Brugada Phobia at the Sudden Cardiac Death conference

This post is also available in: Italiano (Italian)

Yesterday 04/03/2020, an important conference on “Sudden Cardiac Death” was held at the “Sapienza” University of Rome, Italy:

At the conference, I spoke about Brugada Syndrome, and in particular BrugadaPhobia:

Here are the details.

The talk begins with a brief presentation and a summary of the reasons that led me to deal with Brugada and in particular the psychological and social aspects of its diagnosis:

But in order to talk about BrugadaPhobia, it is necessary to talk, albeit briefly and certainly not exhaustively, about Brugada Syndrome, highlighting some historical, epidemiological, diagnostic and prognostic aspects.

As often happens, especially with Italians, discoveries are not attributed to those who made them!

Between 1996 and 2000, a number of important publications provided evidence that laid the foundations for a greater understanding of the condition and for the definition of diagnostic criteria: It is understood that the typical electrocardiographic appearance can be variable over time until complete normalization of the ecg and that these variations, can be modulated by the autonomic nervous system and by the intake of certain drugs such as some antiarrhythmics. The phases of vagal prevalence, during periods of rest, after meals or during the night, accentuate the electrocardiographic abnormality. A first genetic mutation possibly associated with the disease has also been identified in the SCN5A gene on chromosome 3, which codes for cardiac sodium channels. However, even today there are still contrasting opinions and the patho-physiological mechanisms underlying the disease are not yet well understood, although it is becoming increasingly clear that the problem is not exclusively functional, as has always been assumed (apart from Nava’s first description), since more and more evidence from the clinic confirms a possible structural origin of the disorder. Finally, in 2000, a study by the Brugada brothers described the usefulness of using antiarrhythmic drugs that block sodium channels (such as flecainide or ajmaline) to highlight the characteristic type 1 pattern in subjects in whom this pattern does not appear on the basic ecg, with high diagnostic specificity!

In 2002, an initial expert consensus report established electrocardiographic features and diagnostic criteria:

Regarding arrhythmic risk stratification in asymptomatic patients with ‘Brugada-type’ ecg:

The first studies, published between 1998 and 2002, showed a significant arrhythmic risk (about 30% at 3 years), even among asymptomatic patients with a typical electrocardiographic pattern (type 1). Consequently, the term “Brugada syndrome” was used extensively also in this category of patients, but above all this led to a significant, excessive number of defibrillator implants in primary prevention. In jargon we speak of J-ICD REFLEX, i.e. the automatic implantation of a defibrillator at the mere sight on the ecg of a J-wave assimilated to a Brugada ECG pattern!

Fortunately:

These risk levels are probably overestimated, since most studies assess not only the actual cardiac arrest, but also the appropriate defibrillator shock. But this event evidently represents a surrogate for cardiac arrest, since the defibrillator often intervenes to interrupt (self-limiting) arrhythmias, i.e. arrhythmias that would end spontaneously in the absence of a shock.

This can be seen in the following graph:

The line in green refers only to the asymptomatic population and shows the risk percentages on an annual basis (in black), and over an average follow-up period of 3 years (percentage in green), while the numerosity of this population in the different registers is represented by the bar in “pink”.

It is evident how the reported risk percentages assume important values in the first registers (before 2003), which justified an extensive and indiscriminate use of the term “Brugada syndrome”, and then we see that progressively over time, with the increase in the number of enrolments, then we see that progressively over time, as the number of enrolments increases, that is, as the number of patients recognised as suffering from Brugada increases, the percentages of events have reduced and, if we focus on the present day, we note that the percentage of annual events in the asymptomatic population stands at 0.2-0.4% (1% on an average follow up of 3 years).

