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Understanding Brugada syndrome

Gehshan, Janine Mary RPA-C; Rizzolo, Denise PA-C, PhD

Journal of the American Academy of PAs: June 2015 - Volume 28 - Issue 6 - p 32–36
doi: 10.1097/01.JAA.0000465217.11857.ab
CME: Cardiology
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ABSTRACT Brugada syndrome is an established cause of sudden cardiac arrest in patients without structural cardiac abnormalities. Recognition and diagnosis of this syndrome has been slowly increasing. Syncope, ventricular dysrhythmia, or sudden cardiac arrest may be the presenting symptom, although detection of the characteristic right precordial ST-segment elevation on ECG can be a potentially lifesaving intervention. This article reviews the clinical presentation, pathophysiology, genetics, and current management of Brugada syndrome.

Janine Mary Gehshan practices in the cardiac electrophysiology laboratory at New York University Langone Medical Center and works per diem in the postanesthesia care unit at Memorial Sloan Kettering Cancer Center, both in New York City. She is a recent graduate of the Pace completion program in New York City. Denise Rizzolo is an assistant clinical professor in the Pace completion program, an associate professor in the PA program at Seton Hall University in South Orange, N.J., and practices urgent care in Springfield, N.J. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of June 2015.

Box 1

Box 1

In 1992, electrophysiologists Pedro and Josep Brugada reported eight cases of syncope or sudden cardiac arrest in patients with structurally normal hearts who had ST-segment elevation on ECG in the right precordial leads V1 to V3.1 This primary electrical abnormality, known as Brugada syndrome, is estimated to be responsible for 4% of all sudden cardiac deaths and 20% of sudden deaths in patients with structurally normal hearts.1

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EPIDEMIOLOGY

Brugada syndrome is an arrhythmogenic autosomal dominant genetic disorder characterized by a unique ST-segment elevation in the right precordial leads.1,2 The syndrome is associated with an increased risk of sudden cardiac death due to polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF).1,2 Brugada syndrome often manifests in adulthood during patient's 30s and 40s; the mean age at diagnosis is 40 years and the mean age of sudden cardiac death is 41 years.1 Although Brugada syndrome is less common in children and infants, it is a known cause of sudden infant death syndrome.3 The hallmark ECG findings in patients with Brugada syndrome may be seen only transiently, making the exact number of those with the syndrome difficult to discern. Although prevalence is estimated to be between 1 and 5 per 10,000 in the general population, Brugada syndrome is commonly seen in Thailand, the Philippines, and Europe.3 Brugada syndrome occurs more often in men than in women, with a ratio of 8:1; the syndrome may be associated with higher levels of testosterone.2,4

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CLINICAL PRESENTATION

Syncope or sudden cardiac death may be the only presenting symptom of Brugada syndrome.1 Ambulatory monitoring has shown that polymorphic VT is the most common dysrhythmia associated with the syndrome.3 Patients also may have electrical or arrhythmic storms, which are ventricular dysrhythmias that recur over a short span of time. Supraventricular dysrhythmias occur in up to 20% of patients, with atrial fibrillation being a concomitant rhythm disorder in 11% to 14% of patients.1,3,5 Other commonly associated conduction abnormalities are first-degree atrioventricular block with PR interval of greater than 200 ms, right bundle-branch block, and sick sinus syndrome. Sudden death implicates a vagal mechanism initiated by bradycardia because death often occurs between midnight and 6 a.m.3-6 Nocturnal agonal respiration, or erratic gasping breaths during sleep, also can be presenting signs of Brugada syndrome and may be the manifestation of ventricular dysrhythmias that spontaneously self-terminate.1,3,5 This circadian pattern of events means that Brugada syndrome is genetically and phenotypically equivalent to sudden unexplained nocturnal death syndrome.3,7 This predilection of dysrhythmia during nighttime hours is thought to be due to hormonal imbalance or an imbalance of the sympathetic and parasympathetic nervous systems.1,6

