7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Treatment : Peter J Schwartz, MD, Michael J Ackerman, MD, PhD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 02, 2022. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1]. The primary symptoms in patients with LQTS include syncope, seizures, sudden cardiac arrest (SCA), and SCD. This syndrome is associated with an increased risk of a characteristic life- threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" ( waveform 2) [2]. LQTS may be congenital or acquired [1,3-7]. Pathogenic variants in at least 17 genes have been identified thus far in patients with congenital LQTS. An estimated 75 to 80 percent of all congenital LQTS is accounted for by LQTS-causative variants in either KCNQ1-encoded Kv7.1 (LQT1), KCNH2-encoded Kv11.1 (LQT2), or SCN5A-encoded Nav1.5 (LQT3). The minor LQTS genotypes account for at most 5 percent of LQTS and are best referred to by their genetic cause rather than their numerical subtype (eg, CACNA1C-LQTS rather than LQT8) ( table 1) [7]. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2). The treatment of congenital LQTS will be reviewed here. The epidemiology, clinical manifestations, diagnosis, and genetics of congenital LQTS, as well as issues related to the management of acquired LQTS, are discussed separately. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Diagnosis" and https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 1/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate "Congenital long QT syndrome: Pathophysiology and genetics" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) TREATMENT Regardless of genotype, age, and previous symptomatic/asymptomatic status, all patients with congenital LQTS should be advised of simple QT preventive measures and implement them whenever possible. These include avoidance of medications with QT-prolonging potential ( www.crediblemeds.org); replacing electrolytes during vomiting and diarrheal illnesses, as both hypokalemia and hypomagnesemia can be QT aggravating; and lowering fever. Like the 2015 Heart Rhythm Society (HRS) guidelines, the 2017 American Heart Association/American College of Cardiology (AHA/ACC) guidelines continue to recommend universal beta-blocker therapy for all patients with congenital LQTS, whether asymptomatic or symptomatic, in the absence of a contraindication [8]. In the setting of breakthrough cardiac events while on beta-blocker therapy or in the setting of beta-blocker intolerance, patient- specific tailoring of therapy is appropriate, based on the assessed risk from the disease and the potential comorbidities of the various treatments under consideration with the patients and their families also involved in the shared decision making. Recommended options for treatment intensification may include one or more of the following: Other medications (such as mexiletine) Left cardiac sympathetic denervation (LCSD) Placement of a pacemaker to enable intentional atrial pacing Placement of an implantable cardioverter-defibrillator (ICD) The treatment of patients with congenital and acquired LQTS differs greatly because of pathophysiologic differences between the two forms. As an example, bradycardia is usually associated with torsades de pointes (TdP) in acquired LQTS, whereas catecholamine surges trigger TdP in congenital LQTS. The following discussion is limited to the treatment of congenital LQTS. The management of acquired LQTS is presented separately; it involves acute therapy of arrhythmia, discontinuation of any precipitating drug, and correction of any metabolic abnormalities such as hypokalemia or hypomagnesemia. The acute management of TdP is also discussed in detail elsewhere. (See "Overview of the acute management of tachyarrhythmias", section on 'Polymorphic ventricular tachycardia' and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 2/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Our approach to symptomatic patients Because of the appreciable risk of symptoms and SCD without treatment, all previously symptomatic patients with congenital LQTS should be treated [9,10]. Our general approach is as follows: All patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval ( www.crediblemeds.org) and the aggressive treatment of electrolyte imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Initial management'.) Athletes with LQTS who desire to remain athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. For all patients with congenital LQTS and a history of syncope or seizures, we recommend treatment with a beta blocker. We prefer propranolol or nadolol, given their superior efficacy in this patient population. All patients with congenital LQTS who present with resuscitated SCA should be treated with a beta blocker, preferably propranolol or nadolol, given their superior efficacy in this patient population. Additionally, for most patients with