Drug Safety

, Volume 24, Issue 5, pp 323–351 | Cite as

Evaluation of Drug-Induced QT Interval Prolongation

Implications for Drug Approval and Labelling
  • Marek Malik
  • A. John Camm
Leading Article


Assessment of proarrhythmic toxicity of newly developed drugs attracts significant attention from drug developers and regulatory agencies. Although no guidelines exist for such assessment, the present experience allows several key suggestions to be made and an appropriate technology to be proposed.

Several different in vitro and in vitro preclinical models exist that, in many instances, correctly predict the clinical outcome. However, the correspondence between different preclinical models is not absolute. None of the available models has been demonstrated to be more predictive and/or superior to others. Generally, compounds that do not generate any adverse preclinical signal are less likely to lead to cardiac toxicity in humans. Nevertheless, differences in likelihood offer no guarantee compared with entities with a preclinical signal. Thus, the preclinical investigations lead to probabilistic answers with the possibility of both false positive and false negative findings.

Clinical assessment of drug-induced QT interval prolongation is crucially dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. An integral part of this is a precise heart rate correction of QT interval, which has been shown to require the assessment of QT/RR relationship in each study individual. The numbers of electrocardiograms required for such an assessment are larger than usually obtained in pharmacokinetic studies. Thus, cardiac safety considerations need to be an integral part of early phase I/II studies.

Once proarrhythmic safety has been established in phase I/II studies, large phase III studies and postmarketing surveillance can be limited to less strict designs. The incidence of torsade de pointes tachycardia varies from 1 to 5% with clearly proarrhythmic drugs (e.g. quinidine) to 1 in hundreds of thousands with drugs that are still considered unsafe (e.g. terfenadine, cisapride). Thus, not recording any torsade de pointes tachycardia during large phase III studies offers no guarantee, and the clinical premarketing evaluation has to rely on the assessment of QT interval changes. However, since QT interval prolongation is only an indirect surrogate of predisposition to the induction of torsade de pointes tachycardia, any conclusion that a drug is safe should be reserved until postmarketing surveillance data are reviewed.

The area of drug-related cardiac proarrhythmic toxicity is fast evolving. The academic perspective includes identification of markers more focused compared with simple QT interval measurement, as well as identification of individuals with an increased risk of torsade de pointes. The regulatory perspective includes careful adaptation of new research findings.


Moxifloxacin Cisapride Terfenadine Cardiac Toxicity Sparfloxacin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Schouten EG, Dekker JM, Meppelink P, et al. QT interval prolongation predicts cardiovascular mortality in an apparently healthy population. Circulation 1991; 84: 1516–23PubMedCrossRefGoogle Scholar
  2. 2.
    de Bruyne MC, Hoes AW, Kors JA, et al. Prolonged QT interval predicts cardiac and all-cause mortality in the elderly. Eur Heart J 1999; 20: 278–84PubMedCrossRefGoogle Scholar
  3. 3.
    Elming H, Holm E, Jun L, et al. The prognostic values of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens. Eur Heart J 1998; 19: 1391–400PubMedCrossRefGoogle Scholar
  4. 4.
    Kors JA, de Bruyne MC, Hoes AW, et al. T axis as an indicator of risk of cardiac events in elderly people. Lancet 1998; 352: 601–4PubMedCrossRefGoogle Scholar
  5. 5.
    Selzer A, Wray HW. Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 1964; 30: 17–26PubMedCrossRefGoogle Scholar
  6. 6.
    Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986; 111: 1088–93PubMedCrossRefGoogle Scholar
  7. 7.
    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: 806–17PubMedCrossRefGoogle Scholar
  8. 8.
    Bauman JL, Bauernfeind RA, Hoff JV, et al. Torsades de pointes due to quinidine: observations in 31 patients. Am Heart J 1984; 107: 425–30PubMedCrossRefGoogle Scholar
  9. 9.
    Haverkamp W, Martinez RA, Hief C, et al. Efficacy and safety of d,l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997; 30: 487–95PubMedCrossRefGoogle Scholar
  10. 10.
    Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996; 94: 2535–41PubMedCrossRefGoogle Scholar
  11. 11.
    Hohnloser SH. Proarrhythmia with class III antiarrhythmic drugs: types, risks, and management. Am J Cardiol 1997; 80: 82G–9GPubMedCrossRefGoogle Scholar
  12. 12.
    Mishra A, Friedman HS, Sinha AK. The effects of erythromycin on the electrocardiogram. Chest 1999; 115: 983–6PubMedCrossRefGoogle Scholar
  13. 13.
    Lipsky BA, Dorr MB, Magner DJ, et al. Safety profile of sparfloxacin, a new fluoroquinolone antibiotic. Clin Ther 1999; 21: 148–59PubMedCrossRefGoogle Scholar
  14. 14.
    Woywodt A, Grommas U, Buth W, et al. QT prolongation due to roxithromycin. Postgrad Med J 2000; 76: 651–3PubMedCrossRefGoogle Scholar
  15. 15.
