Skip to main content
SpringerLink
Log in

Interpretation of Clinical ECG Data

Understanding the Risk From Non-Antiarrhythmic Drugs

  • Chapter
Cardiac Safety of Noncardiac Drugs

Abstract

Prolongation of the QTc interval on the surface electrocardiogram (ECG) reflects a delay in ventricular repolarization, and, when drug-induced, it is almost always a result of inhibition of the rapid component of the delayed rectifier potassium current (IKr). The other current that is infrequently inhibited is its slow component (IKs). Drug-induced prolongation of the QTc interval, when excessive in the right setting, can be pro-arrhythmic and degenerate into torsade de pointes (TdP), a potentially fatal and unique form of polymorphic ventricular tachycardia. One review in 1993 concluded, “At present, our knowledge base about the relation of the QT interval and torsades de pointes is grossly incomplete” (1). Unfortunately, despite extensive research for more than a decade since, this still remains the case today. It is therefore not surprising that more than any other drug-induced adverse reaction, it has been responsible in recent times for the withdrawal of many drugs from the market.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Morganroth J. Relations of QTc prolongation on the electrocardiogram to torsades de pointes: definitions and mechanisms. Am J Cardiol 1993;72:10B–13B.

    Article  PubMed  CAS  Google Scholar 

  2. Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol 2002;54:188–202.

    Article  PubMed  CAS  Google Scholar 

  3. Committee for Proprietary Medicinal Products. Points to consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products (CPMP/986/96) EMEA, 17 December 1997, London. http://www.emea.eu.int/pdfs/human/swp/098696en.pdf. (Accessed on 10 February 2004.)

  4. US Food and Drug Administration/Health Canada The clinical evaluation of QT/QTc interval prolongation and pro-arrhythmic potential for non-antiarrhythmic drugs Preliminary Concept Paper (15 November 2002) http://www.fda.gov/ohrms/dockets/ac/03/briefing/pubs%5Cprelim.pdf. (Accessed on 10 February 2004.)

  5. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995;81:299–307.

    Article  PubMed  CAS  Google Scholar 

  6. Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA 2000;97:12329–12333.

    Article  PubMed  CAS  Google Scholar 

  7. Chachin M, Kurachi Y. Evaluation of pro-arrhythmic risk of drugs due to QT interval prolongation by the HERG expression system (Article in Japanese). Nippon Yakurigaku Zasshi 2002;119:345–351.

    PubMed  CAS  Google Scholar 

  8. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013–1022.

    Article  PubMed  CAS  Google Scholar 

  9. Fermini B, Fossa AA. The impact of drug-induced QT interval prolongation on drug discovery and development. Nature Rev Drug Dis 2003;2:439–447.

    Article  CAS  Google Scholar 

  10. Anon. Research and development costs: the great illusion. Prescrire Int 2004;13:32–36.

    Google Scholar 

  11. Kang J, Wang L, Chen XL, Triggle DJ, Rampe D. Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol Pharmacol 2001;59:122–126.

    PubMed  CAS  Google Scholar 

  12. Belardinelli L, Antzelevitch C, Vos MA. Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol Sci 2003;24:619–625.

    Article  PubMed  CAS  Google Scholar 

  13. Dessertenne F. La tachycardie ventriculaire á deux foyers opposes variable. Arch Mal Coeur Vaiss 1966;59:263–272.

    PubMed  CAS  Google Scholar 

  14. Stratmann HG, Kennedy HL. Torsades de pointes associated with drugs and toxins: recognition and management. Am Heart J 1987;113:1470–1482.

    Article  PubMed  CAS  Google Scholar 

  15. Tzivoni D, Keren A, Banai S, Stern S. Terminology of torsades de pointes. Cardiovasc Drugs Ther 1991;5:505–507.

    PubMed  CAS  Google Scholar 

  16. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001;85:321–341.

    Article  PubMed  CAS  Google Scholar 

  17. Bauman JL, Bauernfeind RA, Hoff JV, Strasberg B, Swiryn S, Rosen KM. Torsade de pointes due to quinidine: observations in 31 patients. Am Heart J 1984;107:425–430.

    Article  PubMed  CAS  Google Scholar 

  18. Burket MW, Fraker TD, Temesy-Armos PN. Polymorphic ventricular tachycardia provoked by lidocaine. Am J Cardiol 1985;55:592–593.

    Article  PubMed  CAS  Google Scholar 

  19. Nguyen PT, Scheinman MM, Seger J. Polymorphous ventricular tachycardia: clinical characterization, therapy, and the QT interval. Circulation 1986;74:340–349.

    PubMed  CAS  Google Scholar 

  20. Grogin HR, Scheinman M. Evaluation and management of patients with polymorphic ventricular tachycardia. Cardiol Clin 1993;11:39–54.

    PubMed  CAS  Google Scholar 

  21. Eisenberg SJ, Scheinman MM, Dullet NK, et al. Sudden cardiac death and polymorphous ventricular tachycardia in patients with normal QT intervals and normal systolic cardiac function. Am J Cardiol 1995;75:687–692.

    Article  PubMed  CAS  Google Scholar 

  22. Brady WJ, DeBehnke DJ, Laundrie D. Prevalence, therapeutic response, and outcome of ventricular tachycardia in the out-of-hospital setting: a comparison of monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, and torsades de pointes. Acad Emerg Med 1999;6:609–617.

    PubMed  CAS  Google Scholar 

  23. Paltoo B, O’Donoghue S, Mousavi MS. Levofloxacin induced polymorphic ventricular tachycardia with normal QT interval. Pacing Clin Electrophysiol 2001;24:895–897.

    Article  PubMed  CAS  Google Scholar 

  24. Kusano KF, Hata Y, Yumoto A, Emori T, Sato T, Ohe T. Torsade de pointes with a normal QT interval associated with hypokalemia. Jpn Circ J 2001;65:757–760.

