Dealing with the problem rationally rather than emotionally
Bortolo Martini
*Cardiology Consultant, Ospedale di Santorso, (Vicenza)
Elio Catapano
IT engineer, and presumed patient, Rome
Address:
Dr Bortolo Martini
Cardiology Unit
Ospedale dell’Alto Vicentino
Via Garziere, Santorso (VI)
bortolo.martini@gmail.com
Speaking at a congress held in the USA in 2017, Professor Sami Viskin coined the term “Brugadaphobia”, a situation that is increasingly common in medicine and that does not have any scientific basis, but rather a predominant emotional component that is hyped and fuelled by the media [1].
“Brugadaphobia” might be defined as: A constant fear of imminent and sudden death that afflicts asymptomatic patients with a confirmed or even suspected diagnosis of Brugada syndrome [2].
However, although in actual fact this terrifying fear does not have any real justification, it is constantly fuelled by the media, especially the Internet, and itself leads to psychological consequences that can be serious, as well as conditioning the choices of patients, who become willing to undergo all the possible diagnostic tests and therapeutic procedures, including experimental and invasive ones and those that have consequences [2].
The misconceptions that fuel “Brugadaphobia” starts with Google, where it is sufficient to run a search for “Brugada Syndrome” to obtain information such as: “Brugada syndrome: when the heart stops suddenly”, “Brugada, a time-bomb in the chest”, “Brugada syndrome… at least 50,000 deaths a year”, “Sudden cardiac death. This is how Brugada syndrome is killing young athletes”, “Brugada syndrome… one of the major causes of sudden cardiac death in young adults”, “Brugada syndrome … the cause of sudden and devastating deaths in apparently perfectly healthy youngsters”.
Recently, in England, the news of the tragic and sudden death of a young man that went viral on Facebook urged 14,500 Brits to sign a Parliamentary petition, asking for “ALL” asymptomatic patients diagnosed with Brugada syndrome to have a defibrillator (ICD) fitted, even in the absence of clear indicators of an increased arrhythmic risk [2]. The Government, quite rightly, suggested contacting the competent physicians. In Italy, the tragic death of Fiorentina footballer Davide Astori was associated by the media with Brugada syndrome even before the completion of the medicolegal inquiry into the cause of death and in the complete absence of evidence supporting this association, as the inquiry eventually concluded. The information published in connection with this tragic event lead to considerable upset amongst patients diagnosed with Brugada syndrome and the families of young athletes, by making Brugada syndrome out to be an exterminator that suddenly and unexpectedly kills perfectly healthy youngsters.
It’s true in Italy, approximately 50,000 people die each year from sudden cardiac death. However, it is important to point out that in most cases, especially in subjects over 40 years of age>, the cause of these deaths is an underlying heart condition like coronary disease, valve disease and heart failure. In younger subjects, they are primarily caused by cardiomyopathies, some of which with a genetic origin, such as hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic cardiomyopathy. A minor percentage of these deaths is caused by “channelopathies” of genetic origin, such as long QT syndrome, Brugada syndrome, short QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Other causes can be due to the use of medicinal products and/or narcotics. On the basis of this evidence, it is easy to deduce that 50,000 sudden deaths a year certainly does not mean 50,000 sudden deaths due to Brugada syndrome. Brugada syndrome can, in rare cases, account for these deaths [3] In Denmark, where serious studies have been conducted, it would appear that this syndrome causes one heart attack a year per 100,000 people.
But what exactly is Brugada syndrome? It would all appear to start in 1992, when Pedro and Josep Brugada described “a syndrome with distinctive clinical and electrocardiographic signs: right bundle branch block, persistent ST segment elevation and sudden cardiac death”. More specifically, in their study, the Brugada brothers presented the data of 8 patients with recurrent episodes of “aborted sudden cardiac death” that could not be explained on the basis of current knowledge and in the absence of structural cardiac disorders (i.e. of organic origin). The electrocardiographic characteristics common to these patients consisted in right bundle branch block, normal QT interval and ST segment elevation in precordial leads V1-V3. In addition, in 4 patients, a family history of the disorder was suspected. The authors hypothesised that the disorder had a functional origin [4].
