Supporting Families. Saving Lives.
With Dr. Josep Brugada
Interviewer: Jorge González, MD; Interviewee: Josep Brugada, MD, PhD
DISCLOSURES
April 26, 2018
Editor's note: This is an edited translation of an interview posted on Medscape en Español.
Jorge González, MD: I'm Jorge González, and I am here with Dr Josep Brugada.
It is a real pleasure to discuss the past 25 years of the Brugada syndrome. I would love to know how all of this began.
Josep Brugada, MD, PhD: Like so many things in medicine, it began serendipitously. In four patients with sudden death, we observed ECGs that were different from what we were used to—and inexplicable based on the knowledge we had at that time. That led us to investigate more.
We ended up identifying eight patients and published our initial findings in the Journal of the American College of Cardiology in 1992.[1] This sparked worldwide excitement around the Brugada syndrome, with physicians identifying patients and wanting to contribute new information about the syndrome.
González: Did you ever imagine that describing these eight initial patients—with atypical ECGs, sudden death, and structurally healthy hearts—would open the door to a totally different world of cellular, pathogenetic mechanisms?
Brugada: The truth is, no. We thought that these were interesting cases that had to be reported, but we never thought that this would open a door to new knowledge not only about the Brugada syndrome, but for a whole group of diseases of genetically determined ion channelopathies.
A whole new world opened up in sudden death. It helped us explain some patients whom we previously thought of as having idiopathic ventricular defibrillation (basically admitting that we had no idea why they had died). With every new case we were advancing in knowledge. New diseases appeared—the short QT syndrome, catecholaminergic disease, etc—all of that forming what we know today as diseases of ion channelopathies.[2]
González: What do we understand about pathogenesis today that we didn't when you identified the original eight patients?
Brugada: We have learned that genetic mechanisms play an important part in some of these patients—not all, because we know that a proportion do not have any identifiable mutations. The mutation affects the cardiac sodium channel, causing an ionic imbalance in parts of the heart, mainly in the epicardium of the right ventricle. This in turn causes an electrical gradient that is responsible for the electrocardiographic and arrhythmic manifestations in these patients. That has been established for a few years. We have also learned more about what triggers these arrhythmias. Fever, for example, is an important factor.
We have learned that although women and men are equally affected,[3]women are less likely to develop symptoms than men. That distinction is probably related to the distribution of ion channels in the heart. We have gained an understanding of how the arrhythmia occurs, how to identify the patient who is at risk for sudden death, and how to treat it.
González: Brugada type 1 patterns may appear in people with no symptoms. How should we address that?
Brugada: Well, this is a very interesting topic; it is the most complex issue we have. If a person has a family history of sudden death or cardiogenic syncope, and has a Brugada ECG pattern, we must take steps to protect him, because he is at high risk for sudden cardiac death.
The great conflict is in the asymptomatic patient who does not have a family history of sudden death or Brugada syndrome, but instead has a suspicious-looking ECG or sometimes even a diagnosis of Brugada syndrome. In these patients, the first thing to do is eliminate what we call Brugada phenocopies, which are ECG patterns that look like Brugada but are not. There is a list of pathologies that can simulate Brugada syndrome.
The second step is to confirm that it is true Brugada syndrome, using a provocation test with drugs such as ajmaline,[4] flecainide,[5] or procainamide. Once that is confirmed, we stratify the risk. There is debate globally about the use of programmed electrical stimulation, but for us there is no discussion: We have always used it and consider it the most important diagnostic tool to identify patients at risk. If a patient is not inducible, that's a relief; if a patient is inducible, we recommend implanting a defibrillator.
González: For those individuals who are given an ICD based on risk stratification and continue to have ventricular arrhythmias, what is going on?
Brugada: In patients with Brugada syndrome, we know that arrhythmias vary over time. Individuals can go from having four to six episodes a week to having no episodes for 1-2 years. Therefore, when they have these arrhythmic storms, we have to try to control them. We do so using drugs—basically quinidine, which works relatively well in this context. It significantly reduces the number of crashes patients have, but it does not eliminate them completely. We should not consider quinidine the only treatment. An episode of ventricular fibrillation can be fatal and patients must be protected.
In recent years, radiofrequency ablation of the epicardium of the right ventricle has looked compelling. The ionic imbalance characteristic of Brugada syndrome occurs between the epicardium and the endocardium. It has been shown that eliminating a thin layer of epicardium in these patients using an ablation technique can restore the ionic balance between the different parts of the heart. This in turn normalizes the ECG and results in a negative provocation test. The patient becomes noninducible.
These are the criteria we use to assess risk: (1) ECG; (2) provocation test; and (3) arrhythmia induction test. If we normalize these three parameters, we have little syndrome, from the clinical point of view. Genetically, the disease is still there, but we have normalized the expression of this syndrome.
In the future, ablation may be considered the main treatment to prevent the clinical consequences of the syndrome. We are still far from that. We need more long-term follow-up. We have a group of ablation patients (with Dr Pappone in Milan) who are showing extraordinary progress with normalization of all of the clinical characteristics of Brugada.
González: Finally, where will we find ourselves with Brugada syndrome in 25 years' time?
Brugada: I heard a presentation by Dr Ispizúa that left me absolutely fascinated, about the possibility of modifying the DNA. Surely, in 25 years we will be able to identify the problem in the gene and repair it by cutting and pasting a new gene.
Dr Ispizúa said that in 10 years we would have the capacity to repair genes very effectively without complications such as downstream effects in the rest of human DNA. I believe that this will happen.
As for what will happen until then, I believe that we will continue to advance in the use of ablation for the management of Brugada syndrome and patients with severe ventricular arrhythmias. Perhaps in the future, ablation will negate the need for a defibrillator in those patients at intermediate risk.
González: I hope that in the next 20 years we will have a cure for Brugada syndrome. Meanwhile, I thank you very much for your time.
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