congenital LQTS who present with resuscitated SCA while previously undiagnosed and therefore untreated, the treatment program should also include an ICD as secondary prevention. Potential exceptions to this include patients with previously undiagnosed and therefore untreated LQT1. For patients with recurrent arrhythmic events in spite of maximally tolerated doses of a beta blocker, or for patients who discontinue beta blockers due to intolerable side effects, treatment intensification with either concomitant drug therapy, LCSD, and/or an ICD is recommended depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). The risks and benefits of each treatment intensification option need to be reviewed with the patient and shared decision making should be utilized to decide upon and implement the chosen therapeutic strategy. Physical activity and LQTS Before tailoring any LQTS-specific therapies or recommending activity modification, it is vital to confirm the diagnosis of LQTS. Athletes are often flagged for the possibility of LQTS based on their pre-sports participation ECG screen. While a subsequent evaluation is necessary and appropriate, studies show that exercise can elicit a maladaptive remodeling in the repolarization reserve, yielding an acquired, reversible form of QT https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 3/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate prolongation rather than congenital LQTS itself [11]. If such an athlete's genetic test is negative and if their QT normalizes after detraining, they should not be classified as having LQTS or restricted from activity [11]. After establishing the correct diagnosis of LQTS and implementing the initial treatment program, patients with LQTS can continue to be recreationally active, especially those with LQT2 and LQT3. In general, children and adolescents can resume participation in physical education classes and adults should be encouraged to stay aerobically active in accordance with national/international recommendations on active living. Athletes with LQTS who desire to remain competitive athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. There is a divergence of opinions on competitive athletics for individuals with congenital LQTS [12-15]. The 2015 AHA/ACC Scientific Statement on Eligibility and Disqualification Recommendations for Competitive Athletes discusses participation in competitive events and training sessions as allowable and dependent on the existence of an emergency action plan with an automated external defibrillator (AED) immediately available on site. However, a different approach is dictated by the previous European guidelines, which advise precautionary restriction from competitive sports in these instances. The differences in the American and European approaches are outlined as follows: The following approach is proposed in the 2015 AHA/ACC Scientific Statement [12,13]: Asymptomatic persons who are genotype positive/phenotype negative (ie, with normal QTc at rest) can reasonably participate in all competitive sports with appropriate safety precautions, including avoidance of drugs known to exacerbate LQTS; avoidance and/or treatment of fever, hyperthermia, or heat exhaustion/heat stroke; electrolyte repletion; avoidance of dehydration; and establishment of an emergency action plan with an AED immediately available. Symptomatic (or previously symptomatic) patients, or patients with LQTS (QTc >470 milliseconds in males or >480 milliseconds in females), may consider participation in competitive athletics (with the exception of swimming in patients with LQT1 genotype) if they remain asymptomatic after three months of treatment and with appropriate cautionary measures, including an emergency action plan with an AED immediately available. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 4/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate For patients with LQTS and an ICD who have had three or more months without ICD therapy, participation in class IA sports ( figure 1) may be reasonable. Experts disagree on participation in higher levels of sport for patients with an ICD in place. Some experts feel that participation in sports with higher levels of exertion might be considered following counselling of the patient of the potential risks and appropriate cautionary measures, including an emergency action plan to implement should arrhythmias arise. However, other experts disagree and feel it is unwise to expose patients to the risk of ventricular arrhythmias and multiple shocks just to perform a competitive sport. A different approach was stated in the previous European guidelines, which advise precautionary restriction from essentially all competitive sports, based in part on the considerations that the safety measures recommended by the 2015 AHA/ACC guidelines (ie, training and competing in places where an AED is available) are