Patients with an electrocardiogram typical of Brugada syndrome present in a large variety of ways. Analyzing the different clinical presentations one may speak of a spectrum of clinical presentation (illustration).

At one side of this spectrum we have the normal individual and close to him the asymptomatic individual in whom a "Brugada" electrocardiogram (ECG) is discovered after a challenge with an antiarrhythmic drug because he is member of a family where someone has been found to suffer from Brugada syndrome. At the other extreme of the spectrum we have the full-blown patient with Brugada syndrome: usually a middle-aged man recovered from sudden cardiac death caused by ventricular fibrillation, who spontaneously manifests the characteristic ECG. In-between these two extremes we have other manifestations of the disease: The asymptomatic individual (sporadic or familial case) with a spontaneously abnormal ECG, and the patient with syncopal episodes of unknown etiology who manifests the typical ECG spontaneously or after drugs.

Recent data that were presented by our group during the Annual Scientific Session of the European Society of Cardiology in Amsterdam suggest that the spectrum of clinical presentation corresponds to a spectrum of prognosis, particularly when data from programmed ventricular stimulation are considered in some subgroups. Starting with the normal individual with a normal life-expectancy, prognosis becomes worse and worse when going from left to right in the illustration. The asymptomatic individual with an abnormal ECG exposed only after drug challenge has a good prognosis if non-inducible and if not exposed by accident to potentially harmful drugs. The asymptomatic individual with a spontaneously abnormal ECG will most likely develop symptoms during follow-up, particularly if inducible during programmed ventricular stimulation. Patients with syncopal episodes and an abnormal ECG (before or after drug challenge) have a high risk of sudden arrhythmic death. Finally, the individual resuscitated from ventricular fibrillation and a Brugada ECG has practically the certainty of sudden arrhythmic death if not protected by an implantable cardioverter-defibrillator.

Can these spectra of clinical presentation and prognosis relate to a pathophysiologic basis? The disease is caused by mutations affecting channel physiology, and particularly the sodium channel. It may very well be that the clinical manifestations and prognosis relate to the degree of damage to the sodium current (or other currents) as suggested in the bottom of the illustration. Accepting an autosomal dominant mode of inheritance of the disease, the normal individual has no affectation at all of the sodium current. However, we may obtain a "Brugada" ECG in a normal individual if we decrease sodium channel function by toxic means: Suicide attempts with flecainide, extreme hypotermia, compression of the right ventricular wall. At the other site of the spectrum, the full blown syndrome occurs because of a 50% spontaneous affectation of sodium channels. Many of these individuals may develop intrauterine death (early abortions). Those who survive have the typical ECG and may develop sudden infant death around 6 months of age when Ito (transient outward potassium current) becomes prominent in humans. Those with less affectation survive to adulthood and develop the ventricular arrhythmias around 40 years of age, the fascinating age where many other genetically determined diseases manifest their phenotypes for the first time. Less affectation of the sodium channels may lead to the group of patients who develop repeated episodes of syncope because of self-limited ventricular arrhythmias. Asymptomatic individuals with a spontaneously abnormal ECG and inducible may constitute a lucky group with less affectation of the sodium channels, but with still an important risk of developing the spontaneous arrhythmias. The same holds for those individuals who are asymptomatic and in whom the "Brugada" ECG is only uncovered by drugs. The degree of damage to the sodium channel is so low, that they will never manifest the ECG spontaneously and will not develop ventricular arrhythmias unless exposed to potentially harmful circumstances (drugs, fever).

Proving this hypothesis is not for tomorrow, but it may constitute a natural common point of research for clinicians, electrophysiologists, cellular biologists and physiologists, geneticians and the "mutations hunters" that I alluded in my previous editorial. There is certainly quite a lot of exciting work still to be done!

Prof. Dr. Pedro Brugada. Aalst, Belgium. September 2000
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