    Article  PubMed  CAS  Google Scholar 

  25. Takahashi N, Ito M, Inoue T, et al. Torsades de pointes associated with acquired long QT syndrome: observation of 7 cases. J Cardiol 1993;23:99–106.

    PubMed  CAS  Google Scholar 

  26. Dota CD, Edvardsson N, Schutzer KM, et al. Inter-and intraday variability in major electrocardiogram intervals and amplitudes in healthy men and women. Pacing Clin Electrophysiol 2003;26(Pt 2):361–366.

    Article  PubMed  Google Scholar 

  27. Morganroth J, Brozovich FV, McDonald JT, Jacobs RA. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774–776.

    Article  PubMed  CAS  Google Scholar 

  28. Ganput MD, Williams P, Yogendran I, Keene ON, Maconochie JG. QTc, PR interval and heart rate variability in healthy volunteers-a review of 12-lead ECG data from clinical pharmacology studies. Br J Clin Pharmacol 1995;39:577P–578P.

    Google Scholar 

  29. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993;270:2590–2597.

    Article  PubMed  CAS  Google Scholar 

  30. Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome. Cardiology 2000;94:99–102.

    Article  PubMed  CAS  Google Scholar 

  31. Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: a familial cause of sudden death. Circulation 2003;108:965–970.

    Article  PubMed  Google Scholar 

  32. Schimpf R, Wolpert C, Bianchi F, et al. Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery. J Cardiovasc Electrophysiol 2003;14:1273–1277.

    Article  PubMed  Google Scholar 

  33. Makarov OM, Chuprova ON, Kiseleva OI. QT interval shortening in families with history of sudden death at young age (Article in Russian). Kardiologiia 2004;44:51–56.

    PubMed  CAS  Google Scholar 

  34. Bezzina CR, Verkerk AO, Busjahn A, et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc Res 2003;59:27–36.

    Article  PubMed  CAS  Google Scholar 

  35. Pietila E, Fodstad H, Niskasaari E, et al. Association between HERG K897T polymorphism and QT interval prolongation in middle-aged Finnish women. J Am Coll Cardiol 2002;40:511–514.

    Article  PubMed  CAS  Google Scholar 

  36. Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004;109:30–35.

    Article  PubMed  CAS  Google Scholar 

  37. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004;109:2394–2397.

    Article  PubMed  Google Scholar 

  38. DeSilvey DL, Moss AJ. Primidone in the treatment of the long QT syndrome: QT shortening and ventricular arrhythmia suppression. Ann Intern Med 1980;93:53–54.

    PubMed  CAS  Google Scholar 

  39. Pratt CM, Ruberg S, Morganroth J, et al. Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J 1996;131:472–480.

    Article  PubMed  CAS  Google Scholar 

  40. Garson A Jr. How to measure the QT interval-what is normal? Am J Cardiol 1993;72:14B–16B.

    Article  PubMed  Google Scholar 

  41. Bonate PL, Russell T. Assessment of QTc prolongations for noncardiac-related drugs from a drug development perspective. J Clin Pharmacol 1999;39:349–358.

    Article  PubMed  CAS  Google Scholar 

  42. Moss AJ. The QT interval and torsade de pointes. Drug Saf 1999;21(Suppl 1):5–10.

    Article  PubMed  CAS  Google Scholar 

  43. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866–1874.

    Article  PubMed  Google Scholar 

  44. 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;105:671–676.

    Article  Google Scholar 

  45. Funck-Brentano C, Coudray P, Planellas J, Motte G, Jaillon P. Effects of bepridil and diltiazem on ventricular repolarization in angina pectoris. Am J Cardiol 1990;66:812–817.

    Article  PubMed  CAS  Google Scholar 

  46. Oakley D, Jennings K, Puritz R, Krikler D, Chamberlain D. The effect of prenylamine on the QT interval of the resting electrocardiogram in patients with angina pectoris. Postgrad Med J 1980;56:753–756.

    Article  PubMed  CAS  Google Scholar 

  47. Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol 2003;21:3609–3615.

    Article  PubMed  CAS  Google Scholar 

  48. Bonate PL. Rank power of metrics used to assess QTc interval prolongation by clinical trial simulation. J Clin Pharmacol 2000;40:468–474.

    Article  PubMed  CAS  Google Scholar 

  49. Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH. Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans. Clin Pharmacol Ther 1996;60:543–553.

    Article  PubMed  CAS  Google Scholar 

  50. Hartigan-Go K, Bateman ND, Daly AK, Thomas SHL. Stereoselective cardiotoxic effects of terodiline. Clin Pharmacol Ther 1996;60:89–98.

    Article  PubMed  CAS  Google Scholar 

  51. Démolis J-L, Charransol A, Funck-Brentano C, Jaillon P. Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers. Br J Clin Pharmacol 1996;41:499–503.

    Article  PubMed  Google Scholar 

  52. Morganroth J, Hunt T, Dorr MB, Magner D, Talbot GH. The cardiac pharmacodynamics of therapeutic doses of sparfloxacin. Clin Ther 1999;21:1171–1181.

    Article  PubMed  CAS  Google Scholar 

  53. Morganroth J, Talbot GH, Dorr MB, Johnson RD, Geary W, Magner D. Effect of single ascending supratherapeutic doses of sparfloxacin on cardiac repolarisation (QTc interval). Clin Ther 1999;21:818–828.

    Article  PubMed  CAS  Google Scholar 

  54. Démolis J-L, Kubitza D, Tennezé L, Funck-Brentano C. Effect of a single oral dose of moxifloxacin (400mg and 800mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther 2000;68:658–666.

    Article  PubMed  Google Scholar 

  55. Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther 2003;73:292–303.

