#9 |

Brugada syndrome

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Brugada syndrome is an inherited cardiac disorder associated with an increased risk of development of abnormal heart rhythms, such as ventricular fibrillation or ventricular tachycardia, and consequently, may result in syncope, cardiac arrest, and sudden cardiac death.[1][2][3][4] The disorder has been linked to genetic mutations impairing sodium channel function.[1][2][5][6][7][8]

The syndrome was formerly described as occurring in structurally normal hearts. However, recent studies using cardiac biopsies have reported very subtle, localised fibrotic changes in the heart's right ventricle, particularly in the area of the right ventricular outflow tract.[3][4][7][9] No known genetic abnormality was found in about 70% of patients with Brugada syndrome.[1] Up to 30% of cases have an SCN5A mutation,[1][7] and many genes are associated with less than 5% of cases.

The diagnostic criteria changed over time. Currently, based on the 2013 Expert Consensus Document, Brugada syndrome is diagnosed in all patients with ST-segment elevation ≥ 2mm in at least one lead among the leads V1 - V2 positioned in 2nd, 3rd, or 4th intercostal spaces, with a particular coved morphology, called Brugada type 1 ECG, occurring either spontaneously, or as a result of provocation test using intravenous administration of sodium channel blocking agents (such as ajmaline, flecainide, procainamide).[1][5]

Brugada syndrome has to be differentiated from the term Brugada phenotype, which indicates the ECG findings characteristic of Brugada syndrome.[1] Brugada phenotype may result from other, often temporary conditions and does not carry the same mortality risk as Brugada syndrome.[4] To diagnose Brugada syndrome, the presence of all other possible causes of ST-segment elevation should be excluded.[1]

Epidemiology

The prevalence of Brugada syndrome varies from 1:5000 to 1:2000, depending on geographic location.[1][6] The first cases were first described in 1992 by brothers Brugada,[10] but was coined as a separate syndrome in 1996. In Southeast Asian countries, the disease is considered endemic.[1] Based on recent data, ajmaline-induced type 1 ECG is prevalent in 5% of the general population.[2] It makes understanding the syndrome even more valuable than before.

While Brugada syndrome can be diagnosed at early or old age, the syndrome typically manifests in adulthood, with the mean age of presentation around 41 ±15. At this age, Brugada syndrome is 8-10 times more prevalent in males than females.[1][5][7] The diagnosis is equally distributed in genders before puberty.[1][8]

Symptoms

The disease state may vary from asymptomatic to aborted sudden cardiac death. The disease is mostly asymptomatic, ranging from 64% to 79% in various studies.[8] The first presentation may include dizziness, palpitations, nightly agonal respirations, and syncope.[1] The symptoms are caused by runs of abnormal heart rhythms, namely polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) and, in some cases, atrial arrhythmias. Atrial fibrillation is present in more than 20 of Brugada syndrome patients.[1]

Diagnosis and tests

Two distinct electrocardiographic (ECG) patterns are currently associated with Brugada syndrome, all featuring ST-segment elevation in leads V1-V3. They include:

Type 1

Prominent coved ST-segment elevation in leads V1 to V3, followed by a negative T-wave. These changes are the only diagnostic pattern for Brugada syndrome.[1][8]

Type 2

ST-segment elevation ≥ 0.5 in one or more right precordial leads V1 V2 (generally ≥ 2mm in V2), followed by a convex ST of characteristic saddleback configuration followed by a positive T-wave.[1]

Type 1 ECG is the only diagnostic pattern for Brugada syndrome. Type 2 ECG, which has multiple minor details distinguishing it from other ECG abnormalities, only suggests Brugada syndrome. When Brugada syndrome is suspected due to symptoms and/or family history and, on assessment, type 2 Brugada ECG is identified, usually, the provocation test is done with IV sodium channel blockers.[1] The most frequent agent used during the test is ajmaline, although other agents, such as flecainide or procainamide, can also be used. If the test causes a change of type 2 into type 1 Brugada ECG, it is considered positive, and the syndrome is diagnosed.

