Device Ther apy in t h e Setting of Long QT S y n d ro m e Troy Rhodes, MD, PhD, FHRS, CCDSa, Raul Weiss, MD, FHRSb,* KEYWORDS Long QT syndrome Risk factors for cardiac events in long QT syndrome M-FACT risk score Antiadrenergic therapies Cardiac pacing Implantable cardioverter-defibrillators
KEY POINTS Treating patients with congenital long QT syndrome is challenging for several reasons: the age of the patients and the high emotional impact, the type and number of mutations, life events such as pregnancy, and medical compliance and exposure to QT-prolonging medications. The cornerstone for the treatment of these patients should be b-blockers and avoidance of QTprolonging drugs. Left cardiac sympathetic denervation, although effective, is limited by the availability of surgeons with experience in this procedure. Implantable cardioverter-defibrillators (ICDs) are highly effective in the prevention of sudden cardiac death, but they have inherent risks; following implantation, programming should be optimized to minimize the risk for inappropriate ICD therapies.
Case History
Disclosure: The authors have nothing to disclose. a Division of Cardiology, Electrophysiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA; b The Ohio State University Medical Center, Davis Heart and Lung Research Institute, Suite 200, 473 West 12th Avenue, Columbus, OH 43210-1252, USA * Corresponding author. E-mail address: [email protected] Card Electrophysiol Clin 7 (2015) 479–486 http://dx.doi.org/10.1016/j.ccep.2015.05.018 1877-9182/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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A 31-year-old woman with congenital long QT syndrome (LQTS) underwent dual-chamber ICD implantation at 21 years of age for recurrent syncope. Her corrected QT interval (QTc) on presentation was 581 milliseconds and she had not been previously treated with a b-blocker. Because she was adopted, her family history was unknown. Physical examination, echocardiogram, and laboratory data were within normal limits. Following implantable cardioverter-defibrillator (ICD) implantation, she was started on nadolol 80 mg once a day and her QTc shortened to 510 milliseconds. She remained asymptomatic for the next 8 years. As part of family planning, she underwent genetic testing showing double disease-causing mutations, KCNH2 Arg582Cys (transmembrane mutation) and KCNJ2 Arg82Trp (LQT2 and LQT7, respectively). Two months postpartum, at the age of 29 years, she presented with an appropriate ICD shock for ventricular fibrillation (VF). The ICD shock occurred during intercourse and was preceded by near syncope, and VF was not bradycardia or pause dependent. She was compliant with her b-blocker and was not taking any QT-prolonging medications. Nadolol was then increased to 120 mg daily with no further clinical events or therapies thus far.
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Rhodes & Weiss LONG QT SYNDROME Congenital LQTS is an inherited disorder of myocardial repolarization characterized by prolongation of the QT interval and associated with lifethreatening polymorphic ventricular tachycardia (VT) called torsades de pointes (TdP).1,2 Thirteen LQTS genes have been identified, which encode cardiac ion channels.2–4 LQT1 and LQT2 account for 90% of cases, with LQT3 accounting for 5% to 8%.1,2 The treatment of congenital LQTS involves antiadrenergic therapies: b-blockers and surgical left cardiac sympathetic denervation (LCSD) to decrease sympathetic input to the heart; cardiac pacing; and ICDs. Although this article focuses on the role of device therapy for the treatment of LQTS, it also discusses the role of b-blockers and LCSD because they are concomitant with device therapy. Most patients undergo ICD implantation following recurrent symptoms despite b-blocker therapy, whereas some experts recommend that LCSD be performed before ICD implantation for these patients.5 More commonly, LCSD is recommended for patients with frequent ICD therapies despite medical therapy. The challenges are in deciding who can be treated with b-blockers alone, without ICD implantation, and who requires denervation surgery and ICD implantation.6 However, identifying patients with LQTS at high risk for cardiac events who would benefit from ICD implantation remains difficult, and frequently ICDs are implanted based on patient and physician preference and not an evidence-based approach.7
Risk Factors for Cardiac Events in Long QT Syndrome The risk of cardiac events is directly related to the length of the QTc interval8–10; when the QTc is greater than 500 milliseconds and greater than 550 milliseconds there is a 2-fold and 4-fold higher risk of sudden cardiac arrest (SCA) or sudden cardiac death (SCD) than when the QTc is less than 500 milliseconds.11 Age and gender also influence
the risk of cardiac events, with boys being at higher risk than girls during childhood but the risk for girls steadily increases following puberty.11–17 Patients with LQT1 and LQT2 have a higher risk of cardiac events than those with LQT3 but an increased lethality of cardiac events is seen in LQT3.9,10,18 Risk stratification can be assisted by the mutation location, its kinetic abnormality on the ion channel, and the presence of multiple mutations.7 An LQT1 transmembrane mutation is associated with a 2-fold increased risk for cardiac events compared with a nontransmembrane mutation19; however, women with cytoplasmic-loop mutations had a 2.7-fold increased risk for SCA and SCD compared with men.20 In LQT2, an increased risk of cardiac events was seen in patients with mutations involving the S5-S6 transmembrane loop.21 Men with pore-loop LQT2 mutations had a greater than 2-fold higher risk of a first cardiac event compared with those with non–pore-loop mutations, whereas women had a higher rate of SCA and SCD regardless of mutation location.22 The US and European ICD-LQTS registries have shown that most patients had not failed b-blocker therapy or had SCA before ICD implantation.23,24 The European registry of 233 patients with LQTS with ICDs showed that 28% received appropriate ICD therapies, and future appropriate ICD therapies could be predicted by 4 variables (age 500 milliseconds, prior cardiac arrest, and cardiac events despite therapy). The M-FACT (M, Minus 1 point for being free of cardiac events while on therapy for >10 years; F, Five hundred and five hundred and fifty millisecond QTc; A, Age 20 years at implant; C, Cardiac arrest; T, events on Therapy [aborted cardiac arrest]) scoring system (Table 1) was designed to use clinical factors that are readily available during an office visit. Genotype was not considered because genotyping typically takes several months and in many cases is not available at the time the decision for ICD implantation is made. Within 7 years, no appropriate shocks
Table 1 M-FACT Risk Score for evaluating risk of appropriate ICD therapy
Event free on therapy for >10 y QTc (ms) Prior SCA Events on therapy Age at implantation (y)
L1 Point
0 Points
1 Point
2 Points
Yes — — — —
— 500 No No >20
— >501–550 Yes Yes 20
— 551 — — —
Adapted from Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation 2010;122:1278; with permission.
