Long QT Syndrome: Diagnosis and Management

Ijaz A. Khan, MD, FACP, FACC

Disclosures

Am Heart J. 2002;143(1) 

In This Article

Management of LQT Syndrome

Short-Term Treatment

Immediate cardioversion should be done in situations where torsades does not terminate spontaneously and results in hemodynamic compromise. The short-term treatment, which is aimed at prevention of the recurrences of torsades, includes withdrawal of the offending agents, correction of the underlying electrolyte abnormalities, and administration of magnesium, potassium, temporary transvenous cardiac pacing, and rarely intravenous isoproterenol. The magnesium, potassium, and temporary transvenous cardiac pacing are useful for both congenital and acquired forms of the LQT, but use of intravenous isoproterenol is limited to acquired LQT only.

Withdrawal of the Offending Agent. Withdrawal of the offending agent is a crucial first step in the prevention of the recurrence of the torsades. Drugs are the most common offending agents. The important cardiac drugs that have been reported to prolong the QT interval are bepridil; phenylamine; class IA antiarrhythmic agents including, quinidine, procainamide, and disopyramide; and class III antiarrhythmic agents including, sotalol, ibutilide, azimilide, dofetilide, and amiodarone, although amiodarone is rarely associated with torsades. Class IC antiarrhythmic drugs have been implicated in torsades, but such reports are discredited because the QT-interval prolongation, if any, with the use of class IC antiarrhythmic drugs will be due to the prolongation of the QRS-complex duration (depolarization), not the prolongation of the JT interval (repolarization), and it is the prolongation of the repolarization that precipitate torsades, not that of the depolarization. A number of noncardiac drugs have been reported to prolong QT interval, including cisapride, probucol, ketanserin, papaverine, tacrolimus, arsenic trioxide, phenothiazines, haloperidol, tricyclic antidepressants, antimicrobial agents (erythromycin, grepafloxacin, moxifloxacin, pentamidine, amantidine, chloroquine, and trimethoprim-sulphamethoxazole), antifungal agents (ketoconazole and itraconazole), and antihistamines (terfenadine and astemizole).[44] A full list of cardiac and noncardiac drugs that have been reported to prolong the QT interval is available at www.qtdrugs.org.

The QT-interval prolongation resulting from the use of drugs is a patient-specific phenomenon, which indicates that the patients who have a drug-induced long QT interval may be genetically predisposed because of the presence of an underlying mild or attenuated form of congenital LQT.[44,45] The principal ion channel affected by the QT-interval prolonging drugs is IKr (HERG), which, interestingly, is the same ion channel that causes congenital LQT2.[45] Therefore, a physiologic relationship may exist between drug-induced LQT and congenital LQT2, which further strengthens the possibility of a genetic basis for predisposition to the drug-induced LQT. Hence, drug-induced LQT may raise a possibility of the presence of an LQT locus in the family and thus may logically lend an extra caution in using the QT-prolonging drugs in the other family members, although this has not been examined prospectively. Certain acquired factors including left ventricular hypertrophy, myocardial ischemia, and myocardial fibrosis have been reported to facilitate the drug-induced prolongation of the QT interval.[44,46] Therefore the QT prolonging drugs should be used with caution in patients with these conditions.

Magnesium. Magnesium is very effective for suppression of the short-term recurrences of torsades and is the agent of choice for the immediate treatment of the torsades associated with both congenital and acquired forms of LQT, irrespective of serum magnesium levels.[47] A single bolus of 2 g of magnesium sulfate is administered over a period of 2 to 3 minutes, followed by an intravenous infusion of magnesium at a rate of 2 to 4 mg/min, and a second bolus of 2 g of magnesium sulfate may be given if the torsades recurs while the patient is receiving the intravenous infusion of magnesium. The exact mode of action of magnesium in preventing the recurrences of torsades is not clear, but its effect may be mediated by blockade of sodium currents.[48] Magnesium does not shorten the QTc interval significantly and has no significant role in the long-term management of LQT. The treatment with intravenous magnesium is very safe and can be initiated as soon as the diagnosis is made. The only side effect reported with the use of intravenous magnesium therapy is a flushing sensation during the bolus injection.

Potassium. Administration of potassium is considered an important adjunct to the intravenous magnesium therapy for the short-term prevention of the torsades, especially in the cases where the serum potassium level is in the lower limits. Data suggest that in patients with LQT2 high normal (4.5-5 mEq/L) levels of serum potassium are preferable to low normal (4-4.5 mEq/L) levels. In a controlled study, Compton et al[49] examined the effect of potassium administration on QT interval in 7 subjects with mutant HERG gene (LQT2). The serum potassium level was raised by >=1.5 mEq/L by giving oral potassium chloride (60 mEq every 2 hours), intravenous infusion of potassium chloride (20 mEq/h), and oral spironolactone (200 mg, followed by 100 mg every 2 hours). The increase in the serum potassium levels resulted in a significant shortening (24%) in the QTc interval in subjects with mutant HERG gene (from 617 ± 92 ms to 469 ± 23 ms) but not in control subjects. In addition, by increasing the serum potassium level, the QTc dispersion decreased significantly in subjects with mutant HERG gene (133 ± 62 ms to 42 ± 28 ms) but did not change in control subjects. However, caution should be used against the development of hyperkalemia while intending to maintain the serum potassium level in the high normal range.

