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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Prof. Josep Brugada
Although the estimated prevalence of the Brugada Syndrome makes it a rare disease - it ranges from 1-5/10 000 in Europe to 12/ 10 000 inhabitants in Southeast Asia, the implied risk of a tragic and preventable event - sudden death - in young and, otherwise, healthy individuals has attracted great interest from scientists all over the world. The correct recognition and management of these patients should be considered an essential skill for any cardiologist. Learn to recognise and treat these patients in six steps.
Brugada syndrome (BS), first described in 1992, is an inherited arrhythmogenic disease, characterised by coved-type ST-segment elevation in right precordial leads and an increased risk of sudden cardiac death (SCD), due to ventricular fibrillation (VF)1. In all series, approximately 80% of the affected individuals are men2, 3, and the onset of symptoms typically occurs at a mean age of 40 years.
1 ) One true diagnostic brugada pattern, two others may suggest the disease. Three repolarisation patterns are associated with BS4 (figure 1), when found in more than one right precordial leads(V1 to V3):
2) Drug challenge to help with diagnosis. Several studies have informed about the dynamic character of the ECG in BS6, 13, 14. That fact, and the finding that class I AAD were able to reproduce the diagnostic pattern when administered to those patients in whom the ECG spontaneously normalised (based on the results of basic research on the subject15), let to the use of class I antiarrhythmic drugs (AAD) as a diagnostic test for the disease6. Drug challenge for diagnosis of BS is indicated in cases in which the disease is suspected, but in which the basal ECG is normal (e.g.: familial screening) or suspicious, but not diagnostic (types 2 or 3). Flecainide, ajmaline, procainamide, dispyramide, propafenone and pilsicainide have been used to unmask BS16-18. The current recommendations on drugs, doses, route and time of administration are outlined in table 15. Drug challenge is only considered positive when a conversion to the diagnostic type 1 occurs. It is recommended to place the right precordial leads up to the 2nd intercostals space , because it may increase the sensitivity of the ECG (basal and during drug challenge with class I AAD) for detecting the diagnostic BS pattern19-21.
Many conditions may develop ST-segment elevation, mimicking the BS ECG pattern (table 2). In order to attain the diagnosis of BS, they should be carefully excluded. It is also important to be aware that some drugs (listed in table 3) may also produce a Brugada-like ST-segment elevation.
Once we have observed a type 1 ECG in more than 1 precordial leads, and exclude other conditions that may account for it, we should search for clinical data that support the diagnosis of BS. There are three kind of clinical criteria for the disease:
BS is definitely diagnosed when the patient presents 1) a type 1 ECG (either spontaneously or elicited by class I AADs), and 2) at least one of the above mentioned clinical criteria. If a type 1 ECG is observed in the absence of any clinical criteria, this should be referred to as “idiopathic Brugada ECG pattern” and not as BS4. Figure 2 shows a proposed diagnostic algorithm.
Once the diagnosis of BS is made, the next step is risk stratification for which the main objective is the accurate identification and treatment of individuals at high risk of SCD (25% of the total population with BS will experience SCD or VF during lifetime, according to our data22). To date, some markers of high risk in BS patients have been clearly identified, but other issues still remain controversial23, 24:
Current recommendations on risk stratification are summarised on figure 3, based on the conclusions of the second consensus conference on BS5.
a) ICD To date, the only proven effective therapeutic strategy for the prevention of SCD in BS patients is the ICD28-30. It is important to remark that these patients present a considerably high rate of inappropriate shocks (20-36% at 21-47 months follow-up), mostly due to sinus tachycardia, supraventricular tachyarrhythmias and lead complications; emphasising the importance of a careful ICD programming.