    Article  PubMed  CAS  Google Scholar 

  56. Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6(CYP2D6). Clin Pharmacol Ther 1999;65:10–20.

    Article  PubMed  CAS  Google Scholar 

  57. Shapiro E, Shapiro AK, Fulop G, et al. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 1989;46:722–730.

    PubMed  CAS  Google Scholar 

  58. Charbit B, Becquemont L, Lepere B, Peytavin G, Funck-Brentano C. Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine. Clin Pharmacol Ther 2002;72:514–523.

    Article  PubMed  CAS  Google Scholar 

  59. Bindschedler M, Lefevre G, Degen P, Sioufi A. Comparison of the cardiac effects of the antimalarials co-artemether and halofantrine in healthy participants. Am J Trop Med Hyg 2002;66:293–298.

    PubMed  CAS  Google Scholar 

  60. Kivisto KT, Lilja JJ, Backman JT, Neuvonen PJ. Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride. Clin Pharmacol Ther 1999;66:448–453.

    Article  PubMed  CAS  Google Scholar 

  61. Wang SH, Lin CY, Huang TY, Wu WS, Chen CC, Tsai SH. QT interval effects of cisapride in the clinical setting. Int J Cardiol 2001;80:179–183.

    Article  PubMed  CAS  Google Scholar 

  62. van Haarst AD, van’t Klooster GA, van Gerven JM, et al. The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther 1998;64:542–546.

    Article  PubMed  Google Scholar 

  63. Jaillon P, Morganroth J, Brumpt I, Talbot G and the Sparfloxacin Safety Group. Overview of electrocardiographic and cardiovascular safety data for sparfloxacin. J Antimicrob Chemotherap 1996;37(Supp A):161–167.

    CAS  Google Scholar 

  64. Zhou J, Meng R, Li X, Lu C, Fan S, Yang B. The effect of arsenic trioxide on QT interval prolongation during APL therapy. Chin Med J (Engl) 2003;116:1764–1766.

    CAS  Google Scholar 

  65. Khalifa M, Drolet B, Daleau P, et al. Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine. J Pharmacol Exp Ther 1999;288:858–865.

    PubMed  CAS  Google Scholar 

  66. Le Coz F, Funck-Brentano C, Poirier JM, Kibleur Y, Mazoit FX, Jaillon P. Prediction of sotalol-induced maximum steady-state QTc prolongation from single-dose administration in healthy volunteers. Clin Pharmacol Ther 1992;52:417–426.

    Article  PubMed  Google Scholar 

  67. Padrini R, Gusella M, Al Bunni M, et al. Tolerance to the repolarization effects of rac-sotalol during long-term treatment. Br J Clin Pharmacol 1997;44:463–470.

    Article  PubMed  CAS  Google Scholar 

  68. Allen MJ, Nichols DJ, Oliver SD. The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing. Br J Clin Pharmacol 2000;50:247–253.

    Article  PubMed  CAS  Google Scholar 

  69. Geelen P, Drolet B, Rail J, Berube J, et al. Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. Circulation 2000;102:275–277.

    PubMed  CAS  Google Scholar 

  70. Sofowora G, Dishy V, Roden D, Wood AJJ, Stein CM. The effect of sildenafil on QT interval in healthy men. Clin Pharmacol Ther 2001;69:67.

    Google Scholar 

  71. Alpaslan M, Onrat E, Samli M, Dincel C. Sildenafil citrate does not affect QT intervals and QT dispersion: an important observation for drug safety. Ann Noninvasive Electrocardiol 2003;8:14–17.

    Article  PubMed  Google Scholar 

  72. Burton S, Heslop K, Harrison K, Barnes M. Ziprasidone overdose. Am J Psychiatry 2000;157:835. (See Erratum Am J Psychiatry 2000;157:1359.)

    Article  PubMed  CAS  Google Scholar 

  73. Ritrovato CA. Pfizer Briefing Document for Zeldox capsules FDA Psychopharmacological Drugs Advisory Committee http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf. (Accessed on 10 February 2004.)

  74. Desai M, Tanus-Santos JE, Li L, et al. Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6. Pharmacogenomics J 2003;3:105–113.

    Article  PubMed  CAS  Google Scholar 

  75. Antzelevitch C, Shimizu W, Yan GX, Sicouri S. Cellular basis for QT dispersion. J Electrocardiol 1998;30(Suppl):168–175.

    Article  PubMed  Google Scholar 

  76. Franz MR. Bridging the gap between basic and clinical electrophysiology: what can be learned from monophasic action potential recordings? J Cardiovasc Electrophysiol 1994;5:699–710.

    Article  PubMed  CAS  Google Scholar 

  77. Franz MR, Zabel M. Electrophysiological basis of QT dispersion measurements. Prog Cardiovasc Dis 2000;42:311–324.

    Article  PubMed  CAS  Google Scholar 

  78. Yan GX, Shimizu W, Antzelevitch C. Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations. Circulation 1998;98:1921–1927.

    PubMed  CAS  Google Scholar 

  79. el-Sherif N. Electrophysiologic mechanisms of ventricular arrhythmias. Int J Card Imaging 1991;7:141–150.

    Article  PubMed  CAS  Google Scholar 

  80. Mirvis DM. Spatial variation of QT intervals in normal persons and patients with acute myocardial infarction. J Am Coll Cardiol 1985;5:625–631.

    PubMed  CAS  Google Scholar 

  81. Cowan JC, Griffiths CJ, Hilton CJ, et al. Epicardial repolarization mapping in man. Eur Heart J 1987;8:952–964.

    PubMed  CAS  Google Scholar 

  82. Day CP, McComb JM, Campbell RW. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990;63:342–344.

    Article  PubMed  CAS  Google Scholar 

  83. Higham PD, Furniss SS, Campbell RW. QT dispersion and components of the QT interval in ischaemia and infarction. Br Heart J 1995;73:32–36.