    Haefeli WE, Schoenenberger RA, Weiss P, et al. Possible risk for cardiac arrhythmia related to intravenous erythromycin. Intensive Care Med 1992; 18: 469–73PubMedCrossRefGoogle Scholar
  16. 16.
    Katapadi K, Kostandy G, Katapadi M, et al. A review of erythromycin-induced malignant tachyarrhythmia-torsade de pointes. A case report. Angiology 1997; 48: 821–6PubMedCrossRefGoogle Scholar
  17. 17.
    Kamochi H, Nii T, Eguchi K, et al. Clarithromycin associated with torsade de pointes. Jpn Circ J 1999; 63: 421–2PubMedCrossRefGoogle Scholar
  18. 18.
    Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs. Clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J 2000; 21: 1216–31PubMedCrossRefGoogle Scholar
  19. 19.
    Laughren T, Gordon M. FDA background on Zeldox™ (ziprasidone hydrochlorite capsules) Pfizer, Inc. Psychopharmacological Drugs Advisory Committee. July 19, 2000. Available from: URL: [Accessed 2000 Sep]Google Scholar
  20. 20.
    Buckley NA, Sanders P. Cardiovascular adverse effects of antipsychotic drugs. Drug Saf 2000; 23: 512–28CrossRefGoogle Scholar
  21. 21.
    Nakamae H, Tsumura K, Hino M, et al. QT dispersion as a predictor of acute heart failure after high-dose cyclophosphamide. Lancet 2000; 335: 805–6CrossRefGoogle Scholar
  22. 22.
    Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992; 20: 1391–6PubMedCrossRefGoogle Scholar
  23. 23.
    Feng J, Yue L, Wang Z, et al. Ionic mechanisms of regional action potential heterogeneity in the canine right atrium. Circ Res 1998; 83: 541–1PubMedCrossRefGoogle Scholar
  24. 24.
    Hoppe UC, Beuckelmann DJ. Characterization of the hyperpolarization-activated inward current in isolated human atrial myocytes. Cardiovasc Res 1998; 38: 788–801PubMedCrossRefGoogle Scholar
  25. 25.
    Veldkamp MW. Is the slowly activating component of the delayed rectifier current, IKs, absent from undiseased human ventricular myocardium? Cardiovasc Res 1998; 40: 433–5PubMedCrossRefGoogle Scholar
  26. 26.
    El-Sherif N, Caref FB, Yin H, et al. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome: tridimensional mapping of activation and recovery patterns. Circ Res 1996; 79: 474–92PubMedCrossRefGoogle Scholar
  27. 27.
    Surawicz B. Electrophysiological substrate for Torsade de pointes: dispersion of refractoriness or early afterdepolarizations. J Am Coll Cardiol 1989; 14: 172–84PubMedCrossRefGoogle Scholar
  28. 28.
    Verduyn SC, Vos MA, Van der Zande J, et al. Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by magnesium. Cardiovasc Res 1997; 34: 453–63PubMedCrossRefGoogle Scholar
  29. 29.
    Antzelevitch C, Shimizu W, Yan GX, et al. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 1999; 10: 1124–52PubMedCrossRefGoogle Scholar
  30. 30.
    Houltz B, Darpö 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: 1044–57PubMedCrossRefGoogle Scholar
  31. 31.
    Carmeliet E. Effects of cetirizine on the delayed K+ currents in cardiac cells: comparison with terfenadine. Br J Pharmacol 1998; 124: 663–8PubMedCrossRefGoogle Scholar
  32. 32.
    Cavero I, Mestre M, Guillon JM, et al. Preclinical in vitro cardiac electrophysiology: a method of predicting arrhythmogenic potential of antihistamines in humans? Drug Saf 1999; 21Suppl. 1: S19–S31CrossRefGoogle Scholar
  33. 33.
    Gilbert JD, Cahill SA, McCartney DG, et al. Predictors of torsades de pointes in rabbit ventricles perfused with sedating and nonsedating histamine H1-receptor antagonists. Can J Physiol Pharmacol 2000; 78: 407–14PubMedGoogle Scholar
  34. 34.
    Delgado LF, Pferferman A, Sole D, et al. Evaluation of the potential cardiotoxicity of the antihistamines terfenadine, astemizole, loratadine, and cetirizine in atopic children. Ann Allergy Asthma Immunol 1998; 80: 333–7PubMedCrossRefGoogle Scholar
  35. 35.
    DuBuske LM. Second-generation antihistamines: the risk of ventricular arrhythmias. Clin Ther 1999; 21: 281–95PubMedCrossRefGoogle Scholar
  36. 36.
    Pagliara A, Testa B, Carrupt PA, et al. Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic H1-receptor antagonist. J Med Chem 1998; 41: 853–63PubMedCrossRefGoogle Scholar
  37. 37.
    Yue L, Feng JL, Wang Z, et al. Effects of ambasilide, quinidine, flecainide and verapamil on ultra-rapid delayed rectifier potassium currents in canine atrial myocytes. Cardiovasc Res 2000; 46: 151–61PubMedCrossRefGoogle Scholar
  38. 38.
    Zhou Z, Vorperian VR, Gong Q, et al. Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J Cardiovasc Electrophysiol 1999; 10: 836–43PubMedCrossRefGoogle Scholar
  39. 39.