not always feasible in the real world [14]. In a single-center retrospective cohort study of nearly 500 patients with LQTS who were managed with a return-to-play protocol and shared decision-making, the rates of breakthrough cardiac events (ie, seizures, syncope, cardiac arrest) among patients who returned to competitive sport were low [16]. In 494 self-identified athletes who returned to play (mean age 14.8 10.8 years), during follow-up for 4.2 4.8 years, there were no sports-related deaths; 29 patients (5.9 percent) had nonlethal LQTS-associated breakthrough cardiac events, only three (0.6 percent) of which occurred during exercise. Gene-specific management There is an association between genotype and triggers of arrhythmia ( figure 2) [17-20]. In particular: Patients with LQT1 primarily have exercise-related arrhythmic events; in a review that included 371 patients with LQT1, exercise was the trigger in 62 percent of arrhythmic events [17]. In addition, events related to swimming (occurring either immediately after diving into water or during recreational or competitive swimming activities) may be specific for LQT1 [19,21,22]. The sensitivity of patients with LQT1 to exercise may be related to exaggerated prolongation of the QT interval during exercise [23]. Events triggered by auditory stimuli, such as an alarm clock or telephone ringing, are most typically seen in LQT2 [18,19]. Acute arousal events (such as exercise, emotion, or noise) are much more likely triggers in LQT1 and LQT2 than LQT3 (85 and 67 versus 33 percent in one report) [17,20]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 5/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Patients with LQT3 are at highest risk of events when at rest or asleep, while the risk is low during sleep in LQT1, accounting for only 3 percent of events [17]. Patients with LQT3 may have fewer events with exercise or stress because they significantly shorten their QTc with tachycardia [24] and therefore become less susceptible to catecholamine-induced arrhythmias. (See 'Beta blockers' below.) Initial therapy Beta blockers For all patients with congenital LQTS and a history of syncope, seizures, or resuscitated SCA, we recommend treatment with a beta blocker [8]. In general, we suggest propranolol or nadolol, given their superior efficacy in this patient population. The use of atenolol and metoprolol has been associated with an increased rate of recurrences [25]. In addition, if the symptom was resuscitated SCA, then an ICD as secondary prevention is indicated as well in most circumstances. (See 'Implantable cardioverter-defibrillator' below.) Beta blockers are a mainstay of therapy in both asymptomatic and symptomatic patients with congenital LQTS since they reduce both syncope and SCD [8]. Because of extensive observational data and expert consensus on the efficacy of beta blockers in this population, it is widely felt to be unethical to randomize patients to placebo, such that a randomized controlled trial in this population is unlikely. The overall benefit of beta-blocker therapy in congenital LQTS has been demonstrated in a number of observational studies, with many of the patients recruited from the International LQTS Registry [17,26-30]. In a series of 869 registry patients treated with a beta blocker, in whom clinical event rates for the five-year periods before and after beta-blocker therapy were compared, treatment with beta blockers reduced the rate of cardiac events (eg, syncope, aborted cardiac arrest, or SCD) in probands (0.31 events per patient per year on therapy versus 0.97 events per patient per year off therapy) and in affected family members [27]. Despite this benefit, 32 percent of patients with syncope or aborted SCA before beta-blocker therapy had another cardiac event during the five-year period while on a beta blocker (hazard ratio 5.8 compared with asymptomatic patients before therapy, 95% CI 3.7-9.1). Nearly one-half of these events occurred within the first six months of therapy ( figure 3). The importance of compliance with beta-blocker therapy in LQT1 was highlighted in a retrospective study of 216 genotyped patients followed for a median time of 10 years [31]. Among the 12 patients who suffered SCA or SCD after beta blockers were prescribed, 11 were either noncompliant with beta-blocker therapy and/or on a potentially contraindicated QT- prolonging drug. The only death in a beta-blocker-compliant patient not on a QT-prolonging drug occurred in a patient with Jervell and Lange-Nielsen syndrome, which is a more malignant form of LQT1. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Congenital sensorineural deafness'.