    Article  PubMed  CAS  Google Scholar 

  84. Okin PM, Devereux RB, Howard BV, Fabsitz RR, Lee ET, Welty TK. Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians: The Strong Heart Study. Circulation 2000;101:61–66.

    PubMed  CAS  Google Scholar 

  85. Priori SG, Napolitano C, Diehl L, Schwartz PJ. Dispersion of the QT interval. A marker of therapeutic efficacy in the idiopathic long QT syndrome. Circulation 1994;89:1681–1689.

    PubMed  CAS  Google Scholar 

  86. Hii JT, Wyse DG, Gillis AM, Duff HJ, Solylo MA, Mitchell LB. Precordial QT interval dispersion as a marker of torsade de pointes. Disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 1992;86:1376–1382.

    PubMed  CAS  Google Scholar 

  87. van de Loo A, Klingenheben T, Hohnloser SH. Amiodarone therapy after previous sotalol-induced torsade de pointes: Analysis of QT dispersion to predict proarrhythmia. J Cardiovasc Pharmacol Ther 1996;1:75–78.

    PubMed  Google Scholar 

  88. 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;21:1044–1057.

    Article  PubMed  CAS  Google Scholar 

  89. Cantelena LR, Honig PK. QT dispersion as a predictor of proarrhythmia in drug interactions with terfenadine. Clin Pharmacol Ther 1998;63:178.

    Google Scholar 

  90. Touze JE, Heno P, Fourcade L, et al. The effects of antimalarial drugs on ventricular repolarization. Am J Trop Med Hyg 2002;67:54–60.

    PubMed  CAS  Google Scholar 

  91. Bonnar CE, Davie AP, Caruana L, et al. QT dispersion in patients with chronic heart failure: Betablockers are associated with a reduction in QT dispersion. Heart 1999;81:297–302.

    PubMed  CAS  Google Scholar 

  92. Peng DQ, Zhao SP, Chen Y, Li XP. Effect of bisoprolol on QT dispersion in patients with congestive heart failure—the etiology-dependent response. Int J Cardiol 2001;77:141–148.

    Article  PubMed  CAS  Google Scholar 

  93. Yoshiga Y, Shimizu A, Yamagata T, et al. Beta-blocker decreases the increase in QT dispersion and transmural dispersion of repolarization induced by bepridil. Circ J 2002;66:1024–1028.

    Article  PubMed  CAS  Google Scholar 

  94. Kautzner J, Malik M. QT interval dispersion and its clinical utility. Pacing Clin Electrophysiol 1997;20(Pt 2):2625–2640.

    Article  PubMed  CAS  Google Scholar 

  95. Gillis AM. Effects of antiarrhythmic drugs on QT interval dispersion—relationship to antiarrhythmic action and proarrhythmia. Prog Cardiovasc Dis 2000;42:385–396.

    Article  PubMed  CAS  Google Scholar 

  96. Warner JP, Barnes TR, Henry JA. Electrocardiographic changes in patients receiving neuroleptic medication. Acta Psychiatr Scand 1996;93:311–313.

    Article  PubMed  CAS  Google Scholar 

  97. Thomas SHL, Ford GA, Higham PD, Campbell RWF, Rawlins MD. Effects of terodiline on the QT interval and QT dispersion. Clin Pharmacol Ther 1993;53:136.

    Google Scholar 

  98. Yerrabolu M, Prabhudesai S, Tawam M, Winter L, Kamalesh M. Effect of risperidone on QT interval and QT dispersion in the elderly. Heart Dis 2000;2:10–12.

    PubMed  CAS  Google Scholar 

  99. Tutar HE, Kansu A, Kalayci AG, Girgin N, Atalay S, Imamoglu A. Effects of cisapride on ventricular repolarization in children. Acta Paediatr 2000;89:820–823.

    Article  PubMed  CAS  Google Scholar 

  100. Tisdale JE, Rasty S, Padhi ID, Sharma ND, Rosman H. The effect of intravenous haloperidol on QT interval dispersion in critically ill patients: comparison with QT interval prolongation for assessment of risk of torsades de pointes. J Clin Pharmacol 2001;41:1310–1318.

    Article  PubMed  CAS  Google Scholar 

  101. Démolis JL, Funck-Brentano C, Ropers J, Ghadanfar M, Nichols DJ, Jaillon P. Influence of dofetilide on QT interval duration and dispersion at various heart rates during exercise in humans. Circulation 1996;94:1592–1599.

    PubMed  Google Scholar 

  102. Brendorp B, Elming H, Jun L, Kober L, Torp-Pedersen C: DIAMOND Study Group. Danish Investigations Of Arrhythmia and Mortality On Dofetilide. Effect of dofetilide on QT dispersion and the prognostic implications of changes in QT dispersion for patients with congestive heart failure. Eur J Heart Fail 2002;4:201–206.

    Article  PubMed  CAS  Google Scholar 

  103. Zareba W, Moss AJ, Rosero SZ, Hajj-Ali R, Konecki J, Andrews M. Electrocardiographic findings in patients with diphenhydramine overdose. Am J Cardiol 1997;80:1168–1173.

    Article  PubMed  CAS  Google Scholar 

  104. Surawicz B. Will QT dispersion play a role in clinical decision-making? J Cardiovasc Electrophysiol 1996;7:777–784.

    Article  PubMed  CAS  Google Scholar 

  105. Rautaharju PM. Why did QT dispersion die? Card Electrophysiol Rev 2002;6:295–301.

    Article  PubMed  Google Scholar 

  106. Faber TS, Kautzner J, Zehender M, Camm AJ, Malik M. Impact of electrocardiogram recording format on QT interval measurement and QT dispersion assessment. Pacing Clin Electrophysiol 2001;24:1739–1747.

