Congenital long QT syndrome: Considerations for primary care physicians

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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.


  • 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.



Congenital long QT syndrome is one of a group of abnormalities of cardiac repolarization that can cause syncope and sudden death in apparently healthy people. It was once considered very rare, but current estimates of its prevalence range from 1 in 2,500 people to 1 in 7,000,1,2 and its prevalence is expected to increase with heightened awareness and screening.

Our understanding of the genetic basis of long QT syndrome is increasing, giving us the ability to classify different types of the disease. For instance, one type is triggered by exercise, especially swimming. Another is associated with sleep or inactivity, and electrocardiographic abnormalities lessen with an increased heart rate. Yet another type can be triggered by a startle, something as simple as an alarm clock going off.

Given the increasing recognition of long QT syndrome and its risks, primary care providers are likely to find themselves encountering challenging management decisions. In this review, we seek to provide a practical overview to aid in clinical decision-making. Our focus is on congenital forms of long QT syndrome rather than on those that are acquired, eg, by the use of certain drugs. Of note, although there is no cure for this condition, appropriate therapy can dramatically reduce the risk of sudden death.3–5


First described in 1957 by Jervell and Lange-Nielsen,6 congenital long QT syndrome became an area of intensive research, and 25 years ago an international registry of patients and their families was established.7 Initially, research was limited to clinical factors such as symptoms and electrocardiographic features, but advances in molecular genetics have accelerated our understanding of this disease.7,8

Although the homozygous form of QT prolongation, Jervell and Lange-Nielsen syndrome,6 was recognized first because of its greater clinical severity, most affected patients have a heterozygous mutation pattern, termed the Romano-Ward syndrome.9,10

To date, 10 distinct genetic types of long QT syndrome have been identified, designated LQT1 through LQT10. Each is associated with an abnormality in a specific ion channel (or subunit of an ion channel) that regulates the cardiac action potential.

Even though genetic testing is becoming more accessible, a specific mutation cannot be identified in 30% or more of people with clinically confirmed long QT syndrome.11 Most patients successfully genotyped have LQT1, LQT2, or LQT3; of these, 45% to 50% have LQT1, 40% to 45% have LQT2, and 5% to 15% have LQT3.11–13 Given the overwhelming prevalence of LQT1, LQT2, and LQT3 and, hence, the relative robustness of the data on them, we will limit the rest of our discussion to these three types.


Figure 1.
With each heartbeat, cardiac cells go through a cycle of electrical depolarization and repolarization, as sodium, potassium, and calcium ions move across the cell membrane via specific channels. In the ventricles, the cycle (Figure 1) consists of five phases:
  • Phase 0: The cell swiftly depolarizes as sodium rapidly moves into the cell via the INa channel. This depolarization leads to the stimulus for the cell to contract.
  • Phase 1: The cell rapidly partially repolarizes as potassium leaves the cell via the Ito channel.
  • Phase 2: Repolarization reaches a plateau, with sodium continuing to enter the cell via INa channels (although the current is much slower than in phase 0) along with calcium via L-type ICa channels, somewhat balanced by outward movement of potassium (the rapid-acting current, or IKr, and later the slow-acting current, or IKs). During this phase the cell is still relatively refractory, ie, it cannot fire again.
  • Phase 3: The cell repolarizes further, as the outward currents (IKr, IKs, and the inward-rectifier, or IK1) increase.
  • Phase 4: The cell is completely repolarized and ready to go through the cycle again.

Phases 0 through 3 are of longer duration in long QT syndrome, and this longer duration is seen as prolongation of the QT interval on the electrocardiogram.

Complicating the picture, different anatomic areas of the heart have different numbers and types of ion channels, and the resulting electrical heterogeneity is important in understanding the arrhythmogenic mechanisms in long QT syndrome. The ventricle itself comprises three layers: the epicardium, the mid-myocardium (“M-cell” layer), and the endocardium. Each of these layers repolarizes at a different rate, a phenomenon referred to as “transmural dispersion of refractoriness.” The M-cell layer has a stronger late INa current and weaker IKs current than the epicardium and endocardium. A consequence of this difference has been noted during bradycardia, when the large contribution of late INa fosters relatively greater prolongation of the M-cell action potential, which increases transmural dispersion of refractoriness and the potential for reentrant arrhythmias.14


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