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Long QT Syndrome, Brugada & Ion Channelopathies
Information last reviewed: April 2014

Long QT Syndrome 
   
Drugs to Avoid

Download a Long QT patient information leaflet (PDF)

Brugada Syndrome
Progressive Cardiac Conduction Defect
(Lev-Lenegre’s Syndrome)

Catecholaminergic Polymorphic Ventricular Tachycardia

Short QT Syndrome
Idiopathic Ventricular Fibrillation

   

Cardiac ion channelopathies (also sometimes referred to as arrhythmia syndromes) affect the electrical functioning of the heart without affecting the heart's structure. They are a group of rare genetic conditions that are caused by abnormalities of the DNA known as mutations. They are usually inherited from parents although they can occur for the first time in a person. If they occur for the first time they are described as sporadic or ‘de novo’ meaning ‘from new’.

 

The mutations affect certain genes - specific segments of the DNA that are responsible for the production of cardiac ion channels. An ion is a chemical substance - such as sodium, potassium or calcium - that carries an electrical charge and forms the basis of the movement of electricity through the heart muscle. Each heart muscle cell is surrounded by a membrane that separates the inside from the outside of the cell. An ion channel is the route (the gate) that the ions take in and out of the heart muscle cells to allow the movement of electricity. The ion channels regulate the flow of electrical charge. If these channels do not behave normally, the electrical function of the heart becomes abnormal. The person can then be prone to arrhythmias (disturbances in the heart's rhythm) that may cause blackouts or cardiac arrest.

 

Since these channels are microscopic and are not visible to the naked eye, the heart appears normal during post-mortem examination. 

 

The following are the common disorders that affect ion-channels:

 

     Long QT Syndrome (LQTS)

     Brugada Syndrome

     Progressive Cardiac Conduction Defect (also known as Lev-Lenegre's Syndrome)

     Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

     Short QT Syndrome (SQTS)

     Idiopathic Ventricular Fibrillation (without Brugada ECG changes)



 

Long QT Syndrome (LQTS)
Download a Long QT patient information leaflet (PDF)

Long QT syndrome (LQTS) is the most common and best understood type of channelopathy. It occurs in about 1 in 2,000 people. In 70% of people with LQTS, gene testing can identify the ion channels involved.

In most cases, two of the potassium channels that regulate the movement of potassium ions from the inside to the outside of the cell are affected. In a small proportion of people with LQTS, a sodium channel that regulates the flow of sodium ions from the outside to the inside of cells is affected.

In people with potassium channel associated LQTS, the channels do not behave as efficiently as normal. They let potassium ions out of the cell too slowly.

 

Professor Sanjay Sharma talks about long QT syndrome

If the sodium channel is affected, too many sodium ions are allowed into the cell.  This results in an electrical disturbance in the cells of the heart called prolonged repolarisation. This can be seen on an ECG recording as a lengthening of the time period known as the QT interval. This is where the name long QT syndrome comes from.

Long QT syndrome is sometimes also known as the Romano-Ward syndrome (the commonest form) and Jervell and Lange-Nielsen syndrome (a rare form associated with deafness). 

Jervell and Lange-Nielsen syndrome:  Jervell and Lange-Nielsen syndrome is a condition that causes profound hearing loss from birth, in addition to causing prolonged QT interval. Jervell and Lange-Nielsen syndrome is uncommon; it affects an estimated 1.6 - 6 per 1 million people worldwide. This condition is inherited in an autosomal recessive pattern, which means that both parents must be carrying the culprit gene in order to have an affected child.

Romano-Ward syndrome:  Romano-Ward syndrome is the most common form of congenital long QT syndrome, which purely affects cardiac ion channels to produce prolonged QT interval. It does not affect any other systems unlike Jervell and Lange-Nielsen syndrome. It is inherited in an autosomal dominant fashion which means that one parent with the culprit gene is sufficient to produce an affected child.

