variants localizing to Kv11.1's pore have worse clinical outcomes than those with pathogenic variants localizing the channel's C-terminal region. LQT3 This accounts for 5 to 10 percent of cases and is caused by gain-of-function variants in the SCN5A-encoded Nav1.5 sodium channel. Events occurring at rest or during sleep are characteristic of (but not specific for) LQT3. (See 'Type 3 LQTS (LQT3)' above.) LQTS genetic testing This has been available clinically/commercially since 2004 in the United States, and LQTS genetic testing is a class I recommendation for any patient being considered to have LQTS to enable genotype-guided risk stratification and genotype- guided tailoring of therapy and to permit cascade variant-specific testing of the appropriate relatives. (See 'Genetic testing' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Moss AJ. Long QT Syndrome. JAMA 2003; 289:2041. 3. El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol 2003; 18:6. 4. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 5. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 12/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 6. Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes. J Am Coll Cardiol 2016; 67:1639. 7. January CT, Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res 1989; 64:977. 8. Szabo B, Sweidan R, Rajagopalan CV, Lazzara R. Role of Na+:Ca2+ exchange current in Cs(+)- induced early afterdepolarizations in Purkinje fibers. J Cardiovasc Electrophysiol 1994; 5:933. 9. Roden DM, Lazzara R, Rosen M, et al. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation 1996; 94:1996. 10. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol 1994; 23:259. 11. Antzelevitch C, Sun ZQ, Zhang ZQ, Yan GX. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol 1996; 28:1836. 12. Ben-David J, Zipes DP. Torsades de pointes and proarrhythmia. Lancet 1993; 341:1578. 13. Schwartz P, Locati E, Priori E, Zaza A. Cardiac Electrophysiology: From Cell to Bedside. In: Car diac Electrophysiology: From Cell to Bedside, Zipes D, Jalife J (Eds), WB Saunders, Philadelphi a 1990. p.589. 14. Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J 1975; 89:45. 15. Dusi V, Pugliese L, De Ferrari GM, et al. Left Cardiac Sympathetic Denervation for Long QT Syndrome: 50 Years' Experience Provides Guidance for Management. JACC Clin Electrophysiol 2022; 8:281. 16. Tan HL, Hou CJ, Lauer MR, Sung RJ. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995; 122:701. 17. Yan GX, Wu Y, Liu T, et al. Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall. Circulation 2001; 103:2851. 18. Hosseini SM, Kim R, Udupa S, et al. Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome. Circulation 2018; 138:1195. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 13/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 19. Giudicessi JR, Wilde AAM, Ackerman MJ. The genetic architecture of long QT syndrome: A critical reappraisal. Trends Cardiovasc Med 2018; 28:453. 20. Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ. Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing. Circulation 2018; 137:619. 21. Jackman WM, Friday KJ, Anderson JL, et al. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988; 31:115. 22. Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996; 12:17. 23. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011; 8:1308. 24. Ackerman MJ, Khositseth A, Tester DJ, et al. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc 2002; 77:413. 25. 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. 26. Barhanin J, Lesage F, Guillemare E, et al. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 1996; 384:78. 27. Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996; 384:80. 28. Splawski I, Tristani-Firouzi M, Lehmann MH, et al. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 1997; 17:338. 29. Shalaby FY, Levesque PC, Yang WP, et al. Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation 1997; 96:1733. 30. Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003; 299:251. 31. 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. 32. Schwartz PJ, Moreno C, Kotta MC, et al. Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. Eur Heart J 2021; 42:4743. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 14/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 33. Shimizu W, Horie M, Ohno S, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan. J Am Coll Cardiol 2004; 44:117. 34. Crotti L, Spazzolini C, Schwartz PJ, et al. The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratification. Circulation 2007; 116:2366. 35. JERVELL A, LANGE-NIELSEN F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J 1957; 54:59. 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. 37. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102:1178. 38. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103:89. 39. Jiang C, Atkinson D, Towbin JA, et al. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet 1994; 8:141. 40. Furutani M, Trudeau MC, Hagiwara N, et al. Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation 1999; 99:2290. 41. Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation 2002; 105:794. 42. Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995; 80:795. 43. 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. 44. Miller C. The inconstancy of the human heart. Nature 1996; 379:767. 45. Tseng GN. I(Kr): the hERG channel. J Mol Cell Cardiol 2001; 33:835. 46. Berthet M, Denjoy I, Donger C, et al. C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence. Circulation 1999; 99:1464. 