    Roy M, Dumaine R, Brown AM. HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation 1996; 94: 817–23PubMedCrossRefGoogle Scholar
  40. 40.
    Rampe D, Roy ML, Dennis A, et al. A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. FEBS Lett 1997; 417: 28–32PubMedCrossRefGoogle Scholar
  41. 41.
    Chouabe C, Drici MD, Romey G, et al. Effects of calcium channel blockers on cloned cardiac K+ channels IKr and IKs. Therapie 2000; 55: 195–202PubMedGoogle Scholar
  42. 42.
    Suessbrich H, Schonherr R, Heinemann SH, et al. The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. Br J Pharmacol 1997; 120: 968–74PubMedCrossRefGoogle Scholar
  43. 43.
    De Cicco M, Marcor F, Robieux I, et al. Pharmacokinetic and pharmacodynamic effects of high-dose continuous intravenous verapamil infusion: clinical experience in the intensive care unit. Crit Care Med 1999; 27: 332–9PubMedCrossRefGoogle Scholar
  44. 44.
    Dascal N. The use of Xenopus oocytes for the study of ion channels. Crit Rev Biochem Mol Biol 1987; 22: 341–56CrossRefGoogle Scholar
  45. 45.
    Stühmer W, Parekh AB. Electrophysiological recordings from Xenopus oocytes. In: Sackmann B, Neher E, editors. Single-channel recordings. New York (NY): Plenum Press, 1995: 341–56Google Scholar
  46. 46.
    Fishman GI, McDonald TV. Gene transfer of membrane channel proteins. In: Zipes DP, Jalife J. editors. Cardiac electrophysiology. From cell to bedside. 3rd ed. Philadelphia (PA): Saunders Company, 2000: 58–66Google Scholar
  47. 47.
    Bril A, Gout B, Bonhomme M, et al. Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: experimental profile of BRL-32872. J Pharmacol Exp Ther 1996; 276: 637–46PubMedGoogle Scholar
  48. 48.
    Adamantidis MM, Caron JF, Bordet RC. Differential effects of antipsychotics and metabolites on action potentials recorded from rabbit Purkinje fibers: relationship with clinical case reports of QT prolongation and torsade de pointes [abstract]. Thérapie 2000; 55: 431Google Scholar
  49. 49.
    Kang J, Wang L, Chen X-L, et al. Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol Pharmacol 2001; 59: 122–6PubMedGoogle Scholar
  50. 50.
    Patmore L, Fraser S, Mair D, et al. Effects of sparfloxacin, grepafloxacin, moxifloxacin, and ciprofloxacin on cardiac action potential duration. Eur J Pharmacol 2000; 406: 449–52PubMedCrossRefGoogle Scholar
  51. 51.
    Drici MD, Wang WX, Liu XK, et al. Prolongation of QT interval in isolated feline hearts by antipsychotic drugs. J Clin Psychopharmacol 1998; 18: 477–81PubMedCrossRefGoogle Scholar
  52. 52.
    Sosunov EA, Gainullin RZ, Danilo PJ, et al. Electrophysiological effects of LU111995 on canine hearts: in vivo and in vitro studies. J Pharmacol Exp Ther 1999; 290: 146–52PubMedGoogle Scholar
  53. 53.
    Carlsson L, Amos GJ, Andersson B, et al. Electrophysiological characterization of the prokinetic agents cisapride and mosapride in vivo and in vitro: implications for proarrhythmic potential? J Pharmacol Exp Ther 1997; 282: 220–7PubMedGoogle Scholar
  54. 54.
    Detweiler DK. Electrocardiography in toxicological studies. In: Sipes IG, McQueen CA, Gandolfi AJ, editors. Comprehensive toxicology. New York (NY): Pergamon Press, 1977: 95–114Google Scholar
  55. 55.
    Van de Water A, Verheyen J, Xhonneux R, et al. An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. J Pharmacol Methods 1989; 22: 207–17PubMedCrossRefGoogle Scholar
  56. 56.
    Chezalviel-Guilbert F, Davy JM, Poirier JM, et al. Mexiletine antagonizes effects of sotalol on QT interval duration and its proarrythmic effects in a canine model of torsade de pointes. J Am Coll Cardiol 1995; 26: 787–92PubMedCrossRefGoogle Scholar
  57. 57.
    Weissenburger J, Davy JM, Chezalviel F, et al. Arrhythmogenic activities of antiarrhythmic drugs in conscious hypokalemic dogs with atrioventricular block: comparison between quinidine, lidocaine, flecainide, propranolol and sotalol. J Pharmacol Exp Ther 1991; 259: 871–3PubMedGoogle Scholar
  58. 58.
    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: 864–72PubMedCrossRefGoogle Scholar
  59. 59.
    Vos MA, de Groot SHM, 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: 1125–35PubMedCrossRefGoogle Scholar
  60. 60.
    Eckardt L, Haverkamp W, Borggrefe M, et al. Experimental models of torsade de pointes. Cardiovasc Res 1998; 39: 178–93PubMedCrossRefGoogle Scholar
  61. 61.
