Long QT Syndrome

Long QT Syndrome is a condition that is characterized by a delay in repolarization of the heart after the initial depolarization and ventricular contraction. The electrical system of the heart normally functions in a pattern that causes the atria (upper chambers) and then ventricles (lower chambers) to contract. This pattern of normal electrical signals produces a normal ECG with Q, R, S, and T waves. In long QT syndrome, the electrical signals are delayed because the electrical system cannot recharge fast enough to carry a signal. This condition increases the risk of a life-threatening arrhythmia known as ventricular tachycardia.

Long QT syndrome (LQTS) is a familial condition which may be asymptomatic or cause syncope and may cause sudden death through rapid ventricular tachycardia (torsade de pointes), which can deteriorate to ventricular fibrillation, in otherwise fit and healthy young people. Prevalence is approximately 1 in 2,000.

Clinical diagnosis is made from a combination of suspicious history, family history and the twelve lead ECG, which typically reveals a heart-rate corrected QT interval (QT//R-R interval=QTc) of greater than 0.47 in women and 0.46 in men. QT interval behavior after exercise testing is often helpful in making the diagnosis.

LQTS may be diagnosed in an asymptomatic individual on a routine ECG, as a part of family screening of a patient with LQTS or in asymptomatic individual presenting with syncope or resuscitated sudden death during or following exercise or stress or swimming in a young person.

Misdiagnosis of LQTS as epilepsy, particularly “familial epilepsy,” is common. Seizures following exertion, or arousal in the postpartum period , and during sleep, must raise the suspicion of LQTS.

The diagnosis is usually made on clinical grounds. If the presentation is with syncope or resuscitated sudden cardiac death, the ECG shows QTc prolongation and the T-wave morphology is frequently abnormal. QT prolongation due to drugs or biochemical imbalance (low potassium, calcium or magnesium), hypothermia and myocardial disease must be excluded.

Features suggesting arrhythmic syncope include collapse associated with exercise, sudden emotional stress or loud noise, and physical injuries indicating failure to make protective movements when falling – particularly facial injury. Syncope associated with swimming is due to LQTS until proven otherwise.

Syncope secondary to pain or nausea or syncope preceded by nausea is more commonly 1. The implantable digital loop recorder (“reveal device”) can be valuable in detecting or excluding arrhythmia at time of syncope if others tests are inconclusive.

Family history: If Long QT syndrome is suspected, your doctor will ask a very detailed family history, which looks for a history of syncope or sudden unexplained death at a young age in a close relative. Directed questioning is essential, with a family tree being drawn. The history of unexpected drowning in a strong swimmer, or road traffic accidents on a straight road, are suggestive of a possible arrhythmic cause. Familial epilepsy and sudden infant death are also suspicious. Any sudden unexpected natural death with a negative post-mortem should trigger a family investigation for LQTS.

Family screening: ECGs should then be obtained on all first-degree relatives. Up to one third of asymptomatic gene mutation carriers have QTc values within the normal range. QTc values of 0.44 sec or more are treated as suspicious. Values below 0.41 sec are uncommon in gene carriers. The length of the QT interval is linked to the risk of syncope and sudden death, but all gene carriers are at an increased risk, and can still pass on the mutation to 50% of their children.

LQTS is most commonly inherited in an autosomal dominant manner and is sometimes called Romano- Ward syndrome. A single mutation in any one of the LQT1 through LQT13 genes results in this autosomal dominant form of LQTS. Each child of an affected parent has a 50% chance of inheriting a disease-causing gene mutation.

The commonest genotypes are types 1 and 2 (about 40 % each); about 8% are type 3. In each, a dysfunctional cardiac cell channel results in prolongation of the cardiac repolarization, and thus the QT interval. With current genetic techniques, all 13 LQTS genes are screened and the genetic test result may identify the pathogenic mutation (in about 70% of LQTS patients) or the test may be negative or inconclusive in about 30% of LQTS patients. If a pathogenic mutation is found genetic testing is offered to all family members irrespective of their QT intervals as some 30% of LQTS gene carriers have normal QT intervals (concealed LQTS) and are able to pass on the genetic mutation and rarely, develop symptoms.

Studies of the three commonest genotypes (Types 1, 2 and 3) have shown that the life-threatening cardiac events (syncope or sudden death) tend to occur under specific circumstances in a gene-specific manner, and may have characteristic T wave morphologies.

Knowing the genetic type allows advice regarding lifestyle modification to avoid precipitating factors, e.g. swimming and exertion in LQT1 and avoidance of sudden noise or alarm in LQT2.

All gene carriers must avoid medications which prolong the QT interval, can cause torsade de pointes or lower serum potassium levels. A constantly updated list is available at https://crediblemeds.org/.

