Methadone often increases the QTc interval and is a cause of TdP. Concern regarding the proarrhythmic potential of methadone prompted a clinician safety alert from the FDA in 2006, as well as a manufacturer's black-box warning. These issues, as well as safety recommendations for prescribing methadone, are discussed elsewhere [95]. (See "Medication for opioid use disorder", section on 'Prolonged QTc and cardiac arrhythmias'.) Gastrointestinal medications Cisapride, which is not easily available in the United States, was previously one of the most common causes of acquired TdP not due to antiarrhythmic drugs [72,96]. Among 761 cases of drug-induced TdP reported to the World Health Organization Drug Monitoring Centre between 1983 and 1999, the second most common drug was cisapride (13 percent), after sotalol [72]. This has become much less frequent since it was taken off the general market (ie, available only through a limited access program), along with awareness of the potential for QT prolongation, particularly when used concomitantly with other QT-prolonging drugs. The antiemetic agents droperidol and ondansetron have a moderate risk of prolonging the QTc and do so more commonly when given in an intravenous rather than oral formulation. (See "Arrhythmias during anesthesia", section on 'Medications that may prolong the QT interval'.) Antimicrobials QT-prolonging antimicrobial medications include macrolide and fluoroquinolone antibiotics and some antifungal and antiviral drugs. https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 12/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Macrolide antibiotics (eg, erythromycin, azithromycin, clarithromycin), fluoroquinolone antibiotics (eg, ciprofloxacin, gatifloxacin, levofloxacin, etc.), and antifungal drugs (eg, fluconazole, itraconazole, ketoconazole, etc.) can prolong the QT interval. Users of erythromycin in one report had a twofold increased risk of SCD over nonusers [54]. In addition, because erythromycin is metabolized by the CYP3A4 system, medications that inhibit CYP3A4 cause a further increase in risk when used with erythromycin ( table 2). (See "Azithromycin and clarithromycin", section on 'QT interval prolongation and cardiovascular events' and "Fluoroquinolones", section on 'QT interval prolongation'.) Arsenic Arsenic trioxide is used in the treatment of patients with acute promyelocytic leukemia and other advanced malignancies. It appears to be associated with a very high rate of QT prolongation but a lower rate of TdP [97-99]. The unusually high incidence of QT prolongation with arsenic trioxide may be a consequence of a unique effect on potassium flux. Most of the drugs that produce LQTS act by blocking the IKr current. However, arsenic trioxide blocks both IKr and IKs, an effect comparable to the combined effects of genetic LQT1 and LQT2 [100]. Tyrosine kinase inhibitors Tyrosine kinase inhibitors inhibit angiogenesis and are used to treat a variety of solid tumors. Potential toxicities of some tyrosine kinase inhibitors are QT prolongation and TdP. This is discussed in detail separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Prolongation of the QTc interval and cardiac arrhythmias'.) OTHER CAUSES Metabolic abnormalities Hypokalemia and hypomagnesemia can predispose to torsades de pointes (TdP) even in the absence of QT-prolonging drugs. As discussed above, electrolyte abnormalities can predispose to TdP. Multiple electrolyte abnormalities can coexist; hypomagnesemia directly causes hypokalemia. Hypocalcemia alone or induced by hypomagnesemia is a less common cause [101-103]. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Hypokalemia' and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.) The risk of hypokalemia itself may also be related to decreased IKr activity [104]. Further support for the importance of hypomagnesemia is the beneficial effect of magnesium administration in the acute therapy of TdP. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Initial management'.) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 13/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Impaired hepatic and/or renal function can also cause a prolonged QTc, independent of drug administration [68,69]. Patients with anorexia may be predisposed to a long QTc because of catabolic metabolism, electrolyte disturbances, psychotropic medications, or other physiologic changes. This is discussed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Functional changes'.) Ischemia QTc prolongation may be common during the early phase of ischemia. In a series of 74 patients undergoing serial ECGs during angioplasty, all patients developed QT prolongation during balloon inflation [105]. In addition, some patients with acute myocardial infarction (8 of 434 consecutive patients in one series) develop progressive QT interval prolongation that is maximal at days 3 to 11 during the healing phase of the infarct [106]. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Polymorphic VT'.) Bradyarrhythmias The likelihood of developing QT prolongation and TdP in patients taking antiarrhythmic drugs is increased by bradycardia due to reverse use dependency [11]. It is less clear whether bradycardia alone causes TdP [107,108]. This issue was addressed in a report of 14 patients with complete atrioventricular block, six of whom had a history of TdP [107]. The two groups did not differ with respect to the rate of the escape rhythm; however, the corrected QT interval was significantly longer in those who had experienced TdP (0.59 versus 0.48 seconds). After pacemaker placement, the corrected QT interval was also longer in patients who had TdP, with pacemaker set to 50 beats per minute (QTc 0.70 versus 0.53 seconds). