Drug-Induced Torsade de Pointes. Role of Genetic Factors

  • N. El-Sherif
  • G. Turitto
Conference paper


Inherited long QT syndrome (LQTS) is an uncommon cardiac electrophysiologic abnormality that predisposes to a malignant polymorphic ventricular tachyarrhythmia, commonly known as Torsade de Pointes (TdP) [1]. Mutations in several cardiac ion channels genes have been identified that cause the hereditary LQTS/TdP [2]. During the past several years, a number of approved and marketed drugs, both cardiovascular and non-cardiovascular agents, have been associated with QT interval prolongation, TdP, and sudden cardiac death [3]. Several of these drug have been removed from the market or have had restrictive labeling. This has caused significant concern among the regulatory agencies, the pharmateutical industry, the medical profession, and the public. The mechanism of drug-induced LQTS/TdP are not fully understood. It has been suggested that a fruste of the congential LQTS may play key role in the required LQTS/TdP. A better understanding of the factors involved in drug-included LQTS/TdP will help to implement effective preventive and therapeutic measures.


Potassium Current Interval Prolongation HERG Channel Ventricular Repolarization Hypertrophied Heart 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    EL-Sherif N, Turitto G (2003) Torsade de Pointes. Curr Opin Cardiol 18:6–13PubMedCrossRefGoogle Scholar
  2. 2.
    Zareba W, Moss AJ (2001) Long QT syndrome in children. J Electrocardiol 34:167–171PubMedCrossRefGoogle Scholar
  3. 3.
    Haverkamp W, Breithardt G, Camm AJ et al (2000) 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 47:219–233PubMedCrossRefGoogle Scholar
  4. 4.
    Splawski I, Shen J, Timothy KW et al (2000) Spectrum of mutations in long QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102:1178–1184PubMedCrossRefGoogle Scholar
  5. 5.
    Castillo R, Pedalino RP, El-Sherif N, Turitto G (2002) Efavirenz-associated QT prolongation and Torsade de pointes arrhythmia. Ann Pharmacother 36:1006–1008PubMedCrossRefGoogle Scholar
  6. 6.
    El-Sherif N, Caref EB, Yin H, Restivo M (1996) The electrophysiological mechanism of ventricular tachyarrhythmias in the long QT syndrome: tridimensional mapping of activation and recovery patterns. Circ Res 79:474–492PubMedCrossRefGoogle Scholar
  7. 7.
    El-Sherif N, Chinushi M, Caref EB, Restivo M (1997) 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 96:4392–4399PubMedCrossRefGoogle Scholar
  8. 8.
    Kozhevnikov DO, Yamamoto K, Robotis D et al (2002) Electrophysiological mechanisms of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmias. Tridimensional mapping of activation and recovery patterns. Circulation 105:1128–1134PubMedCrossRefGoogle Scholar
  9. 9.
    Mazur A, Anderson ME, Bonney S et al (2001) Pause-dependent polymorphic ventricular tachycardia during long-term treatment with dofetilide: a placebo-controlled, implantable cardioverter-defibrillator-based evaluation. J Am Coll Cardiol 37:1100–1105PubMedCrossRefGoogle Scholar
  10. 10.
    Torpe-Pedersen C, Molar M, Bloch-Thomsen PE et al (1999) Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality in Dofetilide Study Group. N Engl J Med 341:857–865CrossRefGoogle Scholar
  11. 11.
    Huang B, Qin D, El-Sherif N (2000) Early down-regulation of K+ channel genes and currents in the post infarction heart. J Cardiovasc Electrophysiol 11:1252–1261PubMedCrossRefGoogle Scholar
  12. 12.
    Huang B, El-Sherif T, Gidh-Jain M et al (2001) Alterations of sodium channel kinetics and gene expression in the post infarction remodeled myocardium. J Cardiovasc Electrophysiol 12:218–225PubMedCrossRefGoogle Scholar
  13. 13.
    Mitcheson JS, Chen J, Lin M et al (2000) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sei 97:12329–12333CrossRefGoogle Scholar
  14. 14.
    Roden DM (1998) Taking the ‘idio’ out of idiosyncratic: Predicting torsades de pointes. PACE 21:1029–1034PubMedCrossRefGoogle Scholar
  15. 15.
    Houltz B, Darpo B, Edvardsson N et al (1998) Electrocardiographic and clinical predictors of torsade de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter. A prospective study. PACE 21:1044–1057PubMedCrossRefGoogle Scholar
  16. 16.
    Sesti F, Abbott GW, Wei J et al (2000) A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sei USA 97:10613–10618CrossRefGoogle Scholar
  17. 17.
    Chevalier P, Rodriquez C, Bontemps L (2001) Non-invasive testing of acquired long QT syndrome: Evidence of or multiple arrhythmogenic substrates. Cardiovasc Res 50:386–398PubMedCrossRefGoogle Scholar
  18. 18.
    Splawski I, Timothy KW, Tateyama M (2002) Variant of SCNSA sodium channel implicated in risk of cardiac arrhythmias. Science 297:1333–1336PubMedCrossRefGoogle Scholar
  19. 19.
    Priori SG, Napolitano C, Schwartz PJ (1999) Low penetrance in the long-QT syndrome: Clinical impact. Circulation 99:529–533PubMedCrossRefGoogle Scholar
  20. 20.
    Marian J (2002) Modifier genes for hypertrophic cardiomyopathy. Curr Opin CardiOl 17:242–252PubMedCrossRefGoogle Scholar
  21. 21.
    Le Corvoisier P, Park HY, Carlson KM et al (2003) Impact of genetic polymorphism in heart failure prognosis. Arch Mol Coeur Vaiss 96:197–206Google Scholar
  22. 22.
    Committee for Proprietary Medicinal Products. Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-Cardiovascular Medicinal Products. The European agency for the Evaluation of Medicinal products. December 1997Google Scholar
  23. 23.
    Moss AJ, Zareba W, Benhorin J et al (2001 ) ISHNE guidelines for electrocardiographic evaluation of drug-related QT prolongation and other alterations in ventricular repolarization: Task Force summary. A report of the Task Force of the International Society for Holter and Noninvasive Electrocardiology (ISHNE), Committee on Ventricular Repolarization. Ann Noninvasive Electrocardiol 6:333–341PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2004

Authors and Affiliations

  • N. El-Sherif
    • 1
  • G. Turitto
    • 1
  1. 1.Cardiology Division, Department of MedicineState University of New York, Downstate Medical Center and New York Harbor Health Care CenterBrooklynUSA

Personalised recommendations