Device Therapy in Long QT Syndrome occurred in patients with none of these clinical factors, and 70% with all 4 clinical factors received appropriate ICD shocks. Patients with an MFACT score of 0 are unlikely to benefit from ICD implantation.23
ANTIADRENERGIC THERAPIES b-Blockers b-Blockers are first-line treatment of all patients with LQTS, and are effective at preventing long QT–related arrhythmias, syncope, and SCD by shortening the QT interval, reducing sympathetic activation from the left stellate ganglion, and interrupting the trigger for TdP.25 When treated with b-blockers, patients with LQT1 have a very low risk arrhythmic risk provided they are fully compliant and avoid QT-prolonging medications. In one series with 216 patients with LQT1,26 12% had SCA and 73% had arrhythmic symptoms before starting b-blocker therapy. With treatment, 25% remained symptomatic and breakthrough arrhythmias were suppressed with increasing b-blocker doses, with a 70% reduction in the annual event rate. Of the 12 patients experiencing SCA, 8 were noncompliant with b-blocker therapy, 2 were on QT-prolonging medications, and 1 had both. The only death was in a compliant patient with Jervell and Lange-Nielson syndrome, which is a more malignant phenotype. Thus, life-threatening so-called b-blocker failures are caused by noncompliance and use of QTprolonging drugs.26 The 2 most effective b-blockers are propranolol and nadolol. In a retrospective study of 382 patients with LQT1 or LQT2, patients treated with propranolol had significantly greater QTc shortening compared with those treated with metoprolol or nadolol (27 milliseconds vs 14 milliseconds vs 12 milliseconds respectively). More clinical breakthrough events (syncope, SCA, ICD shock, SCD) were seen in patients receiving metoprolol compared with those treated with propranolol or nadolol (27% vs 8% vs 7%, respectively).27 The efficacy of propranolol is likely caused by its ability to also block sodium channels. Nadolol has been preferred because its longer half-life allows once-daily dosing, increasing compliance especially when prescribed to teenagers.5 Patients with LQT1 receive the greatest benefit with b-blockers followed by LQT2, and the efficacy with LQT3 is less clear.28–30 All patients with LQTS, whether symptomatic or not, should be treated with b-blockers unless there is an absolute contraindication.1 Bronchial asthma is no longer an absolute contraindication to b-blockers and they are well tolerated by patients with mild asthma when b1-selective b-blockers are
carefully titrated,31 and may reduce the likelihood of arrhythmic events in patients with LQTS being treated with bronchodilators.32
Left Cardiac Sympathetic Denervation LCSD reduces clinical events in patients with LQTS.33,34 Some clinicians recommend LCSD for patients who have recurrent syncope or SCA despite treatment with b-blockers before ICD implantation.5 More commonly, ICD implantation is performed in patients with clinical events despite b-blockers, and LCSD is only considered for those patients with frequent ICD shocks. Left cervicothoracic sympathectomy involves resection of the left stellate ganglion and the first 4 thoracic ganglia, leading to preganglionic denervation with an associated Horner syndrome. To prevent Horner syndrome, some surgeons perform a high thoracic left sympathectomy in which the cephalic portion of the left stellate ganglion is left intact. Surgery is performed via a small left subclavicular incision with an extrapleural approach, taking an average of 35 to 40 minutes.5 At some centers, LCSD can be safely performed via a minimally invasive video-assisted thoracoscopic approach.35–37 LCSD has both antiarrhythmic and antifibrillatory effects. In the largest series, 147 high-risk patients with LQTS underwent LCSD: 99% were symptomatic, mean QTc was 563 65 milliseconds, 48% of subjects had SCA, and 75% had syncope despite b-blocker therapy. Following LCSD, the mean QTc shortening was 39 milliseconds, and a 91% reduction in cardiac events was seen. Five patients in the series underwent LCSD because of recurrent ICD therapies, and following LCSD there was a 95% reduction in the number of ICD shocks.34 LCSD should be considered in patients with LQTS with syncopal episodes and recurrent ICD shocks despite maximal beta-blockade. However, LCSD is not routinely considered in high-risk patients because of poor availability.5
CARDIAC PACING Patients who remain symptomatic despite b-blockers have been treated with cardiac pacing, especially when bradycardia facilitates TdP.38,39 Some clinicians have suggested that patients with LQT3 may receive particular benefit because bradycardia worsens dispersion of depolarization, which facilitates pause-dependent ventricular arrhythmias.40 The 2012 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) Focused Update, incorporated into the ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac
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Rhodes & Weiss Rhythm Abnormalities, established the following recommendations for permanent pacing in patients with LQTS.41
Class I 1. Permanent pacing is indicated for sustained pause-dependent VT, with or without QT prolongation (level of evidence, C).
