Channelopathies arise from mutations in the genes which encode for ion channels, the glycoproteins embedded in the membrane of cardiac myoctes which allow the flux of ions in and out of the cell. Depolarising currents are mediated mainly by channels that allow the entry of sodium and calcium ions into the cell; repolarising currents are mediated by channels that allow the exit of potassium ions, with the order of activation giving rise to electrical currents that are responsible for myocyte excitability.
“When these channels do not work properly there is a tremendous potential to cause lethal arrhythmias,” says Ramon Brugada Terradellas, who has just been appointed Director of the Cardiovascular Genetics Centre at the University of Girona, Spain (pictured on the left with his two brothers, Pedro, centre, and Josep, who identified the eponymous syndrome)
The four cardiac channelopathies - Long QT syndrome, Brugada syndrome, Short QT syndrome and Catecholaminergic polymorphic ventricular tachycardia (CPVT) - are the main focus of the Seminar.
- Long QT syndrome, which takes its name from the distinctive abnormality of the
electrocardiogram, results from mutations in the potassium channel and more rarely in the sodium and calcium channels. Altogether, ten different subtypes of long QT have been defined, which are thought to affect around one in 5000 people.
- In Brugada syndrome, first described by Pedro and Josep Brugada in 1991, a mutation in the gene encoding the sodium channel reduces inward sodium current. Brugada syndrome, which affects around one in 5000 people, is defined by a characteristic ECG pattern of right bundle branch block and persistent ST segment elevation.
- Short QT syndrome, identified by an extremely short QT interval, has been linked to three separate genes encoding different potassium channel proteins. Since the condition was first identified in 2000, around 50 cases of short QT syndrome have been identified.
- CPVT is caused by enhanced calcium release through a defective ryanodine receptor, one of the proteins found in the potassium channel.
Diagnosis
Diagnosis of Long QT syndrome, Brugada and Short QT syndrome can often be made on the basis of the patient's ECG. However, patients with CPVT produce unremarkable ECG patterns, only developing the typical patterns of bi-directional or polymorphic ventricular tachycardia through exercise (when the heart beat exceeds 110-120 beats per minute) or through catecholamine infusion.
“The bottom line is that if you have a patient with syncopy during exercise and you can't identify anything on ECG, you should always undertake an exercise ECG,” says Christian Wolpert, from University Hospital of Mannheim in Germany.
Wolpert also advises awareness that Long QT, Brugada and Short QT can all be responsible for sudden infant death syndrome. “In all cases of sudden infant death a work-up should be undertaken for family members,” says Wolpert, who believes there is a role for ECGs as part of routine neonatal screening tests for early identification of channelopathies.
One of the major issues in the management of channelopathies is exactly which patients require treatment. “There's no doubt that anyone who has suffered a cardiac arrest should have an implantable cardiac defibrillator,” says Fiorenzo Gaita, from Hospital 
of Asti in Italy, and there is also an established role for patients who suffer frequent syncopy.
Asymptomatic patients
The issues, however, are much less clear for asymptomatic patients who have had an ECG or genetic diagnosis. “Genetic mutations do not affect all family members in the same way," says Wolpert. "One relative may have problems, while another may be a silent carrier, so that it is not clear from the start who'll develop the full disease."
Wolpert adds that a normal ECG does not exclude future events and an abnormal ECG pattern does not necessarily mean that someone will suffer an event - which renders therapeutic decision making difficult in asymptomatic individuals. The current guidelines, however, are helpful on this matter.
Beta blockers offer the mainstay of treatment for LQTs and CPVT, where the rationale is to inhibit the catecholamingeric stimulation. This, therefore, offers a good treatment option for asymptomatic patients, since the approach is largely without risk.
“If despite beta blocker medication syncopy occurs during exercise an implantable cardiac defibrillator - ICD - should be considered,” says Gaita.
Another speaker in the Seminar, Antoine Leenhardt, from the Hôpital Lariboisière in Paris, stresses that patients with long QT and CPVT should avoid competitive sports, even if they are taking beta blockers. “They should only practice 'lazy' sports, such as walking and bike riding, that don't risk raising heart beat above 130 beats per
minute,” he says.
The problem for patients with Brugada and short QT, where no effective drug options are available, is that an ICD is the only proven treatment. ICDs are not without dangers – complications include a risk of infections, lead dislodgement and perforation of the heart. “The situation is particularly challenging for children who require frequent lead changes as they grow older,” says Gaita.
“And in some patients," adds Leenhardt, "the risk of the ICD treatment may be more than the risk of suffering an arrhythmia."
Programmed electrical stimulation
Risk stratification of asymptomatic Brugada patients with programmed electrical stimulation (PES) introduces one of the most heated debates in arrhythmology.
Supporters believe that PES can be used to distinguish - to some extent - high-risk patients from low-risk patients, who can be left alone (with advice to take certain precautions, including, for example, the avoidance of fever and cocaine) and
monitored annually with ECGs to ensure no deterioration in their condition. Opponents do not believe that PES can predict subsequent events.
Even when an arrhythmia can be induced in a PES study, there is still controversy over whether the risk of an event is high enough to warrant both the complications and cost of ICD treatment. “For a 40-year-old, the 2% annual risk of having an event means that by the age of 60 there is a 50% chance of a fatal arrhythmia,” says Brugada. “Since we're talking about healthy individuals, many of whom have dependent children, this appears to be a more than worthwhile intervention."