In actual fact, the syndrome had been discovered 4 years earlier by Professor Andrea Nava and his colleagues Bortolo Martini, Bruno Canciani, Gianfranco Buja, Luciano Daliento and Gaetano Thiene, who reported on the basis of an autoptic case that the syndrome had an organic cause, and more specifically was due to the replacement of the conduction tissue and part of the right ventricle by fibrotic tissue and adipose [5,6]. [5,6].
This is the first ECG of a forty-year-old cook who had a cardiac arrest while chatting to the postman in the hills of Conegliano. Fortunately, he was promptly defibrillated by the first responders and is still alive, without ever having experienced a recurrence. His ECG pattern, which is now known as a type 1 pattern, was very unusual and showed a tepee shaped wave in the precordial leads. Immediately afterwards Nava, Martini et al. published 4 similar cases in the America Heart Journal [6], specifying that the abnormal ECG pattern was associated with a conduction delay in the basal area of the right ventricle (infundibulum), which in all healthy people is the area where cardiac electrical activity ends and where there are very often slight delays known as terminal vectors or incomplete right bundle branch blocks. Nava noticed that the abnormalities did not regard the precordial wave alone and that they were often associated with atrioventricular conduction delays, a right-deviated QRS axis and the presence of late potentials. Two further characteristics were also frequently present: familiarity and a variation in the timing of the type 1 wave, which sometimes temporarily disappears [5, 6]. [5,6] This publication initially seemed to be a random report; however, after the publication of identical cases by the Brugada brothers, the interest in this new syndrome exploded worldwide and to date just under 5000 articles have been published, most of which do not mention the true discoverers of the syndrome, as all too often occurs. Further observations were made in the years to follow: A similar or identical electrocardiogram pattern can be obtained by moving the top electrodes into the upper spaces, or caused by administering by injection or orally medicinal products for arrhythmias, psychological disorders or other conditions, it can be observed during a fever (in 2-4% of perfectly healthy cases) [7] and in other rarer situations.
Unfortunately, there was immediately a great deal of confusion between the actual syndrome – i.e. the association of a type 1 ECG pattern and a severe arrhythmia – , which is extremely rare, and the type 1 ECG pattern alone, which is not as rare. Even international guidelines fail to make this distinction, without realising the detrimental effects that this oversight is having.
The type 1 ECG pattern is found in approximately 1 in 1000 people, which means that in Italy about 60,000 healthy individuals have this ECG pattern. If we also consider those who have a similar ECG pattern (known as types 2 and 3), perhaps recorded in the upper spaces or after taking medicines or after a fever, we can quite easily reach half a million people with a similar ECG pattern but who will never experience the dramatic event that some say or think will certainly occur. The greatest risk they run is that they will come across a doctor with limited experience who overestimates the consequences of an inaccurate diagnosis, which always results in consulting Dr Google, with disastrous consequences.
In Italy, individuals with this ECG pattern have difficulties obtaining a driving licence and either cannot practice sports or may only do so after having unnecessary invasive tests. This is completely unjustified, as no one with this ECG pattern has ever died while running. In Holland, those with a drug-induced or spontaneous type 1 ECG pattern are not in any way restricted when it comes to exercising. [8]. It goes without say that some apply for and many obtain, invalidity status.
Those with a type 1 ECG pattern or even minor forms are given a list of prohibited medicinal products. Once again, there is no clear scientific evidence to support this since, although it is true that these medicinal products may cause a type 1 ECG pattern, this does not mean that they will experience a cardiac arrest, and indeed there are no published reports of this being the case. Caution is one thing, unjustified phobia quite another.