The above syndromes are only a proportion of long QT syndromes.  There are now 13 recognised types of long QT, numbered LQT1 to LQT13.



 

Symptoms

LQTS varies greatly in severity. Symptoms vary according to the type of channel involved, whether the person is male or female, their age, and the length of the QT interval on the ECG. Males are more likely to have symptoms before puberty, while females are more likely to have them in adolescence and early adulthood. Relatives from the same family who have inherited the same mutation may have very different experiences. For example, some may have a normal QT interval and not have any symptoms; some may have a very abnormal QT interval but no symptoms; and some may have a very abnormal QT interval and have many symptoms that put them at risk.

The most common symptom of LQTS is blackouts. Sometimes palpitations due to extra or ectopic heartbeats can be a problem.
 

Signs 

There are usually no physical signs of LQTS. However, certain rare forms of LQTS may be associated with muscle weakness, minor abnormalities of the skull, chin, fingers and toes; or reduced hearing.
 

Diagnosis

Diagnosis involves having an ECG. Sometimes it is possible to tell which ion channel has been affected just by looking at the ECG recording. Unfortunately, in a proportion of people who might be carriers of LQTS, the ECG may not show any sign of the condition. Repeated ECGs, exercise tests and 24-48 hour tape monitoring may be needed before the diagnosis is established.

More recently some doctors have used slow injections of the hormone adrenaline (epinephrine) via a drip to try and improve the diagnosis of some potassium channel long QT syndrome. There is limited evidence however that this is any better than an exercise test.

Genetic testing can identify carriers of the LQTS gene. Unfortunately, this form of testing is limited at the moment, as 3 in every 10 people who are known to have LQTS do not have mutations of the genes known to be associated with LQTS. An additional problem is that many families who do have a mutation appear to have a specific change to the DNA code which is not found in other families (known as a 'private’ mutation). This sometimes makes it difficult to decide whether a mutation is causing the disease or not. Things are further complicated because people with the same mutation can have no signs of it or be severely affected.
 

Management

 

If you have LQTS, your doctor will advise you to avoid excessive exercise or strenuous athletic activities. He or she will also advise you to avoid certain drugs that can make the condition worse and which could increase the risk of blackouts and cardiac arrest. It is also important to avoid low blood potassium levels, known as hypokalaemia.

 

Other treatment options will vary depending on the severity of the condition. Those with one or more of the following features will likely need more intervention than those without:

  • a previous cardiac arrest

  • blackouts

  • a very long QT interval on the ECG

  • specific genetic forms of the condition

  • young, adult women (especially in the first year after pregnancy)

  • boys before puberty

Drugs

The most commonly used drugs for LQTS are beta-blockers. These block the effects of adrenaline and associated natural chemicals in the body that make the heart pump harder and faster. They therefore also block the effects of exercise on the heart. They are effective in the most common forms of LQTS as they reduce symptoms and the risk of cardiac arrest. However, they are less effective in people with the sodium channel form of LQTS. There are other more recent trends in drug treatment that look promising, but their long-term benefits are unknown. These involve using anti-arrhythmic drugs. These drugs block disturbances in the heart rhythm. Potassium supplement pills and ‘potassium sparing’ water tablets (meaning that potassium is not lost in the urine as with most water tablets) have also been tried with occasional success.

Pacemaker or Implantable Cardiac Defibrillator (ICD)

If you are at high risk (for example if you have already had a cardiac arrest), or if drugs have failed to control your symptoms, your doctor may advise you to have a pacemaker or an implantable cardiac defibrillator (ICD) fitted, as well as taking your medication. A pacemaker and an ICD both consist of an electronic box that is inserted under the skin and attached to the heart by special electrical 'leads'. A pacemaker controls the heart rate and stops any excessive slowing of the heart that could trigger an arrhythmia. An ICD acts in the same way as a pacemaker but it can also identify any dangerous arrhythmias and deliver an electrical shock to reset the heart.

