Author + information
- †Cardiovascular Genetics Center, IDIBGI- University of Girona, Girona, Spain
- ‡Medical Sciences Department, School of Medicine, University of Girona, Girona, Spain
- §Familial Cardiomyopathies Unit, Hospital Josep Trueta, Girona, Girona, Spain
- ↵∗Reprint requests and correspondence:
Dr. Ramon Brugada, Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona, Pic de Peguera 15, 17003 Girona, Spain.
In 1992, when Pedro and Josep Brugada published their seminal work on a new association of sudden cardiac death (SCD) with an electrocardiographic (ECG) pattern of right bundle branch block and persistent ST-segment elevation in leads V1 through V3, they presented a cohort of 8 patients (1). In 1997, Nademanee et al. (2) proved that this ECG pattern was also responsible for sudden unexplained death syndrome in South East Asia, a syndrome that has curtailed the lives of young individuals for generations in that area. Thus, what was depicted as a scientific curiosity in 1992 is now known as Brugada syndrome (BrS) and explains an important percentage of deaths previously classified as idiopathic ventricular fibrillation, sudden unexplained death syndrome, or sudden infant death syndrome (3).
In the past 2 decades, thanks to the progress in the development of powerful sequencing tools, the genetic understanding of this disease has been slowly, but steadily, advancing. Currently, ∼25% of all clinically diagnosed cases of BrS carry a pathogenic variant in the SCN5A gene, making this the most prevalent gene associated with this entity. Pathogenic variants in 17 other genes have also been associated with the disease, although all together, these represent only an additional 5% of diagnosed cases. As a consequence, nearly 70% of BrS cases remain genetically undiagnosed after comprehensive screening of all associated genes known to date (3).
In the clinical field, over the past 2 decades, several studies and consensus documents have established guidelines for diagnosis, risk stratification, and care of this lethal disease, providing data to the medical community regarding the value of ECG lead location and provocation tests in the diagnosis, the value of electrophysiological studies and noninvasive parameters in risk stratification, and the value of drugs, devices, and interventional strategies in preventing recurrence of events (3).
Among scientists and clinicians in the field, 2 controversies regarding BrS still remain: first, a pathophysiological argument on whether the disease substrate is a disorder of repolarization or of depolarization and, second, a critical clinical matter referring to how to manage the asymptomatic patient, including whether to perform an EP study for risk stratification. The paper by Nademanee et al. (4) in this issue of the Journal provides new information and updates on both issues.
The repolarization hypothesis claims that genetic variants will cause a loss of equilibrium INa and Ito in phase 1 of the cardiac action potential in favor of the transient outward potassium current. This current alteration can be better seen in the right ventricular outflow tract (RVOT) as it seems that this is the area where the equilibrium is more critical. This disequilibrium will generate a shortening of the subepicardial action potential, with elevation of the ST-segment in the right precordial leads, and cause a susceptibility to phase 2 re-entry. Evidence of this hypothesis has been shown in a canine right ventricular wedge model (5). In human BrS studies, albeit limited to a few cases, these repolarization disparities have yet to be demonstrated (6).
The depolarization hypothesis suggests that the substrate for arrhythmogenicity is a right ventricular conduction delay (5). Evidence of the depolarization hypothesis has been accumulating in the past several years. Abnormal late potentials in the free wall of the RVOT epicardium were recorded by Nagase et al. (7) in patients with BrS in 2002. In 2005, Coronel et al. (6) provided direct human evidence of conduction delay caused by interstitial fibrosis, without transmural repolarization differences, in an explanted heart from a patient with BrS (6). Similarly, a SCN5A knockout animal model has shown increased fibrosis, which becomes more severe in aging males, affecting all cardiac regions, but especially the right ventricle (8). Finally, some of the strongest evidence favoring the depolarization hypothesis became available in 2011, when Nademanee et al. (9) performed electroanatomic mapping in 9 symptomatic BrS patients. They showed abnormal low-voltage fractionated ventricular electrocardiogram in the anterior RVOT epicardium, with marked delayed conduction times. Catheter ablation at this site resulted in the disappearance of the Brugada ECG pattern and prevention of both spontaneous and induced ventricular tachycardia/ventricular fibrillation episodes, suggesting that delayed depolarization was the most likely underlying electrophysiological mechanism.
