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’.
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.
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:
Cardiac Conduction Defect
(also known as Lev-Lenegre's Syndrome)
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.
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
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 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.
above syndromes are only a proportion of long QT syndromes. There
are now 13 recognised types of long QT, numbered LQT1 to LQT13.
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
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 involves having an
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,
and 24-48 hour tape monitoring may be needed before the diagnosis is
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
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.
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:
previous cardiac arrest
long QT interval on the ECG
genetic forms of the condition
adult women (especially in the first year after pregnancy)
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
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
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.
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.
Sanjay Sharma talks
about Brugada syndrome
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.
There are no associated
Diagnosis involves having an
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
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.
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.
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.
Dizziness and blackouts are the usual symptoms,
cardiac arrest may also occur.
There are no physical signs usually except if there
is heart block when the doctor may feel a slow pulse.
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
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.
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.
There are no physical signs.
The diagnosis is usually made after the recording of
arrhythmias that are characteristic of CPVT, while the person is
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.
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.
Recently some groups have carried out sympathectomy
(already used in LQTS) to treat CPVT, with some success.
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.
Palpitations, blackouts and cardiac arrest.
There are no physical signs usually except if there
is atrial fibrillation when an irregular rapid pulse may be felt by the
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.
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
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.