Class IIa 1. Permanent pacing is reasonable for high-risk patients with congenital LQTS (level of evidence, C). Typically dual-chamber pacing has been used to maintain atrioventricular (AV) synchrony and because of the predisposition of AV block in patients with LQTS, especially when treated with high-dose b-blockers. Atrial pacing is favored rather than ventricular pacing because the latter can cause heterogeneous depolarization that can be proarrhythmic and also leads to QT prolongation. Atrial pacing at rates that shorten the QTc may also suppress premature ventricular beats that can trigger TdP. In a report of 37 patients treated with b-blockers and permanent pacing at a mean heart rate (HR) of 82 beats per minute (bpm; range 60–100 bpm), the mean QTc with pacing was 500 milliseconds with an approximately 50-millisecond reduction from baseline. With a mean follow-up of 6.3 years, 76% of patients remained asymptomatic and the incidence of SCA or SCD was 24% overall and 17% in those who remained on b-blocker therapy. Although cardiac pacing and b-blockers is an effective treatment, it does not eliminate the risk of SCA or SCD and, when permanent pacemaker implantation is being considered, an ICD should be considered.38 Permanent pacing was widely used before the advent of nonthoracotomy ICDs. At present, in the United States it is more commonly used with an ICD.
IMPLANTABLE CARDIOVERTERDEFIBRILLATORS The following recommendations for ICD implantation in patients with LQTS were made in the 2012 ACCF/AHA/HRS Focused Update.41
Class I ICD therapy is indicated in patients who are survivors of cardiac arrest caused by VF or hemodynamically unstable sustained VT after evaluation to define the cause of the event and to exclude any completely reversible causes. This indication
is the typical one for secondary prevention of SCD with level A evidence established in SCA survivors with ischemic and nonischemic cardiomyopathy. There is no level A evidence for SCA survivors with LQTS but level B evidence can be considered.
Class IIa ICD implantation is reasonable to reduce SCD in patients with LQTS who are experiencing syncope and/or VT while receiving b-blockers. This indication is the most commonly cited indication for ICD implantation in patients with LQTS because those who experience syncope while on b-blockers have a 3.6-fold increased risk of arrhythmic events and have a similar risk to those patients not on b-blockers.42
Class IIb ICD therapy may be considered for patients with LQTS and risk factors for SCD. Risk factors and risk stratification for cardiac events in LQTS are discussed earlier. These recommendations were unchanged from the 2008 guidelines. The writing group acknowledged the limited role of primary prevention ICDs in asymptomatic genetically confirmed LQTS but, until additional trials or studies are completed, refining ICD implantation criteria for these patients was thought to be inappropriate.41 There is expert consensus that early ICD implantation can be considered in patients with Jervell-Lange-Nielson who have a higher risk of malignant arrhythmias despite therapy.43 Although no large trials are available, smaller studies have shown the efficacy of ICD in congenital LQTS: An initial report of 14 children (mean age, 15 years) who underwent ICD implantation, with 8 receiving appropriate ICD shocks.44 In a retrospective study of 35 patients using 2 ICD manufacturers’ databases, 74% had aborted SCA, 17% had syncope, and 9% had symptomatic TdP, with no deaths with a mean follow-up of 31 months. Three patients had device-related complications: 2 infections and 1 lead malfunction.45 A Mayo Clinic series of 6 patients who underwent ICD implantation because of syncope despite b-blocker therapy, SCA, or family history of SCD, with 4 patients receiving appropriate ICD therapy for VF with a median follow-up of 3 years.46 In a retrospective study, patients with LQTS with SCA and recurrent syncope despite b-blocker therapy (n 5 73) were compared
Device Therapy in Long QT Syndrome with 161 patients with LQTS who had similar indications (89 cardiac arrest and 72 recurrent syncope despite b-blocker therapy) but did not undergo ICD implantation. There was 1 (1.3%) death in 73 patients with ICDs with an average 3-year follow-up, whereas there were 26 deaths (16%) in patients without ICDs during the mean 8-year follow-up.24 Among 12 patients who underwent ICD implantation for high-risk LQTS, during a follow-up of 34.7 16.6 months, 5 received appropriate therapies, 4 with inappropriate therapies, and no therapies in 3 patients. Clusters of appropriate therapies were seen in 3 patients, 1 of whom subsequently died.47 Twenty symptomatic patients with LQTS undergoing ICD therapy (QTc, 540 64 milliseconds; 85% women, 63% with cardiac arrest; 33% with syncope despite b-blockers; 4% with severe phenotype) and 81 genotyped patients with LQTS receiving conventional drug therapy (28 LQT1, 39 LQT2, 1 LQT3, 13 LQT5) were followed for 65 34 months. There were 178 appropriate shocks in 10 of 27 patients (37%), mostly in survivors of cardiac arrest, with 1 death in the ICD group.48 In a retrospective study at 3 children’s hospitals of 128 patients (mean age, 8 years), 98% were treated with b-blockers, 21% underwent ICD implantation because of recurrent symptoms despite beta-blockade, 22% received an appropriate ICD therapy, but 48% experienced device-related reintervention.49
Device Programming for Long QT Syndrome Although formal recommendations for optimal device programming for LQTS are not available, ventricular arrhythmias and TdP may be nonsustained and special attention should be made to device programming to minimize the risk of inappropriate ICD shocks, which typically involves programming high detection rates with an extended detection time. In addition, the release of catecholamines following an appropriate or inappropriate ICD therapy can lead to a vicious cycle of further arrhythmias and ICD shocks. Another feature to consider is enabling the device to overdrive pace following an ICD shock to increase the HR, shorten the QT, and suppress premature ventricular depolarization, which can reinitiate VT. For patients with dual-chamber devices, atrial pacing is favored and ventricular pacing should be minimized because it can cause heterogeneous depolarization that can be proarrhythmic and also leads to QT prolongation. In combination with beta-blockade, atrial pacing at rates that shorten the QTc to less than
440 milliseconds can significantly reduce the risk of recurrent events38 and may also suppress premature ventricular beats that can trigger TdP.