The important difference in risk estimates between the first registers and today is due to the fact that, since at that time the syndrome was only recently described, the number of cases was small and families of patients at particularly high risk were selected (at that time the Brugadas received patients from all over the world, certainly with more severe forms). This phenomenon is very common in medicine and is called “the founders’ effect”: when a new pathology is discovered, cases of patients with more severe expressions of the disease are always collected first, the same thing that happened, for example, with hypertrophic cardiomyopathy.
Today, asymptomatic patients are the predominant population in current caseloads, whose annual frequency of events has reduced, and is steadily reducing over time. Therefore, the majority of those diagnosed today represent a population at very low arrhythmic risk.

In this respect, this cumulative study produced from the analysis of seven large prospective studies is very interesting:

In this study, from the group of Delise et.al., we selected all those studies that allowed us to evaluate separately the prognosis of symptomatic subjects who had
not had an ICD implanted (+ 1550 pts). We found that these patients had an annual incidence of major events (essentially sudden death) of 0.5% – of which 0.9% had a spontaneous type 1 pattern and 0.08% had a drug-induced type 1 pattern (i.e. with a clearly low risk). The study is important because it assesses only cases of actual cardiac arrest, eliminating from the evaluation the appropriate ICD shock which, as mentioned earlier, is a surrogate for cardiac arrest. Moreover, another interesting aspect of the study is the fact that, by eliminating the first registers that collected the cases of the most serious patients, and therefore with obvious selection bias, the event rates were further reduced: 0.38% for spontaneous type 1, and o.06% for pharmacologically induced type 1.

In the light of the above, what are the problems of Brugada?

The first problem is that there are evidently many subjects with Brugada ECG, but few disease-related events (arrhythmic events).

According to the current international guidelines, produced by the European Society of Cardiology, today the presence of a type 1 electrocardiographic appearance (whether spontaneous or drug-induced) is sufficient to allow the diagnosis to be made. This recommendation is of class I, i.e. almost unanimously shared by the experts who drafted the guidelines, but the evidence class is C, i.e. the lowest, which means that there is still no robust evidence to support this recommendation.

The recent SABRUS study, a survey involving 23 centres throughout the world, including 4 centres in Asia, where the disease seems to have a greater diffusion, analysing all the data collected from these centres, documented “”only”” 678 cases of asymptomatic patients who then had a first arrhythmic event. Of course, this figure is not representative of all the cases that have occurred in the world, but it gives an idea of how low the probability of having an event is for asymptomatic patients.

Another major problem is that, in the absence of a gold standard for diagnosis, current diagnostic and prognostic tests, taken individually, have poor specificity:

The drug test is not of proven specificity

In an interesting editorial with the provocative title: ‘Does everyone have Brugada syndrome until proven otherwise?’, published in the prestigious journal ‘Heart Rhythm’, Prof. Sami Viskin, a recognised international expert on the syndrome, points out that the specificity of the drug test is not clear at present, and that this entails the risk of having ‘false positives’, especially if the pre-test probabilities are lower than the pre-test probabilities. Sami Viskin, a recognised international expert on the syndrome, highlights how the specificity of the pharmacological test is not clear at present, and how this entails the risk of having ‘false positives’, especially if the pre-test probability of having the syndrome is low (such as, for example, the occasional finding of an ecg with an undiagnostic morphology, in the absence of any other possible factor indicating suspicion). Based on this, Sami Viskin writes in his editorial: “… It is time to stop and think, before testing with sodium channel blocking drugs, before the specificity of the test is clearly defined by large controlled studies.”

In light of this, a recent international expert consensus conference in Shanghai proposed revising the guidelines for diagnosing Brugada by considering the value of drug testing as probabilistic rather than binary (diagnostic/non-diagnostic): “Patients presenting with an induced type 1 pattern are at particularly low arrhythmic risk. These patients should be informed about the possible psychological consequences of a positive drug test, which is then (rightly) not followed by any therapy.

In this conference, a scoring scheme for the diagnosis of Brugada syndrome is also proposed, where different factors are assigned a score, and to have a diagnosis of Brugada syndrome, a score >= to 3.5 must be achieved. In this scheme, a type 2 or 3 that changes to type 1 after drug testing is assigned a value = 2, which is therefore not sufficient on its own to establish a diagnosis.