The type 1 and 2 Brugada ECG patterns are dynamic and can change from one type to another or disappear from the trace altogether, which may complicate the diagnostic process. Brugada syndrome is often a disease of exclusion, with numerous other cardiac investigations undertaken to eliminate other structural heart diseases. In the process of ruling out other pathologies causing the type 1 ECG changes or symptoms suggestive of Brugada syndrome, many other cardiac tests may be done, such as:

  • Continuous ECG monitoring
  • Exercise stress (EST)
  • Exercise echo or nuclear imaging (SPECT)
  • Magnetic resonance imaging (MRI)
  • Electrophysiological study (EPS) with programmed ventricular stimulation (PVS).

Genetic studies at this time do not have diagnostic significance.[1] The SCN5A gene has been identified as the only one out of more than 20 genes with clinical validity.[6]

Treatment methods and risk stratification

The history of VT/VF or aborted sudden cardiac death is a predictor of a significantly increased chance of future arrhythmic events in patients with Brugada syndrome. Many studies have also proven syncope a known risk factor for future arrhythmic events.[11][12] Atrial fibrillation (AF) in Brugada syndrome patients is suggested to be a possible indicator of more advanced disease.[13] AF is associated with more arrhythmia events in young patients,[14] and worse prognosis.[1][8][15][16]

All patients diagnosed or suspected of having the syndrome are advised to avoid medications that may affect the sodium channel. A list of such medications is available on a website (www.brugadameds.com) and gets updated with time. The patients are also recommended to get optimal control of fever, which can influence ECG patterns and moderate alcohol intake, as it may also influence electrolyte stability. Increased awareness and patient education in effective measures to prevent side effects of affecting substances and arrhythmia-provoking conditions, like a fever is associated with the trend in the reduction of recurrent arrhythmic events and mortality in patients with Brugada syndrome from 1980s to 2000s.[17][18]

Symptomatic patients

The recommended treatment for Brugada syndrome patients that are symptomatic (history of aborted SCD, sustained ventricular arrhythmia or syncope presumed to be caused by such arrhythmia) is implantable cardiac defibrillator (ICD).[11]

Patients who experience several appropriately triggered electric stimulations when on ICD are recommended to have more intensive therapy by adding medication, frequently quinidine (and amiodarone), or having catheter ablation. The same treatment is available for symptomatic patients who are not candidates for ICD and for individuals who decline ICD insertion.[11]

ICD improves survival of BS patients with the history of symptoms, a meta-analysis of multiple studies in 2019, following up on 1539 patients with Brugada syndrome treated with ICD, with a mean duration of 4.9 years demonstrated cardiac mortality rate was 0.03 per 100 person-years.[15] Although the research shows that ICD complications, such as lead malfunctioning or displacement are reducing with time, [19] they still have to be taken in consideration in the decision-making.

Asymptomatic patients

Asymptomatic patients diagnosed with Brugada syndrome have better prognosis than those with a history of symptoms, and the prognosis has improved over the years. Currently, the annual incidence of an arrhythmic event is suggested to be 0.5% in men to 1.2 %, 3.8% at 5 years, and 4.6% at 10 and 15 years.[1][8] In asymptomatic women, the event rate is 0.27% per year.[8]

Spontaneous Brugada type 1 ECG is associated with a higher risk of events than type 1 ECG inducible by provocation (HR 2.14- 3.56 P <0.05).[20][21] For the asymptomatic Brugada syndrome patients that have no spontaneous type 1 ECG, but it is inducible by medical provocation test, just observation is recommended. [11]

Electrical stimulation testing (EPS) has been performed on Brugada syndrome patients as part of the research to distinguish cases with inducible significant ventricular arrhythmia from not inducible. Currently, based on the expert consensus, EPS is neither recommended nor discouraged for risk stratification purposes, but ICD is an optional treatment in asymptomatic patients with inducible arrhythmias as a result of EPS study.[8][17]

