Prognosis and management of congenital long QT syndrome
- Peter J Zimetbaum, MD
Peter J Zimetbaum, MD
- Section Editor — Cardiac Arrhythmias
- Professor of Medicine
- Harvard Medical School
- Stephen P Seslar, MD, PhD
Stephen P Seslar, MD, PhD
- Assistant Professor of Cardiology and Pediatrics
- University of Washington
- Charles I Berul, MD
Charles I Berul, MD
- Section Editor — Cardiac Arrhythmias
- Professor of Pediatrics
- George Washington University
- Mark E Josephson, MD
Mark E Josephson, MD
- Professor of Medicine
- Harvard Medical School
- Section Editors
- John K Triedman, MD
John K Triedman, MD
- Section Editor — Pediatric Cardiology
- Professor of Pediatrics
- Harvard Medical School
- Samuel Asirvatham, MD
Samuel Asirvatham, MD
- Section Editor — Long QT Syndrome
- Professor of Medicine and Pediatrics
- Mayo Clinic College of Medicine
The long QT syndrome (LQTS) represents a diverse group of disorders of myocardial repolarization that is characterized by prolongation of the QT interval on the electrocardiogram (ECG). LQTS is important clinically because it is associated with an increased risk of a life-threatening form of polymorphic ventricular tachycardia called torsades de pointes (TdP) or "twisting of points" (waveform 1A-B).
LQTS can be inherited or acquired. The congenital forms are caused either by autosomal dominant or less often by autosomal recessive genetic mutations, almost all of which encode for abnormal cardiac ion channels (table 1). The acquired forms are caused by a large number of stimuli, most frequently antiarrhythmic and other types of drugs and electrolyte and metabolic abnormalities (table 2). (See "Genetics of congenital and acquired long QT syndrome" and "Acquired long QT syndrome".)
An important distinction between the congenital and acquired forms is that the latter can usually be reversed by correction of the underlying disorder or discontinuation of the offending drug. However, some patients with acquired LQTS appear to have a "forme fruste" of congenital LQTS in which a mutation or polymorphism in one of the LQTS genes is clinically silent until the patient is exposed to a particular drug or other predisposing factor. (See "Acquired long QT syndrome", section on 'Mutations in LQTS genes'.)
The heterogeneity of LQTS makes the diagnosis, therapy, and prognosis of this disorder imprecise and difficult. Nonetheless, certain generalizations and guidelines can be made concerning the management of these patients.
The natural history, prognosis, and treatment of congenital LQTS will be reviewed here. Clinical manifestations and criteria for the diagnosis of congenital LQTS and issues related to the management of acquired LQTS are discussed separately. (See "Clinical features of congenital long QT syndrome" and "Diagnosis of congenital long QT syndrome" and "Acquired long QT syndrome".)
- Vincent GM. The molecular genetics of the long QT syndrome: genes causing fainting and sudden death. Annu Rev Med 1998; 49:263.
- Schwartz PJ. The long QT syndrome. Curr Probl Cardiol 1997; 22:297.
- Schwartz P, Locati E, Napolitano C, Priori S. The long QT Syndrome. In: Cardiac Electrophysiology: From cell to bedside, Zipes D, Jalife J (Eds), WB Saunders, Philadelphia 1995. p.788.
- Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome: a prospective international study. Circulation 1985; 71:17.
- Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998; 97:2237.
- Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270:2590.
- Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996; 94:2535.
- Lehmann MH, Timothy KW, Frankovich D, et al. Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome. J Am Coll Cardiol 1997; 29:93.
- 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.
- Zareba W, Moss AJ, le Cessie S, et al. Risk of cardiac events in family members of patients with long QT syndrome. J Am Coll Cardiol 1995; 26:1685.
- Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation 2001; 104:557.
- Schwartz PJ, Locati E. The idiopathic long QT syndrome: pathogenetic mechanisms and therapy. Eur Heart J 1985; 6 Suppl D:103.
- 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.
- Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol 2007; 49:329.
- 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.
- 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.
- Zareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med 1998; 339:960.
- Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348:1866.
- Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007; 115:2481.
- 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.
- 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.
- 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.
- Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc 1999; 74:1088.
- Batra AS, Silka MJ. Mechanism of sudden cardiac arrest while swimming in a child with the prolonged QT syndrome. J Pediatr 2002; 141:283.
- 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.
- Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation 1995; 92:3381.
- Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 2000; 101:616.
- 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.
- 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.
- European Heart Rhythm Association, Heart Rhythm Society, Zipes DP, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48:e247.
- Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004; 292:1341.
- Hobbs JB, Peterson DR, Moss AJ, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA 2006; 296:1249.
- Goldenberg I, Moss AJ, Peterson DR, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 2008; 117:2184.
- Chockalingam P, Crotti L, Girardengo G, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol 2012; 60:2092.
