Dr Rhea Clubb and Dr Luke Starling

Long QT Syndrome (LQTS) is a rare disease that causes syncope, seizures, and sudden cardiac death. It’s caused by mutations in genes that code for cardiac ion channels, which results in prolonged ventricular repolarisation.

So, patients with LQTS have a predisposition to malignant ventricular arrhythmias: torsades de pointes, polymorphic VT, and ventricular fibrillation. 

What is the QT interval?

The QT interval is simply the time from the beginning of the Q wave to the end of the T wave! Physiologically, it represents the time for the ventricles to depolarise and then repolarise – which is the period of ventricular systole (from the beginning of ventricular contraction until the end of ventricular relaxation). 

When measuring the QT interval you need to measure right from the beginning of the Q wave, to the point where a tangential line from the steepest downward slope of the T wave meets the isoelectric line (base line). If the T wave is notched, you need to draw the tangential line down from the steepest downward slope of the second notch. 

What is a long QT interval? 

As the QT interval represents the total duration of ventricular contraction and relaxation, its duration will be dependent on the heart rate. If the heart rate is fast it should be shorter, and if the heart rate is slow it should be longer. Calculating the corrected QT interval (QTc) takes rate into account. There are lots of different formulas for calculating the QTc. Probably the most commonly used one is the Bazett formula (QT and RR need to be in seconds) :

QTc = QT/√RR

Tip: Bazett formula corrects the heart rate to 60 bpm – so if the heart rate of the patient is already 60 bpm, you can just count the QT interval and not use a formula!

As a rule of thumb, the upper limits of QTc are 440 ms for boys and 460 ms for girls. If you have any concerns about the QTc you should always discuss the case with a paediatric cardiologist.

QTc and cardiac physiology

A longer QT interval can predispose patients to ventricular arrhythmias and subsequent sudden death.

To understand why this happens it’s important to remind ourselves of some physiology:

• The cardiac action potential is a brief change in voltage (membrane potential) across the cell, causing it to contract. 
• At rest, the membrane potential is negative. This is because potassium channels are open, meaning positive potassium ions are leaving the cells, making the inside of the cell more negative than outside of the cell.  

Below is the cardiac action potential of a non-pacemaker myocyte:

• Phase 0 = rapid depolarisation – occurs as result of a transient influx of positive sodium and calcium ions. At the same time, potassium channels, which transport potassium ions out of the cell, close. 
• Phase 1 = early, brief repolarisation. It is caused by the activation of potassium channels that transport potassium ions out of the myocytes. 
• Phase 2 = plateau phase. Influx of calcium is balanced by the outward flow of potassium. The plateau phase delays repolarisation and prolongs the cardiac action potential. 
• Phase 3 = repolarisation. It is caused by the closure of calcium channels while potassium continues to flow out of cells. 
• Phase 4 = resting phase. 

What causes LQTS? 

Basically, it’s all about the abnormal flow of sodium or potassium ions across the myocyte membrane, which makes the action potential longer than it should be.

A prolonged QT interval can happen because there is decreased repolarisation via potassium channels, or persistent influx of sodium that may continue into phase 2 of the action potential. 

Gain in sodium channel function or loss of potassium channel function results in myocytes being more susceptible to early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). Early afterdepolarizations are secondary depolarisations of the cell membrane that occur during the repolarization phase of the action potential. Delayed afterdepolarizations occur directly after repolarisation in phase 4. 

These abnormal depolarisations can turn into torsades de pointes and subsequently, ventricular fibrillation. 

Types of congenital LQTS

There are at least 15 different subtypes of congenital LQTS, each associated with a mutation in a different gene. LQTS1, LQTS2 and LQTS3 are the most common types. (Don’t worry – this level of detail is mostly relevant to paediatric cardiologists, but we have included it for interest!)

• In LQTS1, there is an abnormality in a protein that generates potassium channels, which are important in repolarisation. Upregulation of these channels by beta adrenergic stimulation during exercise is critical in shortening the action potential and allowing for adequate diastolic filling when the heart rate is increased during exercise. This partly explains why cardiac events in children with LQTS1 are triggered by stress or exercise. 
• LSTS2 – there is a mutation that affects a different potassium channel, also affecting repolarisation.
• LQTS3 is associated with a gain in function mutation of sodium channels. While patients with potassium channel associated long QT are predisposed to cardiac events during exercise, those with LQTS3 have an increased risk at rest. However, it is important to remember there is considerable variation in triggers among all the different patients with LQTS3.

Cardiac events in children with LQTS1 are triggered by stress or exercise. 

Acquired LQTS

A long QT interval can also be acquired, which is the more common than LQTS per se and is potentially reversible. Causes include electrolyte imbalances (hypokalaemia, hypocalcaemia, hypomagnesaemia) and medications (a full list can be found at www.crediblemeds.org).