47. Rossenbacker T, Mubagwa K, Jongbloed RJ, et al. Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome. Circulation 2005; 111:961. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 15/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 48. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995; 80:805. 49. Wei J, Wang DW, Alings M, et al. Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. Circulation 1999; 99:3165. 50. Kapplinger JD, Tester DJ, Salisbury BA, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm 2009; 6:1297. 51. Kapplinger JD, Tester DJ, Alders M, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010; 7:33. 52. Kambouris NG, Nuss HB, Johns DC, et al. Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. Circulation 1998; 97:640. 53. Schwartz PJ, Priori SG, Dumaine R, et al. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 2000; 343:262. 54. Wedekind H, Smits JP, Schulze-Bahr E, et al. De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Circulation 2001; 104:1158. 55. Ackerman MJ, Siu BL, Sturner WQ, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001; 286:2264. 56. Grant AO, Carboni MP, Neplioueva V, et al. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest 2002; 110:1201. 57. Clancy CE, Rudy Y. Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism. Circulation 2002; 105:1208. 58. Desch nes I, Baroudi G, Berthet M, et al. Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes. Cardiovasc Res 2000; 46:55. 59. Clancy CE, Kass RS. Defective cardiac ion channels: from mutations to clinical syndromes. J Clin Invest 2002; 110:1075. 60. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA 2005; 294:2975. 61. Westenskow P, Splawski I, Timothy KW, et al. Compound mutations: a common cause of severe long-QT syndrome. Circulation 2004; 109:1834. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 16/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 62. Mullally J, Goldenberg I, Moss AJ, et al. Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. Heart Rhythm 2013; 10:378. 63. Boczek NJ, Best JM, Tester DJ, et al. Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet 2013; 6:279. 64. Splawski I, Timothy KW, Tateyama M, et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002; 297:1333. 65. Reed GJ, Boczek NJ, Etheridge SP, Ackerman MJ. CALM3 mutation associated with long QT syndrome. Heart Rhythm 2015; 12:419. 66. Altmann HM, Tester DJ, Will ML, et al. Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome. Circulation 2015; 131:2051. 67. Boczek NJ, Gomez-Hurtado N, Ye D, et al. Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. Circ Cardiovasc Genet 2016; 9:136. 68. Clemens DJ, Tester DJ, Giudicessi JR, et al. International Triadin Knockout Syndrome Registry. Circ Genom Precis Med 2019; 12:e002419. 69. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 70. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation 1999; 99:518. 71. Li H, Fuentes-Garcia J, Towbin JA. Current concepts in long QT syndrome. Pediatr Cardiol 2000; 21:542. 72. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management part III. Circulation 1999; 99:674. 73. Ackerman MJ, Tester DJ, Jones GS, et al. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc 2003; 78:1479. 74. Ackerman MJ, Splawski I, Makielski JC, et al. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 2004; 1:600. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 17/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 75. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol 2006; 47:764. 76. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993; 88:782. Topic 1009 Version 34.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 18/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate GRAPHICS Single-lead electrocardiogram showing a prolonged QT interval The corrected QT interval (QTc) is calculated by dividing the QT interval (0.60 seconds) by the square root of the preceding RR interval (0.92 seconds). In this case, the QTc is 0.625 seconds (625 milliseconds). Graphic 77018 Version 7.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 19/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 20/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Single lead electrocardiogram (ECG) showing torsades de pointes The electrocardiographic rhythm strip shows torsades de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet, which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet. Graphic 73827 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 21/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Summary of heritable arrhythmia syndrome susceptibility genes: Long QT syndrome (LQTS) Gene Locus Protein Major LQTS genes KCNQ1 (LQT1) 11p15.5 I potassium channel alpha subunit (KVLQT1, Ks Kv7.1) KCNH2 (LQT2) 7q35-36 I potassium channel alpha subunit (HERG, Kr Kv11.1) SCN5A (LQT3) 3p21-p24 Cardiac sodium channel alpha subunit (NaV1.5) Minor LQTS genes AKAP9 7q21-q22 Yotiao CACNA1C 12p13.3 Voltage gated L-type calcium channel (CaV1.2) CALM1 14q32.11 Calmodulin 1 CALM2 2p21 Calmodulin 2 CALM3 19q13.2-q13.3 Calmodulin 3 CAV3 3p25 Caveolin-3 KCNE1 21q22.1 Potassium channel beta subunit (MinK) KCNE2 21q22.1 Potassium channel beta subunit (MiRP1) KCNJ5 11q24.3 Kir3.4 subunit of I channel KACH SCN4B 11q23.3 Sodium channel beta 4 subunit SNTA1 20q11.2 Syntrophin-alpha 1 TRDN 6q22.31 Triadin Adapted from: Tester DJ, Ackerman MJ. Genetics of cardiac arrhythmias. In: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10th