Complications of Implantable CardioverterDefibrillator Therapies However, complications can occur with ICD implantation: pneumothorax, infection, lead dislodgement, perforation, fracture requiring revisions, and inappropriate ICD therapies leading to psychiatric sequelae.23,45,46,50 This consideration is especially important in children and young adults undergoing ICD implantation who may outlive their leads and devices, requiring complex replacement and lead extraction procedures with inherent risk of infection.
Subcutaneous Implantable CardioverterDefibrillator and Long QT Syndrome The subcutaneous ICD (S-ICD) eliminates the risk for vascular injury or pneumothorax given its subcutaneous lead and, if needed, explantation is much simpler and safer than transvenous lead extraction. This advantage is especially important in young patients with an active lifestyle and long life expectancy. Although the S-ICD does not provide antitachycardia pacing (ATP) or bradycardia therapy, it may be a good option for patients with LQTS whose typical clinical arrhythmias are polymorphic VT or VF not amenable to ATP. The S-ICD may be an appropriate device for those patients without bradycardia or pause-dependent VT despite maximal b-blocker.51,52 A special concern with patients with S-ICDs and LQTS is the risk of inappropriate ICD shocks for T-wave oversensing, which may be limited by template acquisition during exercise.
CASE DISCUSSION This patient presented and underwent ICD implantation before the current recommendation that b-blocker alone is sufficient therapy in patients with syncope while not receiving b-blockers. Her indication for ICD implantation at that time was based on her significantly prolonged QT, recurrent syncope, and female gender. The fact that her family history was unknown may have also played a role at the time of recommending ICD implantation by assuming the worst-case scenario. In retrospect, this was the correct decision because she subsequently received an appropriate ICD shock while on nadolol. She had previously refused genetic testing and was subsequently found to have mutations involving KCNH2 and KCNJ2, and patients with multiple mutations are at higher
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Rhodes & Weiss risk for SCD. There is also an increased risk of ventricular arrhythmias postpartum.53
SUMMARY The treatment of patients with congenital LQTS has evolved over the years. The current recommendations are based on consensus statements, the LQTS registries, and small reports of families with different mutations. Treating patients with congenital LQTS is challenging for multiple reasons: the age of the patient and the high emotional impact, the type and number of mutations, life events such as pregnancy, and medical compliance and exposure to QT-prolonging medications. The cornerstone for the treatment of these patients should be b-blockers and avoidance of QT-prolonging drugs. Although effective, LCSD is limited by the availability of surgeons with experience in this procedure. ICDs are highly effective in the prevention of SCD but they have inherent risks and, following implantation, programming should be optimized to minimize the risk for inappropriate ICD therapies.
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10. 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;339:960–5. 11. Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol 2007;49:329–37. 12. Goldenberg I, Moss AJ, Bradley J, et al. LongQT syndrome after age 40. Circulation 2008;117: 2192–201. 13. 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;117:2184–91. 14. 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;296:1249–54. 15. Locati EH, Zareba W, Moss AJ, et al. Age- and sexrelated differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998;97:2237–44. 16. 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: 1685–91. 17. Zareba W, Moss AJ, Locati EH, et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol 2003;42:103–9. 18. Goldenberg I, Zareba W, Moss AJ. Long QT syndrome. Curr Probl Cardiol 2008;33:629–94. 19. 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: 2481–9. 20. Costa J, Lopes CM, Barsheshet A, et al. Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome. Heart Rhythm 2012;9:892–8. 21. Shimizu W, Moss AJ, Wilde AA, et al. Genotypephenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol 2009;54:2052–62. 22. Migdalovich D, Moss AJ, Lopes CM, et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for lifethreatening cardiac events in patients with long QT syndrome. Heart Rhythm 2011;8:1537–43. 23. Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation 2010;122:1272–82. 24. Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter defibrillator in high-risk long QT
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syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery. Heart Rhythm 2009;6:752–9. Hofferberth SC, Cecchin F, Loberman D, et al. Left thoracoscopic sympathectomy for cardiac denervation in patients with life-threatening ventricular arrhythmias. J Thorac Cardiovasc Surg 2014;147: 404–9. Dorostkar PC, Eldar M, Belhassen B, et al. Longterm follow-up of patients with long-QT syndrome treated with beta-blockers and continuous pacing. Circulation 1999;100:2431–6. Viskin S. Cardiac pacing in the long QT syndrome: review of available data and practical recommendations. J Cardiovasc Electrophysiol 2000;11:593–600. 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;35:778–86. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for devicebased therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013;61:e6–75. Jons C, Moss AJ, Goldenberg I, et al. Risk of fatal arrhythmic events in long QT syndrome patients after syncope. J Am Coll Cardiol 2010;55:783–8. Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 2006;113:783–90. Silka MJ, Kron J, Dunnigan A, et al. Sudden cardiac death and the use of implantable cardioverterdefibrillators in pediatric patients. The Pediatric Electrophysiology Society. Circulation 1993;87: 800–7. Groh WJ, Silka MJ, Oliver RP, et al. Use of implantable cardioverter-defibrillators in the congenital long QT syndrome. Am J Cardiol 1996;78:703–6. 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; 77:226–31. Goel AK, Berger S, Pelech A, et al. Implantable cardioverter defibrillator therapy in children with long QT syndrome. Pediatr Cardiol 2004;25:370–8. Monnig G, Kobe J, Loher A, et al. Implantable cardioverter-defibrillator therapy in patients with congenital long-QT syndrome: a long-term followup. Heart Rhythm 2005;2:497–504. Etheridge SP, Sanatani S, Cohen MI, et al. Long QT syndrome in children in the era of implantable defibrillators. J Am Coll Cardiol 2007;50:1335–40.