Box 2

Box 2

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GENETICS

Brugada syndrome is an inherited autosomal dominant genetic mutation with various degrees of phenotypic expression.5 Twelve genes have been linked to Brugada syndrome.4 Between 15% and 30% of patients express a mutation in the gene that encodes for the alpha subunit of the cardiac sodium channel, SCN5A, located on chromosome 3p21-24.8 This sodium channelopathy causes a decrease in the influx of sodium into cardiac cells that shortens the normal action potential of myocytes. Genetic mutations, however, are only present in 25% of patients, suggesting that further heterogeneity has yet to be discovered. Genetic testing is needed only if a definitive diagnosis of Brugada syndrome has been made; genetic testing for family members is recommended if a genotype has been associated with the proband.4

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PATHOPHYSIOLOGY

ST-segment elevation in patients with Brugada syndrome is believed to be caused by alterations in transmembrane ion currents of the cardiac action potential, which appear to affect the right ventricular endocardium differently than the RV epicardium.6 The ST-segment electrically represents the time between ventricular depolarization and repolarization, and normally is isoelectric. Changes in repolarization in patients with Brugada syndrome can lead to a transmural voltage gradient, reexcitation, extrasystolic beats, and an electrophysiologic phenomenon known as phase 2 reentry that can lead to premature ventricular contractions (PVCs), polymorphic VT, and VF.3,6

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DIAGNOSIS

The European Society of Cardiology identified three repolarization patterns associated with Brugada syndrome, all in the right precordial leads V1 to V3.2 The three patterns show two distinct patterns of ST-segment elevation: type 1 and type 2.9 The 2013 expert consensus recommendations on Brugada syndrome diagnosis require ST-segment elevation in one precordial lead.4

Type 1 ST-segment elevation has a J-wave amplitude of 2 mm or greater, a negative T wave, and little if any isoelectric segment between. This pattern has a distinct coved shape ST-segment elevation and is diagnostic of Brugada syndrome.7

Type 2 ST-segment elevation is characterized by a saddleback or downsloping ST-segment and T-wave morphology, with the ST-segment descending to the isoelectric line and rising to a biphasic or positive T wave.7 This pattern may suggest an underlying pathology of Brugada syndrome, but is not diagnostic unless the patient displays a type 1 pattern when administered a class Ia or Ic antiarrhythmic (Figure 1).4,7

FIGURE 1

FIGURE 1

The same patient may display a normal, type 1, or type 2 ECG over his or her lifetime.3 If a type 1 pattern of ST-segment elevation has not been documented and Brugada syndrome is suspected, or, if a type 2 pattern is documented, perform an IV drug challenge with a class Ia or 1c antiarrhythmic to unmask an underlying type 1 pattern. (However, a sodium challenge is not warranted in patients with a type 1 pattern, since the pattern is definitive for Brugada syndrome.)

The drug infusion challenge should be performed with continuous ECG monitoring in a facility capable of advanced cardiac life support because the challenge may induce ventricular dysrhythmias (Table 1). When recording a 12-lead ECG during a drug challenge, or when attempting to rule out Brugada syndrome, place the right precordial leads at the level of the second intercostal space, not the fourth (Figure 2).1,3 This position anatomically traverses the right ventricular outflow tract, which has a greater density of potassium channels and can better display early repolarization, thereby improving the sensitivity of identifying a Brugada pattern.1,3

TABLE 1

TABLE 1

FIGURE 2

FIGURE 2

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TRIGGERS

Several factors can precipitate Brugada syndrome on ECG.1-3,6,10 A study of fever in patients with a genetic mutation for Brugada syndrome found a greater loss of function of the sodium channel current at higher temperatures.6,10 Adler and colleagues also found that febrile patients seen in the ED over a 32-month period were 20 times more likely to have the type 1 pattern.10 Consumption of a large meal, cocaine, and alcohol toxicity are vagatonic and have been known to trigger a Brugada ECG.4,7,10

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DIFFERENTIAL DIAGNOSIS

To arrive at the diagnosis of Brugada syndrome, several benign and pathophysiologic conditions that cause ST-segment elevation in the right precordial leads must be ruled out.3,7 Known causes of this characteristic change in ECG morphology include myocardial ischemia or infarction, electrolyte imbalance (hyperkalemia, hypokalemia, hypercalcemia), early repolarization syndrome as seen in young athletes, arrhythmogenic right ventricular dysplasia/cardiomyopathy, Prinzmetal angina, left ventricular hypertrophy, pulmonary embolism, Duchenne muscular dystrophy, compression of the right ventricular outflow tract via tumor or hemopericardium, pectus excavatum, dissecting aortic aneurysm, and atypical left bundle-branch block.3,4 Echocardiography, stress echocardiography, and cardiac MRI can be used to exclude structural cardiac defects.