    Sicouri S, Antzelevitch D, Heilmann C, et al. Effects of sodium channel block with mexiletine to reverse action potential prolongation in in vitro models of the long term QT syndrome. J Cardiovasc Electrophysiol 1997; 8: 1280–90PubMedCrossRefGoogle Scholar
  62. 62.
    Ko CM, Ducic I, Fan J, et al. Suppression of mammalian K+ channel family by ebastine. J Pharmacol Exp Ther 1997; 281: 233–44PubMedGoogle Scholar
  63. 63.
    Malik M. Problems of heart rate correction in the assessment of drug induced QT interval prolongation. J Cardiovasc Electrophysiology 2001. In pressGoogle Scholar
  64. 64.
    Bazett JC. An analysis of time relations of electrocardiograms. Heart 1920; 7: 353–67Google Scholar
  65. 65.
    Fridericia LS. Die Systolendauer im Elekrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med Scand 1920; 53: 469–86CrossRefGoogle Scholar
  66. 66.
    Hodges M. Rate correction of the QT interval. Cardiac Electrophysiol Rev 1997; 1: 360–3CrossRefGoogle Scholar
  67. 67.
    Waller AD. A demonstration on man of electromotive changes accompanying the heart’s beat. J Physiol 1887; 8: 229–35PubMedGoogle Scholar
  68. 68.
    Mayeda I. On time relation between systolic duration of heart and pulse rate. Acta Sch Med Univ Kioto 1934; 17: 53–5Google Scholar
  69. 69.
    Adams W. The normal duration of the electrocardiographic ventricular complex. J Clin Invest 1936; 15: 335–42PubMedCrossRefGoogle Scholar
  70. 70.
    Ashman R. The normal duration of the Q-T interval. Am Heart J 1942; 522–34Google Scholar
  71. 71.
    Simonson E, Cady LD, Woodbury M. The normal Q-T interval. Am Heart J 1962; 63: 747–53PubMedCrossRefGoogle Scholar
  72. 72.
    Sarma JSM, Sarma RJ, Bilitch M, et al. An exponential formula for heart rate dependence of QT interval during exercise and pacing in humans: reevaluation of Bazett’s formula. Am J Cardiol 1984; 54: 103–8PubMedCrossRefGoogle Scholar
  73. 73.
    Hodges M, Salerno D, Erlien D. Bazett’s QT correction reviewed: evidence that a linear QT correction for heart rate is better. J Am Coll Cardiol 1983; 1: 694Google Scholar
  74. 74.
    Kawataki M, Kashima T, Toda H, et al. Relation between QT interval and heart rate: applications and limitations of Bazett’s Formula. J Electrocardiol 1984; 17: 371–5PubMedCrossRefGoogle Scholar
  75. 75.
    Sagie A, Larson MG, Goldberg RJ, et al. An improved method for adjusting the QT interval for heart rate (the Framingham study). Am J Cardiol 1992; 70: 797–801PubMedCrossRefGoogle Scholar
  76. 76.
    Rautaharju PM, Warren JW, Calhoun HP. Estimation of QT prolongation: a persistent, avoidable error in computer electrocardiography. J Electrocardiol; 23Suppl.: 111–7Google Scholar
  77. 77.
    Karjalainen J, Viitasalo M, Manttari M, et al. Relation between QT intervals and heart rates from 40 to 120 beats/min in rest electrocardiograms of men and a simple method to adjust QT interval values. J Am Coll Cardiol 1994; 23: 1547–53PubMedCrossRefGoogle Scholar
  78. 78.
    Kautzner J, Hnatkova K, Camm AJ, et al. Dependence of resting QTc interval on clinical characteristics of survivors of acute myocardial infarction: comparison of rate correction formulae [abstract]. Pacing Clin Electrophysiol 1997; 19: 334Google Scholar
  79. 79.
    Lazzara R. Antiarrhythmic drugs and torsade de pointes. Eur Heart J 1993; 14Suppl. H: 88–92PubMedCrossRefGoogle Scholar
  80. 80.
    Malik M. If Dr Bazett had had a computer. Pacing Clin Electrophysiol 1996; 19: 1635–39PubMedCrossRefGoogle Scholar
  81. 81.
    Hnatkova K, Malik M. ‘Optimum’ formulae for heart rate correction of the QT interval. Pacing Clin Electrophysiol 1999; 22: 1683–7PubMedCrossRefGoogle Scholar
  82. 82.
    Batchvarov V, Färbom P, Dilaveris P, et al. No single formula for heart rate correction of the QT interval is suitable for all individuals [abstract]. J Am Coll Cardiol 2001: 37Suppl. A; 91AGoogle Scholar
  83. 83.
    Batchvarov V, Ghuran A, Dilaveris P, et al. The 24-hour QT/RR relation in healthy subjects is reproducible in the short- and long term [abstract]. Ann Noninvas Electrocardiol 2000; 5: S57Google Scholar
  84. 84.
    Batchvarov V, Ghuran A, Hnatkova K, et al. Short- and long-term reproducibility of the QT/RR relationship in healthy subjects [abstract]. J Am Coll Cardiol 2001; 37Suppl. A: 101AGoogle Scholar
  85. 85.
