An inherited cardiac syndrome, Brugada syndrome is a condition that predisposes individuals to ventricular arrhythmias and sudden cardiac death. This was originally thought to be associated with the SCN5A gene, encoding for the cardiac sodium channel, but mutations in 18 additional genes have since been implicated in the pathogenesis of Brugada syndrome, as of 2020, and more than 80 mutations within the SCN5A gene itself have been linked to Brugada (Christien et al., 2020; Krahn et al., 2022)
This rare cardiac syndrome (BrS) was first described in 1992, named after the two individuals who identified it, and thought to be responsible for 12% of sudden cardiac deaths, but more recently studies have found the prevalence to be much lower, closer to 0.05% (Christien et al., 2020). Southeast Asians are at an increased risk of BrS as compared to other ethnicities, with only 0.1% showing BrS-type ECG patterns. In Denmark, there is an exceedingly low prevalence of about 0.001% but then the Chinese seem to demonstrate 3.3% prevalence, with that being almost exclusively type 2 pattern, which we will discuss further below. There is a strong male correlation, affecting men four times more frequently than women, and also younger adults are affected more so than infants or children. Interestingly though, Asians seem to have less genetic contribution than Caucasians.
Multiple pathogenic variants of genes have been shown to alter the normal function of sodium, potassium, calcium, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which mediate the ionic currents responsible for the cardiac action potentials. The most common mutation is loss-of-function mutations in the SCN5A, the gene responsible for sodium channel associated with the type 1 ECG pattern described further below. This leads to reduced expression or function of the sodium channels so that conduction and repolarization in the heart is impacted and identifiable by ECG. There are other genes involved as well, such as GPD1L and CACNA1C, the latter impacting calcium channels.
Individuals with this syndrome can present with aborted sudden cardiac death, agonal breathing syncope, or palpitations (Christien et al., 2020). Fever may precipitate these symptoms, increased vagal tone, or medications such as tricyclic antidepressants and alcohol. These ultimately predispose these individuals to malignant ventricular tachycardia and fibrillation (VT/VF) and sudden cardiac death (SCD). This syndrome is also associated with sick sinus syndrome (SSS), atrial flutter, atrial fibrillation, AV nodal reentrant tachycardia and Wolff-Parkinson-White syndrome.
Brugada syndrome is about the electrical rhythm of the heart, or more so the voltage power, and not about the structure itself. These individuals tends not to have any structural concerns, but there is some evidence that potentially there is fibrotic changes in the right ventricle that might create some risk. Ultimately though, this is about how the sodium and calcium channels impact the proteins which are essential for the electrical signaling of neuromuscular cells.
How is Brugada Syndrome Diagnosed?
When individuals are thought to have a cardiac condition, pass out, or feel palpitations and endure an EKG, or maybe just have a routine ECG for screening purposes, a specific pattern may be identified that then diagnoses #Brugada syndrome. Admittedly, this is when I lean into my cardiology specialists as reading ECGs was never an area I was passionate about mastering, but a trained eye will spot either of the two patterns. If there is suspicion, a #Holter monitor may be ordered so this can be worn at home, throughout your typical day or days, and then evaluated by the cardiologist.
For my cardiac colleagues or anyone who may find interest, this first pattern has a classic coved-shaped ST segment elevation for 2mm or more, J-point elevation, a gradually descending ST segment which terminates with a negative T-wave in the right precordial leads with or without a class I anti-arrhythmic drug challenge, such as flecainide (Christien et al., 2020). The second pattern is characterized by a saddleback morphology with a minimum 2 mm J-point elevation along with ST segment elevation of at least 1mm. This second pattern can be converted to a type 1 pattern if given a pharmacological challenge or other stressors such as fever. Keep in mind though, these patterns may be sporadic or fluctuate spontaneously, or they may be triggered. If they aren't identified on initial screening, then the cardiologist may move towards provocation testing.
Individuals at risk, as mentioned above may have no symptoms, and either of the two patterns mentioned above may be identified on an ECG or have a first-degree family member who is diagnosed with Brugada. Those who have passed out due to cardiac reasons, ventricular arrhythmias or if they have ever required cardiopulmonary resuscitation are also at risk and should be evaluated. Initially, they would endure an ECG with high leads and an echocardiogram if symptomatic to exclude structural abnormalities. They may be offered a Holter monitor to wear for a few days, and they might be offered a drug challenge. An ElectroPhysiology study may ordered, which gives more detailed information about the electrical activity or a cardiac MRI.
Diagnoses is based on the presence of a spontaneous or drug-induced coved-type ST segment elevation (Christien et al., 2020), or very specifically, a type 1 ECG change in V1-V2 at 1CS204 (Krahn et al., 2022). One might also attain diagnosis if they experience a type 1 ECG change in V1-V2 at ICS2-4 with fever or provoked by medication. Having said that though, this criteria seems to still be evolving. Remember, this was only first recognized in the early 1990s. The Shanghal Score now exists to offer better guidance for diagnosis, but no longer does the ECG changes seem to be an exclusive criteria for diagnosis. This screening tool includes clinical history, family history, and even genetic testing. A type 1 pattern though without an obvious trigger seems clearly diagnostic though, but there is no current consensus regarding whether this pattern being triggered (fever, certain drugs, large meals, and alcohol) is diagnostic or not.