- Vincent GM, Schwartz PJ, Denjoy I, et al. High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment "failures". Circulation 2009; 119:215.
- Shimizu W, Antzelevitch C. Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J Am Coll Cardiol 2000; 35:778.
- 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.
- 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.
- Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 2004; 109:1826.
- Ouriel K, Moss AJ. Long QT syndrome: an indication for cervicothoracic sympathectomy. Cardiovasc Surg 1995; 3:475.
- Schwartz PJ. The rationale and the role of left stellectomy for the prevention of malignant arrhythmias. Ann N Y Acad Sci 1984; 427:199.
- Schwartz PJ, Stone HL. Left stellectomy and denervation supersensitivity in conscious dogs. Am J Cardiol 1982; 49:1185.
- Viskin S. Cardiac pacing in the long QT syndrome: review of available data and practical recommendations. J Cardiovasc Electrophysiol 2000; 11:593.
- Veldkamp MW, Wilders R, Baartscheer A, et al. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families. Circ Res 2003; 92:976.
- Dorostkar PC, Eldar M, Belhassen B, Scheinman MM. Long-term follow-up of patients with long-QT syndrome treated with beta-blockers and continuous pacing. Circulation 1999; 100:2431.
- Silka MJ, Kron J, Dunnigan A, Dick M 2nd. Sudden cardiac death and the use of implantable cardioverter-defibrillators in pediatric patients. The Pediatric Electrophysiology Society. Circulation 1993; 87:800.
- Groh WJ, Silka MJ, Oliver RP, et al. Use of implantable cardioverter-defibrillators in the congenital long QT syndrome. Am J Cardiol 1996; 78:703.
- Chatrath R, Porter CB, Ackerman MJ. Role of transvenous implantable cardioverter-defibrillators in preventing sudden cardiac death in children, adolescents, and young adults. Mayo Clin Proc 2002; 77:226.
- Shah MJ, Rhodes LA. Resolution of electrical storms after discontinuation of ICD therapy in a child with long QT syndrome. Pediatr Cardiol 2002; 23:213.
- Berul CI, Barrett KS, Walsh EP. Implantable cardioverter defibrillators in pediatrics. In: Cardiac Arrhythmias in Children and Young Adults with Congenital Heart Disease, Walsh EP, Saul JP (Eds), Lippincott Williams & Wilkins, Philadelphia 2001. p.321.
- Bhandari AK, Shapiro WA, Morady F, et al. Electrophysiologic testing in patients with the long QT syndrome. Circulation 1985; 71:63.
- Compton SJ, Lux RL, Ramsey MR, et al. Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation 1996; 94:1018.
- Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW. A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. J Am Coll Cardiol 2003; 42:1777.
- Yang T, Roden DM. Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 1996; 93:407.
- Bisinov E, Mitchell JH, January CT. Potassium and long QT syndrome: a new look at an old therapy. J Am Coll Cardiol 2003; 42:1783.
- Ruan Y, Liu N, Bloise R, et al. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation 2007; 116:1137.
- Benhorin J, Taub R, Goldmit M, et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation 2000; 101:1698.
- Priori SG, Napolitano C, Schwartz PJ, et al. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation 2000; 102:945.
- Shimizu W, Kurita T, Matsuo K, et al. Improvement of repolarization abnormalities by a K+ channel opener in the LQT1 form of congenital long-QT syndrome. Circulation 1998; 97:1581.
- Shimizu W, Antzelevitch C. Effects of a K(+) channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in LQT1, LQT2, and LQT3 models of the long-QT syndrome. Circulation 2000; 102:706.
- Haïssaguerre M, Extramiana F, Hocini M, et al. Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes. Circulation 2003; 108:925.
- Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008; 117:e350.
- Zipes DP, Ackerman MJ, Estes NA 3rd, et al. Task Force 7: arrhythmias. J Am Coll Cardiol 2005; 45:1354.
- NATURAL HISTORY AND PROGNOSIS
- Epidemiologic studies
- - International LQTS Registry
- - Schwartz study
- - International Pediatric Electrophysiology Study
- - Risk factors
- Importance of genotype
- - Clinical course
- - Triggers of arrhythmia
- - Jervell and Lange-Nielsen syndrome
- Influence of pregnancy
- Patient selection
- Beta blockers
- - Effect of genotype
- Left cardiac sympathetic denervation
- Cardiac pacing
- Implantable cardioverter-defibrillator
- - Use in children
- Targeted pharmacologic therapy
- - Potassium
- - Mexiletine
- - Flecainide
- - Nicorandil
- Radiofrequency ablation
- MAJOR SOCIETY GUIDELINES
- INFORMATION FOR PATIENTS
- General measures
- Genotype-specific therapy
- - LQT1
- - LQT3
- Role of beta blockers
- Role of left cardiac sympathetic denervation
- Role of DDD pacing
- Role of ICD