    Choy AM, Lang CC, Roden DM, et al. Abnormalities of the QT interval in primary disorders of autonomic failure. Am Heart J 1998; 136: 664–71PubMedCrossRefGoogle Scholar
  86. 86.
    Antimisiaris M, Sarma JS, Schoenbaum MP, et al. Effects of amiodarone on the circadian rhythm and power spectral changes of heart rate and QT interval: significance for the control of sudden cardiac death. Am Heart J 1994; 128: 884–91PubMedCrossRefGoogle Scholar
  87. 87.
    Fauchier L, Babuty D, Poret P, et al. Effect of verapamil on QT interval dynamicity. Am J Cardiol 1999; 83: 807–808PubMedCrossRefGoogle Scholar
  88. 88.
    Sharma PP, Sarma JS, Singh BN. Effects of sotalol on the circadian of heart rate and QT intervals with a noninvasive index of reverse-use dependency. J Cardiovasc Pharmacol Ther 1999; 4: 15–21PubMedCrossRefGoogle Scholar
  89. 89.
    Gang Y, Guo X, Crook R, et al. Computerised measurement of QT dispersion in healthy subjects. Heart 1998; 80: 459–66PubMedGoogle Scholar
  90. 90.
    Morganroth J, Brown AM, Critz S, et al. Variability of the QTc interval: impact on defining drug effect and low-frequency cardiac event. Am J Cardiol 1993; 72: 26B–31BPubMedCrossRefGoogle Scholar
  91. 91.
    Molnar J, Zhang F, Weiss J, et al. Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events. J Am Coll Cardiol 1996; 27: 76–83PubMedCrossRefGoogle Scholar
  92. 92.
    Neyroud N, Maison-Blanche P, Denjoy I, et al. Diagnostic performance of QT interval variables from 24-h electrocardiography in the long QT syndrome. Eur Heart J 1998; 19: 158–65PubMedCrossRefGoogle Scholar
  93. 93.
    Gang Y, Guo X-H, Reardon M, et al. Circadian variation of the QT interval in patients with sudden cardiac death after myocardial infarction. Am J Cardiol 1998; 81: 950–6CrossRefGoogle Scholar
  94. 94.
    Batchvarov V, Farböm P, Dilaveris P, et al. Bazett formula is not suitable for assessment of the circadian variation of the heart-rate corrected QT interval [abstract]. J Am Coll Cardiol 2001. In pressGoogle Scholar
  95. 95.
    Lau CP, Freeman AR, Fleming SJ, et al. Hysteresis of the ventricular paced QT interval in response to abrupt changes in pacing rate. Cardiovasc Res 1988; 22: 67–72PubMedCrossRefGoogle Scholar
  96. 96.
    Koide T, Ozeki K, Kaihara S, et al. Etiology of QT prolongation and T wave changes in chronic alcoholism. Jpn Heart J 1981; 22: 151–66PubMedCrossRefGoogle Scholar
  97. 97.
    Yokoyama A, Ishii H, Takagi T, et al. Prolonged QT interval in alcoholic autonomic nervous dysfunction. Alcohol Clin Exp Res 1992; 16: 1090–2PubMedCrossRefGoogle Scholar
  98. 98.
    Perera R, Kraebber A, Schwartz MJ. Prolonged QT interval and cocaine use. J Electrocardiol 1997; 30: 337–9PubMedCrossRefGoogle Scholar
  99. 99.
    Gamouras GA, Monir G, Plunkitt K, et al. Cocaine abuse: repolarization abnormalities and ventricular arrhythmias. Am J Med Sci 2000; 320: 9–12PubMedCrossRefGoogle Scholar
  100. 100.
    Watanabe Y. Purkinje repolarization as a possible cause of the U wave in the electrocardiogram. Circulation 1975; 51: 1030–7PubMedCrossRefGoogle Scholar
  101. 101.
    Lepeschkin E. Physiologic basis of the U wave. In: Schlant RC, Hurst JW, editors. Advances in electrocardiography. New York (NY): Grune and Stratton, 1972: 431–7Google Scholar
  102. 102.
    Antzelevich C, Nesterenko VV, Yan GX. The role of M cells in acquired long QT syndrome, U waves and torsade de pointes. J Electrocardiol 1996; 28Suppl. 131–8Google Scholar
  103. 103.
    Yan G-Y, Antzelevich C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation 1998; 98: 1928–36PubMedCrossRefGoogle Scholar
  104. 104.
    Kautzner J, Yi G, Kishore R, et al. Interobserver reproducibility of QT interval measurement and QT dispersion in patients after acute myocardial infarction. Ann Noninvas Electrocardiol 1996; 1: 363–74CrossRefGoogle Scholar
  105. 105.
    Benardeau A, Weissenburger J, Hondeghem L, et al. Effects of the T-type Ca(2+) channel blocker mibefradil on repolarization of guinea pig, rabbit, dog, monkey, and human cardiac tissue. J Pharmacol Exp Ther 2000; 292: 561–75PubMedGoogle Scholar
  106. 106.
