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.
LQT1: Events occur during exercise
People with LQT1, the most common variant of long QT syndrome, are more likely to have a cardiac event during exercise than patients with LQT2 or LQT3. In particular, and for as yet unexplained reasons, many patients with LQT1 have cardiac events while swimming.15 These observations suggest a potential role for beta-blocker therapy in these patients to reduce the maximal heart rate and blunt the effects of adrenaline. The benefits of beta-blockers have been confirmed experimentally and clinically.3,16,17
LQT1 is associated with a mutation in the KvLQT1 gene (also known as KCNQ1), which codes for a protein (alpha subunit) that co-assembles with another protein (minK, or beta subunit) to form the slow component of the delayed rectifier potassium channel IKs. (Interestingly, LQT5 also results from a mutation in minK, therefore explaining some of the clinical similarities between LQT1 and LQT5.)
Under normal circumstances, IKs activity is up-regulated by beta-adrenergic stimulation.14 This, combined with its slow inactivation, leads to a greater number of channels remaining active during rapid heart rates, resulting in a commensurate abbreviation of the action potential duration. In the case of LQT1, however, a decrease in the activity of IKs hinders the normal truncation of the action potential duration, resulting in prolonged repolarization times. Not unexpectedly, this effect is more marked at higher heart rates.
Furthermore, and perhaps more importantly, the addition of beta-adrenergic input to an IKs-deficient system markedly increases the gradient of repolarization across the ventricular myocardium, thereby setting the stage for reentry.14
This heart rate dependency of transmural dispersion of refractoriness manifests clinically when one examines the factors that predispose patients to arrhythmic events in the various genetic types of long QT syndrome.
LQT2: Events triggered by startle or auditory stimuli
Although patients with LQT2 are less likely than patients with LQT1 to have episodes during exertion, they are more likely to have arrhythmic events triggered by auditory stimuli or sudden startle.18
LQT2 is caused by a loss of the rapid component of the delayed rectifying potassium current IKr. The IKr channel, like the IKs channel, is heteromeric, with two subunits labelled HERG and MiRP1. In LQT2 the HERG subunit is affected, resulting in a loss of function and, hence, less repolarizing current. This leads to prolongation of the action potential. Similar effects are seen in LQT6, in which a mutation in the MiRP1 subunit reduces IKr. Under normal conditions, the IKr current activates slightly earlier than IKs. It should also be noted that unlike IKs, the IKr current is not influenced by adrenergic tone.
LQT3: Events occur during sleep or inactivity
Patients with LQT3, unlike those with LQT1, are prone to syncope or cardiac arrest during inactive periods or sleep. In fact, their electrocardiographic abnormalities actually become less marked with increased heart rate due to increased adrenergic tone, a clinical feature that may be useful in discerning this particular genotype.19
LQT3 is caused by a mutation in SCN5A, the gene encoding the sodium channel INa. This mutation results in an increase in sodium influx into the cell during phase 2 and phase 3 and, hence, prolongation of the action potential duration. (A loss-of-function mutation—ie, the opposite change—in this protein is believed to be responsible for the Brugada syndrome.)
Beta-blockade has not been shown to confer the same protection in LQT3 as in LQT1 and LQT2, but it has also not been shown to increase events. There is some evidence to support pacemaker therapy to avoid bradycardia as a means of decreasing the event rate in this population.20 There is also evidence to suggest a benefit from drugs such as flecainide (Tambocor) or mexiletine (Mexitil), which inhibit the late sodium current, but these trials are ongoing and therapy with these agents cannot be recommended at this time.21
CONSIDER THE DIAGNOSIS IF THE QTc IS ABOVE 440 MS
When long QT syndrome is suspected, the diagnosis22 starts with the surface electrocardiogram. The QT interval runs from the onset of the QRS complex to the end of the T wave, with normal values being from 350 to 440 ms. The U-wave should be excluded from the measurement if distinct from the T wave; on the other hand, complex, multiphasic T waves or T-U complexes should be included.23,24
The QT interval is adjusted for heart rate. This corrected QT interval (QTc) equals the QT interval (in seconds) divided by the square root of the RR interval (in seconds). If the QTc is greater than 470 ms (ie, prolonged) or 440–460 ms (borderline), then long QT syndrome must be considered. After puberty, females have a QTc about 10 ms longer on average than males.
However, structural heart disease such as significant hypertrophy,25 ischemia,26 infarction,27 or heart failure28 and other factors may also affect repolarization, and if any of these is present, the prolonged QTc may not represent congenital long QT syndrome. Drug-induced or other acquired causes of a long QT interval (such as hypokalemia) should also be excluded.29
Is the prolonged QT interval ‘high normal’ or pathogenic?
As with many other variables in medicine, the QTc has a Gaussian distribution. Hence, some people who seem normal, ie, they have no identifiable gene mutation or symptoms, may have a QTc of 460 to 470 ms.11 This overlap of “high normal” QTc and true long QT syndrome presents a key diagnostic challenge, ie, how to identify patients truly at risk without incorrectly labeling and restricting normal patients.30–32
Given the relatively low prevalence of long QT syndrome in the general population (= 1 in 2,500), an asymptomatic patient with a borderline QTc (eg, 450 ms), normal T-wave morphology, and no family history of long QT syndrome or sudden death is much more likely not to have the syndrome. Conversely, a QTc that is “normal” does not mean the patient does not harbor a long QT mutation, especially when a family member has been definitively diagnosed.31
Compounding the problem of diagnosis, clinicians and some cardiac specialists often either measure the QTc incorrectly or disagree on how to measure it in actual tracings to diagnose or exclude long QT syndrome.33