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 6/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Differences among various beta blockers Propranolol (either given three times per day or extended-release formulations for improved compliance) and/or nadolol are the preferred beta blockers for therapy of LQTS, particularly for patients with LQT1 or LQT2. Because various beta blockers differ in their pharmacologic properties (eg, beta-1 selectivity, lipophilicity, half-life, etc), there appear to be differences in the efficacy of beta blockers on QT shortening and clinical outcomes. In a retrospective cohort study of 382 patients (56 percent female, median age 14 years) with LQT1 or LQT2 who were treated with propranolol (134 patients), metoprolol (147 patients), or nadolol (101 patients) and followed for up to eight years, the following findings were noted [25]: Patients receiving propranolol had more significant QTc shortening (27 versus 14 versus 12 milliseconds with metoprolol and nadolol, respectively). Patients receiving metoprolol had significantly more breakthrough clinical events (eg, syncope, aborted cardiac arrest, ICD shock, or SCD) compared with those receiving propranolol or nadolol (29 versus 8 versus 7 percent, respectively; odds ratio 3.9, 95% CI 1.2-13.1 for metoprolol versus any other beta blocker). Effect of genotype Patients with LQT1 derive the greatest benefit, but beta-blocker therapy is also very effective for both LQT2 and LQT3 patients [32]. The three genotypes (LQT1, LQT2, and LQT3) account for over 90 percent of known mutations in congenital LQTS [33]. The clinical efficacy of beta blockers in relation to these genotype has been examined in several observational studies. [17,27,28] LQT1 Beta blockers have relatively increased efficacy in LQT1 versus LQT3. This is probably related to the sympathetic sensitivity in this disorder. Most humans with LQT1 show paradoxical prolongation of the QT interval after an infusion of catecholamine, such as epinephrine or isoproterenol. The epinephrine QT stress test was used in the past to unmask patients with concealed LQT1 [34,35]. However, the test is subject to a large amount of interpretation error. Thus, genetic testing for LQTS has largely replaced the epinephrine QT stress test. LQT3 There is reduced efficacy of beta blockers in LQT3 compared with LQT1. Unlike patients with LQT1, patients with LQT3 shorten their QT interval with tachycardia [24], making them less susceptible to catecholamine-induced arrhythmias. This could explain the comparatively reduced efficacy of beta blockers in LQT3 versus LQT1 and the lower rate of events triggered by exercise or stress in patients with the LQT3 subtype ( figure 2) [17,27]. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 1 LQTS (LQT1)'.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 7/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate There is some evidence that females with LQT3 may have greater benefit from beta blockers compared with men, although current data are insufficient to draw definite conclusions. In a multicenter registry study, 391 LQT3 patients (aged 1 to 41 years) were followed for development of a first cardiac events or CE (syncope, aborted cardiac arrest, or long-QT- syndrome-related sudden death). Of these, 118 (77 females) patients experienced at least 1 CE, and 24 patients had LQT3-related aborted cardiac arrest/sudden death. Time-dependent beta-blocker therapy was associated with an 83 percent reduction in CEs in females but not in males (who had many fewer events). Efficacy in males could not be determined conclusively because of the low number of events. Oral contraceptive pills in females One observational study of 1600 females suggested that use of progestin-only oral contraceptive pills (OCPs) was associated with increased cardiac events in women not taking beta-blockers [36]. Use of progestin-only OCPs was associated with the highest burden of cardiac events per 100 patient-years: 14.1 for progestin only, 6.2 in estrogen-only, 7.5 for combined, and 7 events in the no-OCP group. In contrast, in women who were treated with beta blockers, progestin-only OCP use was associated with fewer cardiac events (4.5 events per 100 patient years). Possible misclassification of OCP type and non-randomized design limit our ability to draw firm conclusions from this analysis. Subsequent therapies For patients with recurrent arrhythmic events in spite of maximally tolerated doses of a beta blocker or in the setting of unacceptable beta-blocker-associated side effects, treatment intensification is pursued with either concomitant drug therapy, LCSD, and/or an ICD depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). Treatment intensification for patients with recurrent arrhythmic events should ideally take place in a center with expertise in the management of congenital LQTS, or for patients without access to an expert center, in consultation with a specialist with expertise in congenital LQTS. Other pharmacologic therapies There is a role for select other pharmacologic therapies targeted to specific subsets of congenital LQTS patients. Potassium and/or spironolactone Routine potassium supplementation/replacement and/or use of potassium-retaining medications like spironolactone is not generally indicated. However, for patients with malignant LQTS who continue to receive appropriate ICD shocks or who have a high-risk phenotype but prefer to avoid an ICD, potassium retention strategies are implemented, regardless of the underlying LQTS genotype. