About Brugada syndrome and its prevalence

This editorial refers to ‘Low disease prevalence and inappropriate implantable cardioverter defibrillator shock rate in Brugada syndrome: a nationwide study’ by A.G. Holst et al., on page 1025 Brugada syndrome is an entity associated with premature sudden cardiac death, familial aggregation, and specific electrocardiographic abnormalities in the right precordial leads known as the coved-type or type 1 Brugada syndrome electrocardiogram (ECG). Importantly, the type 1 ECG requires at least a 2 mm elevation of the J point with a coved aspect followed by a negative T wave in two or more right precordial leads (V1, V2, or V3; often also V1 and V2 in the third intercostal space are included).1 This ECG pattern is not specific for Brugada syndrome alone but can also occur in other conditions such as myocardial infarction, severe electrolyte disturbances, or mediastinal tumours.1 Therefore, the diagnosis of Brugada syndrome requires at least one other criterion suggestive of arrhythmias or familial occurrence, namely documented ventricular tachycardia or fibrillation (VT/VF), a family history of sudden cardiac death <45 years of age, coved-type ECGs in family members, inducibility of VT/VF during electrophysiological study, unexplained syncope, or nocturnal agonal respiration. Hence, there is a difference between the Brugada ECG pattern and Brugada syndrome. Since its first description as a separate entity in the early 1990s, there have been many patients around the world who appeared to have this peculiar type 1 Brugada ECG pattern. In the last decade it also became clear that most of these patients had in fact a silent phenotype, they did not have and did not develop symptoms. Moreover, their type 1 ECG could only be uncovered through provocation with potent sodium channel blockers such as ajmaline, flecainide, or pilsicainide. However, because of early reports on Brugada syndrome, which described young patients who often experienced episodes of VF, it has been assumed that this is a highly lethal disease. It is only now that we can recognize that the yearly incidence of arrhythmic events is somewhere between 0.5 and 4% for the vast majority of patients (>90%), that is, the patients who present without a history of aborted sudden cardiac death (Table 1). The yearly event rate for patients who are asymptomatic (>60%) can be estimated at 0.4–1% (Table 1). Still, we do not know whether an annual event rate of 1% will accumulate to 20% after 20 years of follow-up.6 But it should also be noted that the incidence of events, i.e. mainly appropriate shocks, often doubles or trebles the incidence of sudden cardiac death in the control groups of the large implantable cardioverter defibrillator (ICD) trials.7 Prognosis of Brugada syndrome patients in the largest studies aEither appropriate ICD shock or (aborted) sudden cardiac death. bThis subgroup had longer follow-up than average. SCA, sudden cardiac arrest; ICD, implantable cardioverter defibrillator. Prognosis of Brugada syndrome patients in the largest studies aEither appropriate ICD shock or (aborted) sudden cardiac death. bThis subgroup had longer follow-up than average. SCA, sudden cardiac arrest; ICD, implantable cardioverter defibrillator. Risk factors for events include mainly symptoms (aborted cardiac arrest, syncope) and the occurrence of the type 1 ECG in the absence of provocative drugs. QRS fragmentation in the right precordial leads may also be a valuable risk factor.5 Fortunately, most patients with Brugada syndrome appear to be at low risk and can be treated conservatively. This conservative treatment includes outpatient follow-up, avoidance of drugs that may induce the type 1 ECG or arrhythmias (see www.BrugadaDrugs.org),8 and caution in the presence of fever. The latter is due to the fact that some patients may have a fever-sensitive form of the syndrome which may result in malignant arrhythmias during fever and which seems to relate to (specific) sodium channel mutations.9 Avoidance of certain drugs may not always be an easy issue, especially when patients grow older and develop co-morbidities. In patients at high risk, this issue is even more complex. Currently, there are two large debates in Brugada syndrome. The first is its underlying pathophysiology, which relies on either the depolarization hypothesis or the repolarization hypothesis.10 The second large debate relates to the value of electrophysiological testing to risk-stratify asymptomatic patients.11,12 We know that the first symptom may be VF which too often results in sudden cardiac death. This has been referred to as ‘one strike and you are out’.6 To solve this issue some centres have used inducibility of VT/VF to stratify these asymptomatic patients between high and low risk. The most recent evidence in this debate comes from the Italian PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) study.5 In this large prospective study, inducibility of arrhythmias had no additive value in asymptomatic patients—an important message to the community. What is the probability that one will encounter patients with Brugada syndrome? It is believed that Brugada syndrome is more prevalent in South-East Asia, where it may also in part underlie sudden unexpected nocturnal death syndrome (SUNDS). Until now, data on the prevalence of Brugada syndrome, actually the Brugada ECG pattern, have mainly come from