Brugada Syndrome Dr. Salah Atta, MDConsultant of Electrophysiology and pacing, SBCC, Ad-Dammam Ass. Professor of Cardiology, Assiut Universoity
Objectives Definition of Brugada Syndrome and Historical Background Presentation and Diagnosis Differential Diagnosis Genetics and Prevalence. Pathophsiology of Brugada Syndromre How to know which patient to treat ? (Risk Stratification) How to treat? ( Treatment Options )
Brugada Syndrome is… Itis an example of an inherited channelopathy disorder characterized by sudden death due to ventricular fibrillation or polymorphic VT.A clinical-electrocardiographic diagnosis based on syncopal or sudden death episodes in patients with a structurally normal heart with a characteristic electrocardiographic pattern (right bundle branch block, ST segment elevation in V1 to V3) .
Historical Background Is it Brugada or Martini or whom syndrome?! In 1953, Osher and Wolff reported a dynamic ECG abnormality (Osher-Wolff ECG), simulating an acute myocardial infarction, in a healthy man. The description was similar to Brugada pattern.A similar ECG pattern, this time associated with an aborted sudden death and occurring in a 42- year-old male on the 2nd of October 1984, was seen in Padua, Italy.
Historical Background Shortly after, A new “syndrome” characterized by a clinical event (sudden or aborted sudden death) associated with the abnormal ECG findings, was first presented at the National Congress of Italian Cardiologists by Nava et al. who published the first ECG characteristic of the syndrome in 1988. In 1989 Martini et al described six patients with apparently idiopathic VF, 3 of them had upsloping ST elevation, RBBB and inverted T waves. They documented subtle structural abnormalities in the RV (Martini B et al. Ventricular fibrillation without apparent heart disease.. Am Heart J 1989) .
In 1992 Pedro and Josep Brugada described 8 cases and introduced the term ‘Right bundle branch block, ST segment elevation and sudden death syndrome’ . The first patient in their series with this syndrome was seen in 1986. The patient was a three year old boy from Poland. With multiple episodes of loss of consciousness and the childs sister had died suddenly at age two after multiple episodes of aborted sudden death, both had the characterestic ECG.
The ECG of the 1st two patients reported by Brugada et.al 1992
Presentation Brugada syndrome patient may present with syncope due to polymorphic ventricular tachycardia (VT) or resuscitated sudden death in the third or fourth decade of life. affects otherwise healthy men aged 30-50 years, but affected patients aged 0-84 years have been reported. The mean age of patients who die suddenly is 41 years (Antzelevitch C on 2005)
Sex: Brugada syndrome is 8-10 times more prevalent in men than in women, although the probability of having the mutated gene does not differ by sex. The expression of the mutation therefore appears to be much higher in men than in women (Eckardt et al 2008). Animal models suggest that the influence of testosterone on ion currents (particulary outward K+ currents) may contribute to this finding.
Prevalence BS is reported to be responsible for 4% of all sudden deaths and 20% of sudden deaths in those without structural heart disease and is a leading cause of death in subjects under the age of 40 years. A family history is present in about 20 to 30% of patients. It is difficult to estimate the exact incidence of BS in the general population but the prevalence is quoted as 1 in 2000.
Prevalence The condition is particularly common in South East Asia and amongst immigrants of South Asian origin and in the Japanese population the prevalence is reported to be 0.12 to 0.14%. BS has also been reported as Sudden Unexplained Death Syndrome (SUDS) or Sudden Unexplained Nocturnal Death Syndrome (SUNDS). The ECG changes of BS are dynamic and can vary spontaneously which also makes it difficult to assess its exact incidence.
Genetics This condition is genetically transmitted as an autosomal dominant syndrome with incomplete penetrance. It is present in a familial and sporadic pattern. Mutations in SCN5A (Locus 3p21-24), which encodes for the alpha subunit of the cardiac Na+ channel, is found in 18-30% of families with BS. This gene defects leads to a number of abnormalities in the Na+ channel: – Failure of expression – Accelerated inactivation – Prolonged recovery from inactivation
Mutations in SCN5A are also associated with: – Isolated AV conduction defect – Congenital long QT syndrome type 3 – Congenital sick sinus syndrome – Familial dilated cardiomyopathy with conduction defects and susceptibility to AF. Differences in clinical manifestations may be due to differences in electrophysiologic abnormalities induced by specific different mutations.