Unfortunately, when studies began, it seemed that 30% of asymptomatic health individuals with this ECG pattern had problems [4], which led to the Brugadaphobia that recently resulted in Brits demanding a defibrillator for all those with a type 1 ECG pattern. Things have not yet got quite so out of hand in Italy; however, credit is being given to the notion (for which there is no scientific evidence) that the syndrome is the cause of all sudden deaths and that it is essential to take action. This has led to the establishment of “specialised” centres offering sophisticated tests or genetic analyses to identify subjects at risk; unfortunately, at the current time no valid test has been identified for the simple fact that the real syndrome is so rare that to date only 678 true cases have been reported worldwide (SABRUS study) [9], i.e. 0.0009% of the world’s seven billion inhabitants. The study undoubtedly does not report all the cases of the past 30 years, but it does show that the issue is almost exclusively an emotional one.
The high frequency of adverse events in the first series of Brugada cases can be explained by the fact that initially only the more severe cases with the real syndrome – type 1 electrocardiogram + cardiac arrest – were recorded.
Later authors reported a great many cases of subjects with a type 1 ECG not associated with any symptom, and it is now clear that the risk of death is well below 1% in asymptomatic subjects with a spontaneous type 1 ECG pattern, and well below 0.5% for asymptomatic subjects with an ECG pattern that is either drug-induced or measured in the precordial leads.
In the largest cohort study on Brugada syndrome (FINGER registry), the incidence of arrhythmic events in asymptomatic carriers of the Brugada (type 1) pattern is 0.5% per year [11][11], a risk level that differs very little from the risk of all-cause death in the middle-aged general population, which is approximately 0.4% per year [10]. [10]. The results of the FINGER study also showed that in asymptomatic subjects with a pharmacologically-induced type 1 diagnostic pattern, the risk at 3 years is 0.3% [10]. [10] Immediately afterwards, the PRELUDE study reported that amongst asymptomatic subjects with a type 1 ECG pattern the annual incidence of arrhythmic events is 1% [11] [11] and in the study conducted by Sacher et al. on 166 asymptomatic subjects diagnosed with Brugada syndrome who had been fitted with an ICD (implantable cardioverter defibrillator) and were monitored for a period of 77+-42 months, the annual incidence of appropriate defibrillator shocks was around 1% [12], [12]and complications were observed in 24% of implanted subjects.
In the recent pooled analysis on Brugada syndrome on 696 asymptomatic subjects with drug-induced type 1 ECG patterns, the annual arrhythmic risk was 0.25%. It is interesting to note that, in these patients, the risk was seen to be low regardless of whether ventricular fibrillation was induced during the electrophysiology study [13]. [13]
It is important to point out that even asymptomatic subjects with a type 1 Brugada pattern that is only seen on the ECG following a challenge using sodium channel blockers (e.g. Flecainide, Ajmaline, Procainamide) have an extremely low arrhythmic risk and also that the group led by Pedro Brugada has published new data in its registry with 20 years’ follow-up (1992-2013): the arrhythmic risk in asymptomatic patients with a drug-induced type 1 ECG pattern was seen to be 0.4% per year [14]. [14]. It should be taken into account that this registry includes patients followed since 1992, at a time in which patients with more “malignant” forms of the syndrome were diagnosed. The patients diagnosed with Brugada syndrome over the past 10 years, on the other hand, have been seen to have more “benign” forms. It is therefore likely that 0.4% is an overestimation of the problem.