retrospective studies, which were either population studies or studies in cohorts of patients admitted to hospital for various reasons. There are four important limitations of these studies, including: (i) the variable nature of the Brugada syndrome ECG, as it may be present on one day and may be hidden the day after, (ii) the abundance of provocation tests to uncover the type 1 ECG, (iii) the inability to identify the presence of other Brugada syndrome criteria in order to establish whether these patients only have a Brugada ECG pattern or Brugada syndrome, and (iv) large variations in methodology. Nevertheless, from these studies encompassing >400 000 patients, the world-wide prevalence of a Brugada ECG pattern can be estimated at ∼0.05% or 1 in 2000 patients (Figure 1). Whether this can be translated into a prevalence of Brugada syndrome of 1 in 2000 is unclear because of the above-mentioned limitations. Some experts believe that long QT syndrome is more prevalent than Brugada syndrome, and the prevalence of long QT syndrome is already estimated to be close to 1 in 2000. Hence, it might be that the true prevalence of Brugada syndrome may be somewhere between 1 in 2000 and 1 in 5000. Combined prevalence data of the Brugada electrocardiogram pattern in different parts of the world. Bars represent mean prevalence in percentages. Prevalence studies in adolescents or children were discarded for this figure. As the type 1 electrocardiogram was only recognized after the first consensus report, electrocardiograms from two earlier studies were acknowledged as type 1 only. A coved-type electrocardiogram was acknowledged as type 1, a saddleback or suspicious electrocardiogram as types 2–3. It should be recognized that the Brugada electrocardiogram pattern does not equal the Brugada syndrome. Data references can be found online as supplementary material. In the study by Holst et al.13, conducted in several centres in Denmark, a different approach was undertaken to estimate the national prevalence of Brugada syndrome. The authors did their best to identify individuals who are currently diagnosed with Brugada syndrome to calculate its prevalence in Denmark. For this purpose, they used a three-step approach: (i) all tertiary referral centres participated in the study, (ii) an inquiry was sent to all cardiology departments in Denmark, and (iii) two national patient registries were studied. By this, the authors identified only 43 Brugada syndrome patients. To calculate the prevalence of Brugada syndrome in Denmark they simply divided this number by the total number of people in Denmark in the corresponding age group (21–82 years, n= 4 065 152) which resulted in a prevalence of 1.1 per 100 000 persons, or 0.022 per 2000 persons—a stunningly 50 times lower than 1 in 2000. They also reviewed the clinical data of these patients. It appeared to be a highly symptomatic group: 10 (23%) with a history of aborted cardiac arrest and 10 (23%) with a history of syncope. This was reflected by the fact that 9 (26%) ICD recipients (35 of the 43 patients, 81%) experienced appropriate shocks during a median follow-up of 47 months. The overall ICD complication rate was still appreciable (8% received inappropriate shocks, 14% lead replacement, and other complications were not recorded in the database), but at least the appropriate shock rate was not doubled or trebled. This study adds two important points to the quest into the true prevalence of Brugada syndrome. First, the prevalence in Denmark seems to be lower than 1 in 2000. This could establish (or mirror) a lower awareness of physicians about Brugada syndrome in Denmark. Whether this study reflects a low prevalence of Brugada syndrome in Northern Europe is also uncertain, but it is supported by earlier studies from Denmark, Finland, and Germany.14–16 Second, this study is unique in its setup, but by that virtue it also differs considerably from previous studies. To my knowledge, no other group has aimed to establish the total number of patients with a diagnosis of Brugada syndrome in their country in order to calculate its national prevalence. A highly symptomatic group with a high incidence of appropriate shocks is interesting and raises a question whether this is a truly unbiased representation. As the majority of other studies in patients with Brugada syndrome reported very different numbers of symptomatic patients and appropriate shocks (Table 1), it is possible that in this study, a considerable group of asymptomatic low-risk patients may have been missed due to a lack of thorough diagnostic evaluation,17 a lack of cascade screening,18 or an already low awareness.19 Furthermore, the authors did not report on the response rate of centres that have been contacted. In this respect, one should realize that because of the inheritable nature of Brugada syndrome, asymptomatic patients may have highly symptomatic children.9 Still, although (many) patients might not have been diagnosed, the prevalence in Denmark will probably remain lower than 1 in 2000 indeed. Holst et al. proposed that Brugada syndrome has a lower prevalence in Denmark than the generally estimated prevalence of 1 in 2000, although probably a considerable number of (low-risk) patients have not been recognized. Nevertheless, this could indeed reflect a lower prevalence of Brugada syndrome in (Northern) Europe. Supplementary material is available at Europace online.