prolongation [60]. Patients affected with Andersen-Tawil syndrome usually present in childhood with spontaneous attacks of paralysis, which may be associated with low, normal, or elevated potassium levels. The characteristic skeletal and facial phenotype of Andersen-Tawil syndrome includes short stature, hypertelorism, a broad nose, low-set ears, and a hypoplastic mandible [61]. (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.) Patients with hypokalemic periodic paralysis and other typical phenotypic features are diagnosed with Andersen-Tawil syndrome following a 12-lead ECG that reveals QTU prolongation. Characteristic T-U wave morphologies have also been identified in patients with Andersen-Tawil syndrome ( waveform 4) [62]. The ECG features were initially characterized in a series of 39 patients with genetically confirmed ATS1 and then validated in a series of 147 individuals (57 with ATS1, 61 unaffected family members, and 29 with phenotypic features of Andersen-Tawil syndrome, but negative for ATS1). The following abnormalities were identified by visual inspection: Prolonged terminal T wave downslope Biphasic U waves in limb leads Wide T-U junction, in contrast to bifid T waves in LQT2 Enlarged U waves occurring with a distinct isoelectric segment after the end of the T wave Treatment of Andersen-Tawil syndrome is complicated because of the opposing effects of potassium replacement on the QT interval and on skeletal muscle weakness. Elevation of the serum potassium concentration shortens the QT interval and suppresses ventricular arrhythmias, but it may accentuate skeletal muscle weakness. (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.) Timothy syndrome There are rare reports of infants with severe QT prolongation and syndactyly involving both fingers and toes, frequently with associated patent ductus arteriosus and other cardiac abnormalities [63,64]. The constellation of QT prolongation (usually marked), syndactyly, and often developmental delays is called Timothy syndrome. The lack of a family history of LQTS suggested that the disorder resulted from spontaneous de novo variants. Although Timothy syndrome is extremely rare, it may be reasonable to obtain a screening ECG to assess the QT interval in children with complex syndactyly [65,66]. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 12/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval (a prolonged QTc, QT interval corrected for heart rate) on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death. LQTS may be congenital or acquired. (See 'Introduction' above and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Clinical presentations The clinical manifestations of congenital LQTS are highly variable. The majority of patients will never have a symptom, while symptomatic patients (before diagnosis and initiation of effective therapies) can present with arrhythmic syncope with or without generalized seizures, or cardiac arrest. Patients without symptoms typically come to medical attention because they have an affected family member or a prolonged QTc is identified on an ECG obtained for some other reason. (See 'Clinical manifestations' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 13/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Arrythmia presentation Patients with LQTS-triggered arrhythmias may present with syncope, seizures, or sudden cardiac arrest. Most times, the arrhythmias are transient or self-terminating. (See 'Symptoms' above.) Polymorphic ventricular tachycardia The classic arrhythmia associated with congenital LQTS is a form of polymorphic ventricular tachycardia (VT) called torsades de pointes. Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per minute with frequent variations of the QRS axis, morphology, or both. In the specific case of torsades de pointes, these variations take the form of a progressive, sinusoidal, cyclic alteration of the QRS axis ( waveform 2A-B). The peaks of the QRS complexes appear to "twist" around the isoelectric line of the recording, hence the name torsades de pointes or "twisting of the points." (See 'Polymorphic VT/torsades de pointes' above.) Triggers of arrythmias Arrhythmias in patients with LQTS are frequently triggered by external events (eg, noise, exercise, stress, etc) and are often pause-dependent (the beat triggering the arrhythmia is preceded by an ectopic beat and a subsequent pause). In addition, factors that contribute to the development of acquired LQTS, such as medications known to prolong the QT interval and electrolyte disturbances, can provoke arrhythmias in patients with congenital LQTS that is "mild" or previously unknown to the patient. (See 'Triggers of arrhythmia' above.) Congenital syndromes The autosomal recessive form of congenital LQTS, the Jervell and Lange-Nielsen syndrome, is associated with sensorineural deafness and a more malignant clinical course. We recommend that a 12-lead ECG be performed to screen for LQTS in all children with congenital, bilateral sensorineural deafness. (See 'Congenital sensorineural deafness' above.) Some cases of sudden infant death syndrome and intrauterine fetal demise may be caused by LQTS. (See 'Sudden infant death syndrome' 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. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 14/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 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. 6. Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes. J Am Coll Cardiol 2016; 67:1639. 7. 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. 8. Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation 2009; 120:1761. 9. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99:529. 10. Crotti L, Spazzolini C, Tester DJ, et al. Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry. Eur Heart J 2019; 40:2964. 11. Clemens DJ, Tester DJ, Giudicessi JR, et al. International Triadin Knockout Syndrome Registry. Circ Genom Precis Med 2019; 12:e002419. 12. Garson A Jr, Dick M 2nd, Fournier A, et al. The long QT syndrome in children. An international study of 287 patients. Circulation 1993; 87:1866. 13. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation 1991; 84:1136. 14. Rohatgi RK, Sugrue A, Bos JM, et al. Contemporary Outcomes in Patients With Long QT Syndrome. J Am Coll Cardiol 2017; 70:453. 15. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348:1866. 16. Younis A, Zareba W, Goldenberg I, et al. Biological Life-Stage and the Burden of Cardiac Events in Women With Congenital Long QT Syndrome. Circ Arrhythm Electrophysiol 2022; 15:e011247. 17. Rashba EJ, Zareba W, Moss AJ, et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators. Circulation 1998; 97:451. 18. Buber J, Mathew J, Moss AJ, et al. Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2. Circulation 2011; 123:2784. 19. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007; 115:2613. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 15/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 20. Pacia SV, Devinsky O, Luciano DJ, Vazquez B. The prolonged QT syndrome presenting as epilepsy: a report of two cases and literature review. Neurology 1994; 44:1408. 21. Pfammatter JP, Donati F, D rig P, et al. Cardiac arrhythmias mimicking primary neurological disorders: a difficult diagnostic situation. Acta Paediatr 1995; 84:569. 22. Anderson JH, Bos JM, Cascino GD, Ackerman MJ. Prevalence and spectrum of electroencephalogram-identified epileptiform activity among patients with long QT syndrome. Heart Rhythm 2014; 11:53. 23. Bardai A, Blom MT, van Noord C, et al. Sudden cardiac death is associated both with epilepsy and with use of antiepileptic medications. Heart 2015; 101:17. 24. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 25. Gorgels AP, Al Fadley F, Zaman L, et al. The long QT syndrome with impaired atrioventricular conduction: a malignant variant in infants. J Cardiovasc Electrophysiol 1998; 9:1225. 26. Vincent GM. The heart rate of Romano-Ward syndrome patients. Am Heart J 1986; 112:61. 27. Beinder E, Grancay T, Men ndez T, et al. Fetal sinus bradycardia and the long QT syndrome. Am J Obstet Gynecol 2001; 185:743. 28. Lupoglazoff JM, Denjoy I, Villain E, et al. Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. J Am Coll Cardiol 2004; 43:826. 29. Mitchell JL, Cuneo BF, Etheridge SP, et al. Fetal heart rate predictors of long QT syndrome. Circulation 2012; 126:2688. 30. Kirchhof P, Eckardt L, Franz MR, et al. Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. J Cardiovasc Electrophysiol 2003; 14:1027. 31. Johnson JN, Tester DJ, Perry J, et al. Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. Heart Rhythm 2008; 5:704. 32. Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation 2006; 114:2096. 33. 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. 34. Wilde AA, Jongbloed RJ, Doevendans PA, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999; 33:327. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 16/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 35. Khositseth A, Tester DJ, Will ML, et al. Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome. Heart Rhythm 2004; 1:60. 36. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol 2007; 49:1092. 37. Davis AM, Wilkinson JL. The long QT syndrome and seizures in childhood. J Paediatr Child Health 1998; 34:410. 38. 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. 39. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 40. 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. 41. Moss AJ, Robinson JL, Gessman L, et al. Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol 1999; 84:876. 42. Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc 1999; 74:1088. 43. Choi G, Kopplin LJ, Tester DJ, et al. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 2004; 110:2119. 44. Ali RH, Zareba W, Moss AJ, et al. Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome. Am J Cardiol 2000; 85:457. 45. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992; 327:846. 46. Itoh H, Crotti L, Aiba T, et al. The genetics underlying acquired long QT syndrome: impact for genetic screening. Eur Heart J 2016; 37:1456. 47. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 48. Duggal P, Vesely MR, Wattanasirichaigoon D, et al. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation 1998; 97:142. 49. Huang L, Bitner-Glindzicz M, Tranebjaerg L, Tinker A. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. Cardiovasc Res 2001; https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 17/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 51:670. 50. Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M. Jervell and Lange-Nielsen syndrome: a Norwegian perspective. Am J Med Genet 1999; 89:137. 