b) Pharmacological treatment is under study. : Genetic basis and pathophysiology of BS-Rationale for pharmacological treatment. As a result of exhaustive investigation on the subject, some of the genetic basis and pathophysiologic substrate of arrhythmias in BS have been unravelled. Mutations in 4 genes have been linked to BS: SCN5A, encoding for the α-subunit of the cardiac sodium (Na+) channel31 , and resulting in loss of function of the mentioned channel by different mechanisms32 (being responsible for up to 30% of BS cases5) ; glycerol-3-phosphate dehydrogenase 1-like gene (GPD1L), which reduce the inward Na+ current by affecting the trafficking of the cardiac Na+ channel to the cell surface33, 34; finally, mutations in genes encoding the α1-(CACNA1C) and β- (CACNB2b) subunits of the L-type cardiac calcium (Ca+2) channel result in a combined Brugada/short QT syndrome35 (it has not been established yet which percentage of BS patients present these three last types of mutations). To date, the most accepted theory to explain the ECG changes and the arrhythmogenic basis of BS is based on the effect of the decrease of the inward positive currents (Na+ , Ca+2) on the potassium transient outward current (Ito), which expression levels varies across the myocardium layers (epicardium>endocardium). These changes in the ionic imbalance are responsible for the modification of the morphology of the cardiac action potential (presenting a remarked notch during the phase 1, otherwise called “loss of dome”), the typical ECG changes, and constitute the electrophysiological basis of the increased susceptibility of these patients to present episodes of polymorphic VT and/or VF (by a mechanism of phase-2 reentry). With the objective of rebalancing the ionic currents during the cardiac action potential, drugs that inhibit the Ito current or increase the Na+ and Ca+2 currents have been tested in BS: -Quinidine, and Ito and I-Kr inhibitor, has shown to prevent induction of VF and suppress spontaneous ventricular arrhythmias in a clinical setting36, 37, being currently used in patients with ICD and multiple shocks, cases in which ICD implantation is contraindicated, or for the treatment of supraventricular arrhythmias38. It has been suggested that it could be also useful in children with BS, as a bridge to ICD or as an alternative to it39. However, it has also presented a high rate of secondary effects36. -Isoproterenol (which increases the ICaL current), in combination with quinidine, has proved to be useful for the treatment of electrical storms in BS40, 41. -Other drugs being evaluated for BS are tedisamile, phosphodiesterase III inhibitors (cilostazol) and dimethyl lithospermate B.
Figure 1 - The three ECG patterns associated to Brugada syndrome. Only type 1 (first from the left) is diagnostic of the disease. Figure 2 - Diagnostic algorithm for Brugada syndrome Abbreviations:BS, Brugada syndrome; SCD, sudden cardiac death; PVT, polymorphic ventricular tachycardia; VF, ventricular fibrillation; AAD, antiarrhythmic drugs.
Figure 3 - Current risk stratification scheme and recommendations of ICD in BS patients Abbreviations: ICD (implantable cardioverter-defibrillator; BS, Brugada syndrome; SCD, sudden cardiac death; NAR, nocturnal agonal respiration; AAD, antiarrhythmic drugs; PVT, polymorphic ventricular tachycardia; VF, ventricular fibrillation (modified from (16)). Table 1 - Drugs used to unmask Brugada syndrome. Abbreviations: IV, intravenous; PO: per os, orally. (modified from (5)).
Table 2- Abnormalities which may account for ST-segment elevation in right precordial leads Acute myocarditis Acute pericarditisHemopericardiumRight ventricular ischemia/infarctionDissecting aortic aneurysmAcute pulmonary thromboemboliCentral and autonomic nervous system abnormalitiesDuchenne muscular dystrophyFriedreich´s ataxiaThiamine deficiencyHypercalcemiaHyperkalemiaMediastinal tumor compresing right ventricular outflow tractArrhythmogenic right ventricular cardiomyopathyLong QT syndrome type 3Right bundle branch blockLeft bundle branch blockLeft ventricular hypertrophyEarly repolarization syndromeHypothermia
Table 3 - Drug-induced Brugada-Like ECG patterns (reproduced from (10)) I Antiarrhythmic drugs:1. Sodium channel blockers:
2. Calcium channel blockers:
II Beta -blockers:
III-Antianginal drugs: 1. Calcium channel blockers:
3. Potasium channel openers:
III-Psychotropic drugs:1. Tricyclic antidepressants:
2- Tetracyclic antidepressants:
4- Selective serotonine reuptake inhibitors:
IV- Other drugs:
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