Drug-Induced QT Interval Prolongation: Mechanisms, Risk Factors, Genetics and Clinical Management

Abstract

Long QT syndrome LQTS characterized by prolongation of the QT interval, may occur as congenital or drug-induced forms. Drug-induced QT interval prolongation DI-QTP is closely associated with severe ventricular arrhythmias [especially torsade de pointes TdP ] and sudden cardiac death. In particular, development of DI-QTP is generally associated with multiple risk factors. Cardiac and non-cardiac drugs may cause QT interval prolongation QTP and TdP. Most of the QT-prolonging drugs act by blocking the rapid component of the delayed rectifier potassium channel whereas a smaller number of drugs act by modifying Ca2+ and Na+ currents. In addition, pharmacokinetic drug interactions are among the reasons of DI-QTP. The corrected QT interval QTc according to heart rate by Bazett’s formula is the most commonly used. Genetic susceptibility is another important issue in predicting DI-QTP and TdP risk. Silent mutations and/or polymorphisms associated with cardiac ion channels may cause a risk for DI-QTP. Firstly, for treatment, drugs that cause QTP should be stopped rapidly, electrolyte abnormalities and other pathologies should be rapidly corrected. Intravenous magnesium sulphate, overdrive pacing, isoproterenol and plasma alkalinisation via sodium bicarbonate are the main useful treatments for DI-QTP and related TdP therapy. Class 1B antiarrhythmic drugs and intravenous potassium are thought to may be effective in TdP.The purpose of this article is to review the underlying mechanisms of QTP, risk factors and genetics of DI-QTP, how to measurement of QT interval and treatment of acquired LQTS.Key-words: Drugs, QT interval, QT prolongation and torsade de pointes

Keywords

• Drugs, QT interval, QT prolongation and torsade de pointes.

References

1. Van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug- associated QT interval prolongation. Br J Clin Pharmacol 2010;70:16– 23. [CrossRef]
2. Testai L, Cecchetti V, Sabatini S, Martelli A, Breschi MC, Calderone V. Effects of KATP openers on the QT prolongation induced by HERG- blocking drugs in guinea-pigs. J Pharm Pharmacol 2010;62:924–930. [CrossRef]
3. Beitland S, Platou ES, Sunde K. Drug-induced long QT syndrome and fatal arrhythmias in the intensive care unit. Acta Anaesthesiol Scand 2014;58:266–272. [CrossRef]
4. Cubeddu L. Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias. Curr Cardiol Rev 2016;12:141–154. [CrossRef]
5. Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Can Pharm J (Ott) 2016;149:139–152. [CrossRef]
6. Uvelin A, Pejaković J, Mijatović V. Acquired prolongation of QT interval as a risk factor for torsade de pointes ventricular tachycardia: a narrative review for the anesthesiologist and intensivist. J Anesth 2017;31:413–423. [CrossRef]
7. Thomas SHL, Behr ER. Pharmacological treatment of acquired QT prolongation and torsades de pointes. Br J Clin Pharmacol 2016;81:420–427. [CrossRef]
8. Isbister GK. Risk assessment of drug-induced QT prolongation. Aust Prescr 2015;38:20–24. [CrossRef]