    Article  PubMed  CAS  Google Scholar 

  107. Malik M, Batchvarov VN. Measurement, interpretation and clinical potential of QT dispersion. J Am Coll Cardiol 2000;36:1749–1766.

    Article  PubMed  CAS  Google Scholar 

  108. Kors JA, van Herpen G, van Bemmel JH. QT dispersion as an attribute of T-loop morphology. Circulation 1999;99:1458–1463.

    PubMed  CAS  Google Scholar 

  109. Malik M, Camm AJ. Mystery of QTc interval dispersion. Am J Cardiol 1997;79:785–787.

    Article  PubMed  CAS  Google Scholar 

  110. Yan GX, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation 1998;98:1928–1936.

    PubMed  CAS  Google Scholar 

  111. 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;108:1027–1033.

    Article  PubMed  Google Scholar 

  112. 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;102:706–712.

    PubMed  CAS  Google Scholar 

  113. Sicouri S, Moro S, Litovsky S, Elizari MV, Antzelevitch C. Chronic amiodarone reduces transmural dispersion of repolarization in the canine heart. J Cardiovasc Electrophysiol 1997;8:1269–1279.

    Article  PubMed  CAS  Google Scholar 

  114. Drouin E, Lande G, Charpentier F. Amiodarone reduces transmural heterogeneity of repolarization in the human heart. J Am Coll Cardiol 1998;32:1063–1067.

    Article  PubMed  CAS  Google Scholar 

  115. Eckardt L, Breithardt G, Haverkamp W. Electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsade de pointes: low torsadogenic potential despite QT prolongation. J Pharmacol Exp Ther 2002;300:64–71.

    Article  PubMed  CAS  Google Scholar 

  116. Viitasalo M, Oikarinen L, Swan H, et al. Ambulatory electrocardiographic evidence of transmural dispersion of repolarization in patients with long-QT syndrome type 1 and 2. Circulation 2002;106:2473–2478.

    Article  PubMed  Google Scholar 

  117. Tanabe Y, Inagaki M, Kurita T, et al. Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome. J Am Coll Cardiol 2001;37:911–919.

    Article  PubMed  CAS  Google Scholar 

  118. Takenaka K, Ai T, Shimizu W, et al. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation 2003;107:838–844.

    Article  PubMed  Google Scholar 

  119. Khositseth A, Nemec J, Hejlik J, Shen WK, Ackerman MJ. Effect of phenylephrine provocation on dispersion of repolarization in congenital long QT syndrome. Ann Noninvasive Electrocardiol 2003;8:208–214.

    Article  PubMed  Google Scholar 

  120. Shimizu W, Tanabe Y, Aiba T, et al. Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the LQT1 and LQT2 forms of congenital long QT syndrome. J Am Coll Cardiol 2002;39:1984–1991.

    Article  PubMed  Google Scholar 

  121. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 1998;98:2314–2322.

    PubMed  CAS  Google Scholar 

  122. Smetana P, Batchvarov V, Hnatkova K, Camm AJ, Malik M. Sex differences in the rate dependence of the T wave descending limb. Cardiovasc Res 2003;58:549–554.

    Article  PubMed  CAS  Google Scholar 

  123. Smetana P, Pueyo E, Hnatkova K, Batchvarov V, Camm AJ, Malik M. Effect of amiodarone on the descending limb of the T wave. Am J Cardiol 2003;92:742–746.

    Article  PubMed  CAS  Google Scholar 

  124. Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol 2002;17:43–51.

    Article  PubMed  Google Scholar 

  125. Batchvarov V, Hnatkova K, Ghuran A, Poloniecki J, Camm AJ, Malik M. Ventricular gradient as a risk factor in survivors of acute myocardial infarction. Pacing Clin Electrophysiol 2003;26(Pt 2):373–376.

    Article  PubMed  Google Scholar 

  126. Zabel M, Malik M. Practical use of T wave morphology assessment. Card Electrophysiol Rev 2002;6:316–322.

    Article  PubMed  Google Scholar 

  127. Zabel M, Acar B, Klingenheben T, Franz MR, Hohnloser SH, Malik M. Analysis of 12-lead T-wave morphology for risk stratification after myocardial infarction. Circulation 2000;102:1252–1257.

    PubMed  CAS  Google Scholar 

  128. Smetana P, Batchvarov VN, Hnatkova K, Camm AJ, Malik M. Sex differences in repolarization homogeneity and its circadian pattern. Am J Physiol Heart Circ Physiol. 2002;282:H1889–H1897.

    PubMed  CAS  Google Scholar 

  129. Malik M, Acar B, Gang Y, Yap YG, Hnatkova K, Camm AJ. QT dispersion does not represent electrocardiographic interlead heterogeneity of ventricular repolarization. J Cardiovasc Electrophysiol 2000;11:835–843.

    Article  PubMed  CAS  Google Scholar 

  130. Zabel M, Malik M, Hnatkova K, et al. Analysis of T-wave morphology from the 12-lead electrocardiogram for prediction of long-term prognosis in male US veterans. Circulation 2002;105:1066–1070.

    Article  PubMed  Google Scholar 

  131. Smetana P, Batchvarov VN, Hnatkova K, Camm AJ, Malik M. Ventricular gradient and nondipolar repolarization components increase at higher heart rate. Am J Physiol Heart Circ Physiol 2004;286:H131–H136.

    Article  PubMed  CAS  Google Scholar 

  132. http://www.fda.gov/ohrms/dockets/ac/03/slides/4000S1_05_Malik_files/frame.htm. (Accessed 29 February 2004.)

  133. 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–32B.

    Article  PubMed  CAS  Google Scholar 

  134. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 1993;269:1513–1518.

    Article  PubMed  CAS  Google Scholar 

  135. Moss AJ, Morganroth J. Cardiac effects of ebastine and other antihistamines in humans. Drug Saf 1999;21(Suppl 1):69–80.