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RISK STRATIFICATION

Patients with Brugada syndrome who are at highest risk for sudden cardiac arrest have a type 1 pattern with a history of VF, VT, or syncopal episode. Programmed electrical stimulation during a standard electrophysiology study can be used as a tool in risk stratification. However, although initial research by the Brugada brothers determined the inducibility of ventricular dysrhythmia during programmed electrical stimulation to be an important predictor of dysrhythmic events, two major studies have challenged this theory: the FINGER and PRELUDE studies.

The FINGER study was the largest trial conducted to identify prognosis of Brugada syndrome and risk factors for sudden cardiac death.11 Eleven centers in France, Italy, the Netherlands, and Germany enrolled 1,029 patients with type 1 Brugada syndrome occurring spontaneously or following a drug infusion challenge. Patients were grouped into cohorts according to presentation: aborted sudden cardiac arrest, syncope, or asymptomatic. All patients underwent a uniform protocol at programmed electrical stimulation.

In the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) Registry, Priori and colleagues assessed the predictability of inducible VF or VT at programmed electrical stimulation for future dysrhythmic events in patients with no history of sustained VF or VT.12 The study enrolled 308 patients with type 1 Brugada syndrome on ECG and no history of prior sudden cardiac death; patients received uniform programmed electrical stimulation. In a follow-up period of 36 months, inducibility of VF or VT at programmed electrical stimulation did not correlate with an increased risk of future dysrhythmic events. Programmed electrical stimulation thereby was not found to be a useful tool in identifying high-risk patients with Brugada syndrome.7 A multicenter trial by Sacher and colleagues followed 378 patients with Brugada syndrome who received implantable cardioverter defibrillators: 31 for aborted sudden cardiac arrest, 181 for syncope, and 166 who were asymptomatic.13 At 10 years, the device recognized and appropriately treated ventricular dysrhythmias in 48% of the sudden cardiac arrest group, 19% for those with syncope, and 12% for asymptomatic patients. In asymptomatic patients, the devices appropriately recognized and treated ventricular dysrhythmia at a rate of 1% per year.13 The risk of sudden cardiac arrest in asymptomatic patients with Brugada syndrome due to new-onset VF is low.4,14

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PROGNOSIS AND TREATMENT

Research by Postema and colleagues on drug safety in patients with Brugada syndrome led to the establishment of four categories of medications accepted by the American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC): Drugs to be avoided, drugs to be preferably avoided, antiarrhythmic drugs, and diagnostic drugs (Table 2).15 All patients with Brugada syndrome, regardless of the degree of symptoms, should be thoroughly counseled to avoid medications that are known to induce the type 1 pattern and ventricular dysrhythmias.7,15 Among the many categories of drugs that should be avoided when a patient carries this diagnosis are antiarrhythmics, particularly class Ia/Ic, tricyclic antidepressants, and psychotropic drugs, common anesthetics such as propofol and bupivacaine, and a number of antianginal medications. Patients should avoid ventricular dysrhythmia triggers (cocaine, alcohol toxicity, and electrolyte imbalances). Since fever can be a trigger, it should be aggressively treated with antipyretics.

TABLE 2

TABLE 2

Patients who survive sudden cardiac arrest due to an irreversible cause should receive an ICD for secondary prevention.5,7,16 In patients with documented VT, documented self-terminating VT, or those with spontaneous ST-segment elevation and syncope, an ICD is considered reasonable.17