The predominant root cause of Brugada is still disputed, but there are three main hypotheses. These surround abnormal repolarization, depolarization, or current-load match. There seems to be molecular abnormalities that alter the excitation wavelength, which ultimately elevates arrhythmic risk. The challenge is knowing who will suffer from life-threatening ventricular arrhythmic events.
Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion (Christien et al., 2020). Both repolarization and conduction, based on the concept of wavelength, are being evaluated. These may have better predictive values than the existing markers. Either way, Brugada syndrome is classified as part of the J-wave syndromes that include early repolarization variants.
There are also scenarios that can induce Brugada ECG patters, such as high potassium, low potassium, left ventricular aneurysm, pericarditis, pulmonary embolism, and even more (Christien et al., 2020). These need to be identified or distinguished from true Brugada syndrome as these scenarios can be reversed so that the more invasive treatments such as implantable cardioverter-defibrilltors are avoided. Ultimately, the diagnosis of Brugada syndrome is established with a negative drug challenge.
What Can Even Be Done About This Finding?
Current treatment options include pharmacological therapy to reduce the occurrence of arrhythmic events or to abort these episodes, and interventions such as implantable cardioverter-defibrillator insertion or radiofrequency ablation of abnormal arrhythmic substrate (Christien et al., 2020).
Since the underlying cause of Brugada is reduced magnitude of inward currents, pharmacological agents that act to increase the inward currents or decrease the outward currents can help restore the balance and resolve these arrhythmias (Christien et al., 2020). Currently, many are treated with quinidine, bepridil, or cilostazol. These levels do need to be monitored so blood draws will need to be part of treatment (Krahn et al., 2022). Of course there are others, for slightly different purposes, and potentially into the future cardiologists will utilize agents to address the calcium currents, maybe with cilostazol or milrinone or even address others aspects of the pattern.
The implantable defibrillator has shown to lengthen the life of those with Brugada and it does seem to be safe long term, but it does have its disadvantages, primarily lead failure but infections can also occur (Christien et al., 2020). Inappropriate shocks occur in some, most often due to the presence of supraventricular arrhythmias, so radiofrequency ablation can be used to successfully prevent these VT/VF occurrences. The implant really is "required" for those with high risk. There are new developments coming to the market though, such as a subcutaneous defibrillator which may reduce complications, but there is concern that it may have limited sensitivity.
Cardiology is also going to educate about avoiding Brugada drugs, triggers and promptly treating fever (Krahn et al., 2022). Febrile illness seems to unmask the phenotypic manifestations of Brugada syndrome and precipitate arrhythmias in these individuals, especially in the pediatric population. Clinicians would want to avoid prescribing antiarrhythmic, psychotropic, and analgesic agents. This also means avoiding intoxication with alcohol, antihistamines, and certain drugs used illicitly such as cannabis and cocaine. Rapidly addressing any metabolic disturbances would also be important. These individuals will have annual follow-ups with cardiologists, and should report any and all episodes of syncope or seizures. They should also inform and have family members screened.
Genetic Testing is Recommended
Those who exhibit a type 1 Brugada ECG pattern, either spontaneously or provoked, should have genetic testing done (Krahn et al., 2022). Having said that, let's say someone started here and found the presence of a likely or definite pathogenic variant in a Brugada susceptibility gene, this is not diagnostic in itself. Further, in families in which the genetic variant is identified, the penetrance is approximately 50%, but those without the variant still may have or attain a clinical diagnosis for Brugada syndrome. The diagnosis then is based entirely on clinical screening and not genetics, but obtaining genetics can be helpful in screening family, yet still cautiously so. Many experts in the field are only testing for variants in the SCN5A gene, as this represents about 20% of individuals with Brugada syndrome.
Brugada Syndrome Understanding Remains Incomplete
This is a complex condition, with much to consider. The genetics of it alone are fascinating to me but largely because they are still a great mystery to the profession. They are relevant, but not diagnostic. Myocardial inflammation is of interest in understanding the underlying issue, as are autoantibodies, but again, what triggers those genes and what doesn't, and why in some and not in others is still very much a mystery.
There is still much yet to be understood, but what seems clear is that management is much better understood, and has lengthened lives, than the understanding of the underlying cause. If you have a first-degree relative with Brugada syndrome, it seems it would certainly behoove you to have an evaluation with a cardiologist, an EKG and an echocardiogram. While these can be pricey and inconvenient, even invite some anxiety, they certainly are less impactful than sudden cardiac death.
References
Christien, K. H., Lee, S., Yin, C., Liu, T., Ngarmukos, T., Conte, G., Yan, G-X., Sy, R. W., Letsas, K. P., & Tse, G. (2020). Brugada syndrome: a comprehensive review of pathophysiological mechanisms and risk stratification strategies. International Journal of Cardiology Heart Vascularity.
Krahn, A. D., Behr, E. R., Hamilton, R., Probst, V., Laksman, Z., & Han, H-C. (2022). Brugada syndrome. JACC Journals: Clinical Electrophysiology, 8(3), 386-405.
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