Congenital long QT syndrome: Considerations for primary care physicians
ABSTRACTCongenital long QT syndrome is an inherited disorder of cardiac repolarization that predisposes to syncope and to sudden death from polymorphic ventricular tachycardia. The disorder should be suspected when the electrocardiogram shows characteristic QT abnormalities, or when there is a family history of long QT syndrome or of an event that raises suspicion of long QT syndrome, such as sudden death, syncope, or ill-defined “seizure” disorder. We can now classify some types of congenital long QT syndrome according to their genetic mutations and their triggers, such as exercise, rest, or startle.
KEY POINTS
- Because of the heterogeneity of the syndrome, genotyping is often useful in making therapeutic decisions, such as avoiding alarm clocks in bedrooms in patients with long QT genetic type 2, or restricting physical activity (particularly swimming) in patients with genetic type 1.
- When patients on beta-blocker therapy experience further syncopal episodes or aborted cardiac arrest and are considered at high risk, implantation of a cardioverter-defibrillator is appropriate.
- In a select few patients, left cervical-thoracic sympathetic denervation may be appropriate.
THERAPEUTIC CONSIDERATIONS
Beta-blocker therapy
In 2000, Shimizu and Antzelevitch17 studied the effects of beta-adrenergic agonists and antagonists in an experimental model of LQT1, LQT2, and LQT3. The transmural dispersion of refractoriness was indeed increased by beta-agonists in LQT1 and LQT2, whereas it was actually reduced in LQT3. This finding was not entirely unexpected, based on the underlying defect in each subtype; it was also in keeping with the clinical observation of the increased event rate with activity or emotional triggers in LQT1 and LQT2, as opposed to the predisposition for events at rest in LQT3.
A retrospective analysis of the international registry3 found that beta-blockers reduced the overall rate of cardiac events by 68% in probands and 42% in affected family members. Unfortunately, patients who had an event before they started beta-blocker therapy still faced a 32% chance of another event over the next 5 years while on therapy (including a 5% risk of cardiac arrest); in patients who had a history of aborted cardiac arrest, the rate of recurrent arrest on therapy was 14% over the same period. Furthermore, only patients with LQT1 or LQT2 benefitted from beta-blockers.
A subsequent analysis that included only adults showed a 60% reduction in the event rate with beta-blockade.41 The influence of the type and the dose of beta-blocker on prognosis has not been conclusively proven, but experience is greatest with propranolol (Inderal) and nadolol (Corgard).
Implantable cardioverter-defibrillators
Given the incomplete effectiveness of beta-blockers in preventing sudden death in long QT syndrome, implanting a cardioverter-defibrillator may be appropriate in some patients.42
In 2003, Zareba et al40 published a retrospective analysis of cardioverter-defibrillator implantation in 125 patients with long QT syndrome who had an aborted cardiac arrest while taking a beta-blocker. These patients were compared with a group of patients with long QT syndrome who also experienced aborted cardiac arrest while on beta-blockers but who did not receive a cardioverter-defibrillator. In 3 years, 2% of those with cardioverter-defibrillators died, compared with 9% in the medically treated group.
Additional studies have corroborated the effectiveness of implantable cardioverter-defibrillators, including in children.43,44
Sympathetic denervation
Given the early observations of events during times of increased adrenergic tone, removal of sympathetic input to the heart via left cervical-thoracic sympathetic denervation (ganglionectomy) has been used as a means of preventing events in patients with long QT syndrome.45 However, this therapy is not widely available and is used mainly in young children, in patients with Jervell and Lange-Nielsen syndrome, and in patients who receive frequent implantable cardioverter-defibrillator shocks who are taking beta-blockers.
Flecainide, mexiletine, oral potassium
As mentioned above, flecainide and mexiletine, which inhibit the late sodium current, have been suggested as beneficial, but these trials are ongoing, and therapy with these agents is not recommended at this time.21
Potassium supplementation, either directly or via spironolactone (Aldactone), is also being studied, especially for LQT1 and LQT2.
PREGNANCY AND LONG QT SYNDROME
As we have shown, the molecular heterogeneity of long QT syndrome can make it both a diagnostic and a therapeutic challenge under the best of circumstances, and this is even more so in pregnancy.
Relatively little has been published about the natural history of long QT syndrome in pregnancy. One retrospective study22 included 422 women from the international registry who had had at least one pregnancy: 111 probands and 311 first-degree relatives. The first-degree relatives were further classified as “affected,” “borderline,” or “unaffected” on the basis of their QTc. The primary end point was the occurrence of long-QT-related death, aborted cardiac arrest, or syncope.
Events were markedly more frequent in the 40 weeks after delivery than during the 40 weeks of pregnancy or the 40 weeks immediately preceding pregnancy. Other notable findings were that beta-blockers dramatically reduced the event rate and that events were rare in first-degree relatives classified as borderline or unaffected.
The exact cause of the clustering of events in the postpartum period is unknown. While it is tempting to invoke the relative bradycardia of the postpartum period or perhaps the hormonal influence on the sympathetic drive, this remains speculative. Other recent data confirm that the postpartum period is a time of high risk, suggest that women with LQT2 are at higher risk than those with LQT1, and substantiate that beta-blocker therapy is indicated and safe during pregnancy.46–48