    Lepeschkin E, Surawicz B. The measurement of the Q-T interval of the electrocardiogram. Circulation 1952; 6: 378–88PubMedCrossRefGoogle Scholar
  107. 107.
    Malik M. Bradford A. Human precision of operating a digitizing board: implications for electrocardiogram measurement. Pacing Clin Electrophysiol 1998; 21: 1656–62PubMedCrossRefGoogle Scholar
  108. 108.
    Dilaveris P, Batchvarov V, Gialafos J, et al. Comparison of different methods for manual P wave duration measurement in 12-lead electrocardiograms. Pacing Clin Electrophysiol 1999; 22: 1532–8PubMedCrossRefGoogle Scholar
  109. 109.
    Zabel M, Klingenheben T, Franz MR, et al. Assessment of QT dispersion for prediction of mortality or arrhythmic events after myocardial infarction: results of a prospective, long-term follow-up study. Circulation 1998; 97: 2543–50PubMedCrossRefGoogle Scholar
  110. 110.
    Committee for Proprietary Medicinal Products (CPMP). Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. London: The European Agency for the Evaluation of Medicinal Products; 1997 DecGoogle Scholar
  111. 111.
    Hnatkova K, Malik D, Kishore R, et al. Computer system for measurement of QT and QU intervals and for evaluation of QT dispersion in standard 12 lead electrocardiograms. Eur J Card Pac Electrophysiol 1996; 6Suppl. 5: 113Google Scholar
  112. 112.
    Batchvarov V, Yi G, Guo X, et al. QT interval and QT dispersion measured with the threshold method depend on threshold level. Pacing Clin Electrophysiol 1998; 21: 2372–5PubMedCrossRefGoogle Scholar
  113. 113.
    Day CP, McComb LM, Campbell RWF. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990; 63: 342–244PubMedCrossRefGoogle Scholar
  114. 114.
    Surawicz B. Long QT: good, bad, indifferent and fascinating. ACC Curr J Rev 1999; 19–21Google Scholar
  115. 115.
    Kautzner J, Yi G, Camm AJ, et al. Short- and long-term reproducibility of QT, QTc, and QT dispersion measurement in healthy subjects. Pacing Clin Electrophysiol 1994; 17: 928–37PubMedCrossRefGoogle Scholar
  116. 116.
    Macfarlane PW, McLaughlin SC, Rodger C. Influence of lead selection and population on automated measurement of QT dispersion. Circulation 1998; 98: 2160–7PubMedCrossRefGoogle Scholar
  117. 117.
    Surawicz B. Will QT dispersion play a role in clinical decision-making? J Cardiovasc Electrophysiol 1996; 7: 777–84PubMedCrossRefGoogle Scholar
  118. 118.
    Rautaharju PM. QT and dispersion of ventricular repolarization: the greatest fallacy in electrocardiography in the 1990s. Circulation 1999; 18: 2477–8Google Scholar
  119. 119.
    Malik M, Batchvarov VN. Measurement, interpretation and clinical potential of QT dispersion. J Am Coll Cardiol 2000; 36: 1749–66PubMedCrossRefGoogle Scholar
  120. 120.
    Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA 1993; 269: 1513–8PubMedCrossRefGoogle Scholar
  121. 121.
    Benton RE, Honig PK, Zamani K, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther 1996; 59: 383–8PubMedCrossRefGoogle Scholar
  122. 122.
    Honig PK, Woosley RL, Zamani K, et al. Changes in the pharmacokinetics and electrocardiographic pharmacokinetics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992; 52: 231–8PubMedCrossRefGoogle Scholar
  123. 123.
    Honig PK, Wortham DC, Lazarev A, et al. Grapefruit juice alters the systemic bioavailability and cardiac repolarisation of terfenadine in poor metabolizers of terfenadine. J Clin Pharmacol 1996; 36: 345–51PubMedGoogle Scholar
  124. 124.
    Stern RH, Smithers JA, Olson SC. Atorvastatin does not produce a clinically significant effect on the pharmacokinetics of terfenadine. J Clin Pharmacol 1998; 38: 753–7PubMedGoogle Scholar
  125. 125.
    Honig PK, Wortham DC, Zamani K, et al. Effect of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and electrocardiographic effects of terfenadine. Eur J Clin Pharmacol 1993; 45: 41–6PubMedCrossRefGoogle Scholar
  126. 126.
    Honig PK, Wortham DC, Zamani K, et al. Comparison of the effect of the macrolide antibiotics erythromycin, clarithromycin and azithromycin on terfenadine steady-state pharmacokinetics and electrocardiographic parameters. Drug Invest 1994; 7: 148–56CrossRefGoogle Scholar
  127. 127.
    Goldberg M, Ring B, DeSante K, et al. Effect on dirithromycin on human CYP3A in vivo and on pharmacokinetics and pharmacodynamics of terfenadine in vivo. J Clin Pharmacol 1996; 36: 1154–60PubMedGoogle Scholar
  128. 128.
    Honig PK, Wortham DC, Hull R, et al. Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics. J Clin Pharmacol 1993; 33: 1201–6PubMedGoogle Scholar
  129. 129.