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Long-term management'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes" 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 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 14/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate 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 The long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1). This syndrome is associated with an increased risk of polymorphic ventricular tachycardia and a characteristic life-threatening cardiac arrhythmia also known as torsades de pointes (TdP) ( waveform 2A-B). (See 'Definitions' above.) There is potential overlap between acquired and congenital LQTS, as some people with acquired LQTS can have underlying pathogenic genetic variants but do not meet all the clinical criteria for congenital LQTS. (See 'Underlying pathogenic variant in a long QT syndrome gene' above and "Congenital long QT syndrome: Pathophysiology and genetics".) Pathophysiology Nearly all drugs that produce LQTS do so by blocking the IKr current; this is mediated by a potassium channel in myocardial cells. This potassium channel is encoded by the KCNH2 gene. (See 'Pathophysiology' above.) Medication-induced LQTS Risk factors Several patient-specific and medication-related factors can enhance the risk of drug-induced LQTS. (See 'Risk factors for drug-induced long QT syndrome' above.) Drug-induced LQTS is more common in females, and the prevalence increases with age. Other risk factors include metabolic disturbances such as hypokalemia, hypomagnesemia, impaired hepatic and/or renal function, underlying heart disease, and recent conversion from atrial fibrillation https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 15/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Drug regimen associated risk factors for TdP (including rapid infusion high drug concentrations), concurrent use of other drugs that can prolong the QT interval or that slow drug metabolism due to inhibition of cytochrome P450 enzymes, or concurrent intake of grapefruit juice. Electrocardiogram (ECG)-related factors predisposing to drug-induced LQTS include baseline QT prolongation or T-wave lability, development of marked QT prolongation, or T-wave changes during therapy and bradycardia. Specific medications Acquired LQTS is usually secondary to drug therapy. (See 'Drugs that prolong the QT interval' above.) Common medications include antiarrhythmics (sotalol is the most common), psychotropic medications (antidepressants, antipsychotics), synthetic opioids (eg, methadone), gastrointestinal medications (cisapride and the antiemetics droperidol and ondansetron), and antimicrobials (including macrolide antibiotics and fluoroquinolones, antifungals and antivirals). Other causes Causes of acquired LQTS other than drugs include electrolyte abnormalities, structural and ischemic heart disease, and bradyarrhythmias. (See 'Other causes' above.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Stephen Seslar MD, PhD, and the late Mark E. Josephson, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 2. Khan IA. 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Topic 1043 Version 50.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 23/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - 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/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 24/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - 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/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 25/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - 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/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 26/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - 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 ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, Hypocalcemia Diuretic therapy via electrolyte disorders especially with prominent T-wave Starvation particularly hypokalemia and hypomagnesemia Anorexia nervosa Herbs inversions Liquid protein diets Cinchona (contains quinine), iboga Intracranial Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances disease Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide (restricted Lenvatinib Selpercatinib Ajmaline Levoketoconazole Sertindole availability) 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 Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Levofloxacin Carbetocin Erythromycin Ribociclib (systemic) https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 27/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Certinib Escitalopram Lofexidine Risperidone Chloroquine Etelcalcetide Meglumine antimoniate Saquinavir Citalopram Fexinidazole Sevoflurane Midostaurin Clarithromycin Flecainide Sparfloxacin Moxifloxacin Clofazimine Floxuridine Sunitinib Nilotinib Clomipramine Fluconazole Tegafur Olanzapine Clozapine Fluorouracil (systemic) Terbutaline Ondansetrol (IV > Crizotinib Thioridazine oral) Flupentixol Dabrafenib Toremifene Osimertinib Gabobenate Dasatinib Vemurafenib dimeglumine Oxytocin Deslurane Voriconazole Gemifloxacin Pazopanib Domperidone Gilteritinib Pentamidine Doxepin Halofantrine Pilsicainide Doxifluridine Haloperidol (oral) Pimozide Imipramine 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 Romidepsin Anagrelide Foscarnet (systemic) 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 (systemic) Olodaterol 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 Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Periciazine Tropisetron https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 28/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Dexmedetomidine** Leuprolide- norethindrone Pimavanserin Vardenafil Dolasetron Pipamperone Vilanterol Levalbuterol Donepezil Pitolisant Vinflunine Levomethadone Efavirenz Ponesimod Voclosporin Lithium Eliglustat Primaquine Vorinostat Loperamide in Eribulin Promazine Zuclopenthixol overdose Ezogabine Radotinib Lopinavir 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/UCM0 73161.pdf with additional data from CredibleMeds QT drugs list [1,2] . The use of other classification criteria may lead to some agents being classified differently by other sources. 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. 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 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 29/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate 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