ASSESSING LEVEL OF RISK OF SUDDEN CARDIAC DEATH

Management must be guided by an assessment of risk. Data from the international long QT registry show that the most important features are:

Whilst adrenaline challenge and exercise testing can help clarify gene carriage state, there is as yet no evidence supporting the use of such recordings to assess risk. Although the death of a family member may understandably bring a perception of increased risk, there is no evidence that it does. Careful evaluation has demonstrated for example that death of a sibling does not increase risk

LIFESTYLE MODIFICATIONS

With all forms of LQTS, where there is a long QT interval (and not necessarily just gene carriage), some degree of limitation in sporting activity is recommended.

The limitation needs to be more severe with LQT1, or those who have already experienced events during exercise, than LQT2 and 3. They should not become professional athletes, and all highly competitive sports are to be discouraged. With LQT 1, and subjects with a history of exercise induced syncope, swimming and diving are contraindicated.

With LQT 2, or those with a history of auditory evoked events, remove loud alarm clocks and turn down the volume on the phone at night.

BETA BLOCKADE

Beta blockade should be initiated in those who have had symptoms, and those with a definite long QT interval, particularly in pre-adolescent boys, including infants. Overall reduction of risk of sudden cardiac death in high risk subjects is 67% in LQT 1 males and 71% in LQT 2 females. Beta blockers are also used in long QT 3 although the response may not be as good as in KLQT1 and 2 and additional treatment may be required.  Once started, they should not be stopped; there is a period of high risk after stopping beta-blockers due to up-regulation of beta-receptors on treatment.

INTRACARDIAC CARDIOVERTER-DEFIBRILLATORS (ICD)

This issue is reviewed by the Heart Rhythm UK sudden death group recently. These devices are not without morbidity and patients must be selected carefully. AICDs are considered to be indicated for:

1. Resuscitated cardiac arrest,
2. Persistent arrhythmic syncope whilst on beta blockers,
3. When beta blockers are contra-indicated and high risk is established.

A relative indication is the presence of a very long QT interval (QTc>0.55sec) even without symptomatology, particularly adult females and males with LQT 3. Unless inserted for contraindication to beta-blockers, it is important that beta-blockers are continued because of the risk that a defibrillation shock may cause an adrenergic surge and precipitate a further event or electrical storm.

LEFT CERVICAL SYMPATHECTOMY

Minimally invasive selective left cardiac sympathectomy may be considered for:

1. Those with severe disease and in whom beta blockers are contra-indicated or AICD cannot be placed or is refused by the patient.
2. Controlling VT storms in those with an AICD,
3. High risk LQT3 or a personal or family history of events during rest or sleep.

Some individuals at intermediate risk may choose this option rather than take beta blockers, and it may be  considered as a primary prevention, particularly boys with LQT1. Those at high risk should continue beta blockers after the sympathectomy when feasible.

All patients with LQTS should avoid medications contra-indicated in LQTS. A list of these drugs can be found on the net under ‘LQT drugs’ Those with a long QT interval (>500ms), especially young males and adult females need to be treated much as someone who has already presented with syncope. Beta blockers should be proposed and sensible limitations placed on sporting activities and particularly swimming. The role of beta blockers in those without symptoms, a normal QT interval and yet a positive genetic diagnosis is controversial, since evidence is not yet strong to establish a reduction in risk. Those with a family history of adrenergic induced cardiac events, or known to have LQT1, are most likely to benefit. It should be remembered that intermittent adherence to beta blocker therapy may carry its own risk; when the medication is stopped, the up-regulated beta-receptors may lead to an increased risk for a few days after stopping.

The main aim of the clinician is to prevent sudden death though medication and life-style changes. A secondary aim is to assist the family in their adjustments that have to be made. Time and skilled psychological and genetic counselling is required. This is often more than the busy cardiologist can provide and suitable professional assistance should be offered when appropriate. Genetic counselling is particularly important prior to testing an asymptomatic individual with a normal ECG. A positive result may have adverse psychological, social, employment and insurance effects. Some of those at highest risk are adolescents and teenagers. Beta blockers and the limitations on activities are both hard pills to swallow, and whilst encouraging adherence, it is important not to alienate the patient. They will need to feel some retention of control in their lives. This topic has been adapted from the CSANZ guidelines for management of Long QT syndrome Useful websites include:

1. https://crediblemeds.org/ Lists all drugs that are to be avoided in Long QT syndrome
2. https://sads.org  (International site of the Sudden Arrhythmic Death Society)
3. www.sads.org.au  (Australian site)
4. www.cidg.org.nz (Cardiac Inherited Disease Group, New Zealand)