AF in Brugada Pts with BS are at increased risk of atrial arrhythmias, which is consistent with the diffuse nature of the Na+ channel abnormality. In one report where 59 pts with BS were compared to 31 matched controls, spontaneous AF occurred in 20% of the BS pts and none of the controls in three years of follow up. In this study there was a significant correlation between the presence of AF and inducibility of sustained ventricular arrhythmia at EP (Brdachar P et al 2004).
Diagnostic Criteria BS is not well defined. The ECG changes alone of BS type 1 constitute Brugada pattern but not BS. The first consensus report of 2002 proposed the diagnostic ECG criteria mentioned before. In a subsequent consensus report published in 2005, the definitions were revised
Type I- Diagnostic Type I: V1-V3 (in more than one lead) ST segment elevation >2mm, “coved” shape, inverted T-wave. Coupled with one of: – Documented VFib – Polymorphic VT – FH of sudden cardiac death <45 yo – Type I EKG in family members – VT inducable in EP lab – Syncope – Nocturnal agonal respiration
Types II and III- Suggestive II: V1-V3 ST segment elevation >2mm, “saddleback” shape, pos or biphasic T. III: <1 mm elevation, either coved or saddleback. Appearance of type 2 or 3 ST elevation (saddle back) in >1 R precordial lead under baseline conditions, with conversion to type 1 during Na+ channel blocker challenge and one of the Features described previously. The criteria is 77% sensitivity among gene mutation carriers.
Drug Challenge Test– Challenge with sodium channel blockers: In some patients, the intravenous administration of drugs that block sodium channels may unmask or modify the ECG pattern, aiding in diagnosis and/or risk stratification in some individuals.– Only In symptomatic patients with the type 2 or 3 patterns, the drug challenge is recommended to clarify the diagnosis.– Infuse flecainide 2 mg/kg (maximum 150 mg) over 10 minutes, procainamide 10 mg/kg over 10 minutes, ajmaline 1 mg/kg over 5 minutes, or pilsicainide 1 mg/kg over 10 minutes with contiuous ECG and haemodynamic monitoring and readiness for CPR. (Antzelevitch et al 2005).
Provocative Factors Many clinical situations have been reported to unmask or exacerbate the ECG pattern of Brugada syndrome. Examples are a febrile state, hyperkalemia, hypokalemia, hypercalcemia, alcohol or cocaine intoxication, and the use of certain medications, including sodium channel blockers, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, heterocyclic antidepressants, and a combination of glucose and insulin (Antzelevitch 2005)
Pathophysiology The exact mechanisms underlying the ECG alterations and arrhythmogenesis in Brugada syndrome are disputed. (Meregalli PG et al in 2005) Brugada syndrome is an example of a channelopathy, Specifically, in 10-30% of cases, mutations in the SCN5A gene, which encodes the cardiac voltage-gated sodium channel, have been found.
Pathophysiology During phase 1 of the normal action potential, the inward Na+ current and transient outward K+ current, ITo, cause a normal spike and dome morphology. In the presence of weak Na+ current, the unopposed outward K+ current ITo and ICa, cause accentuation of the action potential notch in the RV epicardium, creating voltage gradient with the endocardium resulting in accentuated J wave and ST segment elevation associated with the Brugada pattern.
PathophysiologyArrhythmias develop because of inhomogeneous repolarization in different areas of the RV epicardium leading to the so-called phase 2 re-entry and to the development of closely coupled extrasystoles leading to VT/VF. Triggering extrasystoles have left bundle branch
Defective sodium channels: shorter AP (phase 0), deeper notch (phase I), and shorter phase 2. Creates juxtaposition of depolarized and repolarized cells, setting up possibility of PHASE 2 RENTRY, closely grouped PVCs, and VT or V Fib. On EKG, ST segment not at baseline because no longer have uniform repolarization of the entire ventricle.Nattel and Carlsson Nature Reviews Drug Discovery 5, 1034–1049 (December 2006) | doi:10.1038/nrd2112
Differential DiagnosisAtypical right bundle branch blockLeft ventricular hypertrophyEarly repolarizationAcute pericarditisAcute myocardial ischemia or infarctionPrinzmetal anginaPulmonary embolismDissecting aortic aneurysmMediastinal tumor or hemopericardiumcompressing the right ventricular outflow tract(RVOT)
Differential DiagnosisArrhythmogenic right ventricular dysplasia and/orcardiomyopathyVarious abnormalities of the central and autonomicnervous systemsOverdose of a heterocyclic antidepressantCocaine intoxicationDuchenne muscular dystrophyFriedreich ataxiaThiamine deficiencyHypercalcemiaHyperkalemiaHypothermiaPectus excavatumEffects of athletic training
Risk Stratification To identify patients at high risk of SCD who may benefit from ICD. Many studies done for this purpose. Prior History of SCA: 69% recur within 5 years. SCD reported in about 8.2% of pts with BS during 24 months follow up. A history of syncope, a spontaneously abnormal ECG, and inducibility during programmed electrical stimulation (by one study) significantly increased this risk (Brugada J et al in Circulation 2003 ).
