Torsades de Pointes Frank J. Dowd Creighton University School of Medicine, Omaha, USA ã 2007 Elsevier Inc. All rights reserved. Version 2
Introduction Torsades de pointes (‘‘torsades’’), literally "twisting of the points", is a type of ventricular tachycardia associated with a long QT interval. It is considered separately from other types of ventricular tachycardia because of its unique characteristics and etiology.
Definition Torsades de pointes is a polymorphic ventricular tachycardia, so called because of the changing appearance of successive depolarizations on the electrocardiogram. Ventricular depolarizations have twisted peaks with a rotating axis around the isoelectric point, with the baseline changing over time. These exist as a consequence of long QT intervals. Those polymorphic ventricular tachycardias not associated with long QT intervals are not Torsades de pointesMyerburg et al (2001).
Classification Torsades de pointes is a type of ventricular tachycardia that arises as a result of excessive lengthening of the QT interval.
Consequences Torsades de pointes is a serious, life-threatening arrhythmia. Although Torsades de pointes may resolve spontaneously, it can also lead to ventricular fibrillation and death. Patients experiencing Torsades de pointes may experience palpitations, hypotension, syncope, apprehension, pallor, sweating, nausea, and respiratory arrest.
Associated Disorders The most common disorder associated with Torsades de pointesis a long (>0.46 sec) QT interval, because, by definition, Torsades de pointes is a polymorphic ventricular tachycardia associated with long QT intervals. The long QT interval may be acquired or may be the result of a congenital syndrome. Three syndromes associated with long QT interval are Romano-Ward, Jervell and Lange-Nielsen, and Brugada Syndromes.
Etiology The causes of Torsades de pointes are genetic abnormalities in sodium, potassium or ryanodine-sensitive calcium channels, certain disease states, drugs that lengthen the QT 1
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interval, and electrolyte abnormalities. There are at least six genetic ion channel abnormalities located on five different ion channel genes that account for long QT syndromes (LQT 1-6) Roden (2004) LQT1 (KCNQ1) and LQT5 (KCNE1) mutations are linked to deficiencies in the slow potassium (Ks) channel. This results in a decreased ability of this channel to conduct K+, a delay in repolarization in the ventricle, and lengthening of the QT interval. LQT2 (HERG) and LQT6 (KCNE2) mutations produce similar changes in the rapid potassium (Kr) channel. LQTS3 (SCNSA) mutation is linked to a defect in sodium channels, whereby they remain open beyond the normal phase 3 plateau duration, delaying repolarization in the ventricle. LQT4 is not identified as to genetic origin. Romano-Ward syndrome may involve any of the ion channel mutations indicated above, whereas the Jervell and Lange Nielsen syndrome is linked to changes in Ks channels. The Brugada syndrome involves a sodium channel mutation. Disease states that may give rise to long QT include recent myocardial infarction, central nervous system trauma, subarachnoid hemorrhage, and stroke. Several drugs may cause a lengthening of the QT interval and predispose to Torsades de pointes. These include class Ia antiarrhythmics, such as quinidine and procainamide, as well as class III antiarrhythmics like sotalol, ibutilide, and dofetilide. Phenothiazines, tricyclic antidepressants, erythromycin, and cisapride are examples of other agents that are known to cause Torsades de pointes. The risk associated with these drugs is greater if they are administered concurrently with an agent that slows their elimination, such as a drug that inhibits their metabolism. In addition to certain drugs and congenital ion channel abnormalities, hypokalemia, hypomagnesemia, bradycardia, female gender, diuretic use, and a history of sudden death in the family are risk factors for Torsades de pointes.
Epidemiology About 1 in 5000 individuals is at risk for long QT interval and Torsades de pointes. Long QT interval is more common in females and in patients with bradycardia, on diuretics, with hypokalemia, and those with hypomagnesemia. Congenital ion channelopathies, central nervous system disorders, bradycardia, and certain drugs are very important risk factors for this condition. Long QT interval may be a factor in accidental drownings. The combination of swimming and the presence of congenital long QT syndromes poses a higher risk of developing Torsades de pointes.
Pathophysiology Fig. 1 is a representation of the electrocardiogram pattern of torsades de pointesGoldberger (1999).
Fig. 1. Representation of the electrocardiogram pattern of torsades de pointes.
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A relatively normal P wave and QRS complex (single asterisk) are followed by a prolonged QT interval (double asterisk) (area enlarged). This is followed, in turn, by Torsades de pointes. Over-activity of sodium channels, or under-activity of potassium (Kr or Ks) channels, leads to a prolonged action potential in the affected cell. Fig. 2 is a representative action potential in a ventricular myocardial cell along with the relative contribution of several ion channels as a function of phase of the action potential. The relative magnitudes of the various ionic fluxes, as they apply to the cell, are shown by the size of the arrows above the action potential; ", a depolarizing current; #, a repolarizing current. Predominate channel subtype activities for Ca++ and K+ channels are shown above the respective arrows.
Fig. 2. (T = transient calcium, L = long-lasting calcium, Kr = rapid potassium, Ks = slow potassium, Kur = ultrarapid potassium, Kir = inwardly rectifying potassium). The consequences of the sodium channels remaining open too long, or the potassium channels failing to open at the appropriate time, are a delayed repolarization and long QT interval. This ‘‘pause’’ makes possible an heterogeneity in repolarizations of various regions of the ventricular myocardium and the occurrence of early after-depolarizations that give rise to the tachycardia. The appearance of marked "U" waves and two-phase ST segments also are characteristic of Torsades de pointes. The fact that various layers of myocardial cells may repolarize at different times is another factor contributing to the development of Torsades de pointes. The delay in the repolarization of endocardial and mid-myocardial cells can lead to asynchrony and reentry which, in turn, can promote Torsades de pointes.
