Management of patients with a Brugada ECG pattern

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 men (2, 3) and the onset of symptoms typically occurs at a mean age of 40.

Step 1: Correct recognition of the diagnostic Brugada syndrome ECG pattern

1) There is one true diagnostic of the 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):

1. Type 1: It is characterised by a prominent coved ST-segment elevation displaying J-point amplitude or ST-segment elevation ≥2 mm, followed by a negative T wave.
2. Type 2: It has ≥2 mm J-point elevation, ≥1 mm ST-segment elevation and a saddleback appearance, followed by a positive or biphasic T-wave.
3. Type 3: It has either a saddleback or coved appearance, but with an ST-segment elevation <1 mm.
   It should be stressed that type 1 is the only ECG diagnostic pattern of BS,
   while types 2 and 3 should only be considered suggestive of the disease. (4, 5)

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 subject 15) led to the use of Class I antiarrhythmic drugs (AAD) as a diagnostic test for the disease. (6)
A drug challenge for the 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, routes and times of administration are outlined in Table 15. A 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 second 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 pattern 19-21.

Step 2: Excluding other causes for a BS ECG pattern

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.

Step 3: Excluding the idiopathic Brugada ECG pattern-prognosis

Once we have observed a type 1 ECG in more than one precordial lead and have excluded other conditions that may account for it, we should search for clinical data that support the diagnosis of BS. There are three kinds of clinical criteria for the disease: 

1. Data from the family history:
   SCD in a family member younger than 45.
   ECG type 1 in family members.
2. Arrhythmia-related symptoms:
   Syncope.
   Seizures.
   Nocturnal agonal respiration.
3. Documented ventricular arrhythmias:
   Polymorphic ventricular tachycardia (PVT).
   Ventricular fibrillation (VF).

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.

Step 4: Risk stratification for  accurate identification and treatment of individuals at high risk of SCD

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 their lifetimes, according to our data. (22) To date, some markers of high risk in BS patients have been clearly identified, but other issues still remain controversial: (23, 24)

• Survivors of SCD are at high risk of recurrence or life-threatening arrhythmias (17%-62% at 48-84 months follow-ups (3, 23-27) and should receive an ICD.
• Syncope is also a marker of high risk of presenting ventricular arrhythmias (6%-19% at 24-39 months follow-up for syncope, (3, 25-27) and should receive an ICD, after non-cardiac causes of this symptom have been carefully ruled out.
• Spontaneous ECG type 1 is not an independent predictor of ventricular arrhythmias in multivariate analysis of the largest registries on the subject, (26, 27) but it still identified a subgroup of patients with a higher risk of future arrhythmic events when combined with a history of syncope and inducibility during electrophysiological (EP) study.
• Males show a tendency to develop more arrhythmic events than women and have a worse prognosis during follow-up. (2)
• The value of inducibility of sustained ventricular arrhythmias during EP study as a risk predictor tool in BS is still the most controversial topic. The results of the largest BS registry indicates that inducibility during EP study is an independent predictor for cardiac events (hazard ratio: 8.33, 95% IC: 2.8-25; p=0.0001), (26) while the second and third largest registries did not find similar results. (3, 27) There are several proposed reasons that may account for this and other differences among the registries: different inclusion criteria, different stimulation protocols, different statistical analysis methods, etc. Prospective studies to elucidate the role of EP study in the risk stratification of these patients are currently being performed.

Current recommendations on risk stratification are summarised in Figure , based on the conclusions of the second consensus conference on BS. (5)

Step 5: Treatment recommendations for BS patients

a) ICD

To date, the only proven effective therapeutic strategy for the prevention of SCD in BS patients is the ICD. (28-30) 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 four genes have been linked to BS: SCN5A, encoding for the α-subunit of the cardiac sodium (Na+) channel, (31) and resulting in loss of function of the mentioned channel by different  mechanisms (32) (being responsible for up to 30% of BS cases; (5) 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 surface; (33, 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 syndrome. (35) (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), whose expression levels vary 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. These changes 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 have shown to prevent induction of VF and suppress spontaneous ventricular arrhythmias in a clinical setting, (36, 37), currently being used on patients with ICD and multiple shocks – cases in which ICD implantation is contraindicated, or for the treatment of supraventricular arrhythmias, (38) It has been suggested that it could also be useful in children with BS as a bridge to an ICD or as an alternative to it39. However, it has also presented a high rate of secondary effects. (36)
-Isoproterenol (which increases the ICaL current) in combination with quinidine has proved to be useful for the treatment of electrical storms in BS. (40, 41)
-Other drugs being evaluated for BS are tedisamile, phosphodiesterase III inhibitors (cilostazol) and dimethyl lithospermate B.

Step 6: Recommendations

• It is recommended that BS patients should avoid all drugs that may induce a type 1 class ECG (Table 3).
• As fever may elicit the diagnostic ECG pattern and has also been recognized as a trigger of ventricular arrhythmias in BS, (42, 43) patients should be encouraged to treat it aggressively.
• Patients must contact their cardiologist immediately in case of presenting syncope, seizures or nocturnal agonal respiration.
• Family screening of BS is strongly recommended in first-degree relatives (BS is an inherited disease transmitted in an autosomal-dominant way).
• All patients must have regular follow-ups in order to identify the development of symptoms.
• Genetic testing, when available, is recommended (5) to support clinical diagnosis, early detection of other affected family members and for research purposes. But diagnosis should not be based on it because it still has a low diagnostic yield.

Figure 1 - The Three ECG Patterns Associated with 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, see Reference 16).

Table 1 - Drugs Used to Unmask Brugada Syndrome. Abbreviations: IV – intravenous;
PO – per os, orally (modified, see Reference 5).

Table 2- Abnormalities Which May Account for ST-Segment Elevation in Right Precordial Leads

Acute myocarditis
Acute pericarditis
Hemopericardium
Right ventricular ischemia/infarction
Dissecting aortic aneurysm
Acute pulmonary thromboemboli
Central and autonomic nervous system abnormalities
Duchenne muscular dystrophy
Friedreich´s ataxia
Thiamine deficiency
Hypercalcemia
Hyperkalemia
Mediastinal tumor compresing right ventricular outflow tract
Arrhythmogenic right ventricular cardiomyopathy
Long QT syndrome type 3
Right bundle branch block
Left bundle branch block
Left ventricular hypertrophy
Early repolarization syndrome
Hypothermia

Table 3 - Drug-induced Brugada-Like ECG Patterns (reproduced, see Reference 10).

I Antiarrhythmic drugs:
1. Sodium channel blockers:

• Class IC drugs (Flecainide, propafenone, pilsicainide).
• Class IA drugs (Ajmaline, procainamide, dysopiramide, cibenzoline)

2. Calcium channel blockers:

• Verapamil

II Beta-blockers:

• Propranolol, etc.

III-Antianginal drugs:
1. Calcium channel blockers:

• Nifedipine, diltiazem

2. Nitrate:

• Isosorbide dinitrate, nytroglicerine

3.  Potasium channel openers:

• Nicorandil

IV-Psychotropic drugs:
1. Tricyclic antidepressants:

• Amitriptyline
• Nortriptyline
• Desipramine
• Clomipramine

2- Tetracyclic antidepressants:

• Maprotiline

3-Phenothiazine:

• Perphenazine
• Cyamemazine

4- Selective serotonine reuptake inhibitors:

• Fluoxetine

V- Other drugs:

• Dimenhydrinate
• Cocaine intoxication
• Alcohol intoxication