Risk Straification Gehi et al performed a meta analysis of 30 prospective studies on 1,545 patients and concluded that a history of syncope or sudden death (SCD), the presence of spontaneous Type 1 Brugada ECG and male gender predict a more malignant natural history. Family history of SCD, the presence of SCN5A mutation and EPS were not predictive. J.Cardiovasc Electrophysiol 2006
EPS for risk stratification The role of EPS remains controversial in the Brugada syndrome. Electrophysiological testing had a low positive predictive value (23%), but over a 3-year follow-up, it had a very high negative predictive value (93%) .
EP Testing Onestudy by Brugada et al showed that inducibility may be a good predictor of outcome.However, in circulation 2002, Priori reported a poor predictive value of invasive EP testing.
EP Testing The subsequent study by Gehi published in journal of Carcdiovascular lectrophysiology, 2006 concluded that EPS was not of use in guiding the management of patients with Brugada syndrome . This was further confirmed in larger recent studies. (kamakura et al 2009, Probst V et al Circulation, 2010).
Treatment OptionsMedical tratment: Amiodarone is useless, B blockers and Na+ channel blockers may be deleterious. Quinidine, however, may be beneficial. Possibly by blockade of I(to), the transient outward current, that increases heterogeneity and may promote ventricular premature beats and trigger VT or VF. For this purpose large doses are needed (1200- 1500mg/d (Antzelevitch 1999). Isoproterenol, which boosts the L-type calcium current, can also counteract the ionic current imbalance and can be used in managing electerical storms of BS (Antzelevitch 2001).
Drug therapy So At this stage, apart from quinidine, no other oral drug therapy is available for treatment of BS. This situation may alter in future; phosphodiesterase inhibitors and tedesamil and dimethyl lithospermate B (dmLSB) a Chinese herbal medicine are drugs that are being investigated.
Prophylactic Measures Aggressive treatment of all febrile episodes is recommended with antipyretics like aspirin and paracetamol and cold sponges. Avoid Hypokalemia Avoid large carbohydrate meals and Avoid Alcohol and very hot baths.
Drugs to be avoidedDrugs that can cause Brugada-like changes on the ECG are best avoided and include: Class 1 antiarrhythmic drugs like flecainide, beta and alpha adrenergic blockers, Ca++ channel blockers like verapamil. Nitrates, K+ channel openers like nicorandil, Tricyclic and Tetracyclic antidepressants, phenothiazines and SSRI like fluoxetine, Alcohol and cocaine intoxication.
ICD Therapy ICD therapy can prevent SCD in the BS, however, the risk of SCD varies significantly from patient to patient. Indications for ICD implantation were published in the report of the Second Consensus Conference on Brugada syndrome (Antzelevitch et al 2005)
Report of the Second Consensus Conference on Brugada syndrome Antzelevitch et al2005
ICD Recommendations In2006 ACC/AHA/ESC issued the following guidelines regarding BS: – There is evidence/general agreement to support ICD implantation in all pt’s with a previous cardiac arrest. – The weight of evidence/opinion supports the use of an ICD in pt’s with a spontaneous type 1 ECG and a history of syncope. – The weight of evidence/opinion supports ICD implantation in BS pt’s with a history of VT but not cardiac arrest.
Conclusion Brugada Syndrome is an example of Chanellopathy related disease with special ECG pattern and risk of sudden cardiac death. Genetic origin can only be proved in about 50% of the cases and mostly related to loss of function mutation of the Na chnanels. The common victim is a middle aged male who is otherwise healthy and is more prevalent in SE Asia.
Conclusion History of Cardiac arrest in addition to type one ECG pattern are the most important predictive factors of ominous outcome. EP study has a limited and debatable role in risk stratification of patients. Medical treatment may have a role in the acute situation but ICD is the only definitive treatment of diagnosed patients at risk of SCD.