 

Surgery

Another option for high risk patients is to perform surgery to disrupt the nerves that release adrenaline and related chemicals at the heart. This is performed in only a very small number of people and is known as a sympathectomy and involves operating on the left side of the chest.

Drugs to avoid if you have long QT

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Brugada Syndrome

This condition was first described in the early 1990s. It is an uncommon condition in the western world but seems to be much more common among young men in South East Asia. In the western world it affects mainly young and middle-aged adult men.

 

It has been associated with mutations in the same sodium channel that is affected in LQTS, but this appears to account for only 1 in every 5 people with the condition. The sodium channel behaves abnormally in that movement of sodium ions into the cells is restricted. This results in particular changes on the ECG but no abnormalities in the structure of the heart. Other genes have been described as being involved in Brugada syndrome that produce calcium and potassium ion channels and proteins that interact with the sodium channel. They have, however, only been detected in a small number of carriers.

CRY Consultant Cardiologist Professor Sanjay Sharma talks

about Brugada syndrome

 

Symptoms 

Most people with Brugada syndrome may have no symptoms at all. In others, the most common symptoms are blackouts. Some people may notice palpitations due to ectopic (extra) beats.
 

Signs

There are no associated physical signs.
 

Diagnosis

Diagnosis involves having an ECG. The changes characteristic of Brugada syndrome may appear on the ECG continuously or come and go, or they may not show at all.  Sometimes the presence of a fever or certain medications can bring out the ECG changes and this may be a period when there is higher risk of blackouts or cardiac arrest. If they do not show up on the ECG, there are tests that can make the ECG changes visible. These are called provocation tests and involve having a short injection of an anti-arrhythmic drug while you are having an ECG. The drugs most commonly used for this are ajmaline and flecainide. There is some controversy, however, about how much reassurance a negative result should give. Researchers have found that, in some carriers who have already been identified by genetic testing, changes on the ECG are not seen even with a provocation test. However, in these people the level of risk does appear to be low.

Genetic testing can be useful for Brugada syndrome, although mutations have been found in only a small proportion of people known to have the syndrome.
 

Management

All carriers of Brugada syndrome should avoid certain medications that might worsen their condition. They are also advised to avoid low blood potassium levels, known as hypokalaemia, and should treat all fevers with medications that reduce their body temperature such as paracetamol or ibuprofen. If their fever remains high they should attend hospital for an ECG or monitoring as required.

It is standard practice for people who have suffered a cardiac arrest or a blackout to have an ICD fitted as this is a very successful form of protection. The tablet quinidine has been used in some patients with severe disease and an ICD already in place but its exact role remains under investigation.

Unfortunately it can be very difficult for doctors to decide how to treat those people who do not get symptoms but who have an abnormal ECG. An electrophysiological (EP) study may help to identify those people who do or do not need an ICD although there is great controversy about its true value. Research has suggested that most people with normal ECGs and no symptoms should be safe without any treatment. It is unusual for children to be at high risk.

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Progressive Cardiac Conduction Defect (PCCD) (also known as Lev-Lenegre’s Syndrome)

PCCD is a rare condition. In people with PCCD, the heart's electrical impulses are conducted very slowly and this results in the gradual development over time of heart block. Heart block is a failure of the heart's electrical impulse to conduct properly from the top chambers (the atria) to the bottom chambers (the ventricles).  The severity of the condition and its associated risk can vary.

PCCD can cause arrhythmias - either because the heart's rhythm is too sluggish (bradycardia and asystole), or because of rapid rhythm disturbances (tachycardia) arising from parts of the heart that have escaped normal regulation. In some people PCCD has been associated with sodium channel mutations that cause changes in the channel similar to those found in people with Brugada syndrome.
 

Symptoms

Dizziness and blackouts are the usual symptoms, cardiac arrest may also occur.


Signs

There are no physical signs usually except if there is heart block when the doctor may feel a slow pulse.
 