Signs and Symptoms The signs of Torsades de pointes and a prolonged QT interval can be detected on an EK G. Symptoms include palpitations, syncope, shortness of breath, chest pain and cold sweats. Sudden death is a definite risk.
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Standard Therapies Removal of any drug that may be inducing Torsades de pointes is the first objective. Therapy for Torsades de pointes differs from therapy for other types of ventricular tachycardia because of the presence of a long QT interval. Acute therapy often involves pacing with a pacemaker or implantable cardioventerdefibrillator. Acute therapy includes suppression of early after-depolarizations and is most often accomplished with intravenous magnesium. Potassium or lidocaine given i.v. may also be useful. Pacing effectively shortens the QT interval, which can also be accomplished by increasing the heart rate with isoproterenol, if bradycardia or heart blocks are present. Pacing is also very useful as a chronic. Drug therapy usually involves beta-adrenoceptor antagonists such as propranolol or metoprolol, if bradycardia is absent. Avoidance of stress is important to minimize sympathetic stimulation of the heart.
Agent Name
Discussion
Magnesium
Magnesium, in the form of magnesium sulfate, is used to correct hypomagnesemia and to inhibit early after-depolarization. The latter may occur because magnesium shifts the threshold of the Na+ channel to a less negative voltage. The calcium channel may also be inhibited by magnesium. Potassium is used to correct hypokalemia and probably inhibits the inward current causing the early-after depolarization. It may be particularly helpful in those with potassium channel defects. Lidocaine is a class Ib antiarrhythmic that blocks sodium entry, reducing the automaticity in cells responsible for early after-depolarizations. Isoproterenol is a nonselective beta-adrenoceptor agonist. Its action on the heart is largely, but not exclusively, on beta-1-adrenoceptors. By increasing heart rate, it shortens the QT interval, reducing the risk of Torsades de pointes in patients with bradycardia. By increasing AV nodal conduction rate, it relieves heart block. Propranolol is a nonselective beta-adrenoceptor agonist. It is used in the chronic treatment of Torsades de pointes primarily to reduce sympathetic tone because stress, as well as other causes of sympathetic discharge, increases the risk for this condition. Suppression of early-after depolarizations accounts for much of the benefit of beta-adrenoceptor antagonists. Metoprolol is a beta1-selective adrenoceptor antagonist.
Potassium
Lidocaine Isoproterenol
Propranolol
Metoprolol
Animal Models An arterially perfused canine left ventricular wedge preparation is used to model long QT intervals. The wedge preparation allows examination of action potentials throughout the full thickness of the ventricular wall. Deep muscle fibers have more susceptibility for developing longer action potential durations than the epicardial or endocardial segments. This contributes significantly to the occurrence of heterogeneous action potentials and Torsades de pointes.This wedge preparation is used to screen for therapies that might be of value in treating long QT syndromes and Torsades de pointes Shimizu and Antzelevitch (1997). Using this model, distinctions between the various forms of long QT syndromes are observed. Knockout mice involving relevant genes associated with long QT intervals have been developed Charpentier et al (1998) Arrighi et al (2001), Drici et al (1998).
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Other Information – Web Sites http://www.ecglibrary.com/Torsades.html: This shows an ECG tracing of Torsades de pointes. http://www.medtronic.com/reveal/tachycase_5.html: This describes a relevant case study. http://www.emedicine.com/MED/topic2286.htm: This site contains useful information on several aspects of Torsades de pointes http://www.torsades.org/medical-pros/drug-lists/browse-drug-list.cfm?alpha=T: This list, compiled by R. L. Woosley lists several drugs that can cause Torsades de pointes. http://www.nhlbi.nih.gov/funding/index.htm: This NIH site lists various initiatives and funding sources in the cardiovascular area.
Journal Citations Charpentier, F., Merot, J., Riochet, D., Le-Marec, H., Escande, D., 1998. Adult KCNE1-knockout mice exhibit a mild cardiac cellular phenotype. Biochem. Biophys. Res. Commun., 251(3), 806–810. Drici, M.D., Arrighi, I., Chouabe, C., Mann, J.R., Lazdunski, M., Romey, G., Barhanin, J., 1998. Involvement of IsK-associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome. Circ. Res., 83(1), 95–102. Arrighi, I., Block-Faure, M., Grahammer, F., Bleich, M., Warth, R., Mengual, R., Drici, M.D., Barhanin, J., Meneton, P., 2001. Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome. Proc. Natl. Acad. Sci. USA, 98(15), 8792–8797. Shimizu, W., Antzelevitch, C., 1997. Sodium channel block with mexiletine is effective in reducing disperson of repolarization and preventing torsades des pointes in LQT2 and LQT3 models of the long-AT syndrome. Circulation, 96(6), 2038–2047. Roden, D.M., 2004. Drug-induced prolongation of the QT interval. N. Eng. J. Med., 350(10), 1013–1022.
Book Citations Myerburg, R.J., Castellanos, A., Huikuri, H.V., 2001. Origins, Classification and Significance of Ventricular Arrhythmias. Spooner, P.M., Rosen, M.R. (Ed.), Foundations of Cardiac Arrhythmias: Basic Concepts and Clinical Approaches, pp. 547–569, Marcel Dekker, New York. Goldberger, A.L., 1999. . Goldberger, A.L. (Ed.), Clinical Electrocardiography: A Clinical Approach, Edition 6. , Mosby, St. Louis, MO.
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