Class of drugs	Examples
Antiarrhythmics	amiodarone, sotalol, quinidine
Antibiotics	macrolides (e.g. erythromycin), quinolones
Antihistamines	terfenadine
Antipsychotics	haloperidol, quetiapine
Gastrointestinal motility drugs	domperidone, erythromycin

Presentation and diagnosis

Some children with LQTS will be asymptomatic with incidental findings on their ECG. Others may present with syncope, seizure-like episodes, or sudden death. Some will be diagnosed through family screening after a diagnosis is made in a close relative; sadly, this diagnosis is sometimes made post-mortem via molecular autopsy.

You must always ask about family history in children presenting with palpitations, dizziness, and syncope or in those with an abnormal ECG. Specifically ask about: LQTS in relatives, sudden death, recurrent syncope, and seizures. 

Diagnosis

Diagnosis can be challenging. If there are any suspicions of LQTS from the clinical history or the ECG findings the case should be promptly discussed with a paediatric cardiologist – remember that diagnosis of LQTS on solely QT cut-offs can be difficult. Children with established LQTS may have a normal QTc but abnormal T-wave morphology, positive genetics, and a history of arrhythmias.

Remember to always calculate the QTc when reviewing ECGs and discuss with a paediatric cardiologist if you have any concerns

Clinical scoring systems and genetic testing can help with diagnosis. The Schwartz Score takes into account ECG findings, clinical presentation, and family history to calculate the probability of LQTS.

Investigations 

Children with suspected LQTS need to be investigated by specialist paediatric cardiology centres. Examples of investigations are:

• Exercise test – in some types of LQTS, the QTc will not shorten appropriately when the heart rate increases.
• Holter – in some types of LQTS, diurnal variation may be present (in LQTS3 there may be marked prolongation of the QTc at night). Ventricular ectopics and short episodes of ventricular tachycardia may also be identified. 
• Genetic testing and screening of families.

Management

Management of patients with LQTS is led by paediatric cardiologists who are specialists in inherited arrhythmias. Different subtypes of LQTS may require different treatment. Broadly, treatment options include:

Beta-blockers are the mainstay of treatment in LQTS1 and LQTS2

• Medication – different anti-arrhythmics are used in different subtypes of LQTS. Generally, beta-blockers are the mainstay of treatment in LQTS1 and LQTS2. Mexiletine, a sodium channel blocker, is sometimes used in LQTS3. Families should avoid medications that are known to prolong the QT interval – the CredibleMeds website (and app) is a good resource.
• Cardiac devices – implantable cardiac defibrillators (ICD) and pacemakers ICDs are used in secondary prevention for children who have presented with cardiac arrest or who have breakthrough ventricular arrhythmia and syncope despite medication. Some high risk patients might have a primary prevention ICD prior to a cardiac event. Pacemakers can be used as anti-arrhythmic strategy in cases of pause-dependent or bradycardia-induced VT.
• Left cardiac sympathetic nerve denervation (LCSD) – this is the physical disruption of adrenergic stimulation of the heart and is useful where patients are at risk of exercise-induced arrhythmias, such as in LQT1. It is indicated for patients who have breakthrough cardiac events despite optimal medications or if they are intolerant of medication side effects. Some very small children who are considered high-risk (such KCNQ1 homozygotes with Jervell Lange-Nielsen syndrome) may undergo LCSD before they are big enough to receive an ICD. The procedure is typically now performed via video-assisted thoracoscopy in specialist centres.
• Lifestyle – most children with LQTS are allowed to play sports so long as they are compliant with their beta-blocker (or other medication). They should’t swim unsupervised. They also need to avoid alcohol in excess, illicit drugs, and energy drinks.
• Psychological support – a diagnosis of LQTS is a big deal, and can be a huge stress on children and their families. All families should be offered clinical psychological support and the support of a genetic counsellor.  

Take home messages

• LQTS is a rare disease in which the cardiac action potential is prolonged, due to abnormalities in movement of ions across the myocyte membrane. It can cause syncope, seizures and sudden death. 
• The QT interval can also be prolonged by electrolyte imbalances and certain medications. Acquired LQTS is potentially reversable.
• Remember to always calculate the QTc when reviewing ECGs and discuss with a paediatric cardiologist if you have any concerns. 
• Some children with LQTS may be asymptomatic with incidental ECG findings, others may present with symptoms. It is really important to take a thorough family history in any child who presents with palpitations, syncope, dizziness, or those with an abnormal ECG. 
• Diagnosis can sometimes be challenging. If LQTS is suspected, referral should be made to a paediatric cardiologist who has expertise in inherited arrythmias. 

Dr Rhea Clubb is a paediatric ST2 trainee. This article was reviewed by Dr Luke Starling, Consultant Paediatric Cardiologist at Great Ormond Street Hospital.

References

• ‘Inherited arrhythmias and conduction disorders’ in Oxford Specialist Handbook in Cardiology: Inherited Cardiac Disease, Edited by Perry Elliot, Pier D Lambiase, Dhavendra Kumar. Oxford: Oxford University Press 2011
• Behem, Peng, Robey, Terrenoire,  Iyer, Sampson and Kass Molecular Pathophysiology of Congenital Long QT Syndrome 
• BMJ Best Practice Long QT Syndrome [Updated 2018]
• Life in the Fast Lane ECG library