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the IDE study and EFFORTLESS registry. J Am Coll Cardiol 2015;65:1605–15. 52. Weiss R, Knight BP, Gold MR, et al. Safety and efficacy of a totally subcutaneous implantable-cardioverter defibrillator. Circulation 2013;128:944–53. 53. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol 2007;49:1092–8.
KEY POINTS Treating patients with congenital long QT syndrome is challenging for several reasons: the age of the patients and the high emotional impact, the type and number of mutations, life events such as pregnancy, and medical compliance and exposure to QT-prolonging medications. The cornerstone for the treatment of these patients should be b-blockers and avoidance of QTprolonging drugs. Left cardiac sympathetic denervation, although effective, is limited by the availability of surgeons with experience in this procedure. Implantable cardioverter-defibrillators (ICDs) are highly effective in the prevention of sudden cardiac death, but they have inherent risks; following implantation, programming should be optimized to minimize the risk for inappropriate ICD therapies.
Case History
Disclosure: The authors have nothing to disclose. a Division of Cardiology, Electrophysiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA; b The Ohio State University Medical Center, Davis Heart and Lung Research Institute, Suite 200, 473 West 12th Avenue, Columbus, OH 43210-1252, USA * Corresponding author. E-mail address: [email protected] Card Electrophysiol Clin 7 (2015) 479–486 http://dx.doi.org/10.1016/j.ccep.2015.05.018 1877-9182/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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A 31-year-old woman with congenital long QT syndrome (LQTS) underwent dual-chamber ICD implantation at 21 years of age for recurrent syncope. Her corrected QT interval (QTc) on presentation was 581 milliseconds and she had not been previously treated with a b-blocker. Because she was adopted, her family history was unknown. Physical examination, echocardiogram, and laboratory data were within normal limits. Following implantable cardioverter-defibrillator (ICD) implantation, she was started on nadolol 80 mg once a day and her QTc shortened to 510 milliseconds. She remained asymptomatic for the next 8 years. As part of family planning, she underwent genetic testing showing double disease-causing mutations, KCNH2 Arg582Cys (transmembrane mutation) and KCNJ2 Arg82Trp (LQT2 and LQT7, respectively). Two months postpartum, at the age of 29 years, she presented with an appropriate ICD shock for ventricular fibrillation (VF). The ICD shock occurred during intercourse and was preceded by near syncope, and VF was not bradycardia or pause dependent. She was compliant with her b-blocker and was not taking any QT-prolonging medications. Nadolol was then increased to 120 mg daily with no further clinical events or therapies thus far.