Diagnosis

The ECG abnormalities may be detected either on a standard ECG or with Holter monitoring. An electrophysiological (EP) study may also help the doctor make a diagnosis. If a sodium channel mutation is identified in affected members of a family then it may also be found in other relatives.
 

Management

If you have PCCD you will need to have a pacemaker fitted in order to stop dangerous bradycardia from occurring. This may not prevent tachycardias from occurring so you may also need to take anti-arrhythmic drugs. Some people may need to have an ICD fitted instead of a pacemaker.  Medication alone does not help.

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Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

CPVT is a rare condition mainly associated with two genes that make proteins found inside the cell - the human ryanodine receptor (a calcium ion channel) and calsequestrin (a protein that interacts with the calcium channel). These regulate the release of calcium ions into the rest of the cell. If these do not function normally, the level of calcium inside the cell becomes too high, resulting in arrhythmias.
 

Symptoms

Some people with CPVT have no symptoms at all. Others may have palpitations (a fast or irregular heart beat), or blackouts while exerting themselves or suffering emotional stress. The condition may be found in most age groups but appears to be most severe in children and adolescents and in males.


Signs

There are no physical signs.
 

Diagnosis

The diagnosis is usually made after the recording of arrhythmias that are characteristic of CPVT, while the person is exercising. The exercise ECG is therefore useful although some doctors use adrenaline testing (as in LQTS) as well.

Genetic testing is of use as 1 in 2 people with the condition carry a ryanodine receptor mutation. When a member of a family has been found to carry a mutation, testing is then useful in detecting carriers who have not yet shown any signs of the condition.
 

Management

Your doctor will advise you to take beta-blockers (a type of drug), to restrict the amount of exercise you do and avoid medications that stimulate the heart. This combination can greatly improve the outlook for people with CPVT. Up to 1 in every 3 people with the condition, however, may also need to have an ICD fitted, particularly if they have blackouts while taking beta-blockers. Occasionally some patients will be given additional tablets (flecainide) to help reduce the amount of arrhythmia.


 

Surgery

 

Recently some groups have carried out sympathectomy (already used in LQTS) to treat CPVT, with some success.

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Short QT Syndrome (SQTS)

This rare condition is similar to but distinct from LQTS. As the name suggests the QT interval in carriers is shorter than in normal people. This means that the heart takes a shorter time to repolarise or reset itself, making it prone to ventricular arrhythmias. There is also an increased risk of a less dangerous arrhythmia from the top chambers of the heart (the atria) called atrial fibrillation. This is an irregular and rapid heart rhythm that may go unnoticed or causes breathlessness and palpitations. As in LQTS, potassium channel genes are affected but instead of allowing less potassium through they allow through too much, too quickly.
 

Symptoms

Palpitations, blackouts and cardiac arrest.


Signs

There are no physical signs usually except if there is atrial fibrillation when an irregular rapid pulse may be felt by the doctor.
 

Diagnosis

The ECG abnormalities are usually detected either on a standard ECG or a 24-hour Holter. An electrophysiological (EP) study may also help the doctor make a diagnosis. Genetic testing may find a potassium channel mutation in affected members of a family that may then also be found in other relatives.
 

Management

If you have SQTS it is likely that an ICD will need to be fitted in order to treat dangerous arrhythmias. Quinidine has been used in some patients but it is unclear whether it is safe to rely on medication alone. Tablets may also be used to treat atrial fibrillation.

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Idiopathic Ventricular Fibrillation

Idiopathic ventricular fibrillation (IVF) describes the group of conditions responsible for life-threatening, rapid rhythm disturbances without any signs of the heart diseases described above. In some of these patients, changes on their ECG known as early repolarisation, have been seen. This has become known as early repolarisation syndrome and in a few cases mutations of potassium and calcium ion channel genes have been found. Early repolarisation can, however, be seen on the ECGs of many normal healthy people. The diagnosis and treatment of this condition is therefore still unclear but an ICD is needed in patients who have suffered a cardiac arrest.

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