ed, Mann DL, Zipes DP, Libby P, et al (Eds), Elsevier, Philadelphia 2015. Graphic 114927 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 22/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate [1] Current-centric classification of long-QT syndrome susceptibility genes The clinical phenotypes resulting from the abnormal ventricular cardiac action potential depolarization or repolarization are grouped according to the specific current perturbed by an underlying genetic defect (refer to graphic s key, above). The graphic shows both mutations that confer a loss of function to the specified current and mutations that confer a gain of function (refer to graphic s key, above). Solid lines indicate those disorders that are autosomal dominant, whereas dashed lines indicate those disorders that are autosomal recessive. Thin outlines indicate nonsyndromic genotypes and thick outlines represent multisystem genotypes. COTS: cardiac-only Timothy syndrome; LQTS: long-QT syndrome; ABS: ankyrin-B syndrome; JLNS: Jervell : cardiac and Lange-Neilson syndrome; I : L-type calcium current; TKO: triadin knockout syndrome; I Ca,L Na sodium current; I the delayed rectifier potassium current; I : slow-component of the delayed rectifier potassium current; I : rapid component of KS Kr : G-protein-coupled inwardly rectifying potassium current; KAch I : inwardly rectifying potassium current. K1 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 23/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Reference: 1. Giudicessi JR, Ackerman MJ. Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Transl Res 2013; 161:1. Original gure modi ed for this publication. Illustration used with the permission of Elsevier Inc. All rights reserved. From: Giudicessi JR, Ackerman MJ. Calcium revisited: New insights into the molecular basis of long-QT syndrome. Circ Arrhythm Electrophysiol 2016; 9:1. DOI: 10.1161/CIRCEP.116.002480. Copyright 2016 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 120655 Version 2.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 24/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial GnRH agonist/antagonist therapy ischemia or infarction, Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders especially with Starvation particularly hypokalemia and hypomagnesemia prominent T-wave inversions Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga (ibogaine), licorice extract in overuse via electrolyte disturbances Intracranial disease Hypothyroidism Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate insecticides AV block: Second or third degree Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 25/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole (systemic) Romidepsin Anagrelide Foscarnet Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 26/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- Periciazine Tropisetron norethindrone Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide overdose in Eliglustat Primaquine Vorinostat Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. [1,2] . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 27/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 28/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Myocardial action potential Representation of a ventricular action potential. There are 5 phases of the action potential beginning with phase 0, rapid depolarization by sodium influx. Phase 1 is a rapid repolarization via potassium efflux followed by phase 2 or the plateau phase. The plateau phase results from entry of calcium into the cell and potassium efflux. Phase 3 repolarization is dominated by potassium currents which polarize the cell and potassium inward rectifier maintains the resting potential or phase 4. See text for full description. Graphic 71390 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 29/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 30/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Contributor Disclosures Michael J Ackerman, MD, PhD Consultant/Advisory Boards: Abbott [Education around ICD/device therapy for genetic heart diseases including LQTS]; ARMGO Pharma [Novel therapies for genetic heart diseases, CPVT in particular]; Boston Scientific [Education around ICD/device therapy for genetic heart diseases including LQTS]; Daiichi Sankyo [Drug-induced QT prolongation for one of their drugs]; Invitae [Genetic testing for genetic heart diseases]; LQT Therapeutics [Development of a novel QT-shortening medication]; Medtronic [Education around ICD/device therapy for genetic heart diseases including LQTS]; UpToDate [Genetic heart diseases, especially LQTS]. Other Financial Interest: AliveCor [QTc analytics for smartphone- enabled mobile ECG]; Anumana [Artificial intelligence ECG for early detection of hypertrophic cardiomyopathy]; Pfizer [Gene therapy for genetic heart diseases including LQTS]. All of the relevant financial relationships listed have been mitigated. Peter J Schwartz, MD No relevant financial relationship(s) with ineligible companies to disclose. John K Triedman, MD Consultant/Advisory Boards: Biosense Webster and Sentiar [Supraventricular and ventricular topics]. All of the relevant financial relationships listed have been mitigated. Samuel Asirvatham, MD Grant/Research/Clinical Trial Support: Medtronic [Defibrillators]; St Jude's [Sudden Cardiac Death]. Consultant/Advisory Boards: BioTronik [Defibrillators]; Boston Scientific [Sudden Cardiac Death]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 31/31