    Martin DE, Zussman BD, Everitt DE, et al. Paroxetine does not affect the cardiac safety and pharmacokinetics of terfenadine in healthy adult men. J Clin Psychopharmacol 1997; 17: 451–9PubMedCrossRefGoogle Scholar
  130. 130.
    Harris S, Hilligoss DM, Colangelo PM, et al. Azithromycin and terfenadine: lack of drug interaction. Clin Pharmacol Ther 1995; 58: 310–5PubMedCrossRefGoogle Scholar
  131. 131.
    Vargo D, Suttle A, Wildinson L, et al. Effects of zafirlukast on QTc and area under the curve on terfenadine in healthy men. J Clin Pharmacol 1997; 37: 858–78Google Scholar
  132. 132.
    Clifford C, Adams D, Murray S, et al. The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice. Eur J Clin Pharmacol 1997; 52: 311–5PubMedCrossRefGoogle Scholar
  133. 133.
    Awni W, Cavanaugh J, Leese P, et al. The pharmacokinetic and pharmacodynamic interaction between zileuton and terfenadine. Eur J Clin Pharmacol 1997; 52: 49–54PubMedCrossRefGoogle Scholar
  134. 134.
    van Haarst AD, van’t Klooster GAE, van Gerven JMA, et al. The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther 1998; 64: 542–6PubMedCrossRefGoogle Scholar
  135. 135.
    Kivistö KT, Lilja JJ, Backman JT, et al. Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride. Clin Pharmacol Ther 1999; 66: 448–53PubMedCrossRefGoogle Scholar
  136. 136.
    Pollak PT. Oral amiodarone. Pharmacotherapy 1998; 18: 121S–6SPubMedGoogle Scholar
  137. 137.
    Ebert SN, Liu XK, Woosley RL. Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health 1998; 7: 547–7PubMedCrossRefGoogle Scholar
  138. 138.
    Benton RE, Sale M, Flockhart DA, et al. Greater quinidine-induced QTc interval prolongation in women. Clin Pharmacol Ther 2000; 67: 413–8PubMedCrossRefGoogle Scholar
  139. 139.
    Walker AM, Szeneke P, Weartherby LB, et al. The risk of serious cardiac arrhythmias among cisapride users in the United Kingdom and Canada. Am J Med 1999; 107: 356–62PubMedCrossRefGoogle Scholar
  140. 140.
    Food and Drug Administration. Cisapride. FDC Report 2000, Jan 30Google Scholar
  141. 141.
    Miller JL. FDA, Janssen bolster cardiac risk warnings for cisapride. Am J Health Syst Pharm 2000 57: 414Google Scholar
  142. 142.
    Ludomirsky A, Klein HO, Sarelli P, et al. Q-T prolongation and polymorphous (‘torsade de pointes’) ventricular arrhythmias associated with organophosphorus insecticide poisoning. Am J Cardiol 1982; 49: 1654–8PubMedCrossRefGoogle Scholar
  143. 143.
    Raikhin-Eisenkraft B, Nutenko I, Kniznik D, et al. Death from fluoro-silicate in floor polish [in Hebrew]. Harefuah 1994; 126: 258–9Google Scholar
  144. 144.
    Pratt C, Brow AM, Rampe D, et al. Cardiovascular safety of fexofenadine HCl. Clin Exp Allergy 1999; 29Suppl. 3: S212–S6CrossRefGoogle Scholar
  145. 145.
    Pinto YM, van Gelder IC, Heeringa M, et al. QT lengthening and life-threatening arrhythmias associated with fexofenadine. Lancet 1999; 353: 980PubMedCrossRefGoogle Scholar
  146. 146.
    Tie H, Walker BD, Singleton CB, et al. Inhibition of HERG potassium channels by the antimalarial agent halofantrine. Br J Pharmacol 2000; 130: 1967–75PubMedCrossRefGoogle Scholar
  147. 147.
    Monlun E, Pillet O, Cochard JF, et al. Prolonged QT interval with halofantrine. Lancet 1993; 341: 1541–2PubMedGoogle Scholar
  148. 148.
    Toivonen L, Viitasalo M, Siikamaki H, et al. Provocation of ventricular tachycardia by antimalarial drug halofantrine in congenital long QT syndrome. Clin Cardiol 1994; 17: 403PubMedCrossRefGoogle Scholar
  149. 149.
    Akhtar T, Imran M. Sudden deaths while on halofantrine treatments - a report of two cases from Peshawar. JPMA J Pak Med Assoc 1994; 44: 120–1PubMedGoogle Scholar
  150. 150.
    Bakshi R, Hermeling-Fritz I, Gathmann I, et al. An integrated assessment of the clinical safety of artemether-lumefantrine: a new oral fixed-dose combination antimalarial drug. Trans R Soc Trop Med Hyg 2000; 94: 419–24PubMedCrossRefGoogle Scholar
  151. 151.
    Wesch DL, Dchuster BG, Wang WX, et al. Mechanism of cardiotoxicity of halofantrine. Clin Pharmacol Ther 2000; 67: 521–9CrossRefGoogle Scholar
  152. 152.