Temporary transvenous cardiac pacing. Temporary transvenous cardiac pacing at rates around 100 beats/min is another highly effective measure to prevent the short-term recurrence of the torsades associated with both acquired and congenital forms of LQT.[50] A temporary transvenous pacemaker should be placed if intravenous magnesium therapy fails to prevent the recurrence of the torsades. The cardiac pacing prevents pauses and shortens the QTc interval by enhancing the repolarizing potassium currents as a result of increased heart rates.[51] Although cardiac pacing is effective in preventing the recurrence of the torsades irrespective of the baseline heart rate, it is of particular value in the patients who display bradycardia or pauses.

Isoproterenol. Isoproterenol used to be the drug of choice to prevent the short-term recurrence of torsades before the use of magnesium and cardiac pacing. Isoproterenol controls the short-term recurrence of torsades by increasing the heart rate, especially where recurrence is dependent on the bradycardia or pauses.[52] Isoproterenol may be used when specially trained medical personnel are not available to insert a temporary transvenous pacemaker. When used, it is administered as a continuous intravenous infusion at doses sufficient to maintain the heart rate at around 100 beats/min. Because of its adrenergic effects, isoproterenol should not be used in patients with congenital LQT. For similar reasons, it should be used cautiously in patients with structural heart disease. Another limiting factor in the use of isoproterenol is the scarcity of the drug. The common side effects reported with the use of isoproterenol infusion are palpitations and feeling of flushing sensations.

Long-Term Treatment

Long-term treatment is generally not required in cases with acquired prolongation of the QT interval because the QT interval often becomes normal by treating the underlying cause. The torsades in these situations, however, often require acute emergency treatment along with the withdrawal of the offending agents and correction of the electrolyte imbalance. The long-term treatment of acquired LQT is limited to permanent pacemaker implantation in patients with sick sinus syndrome or atrioventricular block in whom a pause or the bradycardia is a precipitating event for torsades. On the other hand, long-term treatment of congenital LQT is mandatory and is aimed to prevent the recurrence of torsades by shortening the QTc interval. The standard treatment options available for long-term management of the patients with congenital LQT are the use of oral ß-adrenergic blockers, permanent pacemaker placement, and implantation of cardioverter-defibrillator. Therapies targeting the mutated ion channels are under investigation. Education of the patient is crucial to avoid risk-associated behaviors.

ß-Adrenergic blockers. Long-term treatment with ß-adrenergic blockers has shown to result in a significant reduction in the incidence of cardiac events in patients with congenital LQT.[52,53] According to a recently published report,[53] long-term ß-adrenergic blocker therapy has been shown to result in a significant reduction in the rates of cardiac events in probands (0.97 ± 1.42 events/year before vs 0.31 ± 0.86 events/year after initiation of ß-blockers) and in affected family members (0.26 ± 0.84 events/year before vs 0.15 ± 0.69 events/year after initiation of ß-blockers) during a 5-year matched period. Among ß-adrenergic blocking agents, propranolol has been widely used at a daily dose of 2 to 3 mg/kg, but all ß-blockers should be effective, as protection against the precipitation of torsades provided by the use of ß-blocker class effect. The dose of ß-adrenergic blocking agent should be maximized, aiming a maximal heart rate of 130 beats/min or less on treadmill exercise testing. Therapy with ß-adrenergic blockers should be continued for life and should be supplemented with implantation of a permanent pacemaker in cases where bradycardia is a prominent feature of the syndrome.[54] ß-Adrenergic blocking agents are most efficacious in LQT1, where exercise and physical exertion are the most common triggers for an arrhythmic event.[28]

Left thoracic sympathectomy. High left thoracic sympathectomy has been used, chiefly in Europe, as second-line therapy in patients who were nonresponders to ß-adrenergic blockers. It is a highly effective method of surgical antiadrenergic therapy but now has been largely replaced with permanent pacemaker and cardioverter-defibrillator implantation.[55]

Permanent pacemaker and cardioverter-defibrillator. Implantation of a permanent pacemaker is a standard adjunct to ß-adrenergic blocker therapy in patients who are symptomatic despite being on the full doses of ß-adrenergic blockers and in cases where bradycardia is a prominent feature of the syndrome.[56,57] ß-Adrenergic blocker therapy should be continued along with implantation of the permanent pacemaker.[58] Pacing rates should be adjusted to normalize QT interval, and the pacemaker features that allow heart rate slowing beyond the lower rate limit or that may trigger pauses should be turned off because such pauses could be highly proarrhythmic in this patient population.[59] The patients with LQT3 have been reported to more likely benefit from permanent cardiac pacing because they are more prone to have sudden cardiac death at slower heart rates.[54]

