Long QT Interval Syndromes

The congenital long QT interval syndromes result from genetic disorders of cardiac ion channel function or regulation (channelopathies) that prolong ventricular myocyte action potential duration as reflected by prolongation of the rate-corrected QT interval on the ECG (QTc, typically calculated using Bazett's formula).

The dysfunction may involve

• Loss of function of repolarizing potassium current channels OR

• Gain of function of depolarizing sodium or depolarizing calcium current channels

Prolongation of action potentials increases the probability of transmembrane voltage oscillations occurring during the depolarized myocyte action potential (early afterdepolarizations). If the action potential durations of myocytes in a local area vary, these oscillations may reactivate neighboring myocytes that have repolarized and thus create torsades de pointes ventricular tachycardia (TdeP VT). The risk of TdeP VT is dependent on the degree of QTc prolongation, particularly if it is > 0.50 second (1).

LQTS (particularly LQTS3) may also cause paroxysmal atrial fibrillation.

Long QT interval syndromes are classified based on the specific gene that has mutated. However, a specific genetic abnormality is identified in only 70 to 85% of cases (1); likelihood of detecting an abnormality varies depending on clinical factors present.

More than 15 forms of LQTS have been described, but most cases fall into 3 subgroups:

• Long QT syndrome type 1 (LQTS1): Loss-of-function mutation of gene KCNQ1, which encodes an adrenergic-sensitive Kv7.1 channel responsible for the slow outward potassium current (IKs)

• Long QT syndrome type 2 (LQTS2): Loss-of-function mutation of gene KCNH2, which encodes the hERG channel responsible for the rapid outward potassium current (IKr)

• Long QT syndrome type 3 (LQTS3): Gain-of-function mutation of gene SCN5A, which encodes the Nav1.5 channel responsible for the inward sodium current (INa).

The vast majority of cases are LQTS1, LQTS2, or LQTS3. These 3 forms are inherited as autosomal dominant disorders with incomplete penetrance.

Rare forms of LQTS with additional clinical features have been described including Jervell and Lange Nielsen syndrome (with congenital neural deafness), Andersen-Tawil syndrome (with period paralysis and craniofacial dysmorphisms), and Timothy syndrome (with craniofacial dysmorphisms, immunodeficiency, congenital heart disease, developmental delay, and syndactyly).

Overview of Long QT Syndrome

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The LQTS are asymptomatic unless TdeP VT occurs, which can cause palpitations, near syncope, or syncope. Some patients experience myoclonic jerks during syncope; they may incorrectly have a diagnosis of epilepsy pursued. Because the ventricular action potential duration decreases with increasing heart rate, TdeP VT is often self-terminating. However, it may degenerate into ventricular fibrillation and cause cardiac arrest and sudden death. In patients with LQTS, there is a 5-year risk of a first episode of life-threatening arrhythmia ranging from approximately 0.3% to 17% (1). Predictors include the following

• Age

• Sex

• Use of beta-blocker therapy (yes or no)

• Syncope (none, while not on beta-blocker therapy, or while on beta-blocker therapy)

• QTc interval

• Genotype (if available; higher in LQTS2 and LQTS3 than in LQTS-1)

An online risk calculator for patients who have not yet had a life-threatening arrhythmia is available (1).

• Characteristic clinical and electrocardiographic manifestations

• Sometimes exercise testing

• Sometimes ambulatory ECG monitoring

• Often genetic testing

• Screening of relatives

Diagnosis should be considered in patients with unexplained cardiac arrest or syncope or a family history of such when the affected people do not have structural heart disease. It should also be considered in people who are discovered to have a long QT interval when ECG is done for other reasons.

A long QT interval is diagnosed by ECG showing prolongation of the rate-corrected QT interval (QTc). Normal QTc values are < 0.43 second for males and < 0.45 second for females and are considered prolonged when > 0.45 second for males or > 0.47 second for females (1).

However, given the multiplicity of factors affecting the QTc, a normal QTc does not exclude the diagnosis. Nevertheless, at the moment of torsade de pointes VT, the QTc is essentially always prolonged.

When a patient has a significantly prolonged QT interval and documented torsade de pointes VT

Because not all patients with a long QT interval have congenital long QT syndrome and because not all patients with a congenital long QT syndrome have a long QT interval on any given ECG, the Schwartz score has been developed to estimate the probability of a congenital LQTS (see table Schwartz Score for Long QT Syndrome). Probability is estimated as low, intermediate, or high based on clinical, ECG, and exercise testing criteria, provided that the patient is not presently exposed to any environmental causes of QT-interval prolongation. The score can be used to establish candidacy for genetic testing, which can be time-consuming and expensive because of the multiple gene variants to be tested for. Patients with a low probability of a congenital LQTS do not need genetic testing, but patients in whom the probability is intermediate or high do. High-probability patients without a detected genetic abnormality may be considered to represent one of the 15 to 30% of patients with an unidentified mutation. Intermediate-probability patients who are gene mutation–negative are followed closely with repeated electrocardiographic examinations including ECG, ambulatory cardiac monitoring, and exercise testing (2, 3).

First-degree family members of the index case should have clinical evaluation (ie, to detect symptoms suggestive of arrhythmia) and ECG. Thereafter, the first-degree family members of any newly identified patients undergo similar assessment (cascade screening). Genetic testing is done when the index case has a known mutation. Exercise testing is done when the results could alter the Schwartz score probability result.

Some forms of LQTS are more associated with certain triggers than others.

• LQTS1: Physical stress, particularly swimming, or emotional stress

• LQTS2: Sudden loud noises like an alarm clock

• LQTS3: Sleep

Some forms of LQTS are also associated with particular ECG patterns

• LQTS1: Wide T waves

• LQTS2: Low voltage, notched T-waves

• LQTS3: Long-ST segment with normal appearing T-waves

However, neither the triggers nor the ECG findings are very specific and should not be used to confirm type or to direct genetic testing.

• Treatment of any VT/VF

• Alleviation of predisposing causes and triggers, especially electrolyte abnormalities and use of certain medications

• Usually beta-blockade

• Sometimes an ICD

• Sometimes left cardiac sympathetic denervation

Details of treatment of torsade de pointes ventricular tachycardia

Long-term treatment to prevent sudden death includes avoidance of specific triggers (including strenuous exercise in LQTS1 and LQTS2) and QTc-prolonging conditions. When possible, clinicians should stop any predisposing medications and prescribe alternatives (see CredibleMeds for up-to-date information). Patients, particularly those who will not accept exercise restrictions, should be counseled on the need for appropriate cautions (eg, availability of an automated external defibrillator during training and competition).

Permanent pacing to increase the basal ventricular rate and to prevent post-extrasystolic pauses may reduce the probability of recurrent TdeP VT. An implantable cardioverter-defibrillator (ICD) is indicated in patients who have been resuscitated after cardiac arrest and in those who have cardiac syncope despite therapy with a beta-blocker (see table Indications for Implantable Cardioverter-Defibrillators in Ventricular Tachycardia and Ventricular Fibrillation).

Left heart (stellate ganglion) denervation may also be used (1).

• Congenital long QT interval syndromes may cause torsades de pointes ventricular tachycardia, ventricular fibrillation, and sudden death.

• Numerous factors, particularly use of certain medications, increase the risk of ventricular arrhythmias.

• Diagnosis is based on a combination of clinical and electrocardiographic criteria, including exercise and sometimes provocative testing.

• Genetic testing is done on selected patients.

• Family members should be screened.