Brugada Syndrome

Brugada syndrome (BS) is another inherited ion channelopathy which causes unexplained sudden death, particularly in middle-aged males.^1-3 It is more common in southeast Asia and should particularly be considered when looking at unexplained sudden deaths in this ethnic group.⁴

Clinical Features

The Brugada brothers reported eight cases in 1992 of cardiac arrest in young healthy patients with right bundle branch block patterns on electrocardiogram (ECG).⁸ Much of the disease is still unknown, as researchers continue to search for more data to better understand BS.^7,8 As with many of these genetically-based causes of sudden death, it is unclear why some Brugada patients become symptomatic and others remain clinically silent. However, once BS subjects experience a symptom (syncope or aborted cardiac arrest), it becomes a very lethal disease with a high clinical penetrance.^9,10 Several studies have found that the recurrence rate following a resuscitated cardiac arrest was 62% by five years of follow-up.^5,7,9,10 Many such untreated patients could well succumb to sudden death, if you follow them over the next few decades. We don t know for sure the long-term death rate over a Brugada patient s life, since no such long-term studies are yet available. Most arrhythmic events occur for the first time when the Brugada patient is in their early 40 s, but episodes have been described over a wide age range (2 to 77 years). Symptomatic Brugada patients experience polymorphic ventricular tachycardia degenerating into ventricular fibrillation, leading to syncope or even death. The episodes occur most commonly during sleep but may also happen with exercise or at rest. The ECG in the Brugada patient is frequently abnormal and represents the best way to diagnose BS. A right bundle branch block-type of pattern is often noted in the right precordial leads V1-V3 with ST-segment elevation (Figure 1).^1-3 In many patients with Brugada syndrome, the ECG abnormalities can normalize or be unmasked by pharmacologic challenge with a sodium channel-blocking drug like procainamide, flecainide, or ajmaline.^11,12 However, it is well-documented that the ECG can appear normal and can fluctuate over time, so a normal ECG, particularly in a female Brugada patient, does not exclude the diagnosis. Many Brugada patients will have abnormal test results during invasive electrophysiology (EP) study.^13,14 It may be the most useful test available, especially if the ECG is normal-appearing, if the diagnosis is in doubt. Inducibility of malignant ventricular arrhythmias is not rare and portends a worse clinical prognosis than for those patients who have normal EP studies.^1-3,13,14 The usual cardiac tests in Brugada syndrome are normal including echocardiogram, cardiac MRI, and biopsy. Autopsy findings of the heart in BS patients are also unremarkable. The most useful history in such patients is learning of a family history of sudden death, early MI, etc., particularly in males, since it is an autosomal dominant disease.

Pathophysiology

The mutation in the SCN5A gene results in either a reduced sodium channel current or failure of the sodium channel to express. The disease is caused by a defect in the subunit of the cardiac sodium channel gene (SCN5A).^3,7,15 Numerous SCN5A mutations have been described which produce BS, but most lead to a loss of function in the cardiac sodium channel. Interestingly, LQT3 (a completely different disease) is also due to mutations in the SCN5A gene, but leads to a gain of function in the sodium channel.^15,16 As you may recall, patients with LQT3 often have slow heart rates (sinus bradycardia) and can experience cardiac arrests while sleeping. The mutant sodium channel demonstrates more abnormal function at higher temperatures. There are numerous reports in the literature of Brugada syndrome patients experiencing symptoms during febrile illnesses.^1-3

Epidemiology

Brugada syndrome is relatively rare, certainly rarer than hypertrophic cardiomyopathy (estimated at 1 in 500 patients) or long QT syndrome (1 in 5,000 patients), although nobody really knows how many people are affected. A Brugada syndrome consensus report published in 2002 estimated the incidence of the disease world-wide at up to 66 cases per 10,000 people.⁵ Although it is an autosomal dominant disease, it affects males in terms of symptoms more commonly than females, in an 8:1 male:female ratio.^6,7 The cause of this male predominance is unclear, and it contrasts with long QT syndrome, in which the most symptomatic patients are female. The gene is much more prevalent in southeast Asia than in the United States. Brugada syndrome is thought to cause the entity known as Lai Tai (death during sleep) in Thailand, a relatively common cause of sudden unexplained death among young healthy men in that region.⁴ It may also be an important cause of unexplained sudden death among southeast Asian refugees.

Genetics

Brugada syndrome is an ion channelopathy inherited in an autosomal dominant fashion. In practical terms, for counseling your patients, this means that if the father is diagnosed with Brugada syndrome, each child has a 50% chance of inheriting the mutant gene, which can be passed on to their children, and so on. It s important to get such families genetic counseling so that they can understand which other family members may be at risk for sudden death. To date, only 20% of Brugada cases have been linked to the SCN5A gene, so routine screening of these gene will not yield a result for most Brugada patients. The precise ion channel mutations causing the remaining 80% of cases are unknown.^6-8 It remains an exciting area of research in trying to identify what other ion channels could cause Brugada syndrome. The SCN5A gene is one of the largest ion channel genes known, with at least 28 exons identified thus far.¹⁵

Treatment

Medications are largely ineffective at treating Brugada syndrome.⁵ Amiodarone, beta-blocker, and calcium channel blocking agents have all been tried and do not prevent sudden death in high-risk patients. The recommended treatment for symptomatic patients with BS is ICD implantation, particularly as the recurrence rate for such subjects is high. Patients who have not yet experienced an arrhythmic event but spontaneously exhibit the abnormal ECG findings are at intermediate risk for an episode and may benefit from prophylactic implantation of a defibrillator.^13,14,17 A recent report described long-term successful treatment of a symptomatic Brugada male using sotalol.¹⁸ Sotalol might eliminate the trigger that initiates the Brugada arrhythmic event. The IKr blockade of the drug lengthens the action potential duration in the ventricle and could prevent the closely coupled PVCs which can trigger the catastrophic ventricular arrhythmias in these patients.

Dr. Glatter's work was funded in part by a grant from the American Heart Association Beginning-Grant-in-Aid, Western States Affiliates. There are no conflicts or financial relationship to disclose.