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Rhodes & Weiss LONG QT SYNDROME Congenital LQTS is an inherited disorder of myocardial repolarization characterized by prolongation of the QT interval and associated with lifethreatening polymorphic ventricular tachycardia (VT) called torsades de pointes (TdP).1,2 Thirteen LQTS genes have been identified, which encode cardiac ion channels.2–4 LQT1 and LQT2 account for 90% of cases, with LQT3 accounting for 5% to 8%.1,2 The treatment of congenital LQTS involves antiadrenergic therapies: b-blockers and surgical left cardiac sympathetic denervation (LCSD) to decrease sympathetic input to the heart; cardiac pacing; and ICDs. Although this article focuses on the role of device therapy for the treatment of LQTS, it also discusses the role of b-blockers and LCSD because they are concomitant with device therapy. Most patients undergo ICD implantation following recurrent symptoms despite b-blocker therapy, whereas some experts recommend that LCSD be performed before ICD implantation for these patients.5 More commonly, LCSD is recommended for patients with frequent ICD therapies despite medical therapy. The challenges are in deciding who can be treated with b-blockers alone, without ICD implantation, and who requires denervation surgery and ICD implantation.6 However, identifying patients with LQTS at high risk for cardiac events who would benefit from ICD implantation remains difficult, and frequently ICDs are implanted based on patient and physician preference and not an evidence-based approach.7
Risk Factors for Cardiac Events in Long QT Syndrome The risk of cardiac events is directly related to the length of the QTc interval8–10; when the QTc is greater than 500 milliseconds and greater than 550 milliseconds there is a 2-fold and 4-fold higher risk of sudden cardiac arrest (SCA) or sudden cardiac death (SCD) than when the QTc is less than 500 milliseconds.11 Age and gender also influence
the risk of cardiac events, with boys being at higher risk than girls during childhood but the risk for girls steadily increases following puberty.11–17 Patients with LQT1 and LQT2 have a higher risk of cardiac events than those with LQT3 but an increased lethality of cardiac events is seen in LQT3.9,10,18 Risk stratification can be assisted by the mutation location, its kinetic abnormality on the ion channel, and the presence of multiple mutations.7 An LQT1 transmembrane mutation is associated with a 2-fold increased risk for cardiac events compared with a nontransmembrane mutation19; however, women with cytoplasmic-loop mutations had a 2.7-fold increased risk for SCA and SCD compared with men.20 In LQT2, an increased risk of cardiac events was seen in patients with mutations involving the S5-S6 transmembrane loop.21 Men with pore-loop LQT2 mutations had a greater than 2-fold higher risk of a first cardiac event compared with those with non–pore-loop mutations, whereas women had a higher rate of SCA and SCD regardless of mutation location.22 The US and European ICD-LQTS registries have shown that most patients had not failed b-blocker therapy or had SCA before ICD implantation.23,24 The European registry of 233 patients with LQTS with ICDs showed that 28% received appropriate ICD therapies, and future appropriate ICD therapies could be predicted by 4 variables (age 500 milliseconds, prior cardiac arrest, and cardiac events despite therapy). The M-FACT (M, Minus 1 point for being free of cardiac events while on therapy for >10 years; F, Five hundred and five hundred and fifty millisecond QTc; A, Age 20 years at implant; C, Cardiac arrest; T, events on Therapy [aborted cardiac arrest]) scoring system (Table 1) was designed to use clinical factors that are readily available during an office visit. Genotype was not considered because genotyping typically takes several months and in many cases is not available at the time the decision for ICD implantation is made. Within 7 years, no appropriate shocks
Table 1 M-FACT Risk Score for evaluating risk of appropriate ICD therapy
Event free on therapy for >10 y QTc (ms) Prior SCA Events on therapy Age at implantation (y)
L1 Point
0 Points
1 Point
2 Points
Yes — — — —
— 500 No No >20
— >501–550 Yes Yes 20
— 551 — — —
Adapted from Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation 2010;122:1278; with permission.
Device Therapy in Long QT Syndrome occurred in patients with none of these clinical factors, and 70% with all 4 clinical factors received appropriate ICD shocks. Patients with an MFACT score of 0 are unlikely to benefit from ICD implantation.23
ANTIADRENERGIC THERAPIES b-Blockers b-Blockers are first-line treatment of all patients with LQTS, and are effective at preventing long QT–related arrhythmias, syncope, and SCD by shortening the QT interval, reducing sympathetic activation from the left stellate ganglion, and interrupting the trigger for TdP.25 When treated with b-blockers, patients with LQT1 have a very low risk arrhythmic risk provided they are fully compliant and avoid QT-prolonging medications. In one series with 216 patients with LQT1,26 12% had SCA and 73% had arrhythmic symptoms before starting b-blocker therapy. With treatment, 25% remained symptomatic and breakthrough arrhythmias were suppressed with increasing b-blocker doses, with a 70% reduction in the annual event rate. Of the 12 patients experiencing SCA, 8 were noncompliant with b-blocker therapy, 2 were on QT-prolonging medications, and 1 had both. The only death was in a compliant patient with Jervell and Lange-Nielson syndrome, which is a more malignant phenotype. Thus, life-threatening so-called b-blocker failures are caused by noncompliance and use of QTprolonging drugs.26 The 2 most effective b-blockers are propranolol and nadolol. In a retrospective study of 382 patients with LQT1 or LQT2, patients treated with propranolol had significantly greater QTc shortening compared with those treated with metoprolol or nadolol (27 milliseconds vs 14 milliseconds vs 12 milliseconds respectively). More clinical breakthrough events (syncope, SCA, ICD shock, SCD) were seen in patients receiving metoprolol compared with those treated with propranolol or nadolol (27% vs 8% vs 7%, respectively).27 The efficacy of propranolol is likely caused by its ability to also block sodium channels. Nadolol has been preferred because its longer half-life allows once-daily dosing, increasing compliance especially when prescribed to teenagers.5 Patients with LQT1 receive the greatest benefit with b-blockers followed by LQT2, and the efficacy with LQT3 is less clear.28–30 All patients with LQTS, whether symptomatic or not, should be treated with b-blockers unless there is an absolute contraindication.1 Bronchial asthma is no longer an absolute contraindication to b-blockers and they are well tolerated by patients with mild asthma when b1-selective b-blockers are