    Article  PubMed  CAS  Google Scholar 

  136. Zareba W, Moss AJ, le Cessie S, Hall WJ. T wave alternans in idiopathic long QT syndrome. J Am Coll Cardiol 1994;23:1541–1546.

    Article  PubMed  CAS  Google Scholar 

  137. Kroll CR, Gettes LS. T wave alternans and torsades de pointes after the use of intravenous pentamidine. J Cardiovasc Electrophysiol 2002;13:936–938.

    Article  PubMed  Google Scholar 

  138. Fossa AA, Wisialowski T, Wolfgang E, et al. Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig. Eur J Pharmacol 2004;486:209–221.

    Article  PubMed  CAS  Google Scholar 

  139. Shimizu W, Antzelevitch C. Cellular and ionic basis for T-wave alternans under long-QT conditions. Circulation 1999;99:1499–1507.

    PubMed  CAS  Google Scholar 

  140. Watanabe O, Okumura T, Takeda H, et al. Nicorandil, a potassium channel opener, abolished torsades de pointes in a patient with complete atrioventricular block. Pacing Clin Electrophysiol 1999;22:686–688.

    Article  PubMed  CAS  Google Scholar 

  141. Fujimoto Y, Kusano KF, Morita H, Hong K, Yamanari H, Ohe T. Nicorandil attenuates both temporal and spatial repolarization alternans. J Electrocardiol 2000;33:269–277.

    Article  PubMed  CAS  Google Scholar 

  142. Sato T, Hata Y, Yamamoto M, et al. Early afterdepolarization abolished by potassium channel opener in a patient with idiopathic long QT syndrome. J Cardiovasc Electrophysiol 1995;6:279–282.

    Article  PubMed  CAS  Google Scholar 

  143. Armoundas AA, Nanke T, Cohen RJ. Images in cardiovascular medicine. T-wave alternans preceding torsade de pointes ventricular tachycardia. Circulation 2000;101:2550.

    PubMed  CAS  Google Scholar 

  144. Armoundas AA, Tomaselli GF, Esperer HD. Pathophysiological basis and clinical application of T-wave alternans. J Am Coll Cardiol 2002;40:207–217.

    Article  PubMed  Google Scholar 

  145. Brockmeier K, Aslan I, Hilbel T, Eberle T, Ulmer HE, Lux RL. T-wave alternans in LQTS: repolarization-rate dynamics from digital 12-lead Holter data. J Electrocardiol 2001;34(Suppl):93–96.

    Article  PubMed  Google Scholar 

  146. Habbab MA, el-Sherif N. TU alternans, long QTU, and torsade de pointes: clinical and experimental observations. Pacing Clin Electrophysiol 1992;15:916–931.

    Article  PubMed  CAS  Google Scholar 

  147. Klingenheben T, Gronefeld G, Li YG, Hohnloser SH. Effect of metoprolol and d,l-sotalol on microvolt-level T-wave alternans. Results of a prospective, double-blind, randomized study. J Am Coll Cardiol 2001;38:2013–2019.

    Article  PubMed  CAS  Google Scholar 

  148. Emori T, Antzelevitch C. Cellular basis for complex T waves and arrhythmic activity following combined IKr and IKs block. J Cardiovasc Electrophysiol 2001;12:1369–1378.

    Article  PubMed  CAS  Google Scholar 

  149. Song YC. Clinical observation on pause-dependent long QT syndrome and torsade de pointes ventricular tachycardia (Article in Chinese). Zhonghua Xin Xue Guan Bing Za Zhi 1992;20:349–351, 389.

    PubMed  CAS  Google Scholar 

  150. Moss AJ. T-wave patterns associated with the hereditary long QT syndrome. Card Electrophysiol Rev 2002;6:311–315.

    Article  PubMed  Google Scholar 

  151. Nakajima T, Misu K, Iwasawa K, et al. Auditory stimuli as a major cause of syncope in a patient with idiopathic long QT syndrome. Jpn Circ J 1995;59:241–246.

    PubMed  CAS  Google Scholar 

  152. White NJ, Looareesuwan S, Warrell DA. Quinine and quinidine: a comparison of EKG effects during the treatment of malaria. J Cardiovasc Pharmacol 1983;5:173–175.

    Article  PubMed  Google Scholar 

  153. Khongphatthanayothin A, Lane J, Thomas D, Yen L, Chang D, Bubolz B. Effects of cisapride on QT interval in children. J Pediatr 1998;133:51–56.

    Article  PubMed  CAS  Google Scholar 

  154. Shimizu W, Tanaka K, Suenaga K, Wakamoto A. Bradycardia-dependent early afterdepolarizations in a patient with QTU prolongation and torsade de pointes in association with marked bradycardia and hypokalemia. Pacing Clin Electrophysiol 1991;14:1105–1111.

    Article  PubMed  CAS  Google Scholar 

  155. Shah RR. Pharmacogenetic aspects of drug-induced torsade de pointes: Potential tool for improving clinical drug development and prescribing. Drug Saf 2004;27:145–172.

    Article  PubMed  CAS  Google Scholar 

  156. Paulussen AD, Gilissen RA, Armstrong M, et al. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J Mol Med 2004;82:182–188.

    Article  PubMed  CAS  Google Scholar 

  157. Gupta PR, Somani PN, Avasthey P, Singh VP. Prolonged QT and hypertrophic cardiomyopathy in two families with 10 sudden deaths. J Assoc Physicians India 1985;33:353–355.

    PubMed  CAS  Google Scholar 

  158. Martin AB, Garson A Jr, Perry JC. Prolonged QT interval in hypertrophic and dilated cardiomyopathy in children. Am Heart J 1994;127:64–70.