However, it is essential to point out that all the available studies, including those cited, are based on registries constituted by patients with and without ICDs and, when evaluating occurrence in the time of the cardiac arrest, appropriate ICD shock was considered equivalent to an actual cardiac arrest. However, ICDs can intervene in an appropriate manner to interrupt potentially non-fatal arrhythmias or ones that would in any case cease spontaneously even if untreated. Appropriate ICD shock therefore merely represents a “surrogate” for cardiac arrest. It is therefore realistic to consider that the actual risk of cardiac arrest in asymptomatic patients diagnosed with Brugada syndrome is extremely rare, whereas the complications for implanted asymptomatic subjects are frequent [12].[12]
Lastly, a recent cumulative analysis of 7 large published caseloads focused on the study of over 1550 patients without an ICD. The majority of the patients studied had a low risk (85% were asymptomatic and 50% had a pharmacologically-induced type 1 pattern). This type of population provides a good representation of those whom, following a cardiology consultation, are diagnosed with or suspected of having Brugada syndrome. In these subjects, the annual incidence of sudden death was found to be 0.38% amongst those with a spontaneous type 1 ECG pattern and 0.06% amongst those who only had a type 1 pattern after a pharmacological challenge! [15].[15]
Conclusions
The scientific evidence available provides us with a very different picture than the information typically found in the media and on the Internet, which subsequent gives rise to ideas, viral culture and collective fear! Nava-Martini-Thiene (or Brugada) syndrome EXISTS and presents primarily with ventricular tachycardia that often ceases spontaneously, in some cases causing a syncope (fainting), or, more rarely, leads to cardiac arrest. In some of these rare cases, cardiac arrest can represent the first clinical sign of the syndrome. This clinical condition was defined approximately thirty years ago as an association between cardiac arrest and a particular ECG pattern. However, over the past 30 years it has been extensively demonstrated that the syndrome (in the sense of overt signs and symptoms) is a very rare condition, whereas the characteristic electrocardiogram pattern is a relatively common finding in the population! It has also been established that this ECG pattern can have a nonspecific significance and can even be observed in conditions other than Brugada syndrome, some of which are completely physiological. This is particularly true when the typical ECG pattern is only observed after a pharmacological challenge [16]. [16] Despite this, over the years, a significant percentage of patients with a low arrhythmic risk has been provided with an implanted cardioverter defibrillator (ICD) as a primary prevention measure, in disaccord with the scientific evidence and guidelines. According to a number of studies, 1 in 5 patients with type 1 Brugada patterns who are asymptomatic for cardiac arrest have been fitted with an ICD as a primary prevention measure [17]. [17] the situation is quite different for long QT syndrome, which has a similar incidence and similar risk. This is because long QT syndrome was discovered 20 years before the advent of the defibrillator and doctors therefore had the time to understand it better, without getting carried away and immediately prescribing an invasive treatment with consequences that are often severe, including from a psychological standpoint: 25% of patients end up either in the psychologist’s or the psychiatrist’s office.
Today, the main reason for implanting a defibrillator (ICD) would appear to be a “positive result on Ajmaline challenge test with inducible ventricular fibrillation on the electrophysiology test”, although at the current time, neither the specificity of the pharmacological test nor the positive predictive value of the electrophysiological test have been clearly established [1, 16]. [1,16] The industry is extremely sensitive to these phenomena and a recent analysis published on the Internet forecast a 6.5% increase in global sales. [18].[18]
The consequence of “Brugadaphobia” is a collective evil that encourages those involved to assume an extremely protective attitude for themselves or their families, which translates into the inclination to do everything possible the protect themselves from a terrifying but unrealistic threat, without considering that “doing everything possible” does not necessarily mean “doing best” [2]. They therefore willing, at whatever cost, to undergo all possible diagnostic investigations and therapeutic procedures, without considering that in some cases certain diagnostic tests could give positive results even when the syndrome is not present, consequently labelling as “sick” people who are completely healthy and therefore advising them to undergo invasive therapeutic procedures, that are not without consequences, some of which serious.
Unfortunately, at the current time, no doctor is able to establish a risk stratification not only for subjects who actually have the syndrome (as in the first case described, who never had a recurrence), but also, and especially, for asymptomatic subjects. Given this lack of knowledge and the impossibility to foresee the future, both science and ethics advise against fuelling Brugadaphobia and rather to adopt a serious attitude of reassurance and rational discussion on the course of a long life ahead. It is time to stop for a minute, take a deep breath, and reflect!!! [19,20]
Bibliography
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