Long QT Syndrome 

Long QT syndrome (LQTS) is a congenital disorder characterized by a prolongation of the QT interval on ECG and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death.

The QT interval on the ECG, measured from the beginning of the QRS complex to the end of the T wave, represents the duration of activation and recovery of the ventricular myocardium. QT intervals corrected for heart rate (QTc) longer than 0.44 seconds are generally considered abnormal, though a normal QTc can be more prolonged in females (up to 0.46 sec). The Bazett formula is the formula most commonly used to calculate the QTc, as follows: QTc = QT/square root of the R-R interval (in seconds).

To measure QT interval accurately, the relationship of QT to the R-R interval should be reproducible. This issue is especially important when the heart rate is < 50 bpm or >120 bpm and when athletes or children have marked beat-to-beat variability of the R-R interval. In such cases, long recordings and several measurements are required. The longest QT interval is usually observed in the right precordial leads. When marked variation is present in the R-R interval (atrial fibrillation, ectopy), correction of the QT interval is difficult to define precisely.

The QT interval represents the duration of activation and recovery of the ventricular myocardium. Prolonged recovery from electrical excitation increases the likelihood of dispersing refractoriness, when some parts of myocardium might be refractory to subsequent depolarization.

From a physiologic standpoint, dispersion occurs with repolarization between 3 layers of the heart, and the repolarization phase tends to be prolonged in the myocardium. This is why the T wave is normally wide and the interval from T_peak to T_end (T_p-e) represents the transmural dispersion of repolarization (TDR). In long QT syndrome (LQTS), TDR increases and creates a functional substrate for transmural reentry.

In LQTS, QT prolongation can lead to polymorphic ventricular tachycardia, or torsade de pointes, which itself may lead to ventricular fibrillation and sudden cardiac death. Torsade de pointes is widely thought to be triggered by reactivation of calcium channels, reactivation of a delayed sodium current, or a decreased outward potassium current that results in early afterdepolarization (EAD), in a condition with enhanced TDR usually associated with a prolonged QT interval. TDR serves as a functional reentry substrate to maintain torsade de pointes. TDR not only provides a substrate for reentry but also increases the likelihood of EAD, the triggering event for torsade de pointes, by prolonging the time window for calcium channels to remain open. Any additional condition that accelerates the reactivation of calcium channels (eg, increased sympathetic tone), increases the risk of EAD.

LQTS has been recognized as mainly Romano-Ward syndrome (ie, familial occurrence with autosomal dominant inheritance, QT prolongation, and ventricular tachyarrhythmias) or as Jervell and Lang-Nielsen (JLN) syndrome (ie, familial occurrence with autosomal recessive inheritance, congenital deafness, QT prolongation, and ventricular arrhythmias). Two other syndromes are described, namely, Andersen syndrome and Timothy syndrome, though some debate centers on whether they should be included in LQTS.

LQTS is known to be caused by mutations of the genes for cardiac potassium, sodium, or calcium ion channels; at least 10 genes have been identified. Based on this genetic background, 6 types of Romano-Ward syndrome, 1 type of Andersen syndrome and 1 type of Timothy syndrome, and 2 types of JLN syndrome are characterized (see Table 1).

Table 1. Genetic Background of Inherited Forms of LQTS (Romano-Ward syndrome: LQT1-6, Anderson syndrome: LQT7, Timothy syndrome: LQT8, and Jervell and Lang-Nielsen syndrome: JLN1-2) (Open Table in a new window)

LQT1, LQT2, and LQT3 account for most cases of LQTS, with estimated prevalences of 45%, 45%, and 7%, respectively. In LQTS, QT prolongation is due to overload of myocardial cells with positively charged ions during ventricular repolarization. In LQT1, LQT2, LQT5, LQT6, and LQT7, potassium ion channels are blocked, they open with a delay, or they are open for a shorter period than they are in normally functioning channels. These changes decrease the potassium outward current and prolong repolarization.

