Sudden Arrhythmias - what causes SADS?

The conditions responsible for SADS cause a cardiac arrest by bringing on a 'ventricular arrhythmia' (a disturbance in the heart's rhythm), even though the person has no structural heart disease.

There is a group of relatively rare diseases called ion channelopathies that affect the electrical functioning of the heart without affecting the heart's structure. This means that they can only be detected in life and not at post-mortem. Ion channelopathies are probably responsible for 4 in every 10 cases of Sudden Arrhythmia Death Syndrome. There are several different types of ion channelopathies including:

Long QT Syndrome (LQTS)

Brugada Syndrome

CPVT (catecholaminergic polymorphic ventricular tachycardia

PCCD (progressive cardiac conduction defect)

IVF (idiopathic ventricular fibrillation), and

sodium channel disease.

Structural heart disease is occasionally found to be a cause of SADS (between 1 and 2 in every 10 cases).

Ion channelopathies

Ion channelopathies are 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 family. If they occur for the first time they are described as 'sporadic'.

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 or potassium - that carries an electrical charge and forms the basis of the movement of electricity through the heart muscle. An 'ion channel' is the route 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 can cause blackouts, cardiac arrest and in some cases sudden death.

Below we describe the different types of channelopathies, the tests needed to diagnose them and the treatment that may be needed for each one.

Long QT Syndrome (LQTS)

LQTS is the most common and best understood type of channelopathy. It occurs in about 1 in 5,000 people. In 7 in every 10 people with LQTS, the ion channels involved have been identified. 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 into the cell too slowly. If the sodium channel is affected, too many sodium ions are allowed into the cell. (See the LQTS diagram - figure 2B - below.) 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.

Rare forms of LQTS known as Andersen's and Timothy Syndromes have been associated with potassium and calcium channel abnormalities respectively.

What are the 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 events 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.

Potassium channel LQTS is associated with sudden death which is related to exercise or when the person has been startled or awoken suddenly ('sudden arousal'). The sodium channel form is associated with death while asleep.

Are there any physical signs?

There are no physical signs of LQTS. However, people with Andersen's Syndrome may also have muscle weakness or minor abnormalities of the skull, chin, fingers and toes.

Brugada Syndrome

This condition was first identified 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.

What are the symptoms?

Some 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 beats. Sudden death may occur. If it does, it usually happens while the person is sleeping.

Are there any physical signs?  There are no associated physical signs.

CPVT (Catecholaminergic polymorphic ventricular tachycardia)

CPVT is a rare condition found in young people and children. It causes a particular type of arrhythmia. It has been 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 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 the arrhythmias characteristic of CPVT.

What are the symptoms?

Some people with CPVT have no symptoms at all. Others may have blackouts. Sudden death may occur while the person is exerting themselves or suffering emotional stress.

The condition can affect children and seems to cause more blackouts in males than in females.

Are there any physical signs?  There are no physical signs.

PCCD (Progressive cardiac conduction defect)

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 channel behaviour similar to those found in people with Brugada Syndrome.

What are the symptoms?

Dizziness and blackouts are the usual symptoms. Sudden death may also occur.

Are there any physical signs?  There are no physical signs.

IVF (Idiopathic ventricular fibrillation)

This term describes the group of conditions responsible for life-threatening, rapid rhythm disturbances without any signs of heart disease. Brugada Syndrome and CPVT form part of this group but there have been reports of patients with IVF who do not have the ECG changes characteristic of the Brugada Syndrome but who do have sodium channel mutations. Treatment includes having an ICD fitted, and can be successful in protecting the person.

Sodium channel disease

There are very rare and specific sodium channel mutations that can cause Long QT Syndrome, Brugada Syndrome and/or PCCD in the same family. They can be diagnosed and treated as described above and can be identified by genetic testing.

Structural heart disease

In some cases, the pathologist cannot confirm a diagnosis of structural heart disease - either because there is no evidence of it, or because there is not enough evidence and the heart is felt to be relatively normal. So the death will be recorded as SADS. This may happen even in cases where evidence of inherited structural heart disease is subsequently detected in other members of the victim's family. The presence of very subtle structural heart disease in the victim may, however, have been enough to cause sudden cardiac death.

In these circumstances the most common causes of death are:

arrhythmogenic right ventricular cardiomyopathy (ARVC)

dilated cardiomyopathy (DCM)

hypertrophic cardiomyopathy (HCM)

mitral valve prolapse (MVP)

Wolff-Parkinson-White Syndrome (WPW)

Information courtesy of www.sads.org.uk