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 8/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Mexiletine For patients with LQT3, mexiletine pharmacotherapy is not only QT- attenuating but also confers a significant protective effect. Increasingly, combination therapy with propranolol and mexiletine is utilized in patients with LQT3. Targeted dosing for mexiletine is generally 4 to 6 mg/kg/dose administered approximately every eight hours. Mexiletine trough levels can be obtained. Both mexiletine and propranolol are metabolized via cytochrome P4502D6 (CYP2D6) and approximately 10 percent of the White populations are either poor metabolizers of 2D6 substrates like mexiletine or are ultra-rapid metabolizers. CYP2D6 genotype status can be obtained to help guide dosing strategy. Although blocking the LQT3-associated accentuation of the late sodium current with mexiletine makes sense, in our authors experience, a significant QTc attenuation effect has also been seen in patients with other LQTS genotypes, particularly LQT2. As such, for patients with higher-risk LQT2, combination drug therapy with a beta blocker and mexiletine can be considered as well [37]. Left cardiac sympathetic denervation LCSD is an effective therapy in patients with congenital LQTS and persistent arrhythmias on beta blockers as well as in those who cannot tolerate beta blockers [8,38-41]. While LCSD produces significant reductions in the number of subsequent cardiac events per patient overall, postdenervation recurrences can occur especially when the predenervation expressivity was malignant and extreme [42]. However, in most patients, LCSD offers an additional risk reduction prior to considering an ICD, although it does not preclude ICD placement in appropriate high-risk patients. LCSD interrupts the major source of norepinephrine released in the heart via preganglionic denervation [43]. Since denervation is preganglionic, there is no reinnervation. The procedure does not completely eliminate catecholamines in the ventricles, and it does not lead to post- denervation supersensitivity to catecholamines [44]. LCSD is similarly effective across genotypes, when infants with events in the first year of life are not considered [45-47]. LCSD is similarly effective in LQT1 and LQT2 patients [41]. Implantable cardioverter-defibrillator ICDs are an important component of therapy for patients with congenital LQTS, particularly among patients who present with resuscitated SCA or those who have recurrent major events [48-51]. However, complications, including infection, lead fracture and dislodgement, inappropriate discharges, and psychiatric sequelae, are not uncommon with ICDs (25 percent within five years) [52]. For these reasons, it is not appropriate to consider ICDs in all patients with congenital LQTS. In fact, most patients with LQTS (90 percent or more in LQTS expert centers) do not need and should not receive an ICD just because they have been diagnosed with LQTS in general or even LQT3 in particular (where highest ICD implant https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 9/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate rates have been noted). Instead, our approach to the utilization of ICDs in this population is as follows [8]: We recommend an ICD in most patients whose initial presentation was SCA and in whom a reversible cause is not identified. We recommend an ICD in patients with LQTS-associated SCA while compliant with beta- blocker therapy. If an ICD was chosen instead of additional medications or LCSD following this on-therapy SCA, then LCSD therapy is often kept as a subsequent treatment option if an appropriate ICD shock occurs. Although we generally recommend an ICD for patients with resuscitated SCA occurring prior to diagnosis of and treatment for their LQTS, it may be possible to assemble a non- ICD treatment program for some of these patients. However, this should be considered only in LQTS specialty centers because guidelines essentially recommend an ICD for any LQTS patient (diagnosed or previously undiagnosed) who experiences SCA [8,12,13]. For example, one potential exception to this in our practices are patients with a sentinel event of SCA with previously undiagnosed and therefore untreated LQT1 substrate. For such LQT1 patients who are trying to avoid an ICD if at all possible, we have configured beta- blocker therapy plus LCSD as part of their initial treatment program. We suggest an ICD for patients with