Nademanee et al. (4) bring new evidence favoring the depolarization hypothesis, with histopathological and expression pattern changes, which increases our understanding of the conduction alterations underlying the disease. They performed genetic and immunohistological analyses of 6 forensic samples from family members who were affected with BrS. They also performed the same experiments in 6 biopsy samples of patients with a diagnosis of BrS. Notwithstanding the limitations of a very limited genetic analysis, only performing a screening of SCN5A, and the inability to confirm the potentially pathogenic variant in the forensic sample, it could be assumed that the sudden death victims died of the same familial disease. Of 11 samples analyzed, they identified 3 genetic variants potentially associated with the disease (p.Ser528Cys, p.Leu846Arg, and p.Leu1462Gln) in relatives of 3 different families. Two variants are novel (p.Ser528Cys and p.Leu1462Gln), whereas p.L846R_SCN5A (p.Leu846Arg) was reported as pathogenic (CM119205) and associated with ventricular fibrillation (10). In silico analyses predicted all 3 variants to be deleterious/pathogenic, supporting their potential pathogenic role. Hence, these variants could be the most plausible cause of BrS despite the fact that neither in vitro nor in vivo analysis was performed. Most interestingly, irrespective of whether a genetic variant was detected, the immunohistological analysis showed an increase in epicardial collagen and fibrosis and a decrease in gap junction Connexin43 expression, especially in the RVOT area.
Thus, we know that BrS is an inherited disease, mainly associated with cardiac channelopathies, that typically causes SCD in the third to fourth decades of life. From the data presented, symptomatic patients, with or without an identified pathogenic genetic variant, may present with fibrosis and an altered pattern of expression of connexin-43. The murine animal model indicates that the genetic background is more than simply a bystander, and it probably plays a causative role in the histological phenotype. Putting it all together, we could assume that the histological changes are genetically related morphological defects that appear later in life and trigger malignant arrhythmias. This could be a very reasonable explanation linking genetics, age, fibrosis, and symptoms. Because histological alterations were observed in the post-mortem cases as well as in the biopsy specimens of symptomatic patients, histological and immunohistochemical analyses could become new tools for the diagnosis of BrS, as the authors claim. However, a key question comes to mind: do asymptomatic patients with a type 1 electrocardiogram present also with morphological defects? If they do, the test will be of no use for defining risk, but it will reinforce the hypothesis that the ECG alteration is caused by conduction delay. If they do not show the changes, the test could be potentially used even for risk stratification, but the ST-segment elevation will not be a sign of histological disease, and the repolarization hypothesis will regain strength. In favor of this latter argument is the fact that the electrocardiogram normalizes very quickly in a large percentage of patients, which is difficult to comprehend if the ECG pattern is caused purely by a fixed structural disease and not by continuously changing ionic current equilibriums.
The paper by Nademanee et al. (4) sheds some light on the repolarization or depolarization controversy and in addition provides new evidence of the ablation approach to symptomatic patients with BrS. RVOT ablation makes the ST-segment elevation disappear and reduces symptoms in symptomatic patients.
It is not farfetched to suggest that ablation therapy will rapidly become another controversial issue in the asymptomatic patient. Let us not forget that all symptomatic individuals have remained asymptomatic for many years until their first symptom. We are currently at the learning curve of ablation in BrS, and it is probably too soon to propose RVOT ablation for the asymptomatic patient. With more experience, it will be difficult to argue against eliminating this dreaded ECG pattern. Although normalization of the electrocardiogram by ablation can become a reassuring exercise, only time will tell whether the risk of sudden death will be completely eliminated.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Brugada is a consultant for Ferrer-Incode. Dr. Campuzano has reported that he has no relationships relevant to the contents of this paper to disclose.
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