Age groups

Brugada syndrome diagnosis is infrequent in seniors, but it is associated with a better prognosis in older patients. Based on a small study published in 2017, none of the previously asymptomatic patients aged 60 or above with type 1 ECG had documented fatal ventricular arrhythmias during the follow up of 7.6 (+- 5.8 years). [18] In a study published in 2019, where 1613 patients were followed for 6.5 ±4.7 years. Age >60 years was a favorable finding as an event predictor HR 0.11 (95% CI 1.8 4.9 p<0.0003).[20]

The incidence of Brugada syndrome in pediatric patients is low, but patients have an unfavorable prognosis demonstrating high recurrence of arrhythmic events. This group also had a high incidence of fever-induced arrhythmias.[9][14] The mortality of this group is prohibitive to offer insurance.

Image: Lee Edwards/KOTO - stock.adobe.com

Risk stratification based on genetic information

In a study published in 2019, SCN5A mutation and polygenic risk score (PRS), derived from published genome-wide association studies, were assessed as predictors of sodium channel blocker ajmaline test positivity. SCN5A mutation was associated with an increased probability of positive provocation test in univariate models but did not show significance in multivariate models. The same study identified that a lower ajmaline dose was necessary for converting type 2 ECG to type 1 in patients with higher polygenic risk score (PRS) of Brugada syndrome.[2]

In a meta-analysis published in 2019 SCN5A positivity in symptomatic patients suggested an increased rate of expected arrhythmic events or SCD (OR 1,98, 95% CI: 1,06–3,70, P = 0.03).[16] The meta-analysis results also demonstrated that neither family history of SCD, spontaneous type 1 ECG vs. induced, nor atrial fibrillation changes the prognosis of arrhythmia or SCD in patients with SCN5A mutation compared to patients who are negative for the mutation. In the patients that were negative for NSC5A, atrial fibrillation was associated with a higher number of future events (p =0.021). Based on analysis of three studies involving patients with Brugada syndrome, it was found that while SCN5A positivity status did not alter the risk of future arrhythmic events and SCD in patients with positive EPS study, positivity for SCN5A mutation was associated with increased risk of arrhythmic events in patients with negative EPS in comparison with SCN5A mutation-negative patients. These findings suggest SCN5A plays a role in the risk of arrhythmia, and further studies are needed to understand the role better.[16]

Currently, SCN5A is considered helpful in screening the relatives of the proband diagnosed with Brugada syndrome and are positive for SCN5A.

Conclusion

The diagnosis of Brugada syndrome is more frequent due to increased awareness of the condition. Applicants that are diagnosed with Brugada syndrome have different mortality risk based on presence or absence of the symptoms, treatment, the response to the treatment such as ICD, and history of the complications. In asymptomatic patients, risk can be further differentiated by presence or absence of spontaneous type 1 ECG and to EPS test results. Age group and gender also make the difference in assessment of the risk as well as history of atrial fibrillation. Genetic information such as SCN5A and PRS may aid in more nuanced assessment of the risk when such information is available.