    Cavuto NJ, Woosley RL, Sale M, et al. Pharmacies and prevention of potentially fatal drug interactions. JAMA 1996; 275: 1086–7PubMedCrossRefGoogle Scholar
  153. 153.
    Thompson D, Oster G. Use of terfenadine and contraindicated drugs. JAMA 1996; 275: 1339–41PubMedCrossRefGoogle Scholar
  154. 154.
    Anon. Janssen Propulsid prescribing for inpatients questioned in three studies. FDC Rep 1998; 60: 26Google Scholar
  155. 155.
    Puddu PE, Bernard PM, Chaitman BR, et al. QT interval measurement by a computer assisted program: a potentially useful clinical parameter. J Electrocardiol 1982; 15: 15–21PubMedCrossRefGoogle Scholar
  156. 156.
    Fayn J, Rubel P, Mohsen N. An improved method for the precise measurement of serial ECG changes in QRS duration and QT interval. Performance assessment on the CSE noise-testing database and a healthy 720 case-set population. J Electrocardiol 1992; 24Suppl.: 123–7PubMedGoogle Scholar
  157. 157.
    Bhullar HK, Fothergill JC, Goddard WP, et al. Automated-measurement of QT interval dispersion from hard-copy ECGs. J Electrocardiol 1993; 26: 321–31PubMedCrossRefGoogle Scholar
  158. 158.
    Laguna P, Jane R, Caminal P. Automatic detection of wave boundaries in multilead ECG signals: validation with the CSE database. Comput Biomed Res 1994; 27: 45–60PubMedCrossRefGoogle Scholar
  159. 159.
    Rubel P, Hamidi S, Behlouli H, et al. Are serial Holter QT, late potential, and wavelet measurement clinically useful? J Electrocardiol 1996; 29Suppl.: 52–61PubMedCrossRefGoogle Scholar
  160. 160.
    Reddy BR, Xue Q, Zywietz C. Analysis of interval measurements on CSE multilead reference ECGs. J Electrocardiol 1996; 29Suppl.: 62–6PubMedCrossRefGoogle Scholar
  161. 161.
    Hoon TJ. Performance of an electrocardiographic analysis system: implications for pharmacodynamic studies. Pharmacotherapy 1996; 16: 230–6PubMedGoogle Scholar
  162. 162.
    Glancy JM, Weston PJ, Bhullar HK, et al. Reproducibility and automatic measurement of QT dispersion. Eur Heart J 1996; 17: 1035–9PubMedCrossRefGoogle Scholar
  163. 163.
    Xue Q, Reddy S. Algorithms for computerized QT analysis. J Electrocardiol 1998; 30: 181–6PubMedCrossRefGoogle Scholar
  164. 164.
    Tikkanen PE, Sellin LC, Kinnunen HO, et al. Using simulated noise to define optimal QT intervals for computer analysis of ambulatory ECG. Med Eng Phys 1999; 21: 15–25PubMedCrossRefGoogle Scholar
  165. 165.
    Savelieva I, Yi G, Guo X, et al. Agreement and reproducibility of automatic versus manual measurement of QT interval and QT dispersion. Am J Cardiol 1998; 81: 471–7PubMedCrossRefGoogle Scholar
  166. 166.
    Vila JA, Yi G, Rodríguez Presedo AM, et al. A new approach for TU complex characterization. IEEE Trans Biomed Eng 2000; 47: 764–72PubMedCrossRefGoogle Scholar
  167. 167.
    Acar B, Yi G, Hnatkova K, et al. Spatial, temporal and wavefront direction characteristics of 12-lead T wave morphology. Med Biol Eng Comput 1999; 37: 574–84PubMedCrossRefGoogle Scholar
  168. 168.
    Zabel M, Acar B, Klingenheben T, et al. Analysis of twelve-lead T wave morphology for risk stratification after myocardial infarction. Circulation 2000; 102: 1252–7PubMedCrossRefGoogle Scholar
  169. 169.
    Hnatkova K, Ryan SJ, Bathen J, et al. T-wave morphology differentiates between patients with and without arrhythmic complications of ischaemic heart disease. J Electrocardiol 2001. In pressGoogle Scholar
  170. 170.
    Zhang L, Timothy KW, Vincent M, et al. Spectrum of ST-T wave patterns and repolarisation parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation 2000; 102: 2849–55PubMedCrossRefGoogle Scholar
  171. 171.
    Sesti F, Abbott GW, Wei J, et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A 2000; 97: 10613–8PubMedCrossRefGoogle Scholar
  172. 172.
    Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol 2000; 11: 691–6PubMedCrossRefGoogle Scholar
  173. 173.
    Clancy CE, Rudy Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature 1999; 400: 566–9PubMedCrossRefGoogle Scholar
  174. 174.
    Roden DM, Kupershmidt S. From genes to channels: normal mechanisms. Cardiovasc Res 1999; 42: 318–26PubMedCrossRefGoogle Scholar
  175. 175.
    Darbar D, Smith M, Morike K, et al. Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem. Am J Cardiol 1996; 77: 1351–5PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Department of Cardiological SciencesSt George’s Hospital Medical SchoolLondonEngland

Personalised recommendations