The LQT1 gene (KVLQT1 or KCNQ1) encodes for part of the IKs slowly deactivating, delayed rectifier potassium channel. More than 170 mutations (most missense) of this gene have been reported. Their net effect is a decreased outward potassium current. Therefore, the channels remain open longer than usual, with a delay in ventricular repolarization and with QT prolongation.

The LQT2 gene (HERG or KCNH2) encodes for part of IKr rapidly activating, rapidly deactivating, delayed rectifier potassium channel. Mutations in this gene cause rapid closure of the potassium channels and decrease the normal rise in I_Kr. They also result in delayed ventricular repolarization and QT prolongation. About 200 mutations in this gene have been detected.

In LQT3, caused by mutations of the SCN5A gene for the sodium channel, a gain-of-function mutation causes persistent inward sodium current in the plateau phase, which contributes to prolonged repolarization. Some loss-of-function mutations in the same gene may lead to different presentations, including Brugada syndrome. More than 50 mutations have been identified in this gene.

In some patients, caveolae proteins have been recognized as responsible for the increased Na+ current in LQTS3.^[1] Caveolae are small (50–100 nm) microdomains that exist on the membrane of a variety of cells, including cardiac myocytes and fibroblasts. Some ion channels, and in particular the SCN5A encoded voltage–gated Na+ channels, are mainly colocalized with caveolae on the membrane. Thus, absence or abnormal formation of caveolae may have some effects on the availability of Na+ channels. For instance, Vatta and colleagues demonstrated that mutations in caveolin-3 protein exist in LQTS3 and that they can cause an increase in late Na+ current.^[1]

Nevertheless, caveolae are present in the membrane of many other cell types and are involved in many cellular activities, thus, their impairment is expected to be associated with multisystemic diseases. For example, Rajab and colleagues reported genetic mutations resulting in defective caveolae in families with congenital generalized lipodystrophy who have several systemic manifestations such as hypertrophic pyloric stenosis, impaired bone formations, ventricular arrhythmia, and sudden cardiac death.^[2] The fact that mutations in proteins associated with ion channels may result in change in the availability of channels on the membrane and therefore a significant change in total current has added a new window for investigating the genetic abnormalities resulting in LQTS.

The LQT4 gene (ANK2 or ANKB) encodes for the ankyrin-B. Ankyrins are adapter proteins that bind to several ion channel proteins, such as the anion exchanger (chloride-bicarbonate exchanger), sodium-potassium adenosine triphosphatase (ATPase), the voltage-sensitive sodium channel (INa), and the sodium-calcium exchanger (NCX, or INa-Ca), and calcium-release channels (including those mediated by the receptors for inositol triphosphate [IP₃] or ryanodine). Mutations in this gene interfere with several of these ion channels. The end result is increased intracellular concentration of calcium and, sometimes, fatal arrhythmia. Five mutations of this gene are reported. LQT4 is interesting because it provides an example of how mutations in proteins other than ion channels can be involved in the pathogenesis of LQTS.

The LQT5 gene encodes for the IKs potassium channel. Similar to LQT1, LQT5 results in a decreased outward current of potassium and in QT prolongation.

LQT6 involves mutations in the gene MiRP1, or KCNE2, which encodes for the potassium channel beta subunit MinK-related protein 1 (MiRP1). KCNE2 encodes for beta subunits of IKr potassium channels.

The LQT7 gene (KCNJ2) encodes for potassium channel 2 protein that plays an important role in inward repolarizing current (IKi), especially in phase 3 of the action potential. In this subtype, QT prolongation is less prominent than in other types, and the QT interval is sometimes in the normal range. Because potassium channel 2 protein is expressed in both cardiac and skeletal muscle, Andersen syndrome is associated with skeletal abnormalities, such as short stature and scoliosis.

Mutations in the LQT8 gene (CACNA1C) cause loss of L-type calcium current. So far, a limited number of cases of Timothy syndrome have been reported. They have been associated with abnormalities such as congenital heart disease, cognitive and behavioral problems, musculoskeletal diseases, and immune dysfunction.