recurrent cardiac syncope in spite of beta blockers and LCSD, or for patients with recurrent cardiac syncope while taking beta blockers in whom LCSD is not an option. Importantly, an ICD is never indicated based solely on the family history. A family history of LQTS-associated SCD is not a personal risk factor for the patient with LQTS. Overall, most patients with LQTS do not need and should not receive an ICD. The vast majority of LQTS patients can be treated effectively without an ICD. Combined, among all of the patients with LQTS that are evaluated, risk stratified, and treated at expert LQTS centers, approximately 3 to 10 percent of them have an ICD [47]. Cardiac pacing Cardiac pacing is seldom utilized in isolation when treating patients with LQTS. For the patient with an indication for an ICD, a single-lead system is generally advised. If the patient then goes on to experience an appropriate ventricular fibrillation (VF)-terminating ICD shock where a bradycardia or long-short-long pause mechanism is documented, an upgrade to the device to include atrial pacing is sometimes performed. In our experience, the therapeutic role of atrial pacing, with an intentional lower rate limit of 80 beats per minute, may be best realized in women with LQT2 [53]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 10/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate Our approach to asymptomatic patients Asymptomatic patients with congenital LQTS have different levels of risk for experiencing an LQTS-associated sentinel event, and it can be difficult to identify patients who will become symptomatic. Our general approach to asymptomatic patients with congenital LQTS is as follows: As with symptomatic patients, asymptomatic patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval and the aggressive treatment of electrolyte imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). As with symptomatic patients, the 2015 AHA/ACC Scientific Statement supports continuation of competitive sports in asymptomatic patients with LQTS with appropriate cautionary measures, including an AED safety plan, while the European guidelines remain more restrictive. Some disagreement among experts persists, however. (See 'Physical activity and LQTS' above.) For most asymptomatic patients with congenital LQTS, we suggest treatment with a beta blocker [1]. In general, we prefer propranolol or nadolol. However, for asymptomatic patients with a QTc <470 milliseconds, beta-blocker therapy may not always be required. Accordingly, there may be times when the risk-benefit calculus clearly favors intentional non-therapy with implementation of only the aforementioned preventative measures. As one example, beta-blocker therapy may not be necessary in the asymptomatic 55-year-old male with LQT1 and a resting QTc <440 milliseconds. For asymptomatic patients who wish to follow preventative measures only and intentionally forego beta-blocker therapy, an evaluation with an LQTS specialist may be beneficial to best assess the potential for a sentinel event and the comfort/confidence with intentional non-therapy [54]. (See 'Beta blockers' above.) In asymptomatic patients with either LQT2 or LQT3 whose resting QTc is >550 milliseconds or postpubertal women with LQT2, a prophylactic LCSD at a lower QTc threshold (QTc >500 milliseconds) is reasonable. These profiles in asymptomatic patients may warrant more aggressive surgical or device-related interventions. However, if the addition of QT-shortening therapies like mexiletine produced a now-on- therapy baseline QTc <500 ms, we continue with pharmacotherapy alone, or add additional anti-fibrillatory protection with LCSD (rather than adding a prophylactic ICD) [37,45,55]. Patients with high-risk genetic mutations such as those in the KCNQ1 S6 region require closer and more aggressive therapy to prevent SCA/SCD [56]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 11/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the ECG ( waveform 1). LQTS can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD). (See 'Introduction' above.) Symptomatic patients Our general approach to treatment of symptomatic (or previously symptomatic) patients with congenital LQTS is as follows: General measures All patients with congenital LQTS should adhere to standard general preventive measures, such as the avoidance of medications known to prolong the QT interval ( www.crediblemeds.org) and the aggressive treatment of electrolyte https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 12/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate imbalances (eg, hypokalemia in the setting of vomiting, diarrhea, or diuretic use). (See 'Our approach to symptomatic patients' above.) Activity After establishing the correct diagnosis of LQTS and implementing the initial treatment program, patients with LQTS can continue to be recreationally active, especially