Author

Dr Tea Mamaladze

Medical Consultant

Life & Health - Risk Assessment

September 2024

References

  1. Brugada, Campuzano, Arbelo, Sarquella-Brugada, Brugada. Present Status of Brugada Syndrome. J Am Coll Cardiol. 2018;72(9):1046-1059. doi:10.1016/j.jacc.2018.06.037.
  2. Tadros R, Tan HL, el Mathari S, et al. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores. Eur Heart J. 2019;40(37):3097-3107. doi:10.1093/eurheartj/ehz435.
  3. Çinier G, Tse G, Baranchuk A. Brugada phenocopies: Current evidence, diagnostic algorithms and a perspective for the future. Turk Kardiyol Dern Ars. 2020;48(2):158-166. doi:10.5543/tkda.2020.06118.
  4. de Oliveira Neto, de Oliveira, Mastrocola, Sacilotto. Brugada phenocopy: Mechanisms, diagnosis, and implications. J Electrocardiol. 2019;55:45-50. doi:10.1016/j.jelectrocard.2019.04.017.
  5. Priori, Wilde, Horie, et al. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes. Heart Rhythm. 2013;10(12):1932-1963. doi:10.1016/j.hrthm.2013.05.014.
  6. Hosseini SM, Kim R, Udupa S, et al. Reappraisal of Reported Genes for Sudden Arrhythmic Death. Circulation. 2018;138(12):1195-1205. doi:10.1161/CIRCULATIONAHA.118.035070.
  7. Pieroni, Notarstefano, Oliva, et al. Electroanatomic and Pathologic Right Ventricular Outflow Tract Abnormalities in Patients With Brugada Syndrome. J Am Coll Cardiol. 2018;72(22):2747-2757. doi:10.1016/j.jacc.2018.09.037.
  8. Sieira J, Brugada P. Brugada Syndrome: Defining the Risk in Asymptomatic Patients. Arrhythm Electrophysiol Rev. 2016;5(3):164-169. doi:10.15420/aer.2016:22:3.
  9. Pieroni, Notarstefano, Bolognese. Brugada Syndrome in the Young and in the Adult. J Am Coll Cardiol. 2019;73(14):1766-1768. doi:10.1016/j.jacc.2019.01.047.
  10. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20(6):1391-1396. doi:10.1016/0735-1097(92)90253-J.
  11. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. Circulation. 2018;138(13):E272-E391. doi:10.1161/CIR.0000000000000549.
  12. Probst V, Anys S, Sacher F, et al. P5027Prognosis and evaluation of the risk markers of arrhythmia in a large population of Brugada syndrome patients. Eur Heart J. 2019;40(Suppl). doi:10.1093/eurheartj/ehz746.0205.
  13. Conte, Sieira, Ciconte, et al. Implantable Cardioverter-Defibrillator Therapy in Brugada Syndrome. J Am Coll Cardiol. 2015;65(9):879-888. doi:10.1016/j.jacc.2014.12.031.
  14. Michowitz, Milman, Andorin, et al. Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome. J Am Coll Cardiol. 2019;73(14):1756-1765. doi:10.1016/j.jacc.2019.01.048.
  15. Dereci A, Yap S-C, Schinkel AFL. Meta-Analysis of Clinical Outcome After Implantable Cardioverter-Defibrillator Implantation in Patients With Brugada Syndrome. JACC Clin Electrophysiol. 2019;5(2):141-148. doi:10.1016/j.jacep.2018.09.005.
  16. Yang Y, Hu D, Sacher F, et al. Meta-Analysis of Risk Stratification of SCN5A With Brugada Syndrome: Is SCN5A Always a Marker of Low Risk? Front Physiol. 2019;10:103. doi:10.3389/fphys.2019.00103.
  17. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2015;36(41):2793-2867. doi:10.1093/eurheartj/ehv316.
  18. Kitamura T, Fukamizu S, Kawamura I, et al. Clinical Characteristics and Long-Term Prognosis of Senior Patients With Brugada Syndrome. JACC Clin Electrophysiol. 2017;3(1):57-67. doi:10.1016/j.jacep.2016.04.004.
  19. Knops RE, Olde Nordkamp LRA, Delnoy P-PHM, et al. Subcutaneous or Transvenous Defibrillator Therapy. N Engl J Med. 2020;383(6):526-536. doi:10.1056/NEJMoa1915932.
  20. Probst V, Arnaud M, Behar N, et al. P6585Number of ECG leads and prognosis of spontaneous type 1 Brugada syndrome. Eur Heart J. 2019;40(Suppl). doi:10.1093/eurheartj/ehz746.1173.
  21. Honarbakhsh S, Providencia R, Garcia-Hernandez J, et al. P6586Brugada syndrome risk stratification - Evaluation of clinical and ECG risk markers in a multicenter international primary prevention cohort. Eur Heart J. 2019;40(Suppl). doi:10.1093/eurheartj/ehz746.1174.

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