51. 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. 52. 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. 53. 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. 54. Ackerman MJ, Siu BL, Sturner WQ, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001; 286:2264. 55. Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007; 115:361. 56. Wang DW, Desai RR, Crotti L, et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation 2007; 115:368. 57. Crotti L, Tester DJ, White WM, et al. Long QT syndrome-associated mutations in intrauterine fetal death. JAMA 2013; 309:1473. 58. Tester DJ, Wong LCH, Chanana P, et al. Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. J Am Coll Cardiol 2018; 71:1217. 59. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand 1971; 60:559. 60. Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 2002; 110:381. 61. Sansone V, Griggs RC, Meola G, et al. Andersen's syndrome: a distinct periodic paralysis. Ann Neurol 1997; 42:305. 62. Zhang L, Benson DW, Tristani-Firouzi M, et al. Electrocardiographic features in Andersen- Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation 2005; 111:2720. 63. Marks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol 1995; 25:59. 64. Marks ML, Trippel DL, Keating MT. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol 1995; 76:744. 65. Krause U, Gravenhorst V, Kriebel T, et al. A rare association of long QT syndrome and syndactyly: Timothy syndrome (LQT 8). Clin Res Cardiol 2011; 100:1123. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 18/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 66. Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004; 119:19. Topic 1036 Version 34.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 19/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - 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-epidemiology-and-clinical-manifestations/print 20/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - 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-epidemiology-and-clinical-manifestations/print 21/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - 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-epidemiology-and-clinical-manifestations/print 22/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - 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-epidemiology-and-clinical-manifestations/print 23/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - 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-epidemiology-and-clinical-manifestations/print 24/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - 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-epidemiology-and-clinical-manifestations/print 25/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - 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-epidemiology-and-clinical-manifestations/print 26/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - 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-epidemiology-and-clinical-manifestations/print 27/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate ECG macroscopic T wave alternans Example of T wave alternans from a 3-year-old patient with long QT syndrome with multiple episodes of cardiac arrest. Tracings are from a 24-hour Holter recording. ECG: electrocardiogram. Reproduced from: Schwartz PJ, Crotti L. Long QT and short QT syndromes. In: Cardiac Electrophysiology: From Cell to Bedside, 6th ed, Zipes DP, Jalife J (Eds), Saunders, Philadelphia 2014. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 115857 Version 1.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 28/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Triggers for cardiac events in long QT syndrome are related to genotype In a study of 670 patients with long QT syndrome and known genotype, all symptomatic (syncope, aborted cardiac arrest, or sudden death), the occurrence of a lethal cardiac event (n = 110) provoked by a specific trigger (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced most of their events (90%) during exercise or emotion. These percentages were almost reversed among LQT2 and LQT3 patients who had most of their events during rest or sleep (63 and 80%, respectively); by contrast, they were at almost no risk of major events during exercise (arrows), which is explained by their having a normal I current. Ks ACA: aborted cardiac arrest; SCD: sudden cardiac death. Modi ed from: Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-speci c triggers for life-threatening arrhythmias. Circulation 2001; 103:89. Graphic 64239 Version 3.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 29/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 12-lead electrocardiogram (ECG) in Andersen-Tawil syndrome 12-lead electrocardiogram (ECG) in a patient with Andersen-Tawil syndrome showing QTU prolongation with biphasic U waves Biphasic U wave. Arrows indicate U wave. Graphic 98517 Version 3.0 https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 30/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Contributor Disclosures Peter J Schwartz, MD No relevant financial relationship(s) with ineligible companies to disclose. 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. 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-epidemiology-and-clinical-manifestations/print 31/31