those with LQT2 and LQT3. Athletes with LQTS who desire to remain athletes should be evaluated by an LQTS specialist to enable shared decision making to occur successfully. Importantly, there are laws in some countries that supersede professional society guidelines regarding return-to-play issues. (See 'Physical activity and LQTS' above.) Asymptomatic persons who are genotype positive/phenotype negative (ie, with normal QTc at rest) can reasonably participate in all competitive sports with appropriate safety precautions. Symptomatic (or previously symptomatic) patients, or patients with LQTS (QTc >470 milliseconds in males or >480 milliseconds in females) may consider participation in competitive athletics (with the possible exception of swimming in patients with LQT1 genotype) if they remain asymptomatic after three months of treatment and with appropriate cautionary measures, including an emergency action plan with an automated external defibrillator immediately available. Local laws and regulations may apply. Experts disagree on participation in higher levels of sport for patients with an implantable cardioverter-defibrillator (ICD) in place, with some experts allowing participation following counselling of the patient of potential risks and appropriate cautionary measures, while other experts feel it is unwise to expose patients to the risk of ventricular arrhythmias and multiple shocks just to perform a competitive sport. Beta blockers For all patients with congenital LQTS and a history of syncope or seizures, we recommend treatment with a beta blocker (Grade 1B). We suggest propranolol or nadolol, given their superior efficacy in this patient population (Grade 2C). (See 'Beta blockers' above.) Implantable cardiac defibrillator Patients with LQTS-associated sudden cardiac arrest (SCA), while compliant with beta-blocker therapy, should generally receive an ICD. Importantly, self-limiting syncope/seizures, even if assessed to be LQTS-triggered (ie, secondary to TdP) are not equivalent to SCA. (See 'Implantable cardioverter-defibrillator' https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 13/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Treatment intensification For patients with recurrent, LQTS-triggered arrhythmic events in spite of maximally tolerated doses of a beta blocker, or for patients who discontinue beta blockers due to intolerable side effects, treatment intensification is pursued with either concomitant drug therapy, left cardiac sympathetic denervation, and/or an ICD depending on the nature of the arrhythmic event, the genotype, and the patient's degree of QT prolongation at rest (ie, their resting QTc). Treatment intensification for patients with recurrent arrhythmic events should ideally take place in a center with expertise in the management of congenital LQTS, or for patients without access to an expert center, in consultation with a specialist with expertise in congenital LQTS. (See 'Subsequent therapies' above.) Asymptomatic patients Our general approach to treatment of asymptomatic patients with congenital LQTS is as follows (see 'Our approach to asymptomatic patients' above): For most asymptomatic patients with congenital LQTS, we suggest a beta blocker (Grade 2C). In general, the choice of a beta blocker is the same as in symptomatic patients (ie, propranolol or nadolol). However, for asymptomatic patients with a QTc <470 milliseconds, beta-blocker therapy may not be required. If an asymptomatic patient with either LQT2 or LQT3 maintains a QTc >550 ms while on pharmacotherapy, we suggest either a prophylactic left cardiac sympathetic denervation (LCSD) or a prophylactic ICD (Grade 2C). For postpubertal women with LQT2, either prophylactic LCSD or a prophylactic ICD at a lower QTc threshold (QTc >500 milliseconds) is reasonable again if pharmacotherapy (namely mexiletine) has not attenuated the QTc to <500 ms. Importantly, an ICD is never indicated based solely on a family history of LQTS-associated SCD, as family history is not a personal risk factor for the patient. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350:1013. https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/print 14/31 7/6/23, 3:08 PM Congenital long QT syndrome: Treatment - UpToDate 3. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002; 112:58. 4. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the congenital long QT syndrome. Ann Intern Med 2002; 137:981. 5. Camm AJ, Janse MJ, Roden DM, et al. Congenital and acquired long QT syndrome. Eur Heart J 2000; 21:1232. 6. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000; 36:1. 7. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62:169. 8. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline 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 on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 9. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical