A short story of the short QT syndrome
ABSTRACTShort QT syndrome is a recently recognized cause of cardiac rhythm disorders, including sudden cardiac death. Although the syndrome is rare, its potential lethality justifies routinely screening the electrocardiograms of patients with syncope or unexplained atrial or ventricular arrhythmias to look for this diagnosis. This review discusses recent advances in the understanding of the pathogenesis of this syndrome and outlines some of the challenges in establishing the diagnosis.
KEY POINTS
- Short QT syndrome is a genetic disease described initially in young patients who had atrial fibrillation or who died suddenly with no apparent structural heart disease.
- The diagnosis is established by the finding of a short QT interval. However, other factors including personal and family history are also important in establishing the diagnosis.
- The current recommendations for managing patients with short QT syndrome are not evidence-based. We encourage consultation with centers that have special interest in QT-interval-related disorders.
- Placement of an implantable cardioverter-defibrillator is considered the standard of care, especially in survivors of sudden cardiac death, ventricular fibrillation, or ventricular tachycardia. Unfortunately, a higher incidence of inappropriate shocks adds to the challenges of managing this potentially deadly disease.
ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME
Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.
Differential diagnosis of short QT interval
In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.
- Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex16
- Hyperkalemia17
- Acidosis17
- Increased vagal tone17
- After ventricular fibrillation (thought to be related to increased intracellular calcium)18
- Digitalis use19
- Androgen use.20
Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.21
Which interval to use: QT or QTc?
Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.16
In a review of cases of short QT syndrome worldwide, Bjerregaard et al22 found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.
Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.16,22
To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.22 In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.16
Recently, Gollob et al23 proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).
For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.
Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.
THE SCOPE OF THE DISEASE
In a recent review of the literature, Gollob et al23 found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.
Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.14,15
MUTATIONS IN CARDIAC ION CHANNELS
Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).
The cardiac action potential
To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.24 In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).
In phase 0, the cardiac cell rapidly depolarizes.
Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:
- The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
- The relative refractory period: the cell can respond to a stimulus that is stronger than normal
- The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.
In phase 4, the cell is completely repolarized, and the cycle can start again.