    Article  PubMed  CAS  Google Scholar 

  159. Peters S, Rust H, Trummel M, Brattstrom A. Familial hypertrophic cardiomyopathy associated with prolongation of the QT interval. Z Kardiol 2000;89:624–629.

    Article  PubMed  CAS  Google Scholar 

  160. MacNeil DJ, Davies RO, Deitchman D. Clinical safety profile of sotalol in the treatment of arrhythmias. Am J Cardiol 1993;72:44A–50A.

    Article  PubMed  CAS  Google Scholar 

  161. Kaab S, Dixon J, Duc J, et al. Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 1998;98:1383–1393.

    PubMed  CAS  Google Scholar 

  162. Schwartz PJ, Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 1978;57:1074–1077.

    PubMed  CAS  Google Scholar 

  163. Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998;338:1709–1714.

    Article  PubMed  CAS  Google Scholar 

  164. Marques JL, George E, Peacey SR, et al. Altered ventricular repolarization during hypoglycaemia in patients with diabetes. Diabet Med 1997;14:648–654.

    Article  PubMed  CAS  Google Scholar 

  165. Bernardi M, Calandra S, Colantoni A, et al. Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors. Hepatology 1998;27:28–34.

    Article  PubMed  CAS  Google Scholar 

  166. Bal JS, Thuluvath PJ. Prolongation of QTc interval: relationship with etiology and severity of liver disease, mortality and liver transplantation. Liver Int 2003;23:243–248.

    Article  PubMed  Google Scholar 

  167. Choy AM, Lang CC, Roden DM, et al. Abnormalities of the QT interval in primary disorders of autonomic failure. Am Heart J 1998;136:664–671.

    Article  PubMed  CAS  Google Scholar 

  168. Ishizaki F, Harada T, Yoshinaga H, Nakayama T, Yamamura Y, Nakamura S. Prolonged QTc intervals in Parkinson’s disease—relation to sudden death and autonomic dysfunction (Article in Japanese). No To Shinkei 1996;48:443–448.

    PubMed  CAS  Google Scholar 

  169. Kocheril AG, Bokhari SA, Batsford WP, Sinusas AJ. Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997;20:2810–2816.

    Article  PubMed  CAS  Google Scholar 

  170. Pourmoghaddas A, Hekmatnia A. The relationship between QTc interval and cardiac autonomic neuropathy in diabetes mellitus. Mol Cell Biochem 2003;249:125–128.

    Article  PubMed  CAS  Google Scholar 

  171. Veglio M, Chinaglia A, Cavallo Perin P. The clinical utility of QT interval assessment in diabetes. Diabetes Nutr Metab 2000;13:356–365.

    PubMed  CAS  Google Scholar 

  172. Veglio M, Sivieri R, Chinaglia A, Scaglione L, Cavallo-Perin P. QT interval prolongation and mortality in type 1 diabetic patients: A 5-year cohort prospective study. Neuropathy Study Group of the Italian Society of the Study of Diabetes, Piemonte Affiliate. Diabetes Care 2000;23:1381–1383.

    Article  PubMed  CAS  Google Scholar 

  173. Whitsel EA, Boyko EJ, Siscovick DS. Reassessing the role of QTc in the diagnosis of autonomic failure among patients with diabetes: a meta-analysis. Diabetes Care 2000;23:241–247.

    Article  PubMed  CAS  Google Scholar 

  174. Rossing P, Breum L, Major-Pedersen A, et al. Prolonged QTc interval predicts mortality in patients with Type 1 diabetes mellitus. Diabet Med 2001;18:199–205.

    Article  PubMed  CAS  Google Scholar 

  175. Wysowski DK, Corken A, Gallo-Torres H, Talarico L, Rodriguez EM. Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. Am J Gastroenterol 2001;96:1698–1703.

    Article  PubMed  CAS  Google Scholar 

  176. Hatta K, Takahashi T, Nakamura H, Yamashiro H, Asukai N, Yonezawa Y. Hypokalemia and agitation in acute psychotic patients. Psychiatry Res 1999;86:85–88.

    Article  PubMed  CAS  Google Scholar 

  177. Hatta K, Takahashi T, Nakamura H, Yamashiro H, Yonezawa Y. Prolonged QT interval in acute psychotic patients. Psychiatry Res 2000;94:279–295.

    Article  PubMed  CAS  Google Scholar 

  178. Huikuri H. Dispersion of repolarisation and the autonomic system-can we predict torsade de pointes? Cardiovasc Drugs Ther 2002;16:93–99.

    Article  PubMed  Google Scholar 

  179. Antzelevitch C. Sympathetic modulation of the long QT syndrome. Eur Heart J 2002;23:1246–1252.

    Article  PubMed  CAS  Google Scholar 

  180. Urao N, Shiraishi H, Ishibashi K, et al. Idiopathic long-QT syndrome with early after depolarizations induced by epinephrine. Circ J 2004;68:587–591.

    Article  PubMed  Google Scholar 

  181. Karle CA, Zitron E, Zhang W, Kathofer S, Schoels W, Kiehn J. Rapid component IKr of the guineapig cardiac delayed rectifier K+ current is inhibited by beta1-adrenoreceptor activation, via cAMP/protein kinase A-dependent pathways. Cardiovasc Res 2002;53:355–362.

    Article  PubMed  CAS  Google Scholar 

  182. Ben-David J, Zipes DP. Alpha-adrenoceptor stimulation and blockade modulates cesium-induced early afterdepolarizations and ventricular tachyarrhythmias in dogs. Circulation 1990;82:225–233.

    PubMed  CAS  Google Scholar 

  183. Schwartz PJ. Do animal models have a clinical value? Am J Cardiol 1998;81(6A):14D–20D.

    Article  PubMed  CAS  Google Scholar 

  184. Rampe D, Murawsky MK, Grau J, Lewis EW. The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther 1998;286:788–793.

