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 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/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 30/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - 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/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 31/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and Conivaptan Lumacaftor Dexamethasone cobicistat- containing Crizotinib Lumacaftor- Dipyrone ivacaftor Cyclosporine Efavirenz coformulations Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone Duvelisib Idelalisib therapy pack Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- Mifepristone* Pexidartinib palonosetron Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- Sotorasib Isavuconazole ritonavir (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- Netupitant paritaprevir- Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 32/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. [1,2] These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 33/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 34/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 35/36 7/6/23, 11:06 AM Acquired long QT syndrome: Definitions, pathophysiology, and causes - UpToDate Contributor Disclosures Charles I Berul, MD Patent Holder: PeriCor LLC [Pacemakers/defibrillators]. Grant/Research/Clinical Trial Support: Medtronic Inc [Pacemakers/defibrillators]. 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/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/print 36/36