9. Trinkley KE, Page RL 2nd, Lien H, Yamanouye K, Tisdale JE. QT interval prolongation and the risk of torsades de pointes: essentials for clinicians. Curr Med Res Opin 2013;29:1719–1726. [CrossRef]
10. Konstantopoulou A, Tsikrikas S, Asvestas D, Korantzopoulos P, Letsas KP. Mechanisms of drug-induced proarrhythmia in clinical practice. World J Cardiol 2013;5:175–185. [CrossRef]
11. Li G, Cheng G, Wu J, Zhou X, Liu P, Sun C. Drug-induced long QT syndrome in women. Adv Ther 2013;30:793–802. [CrossRef]
12. Kallergis EM, Goudis CA, Simantirakis EN, Kochiadakis GE, Vardas PE. Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review. Sci World J 2012;2012:212178. [CrossRef]
13. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf 2012;3:241–253. [CrossRef]
14. Lazzara R. Amiodarone and torsade de pointes. Ann Intern Med 1989;111:549–551. [CrossRef] https://doi.org/10.7326/0003-4819- 111-7-549
15. Letsas KP, Efremidis M, Filippatos GS, Sideris AM. Drug-induced long QT syndrome. Hellenic J Cardiol 2007;48:296–299. Available at: https:// www.hellenicjcardiol.org/archive/full_text/2007/5/2007_5_296.pdf
16. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003;89:1363–1372. [CrossRef]
17. Isbister GK, Page CB. Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice. Br J Clin Pharmacol 2013;76:48–57. [CrossRef]
18. Barra S, Agarwal S, Begley D, Providência R. Post-acute management of the acquired long QT syndrome. Postgrad Med J 2014;90:348–358. [CrossRef]
19. Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics 2013;54:1–13. [CrossRef]
20. Kannankeril PJ, Roden DM. Drug-induced long QT and torsade de pointes: recent advances. Curr Opin Cardiol 2007;22:39–43. [CrossRef]
21. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013–1022. [CrossRef]
22. Kannankeril P, Roden DM, Darbar D. Drug-induced long QT syndrome. Pharmacol Rev 2010;62:760–781. [CrossRef]
23. Antzelevitch C. Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes. Heart Rhythm 2005;2:S9–S15. [CrossRef]
24. Smits JP, Blom MT, Wilde AA, Tan HL. Cardiac sodium channels and inherited electrophysiologic disorders: a pharmacogenetic overview. Expert Opin Pharmacother 2008;9:537–549. [CrossRef]
25. Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J 2007;153:891–899. [CrossRef]
26. Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010;55:934–947. [CrossRef]
27. Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug- Induced QT Prolongation and Torsades de Pointes. J Am Coll Cardiol 2016;67:1639–1650.[CrossRef]
28. Tamargo J. Drug-induced torsade de pointes: from molecular biology to bedside. Jpn J Pharmacol 2000;83:1–19. [CrossRef]
29. Varró A, Baczkó I. Cardiac ventricular repolarization reserve: a principle for understanding drug-related proarrhythmic risk. Br J Pharmacol 2011;164:14–36. [CrossRef]
30. Spellmann I, Reinhard MA, Veverka D, et al. QTc prolongation in short-term treatment of schizophrenia patients: effects of different antipsychotics and genetic factors. Eur Arch Psychiatry Clin Neurosci 2018;268:383–390. [CrossRef]
31. Nakano Y, Shimizu W. Genetics of long-QT syndrome. J Hum Genet 2016;61:51–55. [CrossRef]
32. Shimizu W. Clinical impact of genetic studies in lethal inherited cardiac arrhythmias. Circ J 2008;72:1926–1936. [CrossRef]
33. Yang P, Kanki H, Drolet B, et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002;105:1943–1948. [CrossRef]
34. 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;97:10613–10618. [CrossRef]
35. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms I Kr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175–187. [CrossRef]
36. Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 2006;113:783–790. [CrossRef]
37. Eftekharian A, Mahani MH. Jervell and Lange-Nielsen syndrome in cochlear implanted patients: our experience and a review of literature. Int J Pediatr Otorhinolaryngol 2015;79:1544–1547. [CrossRef]
38. Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M. Jervell and Lange-Nielsen syndrome: a Norwegian perspective. Am J Med Genet 1999;89:137–146. [CrossRef]
39. Roston TM, Cunningham T, Lehman A, Laksman ZW, Krahn AD, Sanatani S. Beyond the Electrocardiogram: Mutations in Cardiac Ion Channel Genes Underlie Nonarrhythmic Phenotypes. Clin Med Insights Cardiol 2017;11:1179546817698134. [CrossRef]
40. Pfeufer A, Sanna S, Arking DE, et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet 2009;41:407–414. [CrossRef]
41. Newton-Cheh C, Eijgelsheim M, Rice KM, et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet 2009;41:399–406. [CrossRef]
42. Bektaşoğlu G, Yılmaz M, Turgut O, Tandoğan İ. Uzun QT sendromları. Cumhuriyet Med J 2009;31:487–501. Available at: https://dergipark. org.tr/tr/download/article-file/47583
43. Khan IA. Long QT syndrome: diagnosis and management. Am Heart J 2002;143:7–14. [CrossRef]
44. Khan IA, Gowda RM. Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004;95:1–6. [CrossRef]