    PubMed  CAS  Google Scholar 

  185. Maginn M, Frederiksen K, Adamantidis MM, Bischoff U, Matz J. The effects of sertindole and its metabolites on cardiac ion channels and action potentials. J Physiol 2000;525:79P.

    Google Scholar 

  186. Thomsen MB, Volders PG, Stengl M, et al. Electrophysiological safety of sertindole in dogs with normal and remodeled hearts. J Pharmacol Exp Ther 2003;307:776–784.

    Article  PubMed  CAS  Google Scholar 

  187. Presentations at the FDA Cardiovascular and Renal Drugs Advisory Committee, 29 May 2003.

    Google Scholar 

  188. Richardson MG, Roark GL, Helfaer MA. Intraoperative epinephrine-induced torsades de pointes in a child with long QT syndrome. Anaesthesiology 1992;76:647–649.

    Article  CAS  Google Scholar 

  189. Fujikawa H, Sato Y, Arakawa H, et al. Induction of torsades de pointes by dobutamine infusion in a patient with idiopathic long QT syndrome. Intern Med 1998;37:149–152.

    PubMed  CAS  Google Scholar 

  190. Furushima H, Chinushi M, Washizuka T, Aizawa Y. Role of alpha1-blockade in congenital long QT syndrome: investigation by exercise stress test. Jpn Circ J 2001;65:654–658.

    Article  PubMed  CAS  Google Scholar 

  191. Grubb BP. The use of oral labetalol in the treatment of arrhythmias associated with the long QT syndrome. Chest 1991;100:1724–1725.

    Article  PubMed  CAS  Google Scholar 

  192. Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long QT syndrome J Am Coll Cardiol 2003;41:633–642.

    Article  PubMed  CAS  Google Scholar 

  193. Noda T, Takaki H, Kurita T, et al. Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome. Eur Heart J 2002;23:975–983.

    Article  PubMed  CAS  Google Scholar 

  194. Henriksen JH, Bendtsen F, Hansen EF, Moller S. Acute non-selective beta-adrenergic blockade reduces prolonged frequency-adjusted QT interval (QTc) in patients with cirrhosis. J Hepatol 2004;40:239–246.

    Article  PubMed  CAS  Google Scholar 

  195. Kang J, Chen X-L, Wang H, et al. Cardiac ion channel effects of tolterodine. J Pharmacol Exp Ther 2004;308:935–940.

    Article  PubMed  CAS  Google Scholar 

  196. Thomas D, Gut B, Wendt-Nordahl G, Kiehn J. The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. J Pharmacol Exp Ther 2002;300:543–548.

    Article  PubMed  CAS  Google Scholar 

  197. Witchel HJ, Pabbathi VK, Hofmann G, Paul AA, Hancox JC. Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents. FEBS Lett 2002;512:59–66.

    Article  PubMed  CAS  Google Scholar 

  198. Xu X, Yan GX, Wu Y, Liu T, Kowey PR. Electrophysiologic effects of SB-237376: a new antiarrhythmic compound with dual potassium and calcium channel blocking action. J Cardiovasc Pharmacol 2003;41:414–421.

    Article  PubMed  CAS  Google Scholar 

  199. Committee for Proprietary Medicinal Products. European Public Assessment Report (EPAR) for Levitra (vardenafil) http://www.emea.eu.int/humandocs/Humans/EPAR/levitra/levitra.htm (Accessed on 2 February 2004.)

  200. Karunajeewa H, Lim C, Hung T-Y, et al. Safety evaluation of fixed combination piperaquine plus dihydroartemisinin (Artekin) in Cambodian children and adults with malaria. Br J Clin Pharmacol 2004;57:93–99.

    Article  PubMed  CAS  Google Scholar 

  201. Rust DM, Soignet SL. Risk/benefit profile of arsenic trioxide. Oncologist 2001;6(Suppl 2):29–32.

    Article  PubMed  CAS  Google Scholar 

  202. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852–3860.

    PubMed  CAS  Google Scholar 

  203. Ohnishi K, Yoshida H, Shigeno K, et al. Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia: need for careful electrocardiogram monitoring. Leukemia 2002;16:617–622.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medicines and Healthcare products Regulatory Agency, London, UK

    Rashmi R. Shah MD, BSC, MBBS, FRCP, FFPM (Senior Clinical Assessor)

Authors
  1. Rashmi R. Shah MD, BSC, MBBS, FRCP, FFPM
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. eResearchTechnology Inc., Philadelphia, PA, USA

    Joel Morganroth MD (Chief Scientist, Clinical Professor of Medicine) (Chief Scientist, Clinical Professor of Medicine)

  2. University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Joel Morganroth MD (Chief Scientist, Clinical Professor of Medicine) (Chief Scientist, Clinical Professor of Medicine)

  3. Global Medical Affairs, eResearchTechnology Inc., Bridgewater, NJ

    Ihor Gussak MD, PhD, FACC (Vice President, Clinical Associate Professor of Medicine, Associate Editor) (Vice President, Clinical Associate Professor of Medicine, Associate Editor)

  4. UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

    Ihor Gussak MD, PhD, FACC (Vice President, Clinical Associate Professor of Medicine, Associate Editor) (Vice President, Clinical Associate Professor of Medicine, Associate Editor)

  5. Journal of Electrocardiology, Bridgewater, NJ, USA

    Ihor Gussak MD, PhD, FACC (Vice President, Clinical Associate Professor of Medicine, Associate Editor) (Vice President, Clinical Associate Professor of Medicine, Associate Editor)

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Shah, R.R. (2005). Interpretation of Clinical ECG Data. In: Morganroth, J., Gussak, I. (eds) Cardiac Safety of Noncardiac Drugs. Humana Press. https://doi.org/10.1007/978-1-59259-884-7_15

Download citation

Publish with us

Policies and ethics

Search

Navigation