The LQT9 gene encodes for caveolin 3, a caveolae plasma membrane component protein involved in scaffolding proteins. The voltage-gated sodium channel (Na_V b3) is associated with this protein. Functional studies have demonstrated that CAV3 mutations are associated with persistent late sodium current and have been reported in cases of sudden infant death syndrome (SIDS).^[3] LQT9 and LQT4 serve as examples of LQTS with nonchannel mutations.

A novel mutation in the LQTS10 gene encoding the protein Na_V b4, a subunit of the voltage-gated sodium channel of the heart Na_V 1.5 (gene: SCN5), results in a positive shift in the inactivation of the sodium current. To date, only a single mutation in 1 patient has been described.^[4]

The newest genetic missense mutation associated with LQTS has been described in the alpha-1-syntrophin gene and results in gain of function of the sodium channel similar to that observed in LQT3.^[5]

In patients with LQTS, a variety of adrenergic stimuli, including exercise, emotion, loud noise, and swimming may precipitate an arrhythmic response. However, it also may occur without such preceding conditions.

Drug-induced QT prolongation may also increase the risk of ventricular tachyarrhythmias (eg, torsade de pointes) and sudden cardiac death. The ionic mechanism is similar to that observed in congenital LQTS, ie, mainly intrinsic blockade of cardiac potassium efflux. In addition to the medications that potentially can prolong the QT interval, several other factors play a role in this phenomenon. Important risk factors for drug-induced QT prolongation are female sex, electrolyte disturbances (hypokalemia and hypomagnesemia), hypothermia, abnormal thyroid function, structural heart disease, and bradycardia. Some have also suggested that affected individuals have mutations that affect cardiac ion channels, altering repolarization reserve.

Frequency

United States

Long QT syndrome (LQTS) remains an underdiagnosed disorder, especially because at least 10-15% of LQTS gene carriers have a normal QTc duration.

The prevalence of LQTS is difficult to estimate. However, given the currently increasing frequency of diagnosis, LQTS may be expected to occur in 1 in 10,000 individuals.

International

The occurrence of long QT syndrome internationally is similar to that in the United States.

Mortality/Morbidity

Mortality, morbidity, and responses to pharmacologic treatment differ in the various types of long QT syndrome (LQTS). This issue is under investigation.

LQTS may result in syncope and lead to sudden cardiac death, which usually occurs in otherwise healthy young individuals. LQTS is thought to cause about 4000 deaths in the United States each year. The cumulative mortality rate reaches approximately 6% by the age of 40 years.

Although sudden death usually occurs in symptomatic patients, it happens with the first episode of syncope in about 30% of the patients. This occurrence emphasizes the importance of diagnosing LQTS in the presymptomatic period.

• Depending on the type of mutation present, sudden cardiac death may happen during exercise, emotional stress, at rest, or at sleep.
• LQT4 is associated with paroxysmal atrial fibrillation.
• Studies have shown an improved response to pharmacologic treatment with a lowered rate of sudden cardiac death in LQT1 and LQT2 compared with LQT3.

Race

No clear evidence suggests race-related differences in the occurrence of long QT syndrome.

Sex

New cases of long QT syndrome are diagnosed more in female patients (60-70% of cases) than male patients. The female predominance may be related to the relatively prolonged QTc (as determined by using the Bazett formula) in women compared with men and to a relatively higher mortality rate in young men.

In women, pregnancy is not associated with an increased incidence of cardiac events, whereas the postpartum period is associated with a substantially increased risk of cardiac events, especially in the subset of patients with LQT2. Cardiac events have been highly correlated with menses. Also, a significantly higher risk of cardiac events (a 3-fold to 8-fold increase) has been reported in women with LQT2 syndrome during and after the onset of menopause compared with the reproductive years, mainly in the form of recurrent episodes of syncope.^[6]

Age

Patients with LQTS usually present with cardiac events (eg, syncope, aborted cardiac arrest, sudden death) in childhood, adolescence, or early adulthood. However, LQTS has been identified in adults as late as in the fifth decade of life. The risk of death from LQTS is higher in boys than in girls younger than 10 years, and the risk is similar in male and female patients thereafter.