Implantable cardioverter-defibrillators are used when the combination of the ß-adrenergic blocker therapy and the pacing fails to prevent presyncopal or syncopal episodes or when the initial presenting event is a resuscitated cardiac arrest.[60] Because of the availability of the cardioverter-defibrillator with dual-chamber pacing capabilities and because of the potential lethality of the failure of ß-blocker therapy, many electrophysiologists today prefer to use this device as first-line therapy to prevent sudden cardiac death in all symptomatic patients with congenital LQT. The implantable cardioverter-defibrillator will not prevent the precipitation of torsades but will prevent sudden cardiac death when torsades is prolonged or degenerates to ventricular fibrillation. Therefore, to prevent the precipitation of torsades, the use of a ß-adrenergic blocking agent should be continued along with the implantation of the cardioverter-defibrillator. The unnecessary shocks from the cardioverter-defibrillator device and the emotional distress associated with these shocks may cause adrenergic stimulation sufficient to result in the precipitation of torsades, which gives an even stronger position for continuation of the ß-adrenergic blocker therapy after implantation of a cardioverter-defibrillator.[52]

Mutation-specific therapies. Knowledge about the mutations causing congenital LQT has initiated research on the therapies targeted at the mutant ion channels.[61] The sodium channel blockers flecainide and mexiletine have been reported beneficial in the LQT3, which is caused by a gain in function-type mutations in SCN5A -- a gene that encodes for a cardiac sodium channel.[62,63,64] Benhorin et al[62] tested the effect of flecainide (75 to 150 mg twice daily orally) on QTc interval in 8 asymptomatic carriers of the SCN5A mutation (LQT3). Flecainide therapy significantly shortened the QT interval (from 523 ± 94 ms to 435 ± 40 ms) and QTc interval (from 517 ± 45 ms to 468 ± 36 ms). In an animal model, mexiletine was also reported to markedly shorten the erythromycin-induced prolongation of the action potential duration and abolish the erythromycin-induced early afterdepolarizations.[65] Other sodium channel blockers including lidocaine, phenytoin, and pentisomide have been reported to be beneficial for termination or prevention of short-term recurrences of the torsades, but the effectiveness of these agents has not been consistent.[66] Similarly, many other experimental agents tested, including potassium channel activators (nicorandil, pinacidil) and calcium channel blockers, have shown inconsistent results and await further investigation.[67,68] Currently, these agents may be considered only as adjuncts to the standard therapy.

Screening of family members. Each child of a parent affected with Romano Ward syndrome has a 50% chance of inheriting the LQT gene. The ECGs of all the family members of a patient with LQT are recorded for screening. The identification of QTc interval prolongation and T-wave abnormalities in the family members of a patients with sudden cardiac death is suggestive of presence of the LQT gene in the family and will likely establish LQT as the cause of death in the deceased family member. The genetic screening is available but primarily as a research tool. Routine genetic screening is not feasible currently because only about 60% of families that have been clinically diagnosed with LQT can be genotyped.[69] Furthermore, numerous different genetic mutations have been discovered involving each of the known LQT genes, making screening laborious.[70,71] Nonetheless, genetic testing is available on a limited basis for those who want to know whether they are genetic carriers, but with the caution that negative results would not entirely rule out the possibility of harboring the LQT gene. Family-grouped ECG analysis improves the accuracy of genotype identification and can simplify genetic screening by targeting the gene for initial study.[40]

Treatment of asymptomatic patients. The treatment option offered for asymptomatic patients with LQT is the long-term use of a ß-adrenergic blocker agent, the dose of which should be maximized aiming at a maximal heart rate of <=130 beats/min on treadmill exercise testing. It is generally recommended to treat all asymptomatic patients <40 years old at the time of diagnosis because it is not possible to predict which asymptomatic patient will become symptomatic and 30% to 40% of sudden deaths occur at the first event.[72,73] Furthermore, although most cases of inherited LQT usually manifest clinically in early childhood, the possibility of a late manifestation of the disease cannot be ruled out, which makes the case stronger for treating asymptomatic patients.[74] However, on the other hand, some investigators have recommended treating asymptomatic patients only if they have high-risk characteristics, including the presence of congenital deafness, QTc interval >600 milliseconds, T-wave alternans, neonates and infants, or affected siblings of children who have died suddenly or if the family desires treatment.[75]

Patient education. Patients with congenital LQT should be well informed about the risk-associated behaviors to prevent sudden death, about compliance to ß-blocker therapy, and about the resources available to provide information on the progress being made in the management of LQT. They should be aware of the drugs and substances with known risk of precipitating torsades. Educational information for patients is provided at several Web sites, including www.sads.org and www.qtsyndrome.ch.

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