carefully titrated,31 and may reduce the likelihood of arrhythmic events in patients with LQTS being treated with bronchodilators.32
Left Cardiac Sympathetic Denervation LCSD reduces clinical events in patients with LQTS.33,34 Some clinicians recommend LCSD for patients who have recurrent syncope or SCA despite treatment with b-blockers before ICD implantation.5 More commonly, ICD implantation is performed in patients with clinical events despite b-blockers, and LCSD is only considered for those patients with frequent ICD shocks. Left cervicothoracic sympathectomy involves resection of the left stellate ganglion and the first 4 thoracic ganglia, leading to preganglionic denervation with an associated Horner syndrome. To prevent Horner syndrome, some surgeons perform a high thoracic left sympathectomy in which the cephalic portion of the left stellate ganglion is left intact. Surgery is performed via a small left subclavicular incision with an extrapleural approach, taking an average of 35 to 40 minutes.5 At some centers, LCSD can be safely performed via a minimally invasive video-assisted thoracoscopic approach.35–37 LCSD has both antiarrhythmic and antifibrillatory effects. In the largest series, 147 high-risk patients with LQTS underwent LCSD: 99% were symptomatic, mean QTc was 563 65 milliseconds, 48% of subjects had SCA, and 75% had syncope despite b-blocker therapy. Following LCSD, the mean QTc shortening was 39 milliseconds, and a 91% reduction in cardiac events was seen. Five patients in the series underwent LCSD because of recurrent ICD therapies, and following LCSD there was a 95% reduction in the number of ICD shocks.34 LCSD should be considered in patients with LQTS with syncopal episodes and recurrent ICD shocks despite maximal beta-blockade. However, LCSD is not routinely considered in high-risk patients because of poor availability.5
CARDIAC PACING Patients who remain symptomatic despite b-blockers have been treated with cardiac pacing, especially when bradycardia facilitates TdP.38,39 Some clinicians have suggested that patients with LQT3 may receive particular benefit because bradycardia worsens dispersion of depolarization, which facilitates pause-dependent ventricular arrhythmias.40 The 2012 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) Focused Update, incorporated into the ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac
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Rhodes & Weiss Rhythm Abnormalities, established the following recommendations for permanent pacing in patients with LQTS.41
Class I 1. Permanent pacing is indicated for sustained pause-dependent VT, with or without QT prolongation (level of evidence, C).
Class IIa 1. Permanent pacing is reasonable for high-risk patients with congenital LQTS (level of evidence, C). Typically dual-chamber pacing has been used to maintain atrioventricular (AV) synchrony and because of the predisposition of AV block in patients with LQTS, especially when treated with high-dose b-blockers. Atrial pacing is favored rather than ventricular pacing because the latter can cause heterogeneous depolarization that can be proarrhythmic and also leads to QT prolongation. Atrial pacing at rates that shorten the QTc may also suppress premature ventricular beats that can trigger TdP. In a report of 37 patients treated with b-blockers and permanent pacing at a mean heart rate (HR) of 82 beats per minute (bpm; range 60–100 bpm), the mean QTc with pacing was 500 milliseconds with an approximately 50-millisecond reduction from baseline. With a mean follow-up of 6.3 years, 76% of patients remained asymptomatic and the incidence of SCA or SCD was 24% overall and 17% in those who remained on b-blocker therapy. Although cardiac pacing and b-blockers is an effective treatment, it does not eliminate the risk of SCA or SCD and, when permanent pacemaker implantation is being considered, an ICD should be considered.38 Permanent pacing was widely used before the advent of nonthoracotomy ICDs. At present, in the United States it is more commonly used with an ICD.
IMPLANTABLE CARDIOVERTERDEFIBRILLATORS The following recommendations for ICD implantation in patients with LQTS were made in the 2012 ACCF/AHA/HRS Focused Update.41
Class I ICD therapy is indicated in patients who are survivors of cardiac arrest caused by VF or hemodynamically unstable sustained VT after evaluation to define the cause of the event and to exclude any completely reversible causes. This indication
is the typical one for secondary prevention of SCD with level A evidence established in SCA survivors with ischemic and nonischemic cardiomyopathy. There is no level A evidence for SCA survivors with LQTS but level B evidence can be considered.
Class IIa ICD implantation is reasonable to reduce SCD in patients with LQTS who are experiencing syncope and/or VT while receiving b-blockers. This indication is the most commonly cited indication for ICD implantation in patients with LQTS because those who experience syncope while on b-blockers have a 3.6-fold increased risk of arrhythmic events and have a similar risk to those patients not on b-blockers.42
Class IIb ICD therapy may be considered for patients with LQTS and risk factors for SCD. Risk factors and risk stratification for cardiac events in LQTS are discussed earlier. These recommendations were unchanged from the 2008 guidelines. The writing group acknowledged the limited role of primary prevention ICDs in asymptomatic genetically confirmed LQTS but, until additional trials or studies are completed, refining ICD implantation criteria for these patients was thought to be inappropriate.41 There is expert consensus that early ICD implantation can be considered in patients with Jervell-Lange-Nielson who have a higher risk of malignant arrhythmias despite therapy.43 Although no large trials are available, smaller studies have shown the efficacy of ICD in congenital LQTS: An initial report of 14 children (mean age, 15 years) who underwent ICD implantation, with 8 receiving appropriate ICD shocks.44 In a retrospective study of 35 patients using 2 ICD manufacturers’ databases, 74% had aborted SCA, 17% had syncope, and 9% had symptomatic TdP, with no deaths with a mean follow-up of 31 months. Three patients had device-related complications: 2 infections and 1 lead malfunction.45 A Mayo Clinic series of 6 patients who underwent ICD implantation because of syncope despite b-blocker therapy, SCA, or family history of SCD, with 4 patients receiving appropriate ICD therapy for VF with a median follow-up of 3 years.46 In a retrospective study, patients with LQTS with SCA and recurrent syncope despite b-blocker therapy (n 5 73) were compared
Device Therapy in Long QT Syndrome with 161 patients with LQTS who had similar indications (89 cardiac arrest and 72 recurrent syncope despite b-blocker therapy) but did not undergo ICD implantation. There was 1 (1.3%) death in 73 patients with ICDs with an average 3-year follow-up, whereas there were 26 deaths (16%) in patients without ICDs during the mean 8-year follow-up.24 Among 12 patients who underwent ICD implantation for high-risk LQTS, during a follow-up of 34.7 16.6 months, 5 received appropriate therapies, 4 with inappropriate therapies, and no therapies in 3 patients. Clusters of appropriate therapies were seen in 3 patients, 1 of whom subsequently died.47 Twenty symptomatic patients with LQTS undergoing ICD therapy (QTc, 540 64 milliseconds; 85% women, 63% with cardiac arrest; 33% with syncope despite b-blockers; 4% with severe phenotype) and 81 genotyped patients with LQTS receiving conventional drug therapy (28 LQT1, 39 LQT2, 1 LQT3, 13 LQT5) were followed for 65 34 months. There were 178 appropriate shocks in 10 of 27 patients (37%), mostly in survivors of cardiac arrest, with 1 death in the ICD group.48 In a retrospective study at 3 children’s hospitals of 128 patients (mean age, 8 years), 98% were treated with b-blockers, 21% underwent ICD implantation because of recurrent symptoms despite beta-blockade, 22% received an appropriate ICD therapy, but 48% experienced device-related reintervention.49
Device Programming for Long QT Syndrome Although formal recommendations for optimal device programming for LQTS are not available, ventricular arrhythmias and TdP may be nonsustained and special attention should be made to device programming to minimize the risk of inappropriate ICD shocks, which typically involves programming high detection rates with an extended detection time. In addition, the release of catecholamines following an appropriate or inappropriate ICD therapy can lead to a vicious cycle of further arrhythmias and ICD shocks. Another feature to consider is enabling the device to overdrive pace following an ICD shock to increase the HR, shorten the QT, and suppress premature ventricular depolarization, which can reinitiate VT. For patients with dual-chamber devices, atrial pacing is favored and ventricular pacing should be minimized because it can cause heterogeneous depolarization that can be proarrhythmic and also leads to QT prolongation. In combination with beta-blockade, atrial pacing at rates that shorten the QTc to less than
440 milliseconds can significantly reduce the risk of recurrent events38 and may also suppress premature ventricular beats that can trigger TdP.
Complications of Implantable CardioverterDefibrillator Therapies However, complications can occur with ICD implantation: pneumothorax, infection, lead dislodgement, perforation, fracture requiring revisions, and inappropriate ICD therapies leading to psychiatric sequelae.23,45,46,50 This consideration is especially important in children and young adults undergoing ICD implantation who may outlive their leads and devices, requiring complex replacement and lead extraction procedures with inherent risk of infection.
Subcutaneous Implantable CardioverterDefibrillator and Long QT Syndrome The subcutaneous ICD (S-ICD) eliminates the risk for vascular injury or pneumothorax given its subcutaneous lead and, if needed, explantation is much simpler and safer than transvenous lead extraction. This advantage is especially important in young patients with an active lifestyle and long life expectancy. Although the S-ICD does not provide antitachycardia pacing (ATP) or bradycardia therapy, it may be a good option for patients with LQTS whose typical clinical arrhythmias are polymorphic VT or VF not amenable to ATP. The S-ICD may be an appropriate device for those patients without bradycardia or pause-dependent VT despite maximal b-blocker.51,52 A special concern with patients with S-ICDs and LQTS is the risk of inappropriate ICD shocks for T-wave oversensing, which may be limited by template acquisition during exercise.
CASE DISCUSSION This patient presented and underwent ICD implantation before the current recommendation that b-blocker alone is sufficient therapy in patients with syncope while not receiving b-blockers. Her indication for ICD implantation at that time was based on her significantly prolonged QT, recurrent syncope, and female gender. The fact that her family history was unknown may have also played a role at the time of recommending ICD implantation by assuming the worst-case scenario. In retrospect, this was the correct decision because she subsequently received an appropriate ICD shock while on nadolol. She had previously refused genetic testing and was subsequently found to have mutations involving KCNH2 and KCNJ2, and patients with multiple mutations are at higher
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Rhodes & Weiss risk for SCD. There is also an increased risk of ventricular arrhythmias postpartum.53
SUMMARY The treatment of patients with congenital LQTS has evolved over the years. The current recommendations are based on consensus statements, the LQTS registries, and small reports of families with different mutations. Treating patients with congenital LQTS is challenging for multiple reasons: the age of the patient and the high emotional impact, the type and number of mutations, life events such as pregnancy, and medical compliance and exposure to QT-prolonging medications. The cornerstone for the treatment of these patients should be b-blockers and avoidance of QT-prolonging drugs. Although effective, LCSD is limited by the availability of surgeons with experience in this procedure. ICDs are highly effective in the prevention of SCD but they have inherent risks and, following implantation, programming should be optimized to minimize the risk for inappropriate ICD therapies.
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the IDE study and EFFORTLESS registry. J Am Coll Cardiol 2015;65:1605–15. 52. Weiss R, Knight BP, Gold MR, et al. Safety and efficacy of a totally subcutaneous implantable-cardioverter defibrillator. Circulation 2013;128:944–53. 53. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol 2007;49:1092–8.
