, Chang KC, Hsieh YK, et al. Torsade de pointes due to consumption of Sauropus androgynus as a weight-reducing vegetable. Am J Cardiol 1996; 78(10): 1186–7PubMedCrossRefGoogle Scholar
  308. 308.
    Marinucci P. Risk of torsades de pointes with non-cardiac drugs: grapefruit juice is source of potentially life threatening adverse drug reactions. BMJ 2001; 322(7277): 47PubMedCrossRefGoogle Scholar
  309. 309.
    Sagir A, Schmitt M, Dilger K, et al. Inhibition of cyto-chrome P450 3A: relevant drug interactions in gastroenterology. Digestion 2003; 68(1): 41–8PubMedCrossRefGoogle Scholar
  310. 310.
    Isner JM, Roberts WC, Heymsfield SB, et al. Anorexia nervosa and sudden death. Ann Intern Med 1985; 102(1): 49–52PubMedGoogle Scholar
  311. 311.
    Suri R, Poist ES, Hager WD, et al. Unrecognized bulimia nervosa: a potential cause of perioperative cardiac dysrhythmias. Can J Anaesth 1999; 46(11): 1048–52PubMedCrossRefGoogle Scholar
  312. 312.
    Pringle TH, Scobie IN, Murray RG, et al. Prolongation of the QT interval during therapeutic starvation: a substrate for malignant arrhythmias. Int J Obes 1983; 7(3): 253–61PubMedGoogle Scholar
  313. 313.
    Kocheril AG, Bokhari SA, Batsford WP, et al. Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997; 20(11): 2810–6PubMedCrossRefGoogle Scholar
  314. 314.
    Paran Y, Mashav N, Henis O, et al. Drug-induced torsades de pointes in patients aged 80 years or more. Anadolu Kardiyol Derg 2008; 8(4): 260–5PubMedGoogle Scholar
  315. 315.
    Hermans K, Stockman D, Van den Branden F. Grapefruit and tonic: a deadly combination in a patient with the long QT syndrome. Am J Med 2003; 114(6): 511–2PubMedCrossRefGoogle Scholar
  316. 316.
    Wilcock A, Beattie JM. Prolonged QT interval and methadone: implications for palliative care. Curr Opin Support Palliat Care 2009; 3(4): 252–7PubMedCrossRefGoogle Scholar
  317. 317.
    von Moltke LL, Greenblatt DJ, Duan SX, et al. Invitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J Clin Pharmacol 1994; 34(12): 1222–7Google Scholar
  318. 318.
    Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA 1993; 269(12): 1513–8PubMedCrossRefGoogle Scholar
  319. 319.
    Thanacoody RH, Daly AK, Reilly JG, et al. Factors affecting drug concentrations and QT interval during thioridazine therapy. Clin Pharmacol Ther 2007; 82(5): 555–65PubMedCrossRefGoogle Scholar
  320. 320.
    Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348(19): 1866–74PubMedCrossRefGoogle Scholar
  321. 321.
    Bednar MM, Harrigan EP, Ruskin JN. Torsades de pointes associated with nonantiarrhythmic drugs and observations on gender and QTc. Am J Cardiol 2002; 89(11): 1316–9PubMedCrossRefGoogle Scholar
  322. 322.
    Johnson JN, Ackerman MJ. QTc: how long is too long? Br J Sports Med 2009; 43(9): 657–62PubMedCrossRefGoogle Scholar
  323. 323.
    Viskin S. The QT interval: too long, too short or just right. Heart Rhythm 2009; 6(5): 711–5PubMedCrossRefGoogle Scholar
  324. 324.
    Shah RR. Cardiac repolarisation and drug regulation: assessing cardiac safety 10 years after the CPMP guidance. Drug Saf 2007; 30(12): 1093–110PubMedCrossRefGoogle Scholar
  325. 325.
    Fabritz L, Breithardt G, Kirchhof P. Preclinical testing of drug-induced proarrhythmia: value of transgenic models. Cardiovasc Hematol Agents Med Chem 2007; 5(4): 289–94PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  1. 1.Department of Medicine and Research CenterMontreal Heart Institute and University of MontrealMontrealCanada
  2. 2.Department of PharmacologyMcGill UniversityMontrealCanada
  3. 3.Montreal Heart Institute Research CenterMontrealCanada

Personalised recommendations