The PES is not specific

In addition to what is described in the slide, a recent pooled analysis shows that an electrophysiological study carried out with less aggressive protocols is more specific in identifying patients at increased risk, but it is clear that this test is of particular value when carried out in patients with multiple risk factors (spontaneous ECG, family history, undetermined syncope).

Genetics is not specific

Genetics is not currently used to make a diagnosis, but it can be used for family screening, in the case of a clinical diagnosis of Brugada and the finding of the genetic mutation in the proband. For patients: It is important to understand that having a genetic mutation does not mean having Brugada Syndrome! In a recent congress held in Rome: “PLACE 2019”, Prof. Priori stated in a speech that the knowledge of the molecular basis of Brugada syndrome is limited, so the current role of genetics is low.

Electrocardiographic variability

In the slide, there are some ECG tracings from the case history of Dr. Andrea Ghidini Ottonelli, who kindly provided me and for which I publicly thank him. As can be seen, the ECGs can vary even within a few minutes, from a picture of electrocardiographic normality, to one of type 2 or 3 aspects, up to an evident type 1 ECG aspect. This essentially poses two types of problem: on the one hand, the possibility of not diagnosing the Brugada pattern, especially in subjects who need special attention (e.g. with a family history or with undetermined syncope), and on the other hand, a certain doggedness in wanting to identify a Brugada pattern at all costs, in asymptomatic subjects who present only the occasional occurrence of non-diagnostic patterns (e.g. type 2 or 3), e.g. by administering a drug test indiscriminately.

Be careful to correctly recognise a type 2 or type 3 pattern! Similar patterns are relatively common in the young, healthy population and, not to be overlooked, can be produced erroneously on the ECG by incorrect positioning of the electrodes on the V1 and V2 precordial leads, which MUST be positioned at the 4th intercostal space.

In this regard, an interesting article published in “The American Journal of Emergency Medicine” by Dr. Walsh points out that in clinical practice, the electrodes in the precordial leads V1 and V2 are often not positioned correctly. This can lead to electrocardiographic aspects that can be interpreted as a Brugada type 2 pattern and thus erroneously lead to a diagnostic suspicion.

What can happen to a patient, for example, who is shown to have a type 2 appearance on the ecg due to incorrect electrode placement? Probably a suspected Brugada followed by an Ajmaline test, which, if positive, establishes a diagnosis of ‘Brugada syndrome’!

The slide shows information from two important studies, the European multicentre study by Sacher, et. al, and the results of Pedro Brugada’s group centre over 20 years. The two studies may be representative of the current situation in Europe:

Seventy per cent of the subjects in the registers are diagnosed with Brugada on the basis of a positive drug test alone.
The most common reason for defibrillator implantation appears to be: “a positive drug test + induction of PV on electrophysiological study”.
Population with very low risk of arrhythmic events, versus a relatively high risk of developing adverse events related to defibrillator implantation

But what are the risks of having a defibrillator implanted?

Also from the studies mentioned in the previous slide, it appears that in a population characterised mainly by a low arrhythmic risk profile, the events linked to inappropriate ICD intervention is by no means negligible (16% in the P.Brugada registry, 37% in the Sacher study). Furthermore, a study based on long-term follow-up of a Brugada population with defibrillator implantation highlights the possible side effects in this category of patients, ranging from catheter rupture to the possible pro-arrhythmic effects of the defibrillator

To sum up:

But what are the problems for patients?

The slide clarifies what problems an asymptomatic person with an occasional Brugada pattern ECG may face, bearing in mind that such individuals are representative of the category of patients who commonly come to a cardiology clinic.

So let’s put everything on the scales and draw the necessary conclusions.

What is BrugadaPhobia.

Prof. Sami Viskin, in a recent conference held in the United States and later in an article published in the prestigious journal “Circulation”, defined “BrugadaPhobia” as “the terror of sudden death that afflicts asymptomatic patients diagnosed with or even suspected of having Brugada syndrome. Viskin writes in his article: ‘Based on the frequent email consultations I receive from patients with suspected Brugada syndrome, it appears that a terrifying anticipation of death afflicts these patients, and that this prevails in asymptomatic Brugada patients, compared with other arrhythmogenic disorders.

As the number of diagnoses in asymptomatic individuals increases over time, BrugadaPhobia is a problem of social importance that is unfortunately still little known and considered, but which can have deleterious consequences for patients and their families.

BrugadaPhobia finds particular nourishment in the ‘Fake News’ circulating ‘virally’ on social networks and the web:

Possible consequences:

Now, i would like to talk about an aspect that I think is particularly important: the vision that one gets from listening to the real experiences of patients and that provides a picture of reality, which does NOT emerge in scientific conferences, far from the “cold statistics” and guidelines. As we know, for better or for worse, social networks provide the real picture of a cross-section of society.

To this end, the experience of co-administering, together with other friends, a Facebook group dedicated to the ‘Brugada syndrome’ was extremely important to me.

This is what is happening on the Facebook group, whose growth trend in terms of new entries in the month of February alone is shown in the graph at the top right of the slide. It should be borne in mind that the number of new entries is on average 1-2 per day and that when asked to join the group the typical answer is “just been diagnosed with Brugada syndrome”.

This is the real representation of ‘BrugdaPhobia’!

So what can be done to counteract it?

I humbly take the liberty of giving you some advice: after so many years since its discovery, the electrocardiogram remains an important, central, and fundamental investigative tool; electrocardiographic screening is also fine, but beware, the ECG is an element of a diagnostic procedure, it can provide a “warning”, but its interpretation must always be contextualised with respect to the patient’s particular clinical and anamnesis (e.g., is there a family history that is strongly indicative or suspicious? (e.g. is there a family history that is strongly indicative or suspicious? Are there relevant symptoms?)… There is the patient as a whole! And the advisability of going ahead or not with a particular diagnostic procedure must always be assessed in relation to the benefit that this procedure can give to the patient: doing everything possible does not always mean doing the best!

In this regard, it is important to specify well to a certain category of patients, at particularly low arrhythmic risk, that a possible diagnosis, perhaps of Brugada pattern and not necessarily of Brugada syndrome (for patients, the use of terms is very important), may have its importance not because it puts them at particular risk of sudden death, but because it gives them the possibility of being included in a regular clinical follow-up pathway, and allows them to follow certain indications such as avoiding certain drugs, and treating fever effectively, as a precautionary measure and without unnecessary anxiety.

Countering fake news on the web, through targeted information campaigns (such as this one), promoted by the academic scientific world, associations and specialist centres.

On the part of the doctors, avoid ‘defensive medicine’ and even a certain possible diagnostic overkill, for fear (justified) of underestimating the problem, also as a result of the fragility of the current scientific data. From the medico-legal point of view, it should be remembered that if the doctor follows the international guidelines (which, for example, currently adopt fairly restrictive criteria on the indication of the ICD) he cannot be prosecuted by law if he has used skill, diligence and prudence.

In addition:

In conclusion:

Thank you all, and allow me before closing a further slide, as a small tribute and in memory of Prof. Andrea Nava, who passed away exactly two years ago, in March 2018, and who gave an enormous contribution and impetus to research into sudden cardiac death, and in particular the arrhythmic cardiac pathologies that underlie it!

In the photo, on the right Prof. Andrea Nava, on the left Dr. Bortolo Martini, a very close collaborator who, together with Nava, described the first case of the syndrome, that of the patient you see in the centre: a cook who, at the age of 42, in 1984, suffered a cardiac arrest while talking to the postman in the hills of Conegliano. Luckily for him, he was promptly defibrillated by the rescue services, and is still alive today without ever having had a recurrence…. This shows how difficult it is to predict arrhythmic risk, even in those who have already had a previous event!