Drug therapy to prevent ventricular dysrhythmias in patients with Brugada syndrome is not the standard of care, as no trials have proven its efficacy.8 According to the 2006 ACC/AHA/ESC guidelines, however, an IV infusion of the beta-adrenergic agonist isoproterenol can be used to treat dysrhythmic or electrical storm. Quinidine, a class Ia antiarrhythmic, is being investigated as a potential treatment for patients with recurring VT. Quinidine reduces the risk of ventricular dysrhythmias by decreasing potassium outflow, making right ventricular outflow tract action more consistent.3,13,15 A study by Belhassen and Viskin demonstrated quinidine's prospective effectiveness by studying 25 patients with Brugada syndrome (15 symptomatic and 10 asymptomatic).18 All patients underwent programmed electrical stimulation, were inducible for ventricular dysrhythmia at baseline, and were treated with quinidine. In follow-up programmed electrical stimulation testing on quinidine, 22 of the 25 patients were noninducible.18

Treatment in the asymptomatic patients with Brugada syndrome is highly controversial.3,5,16 Although inducibility of VT or VF at programmed electrical stimulation was initially thought to be a predictor of future arrhythmic events by Brugada and colleagues, the FINGER study, the largest study of patients with Brugada syndrome thus far, disproved this theory.13 Programmed electrical stimulation in asymptomatic patients remains a topic of debate.

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CONCLUSION

Brugada syndrome, an inherited arrhythmogenic disease transmitted in an autosomal dominant fashion, is associated with increased risk of sudden cardiac arrest due to ventricular dysrhythmias. Syncope, polymorphic VT, VF, or sudden cardiac death may be the initial presenting signs, and occur most often in men in their 40s. Proper identification and workup for the characteristic ST-segment elevation in the right precordial leads V1 to V3 on ECG can be potentially lifesaving. A type 1 or coved ST-segment elevation is a diagnostic pattern; a type 2 or downsloping pattern may require an IV drug challenge to reveal a concealed type 1 pattern. Ventricular dysrhythmias, syncope, and sudden cardiac death are poor prognostic factors. Patients may need an ICD for primary or secondary prevention of sudden cardiac arrest. Asymptomatic patients have decreased incidence of dysrhythmia, and often require close follow-up and monitoring. New guidelines suggest that patients with Brugada syndrome be treated at an experienced center.4

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REFERENCES

1. Antzelevitch C, Brugada P, Borggrefe M, et al Brugada syndrome: report of the Second Consensus Conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005;111(5):659–670.
2. Wilde AA, Antzelevitch C, Borggrefe M, et al Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. 2002;106(19):2514–2519.
3. Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol. 2006;29(10):1130–1159.
4. Priori SG, Wilde AA, Horie M, et al HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932–1963.
5. Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol. 2012;5(3):606–616.
6. Kusano K. Brugada syndrome: recent understanding of pathophysiological mechanism and treatment. J Arrhythmia. 2013;2:77–82.
7. Wylie JV, Garlitski AC. Brugada syndrome. UpToDate. http://http://www.uptodate.com/contents/brugada-syndrome?detectedLanguage=en&source=search_result&search=brugada+syndrome&selectedTitle=1%7E50&provider=noProvider. Accessed March 2, 2015.
8. Brugada R, Campuzano O, Brugada P, et al Brugada syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle, WA: University of Washington; 1993–2013. http://http://www.ncbi.nlm.nih.gov/books/NBK1517. Accessed March 2, 2015.
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11. Probst V, Veltmann C, Eckardt L, et al Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation. 2010;121(5):635–643.
12. Priori SG, Gasparini M, Napolitano C. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol. 2012;59(1):37–45.
13. Sacher F, Probst V, Maury P, et al Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study-part 2. Circulation. 2013;128(16):1739–1747.
14. Tagaki M. Risk stratification in Brugada syndrome: role of programmed electrical stimulation. J Clinic Experiment Cardiol. 2013;S10:004. http://omicsonline.org/risk-stratification-in-brugada-syndrome-role-of-programmed-electrical-stimulation-2155-9880.S10-004.php?aid=12668. Accessed March 31, 2015.
15. Postema PG, Wolpert C, Amin AS, et al Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org). Heart Rhythm. 2009;6(9):1335–1341.
16. Shimizu A. Indication of ICD in Brugada syndrome. J Arrhythmia. 2013;29:110–116.
17. Epstein AE, DiMarco JP, Ellenbogen KA, et al ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;51(21):e1–e62.
18. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004;110(13):1731–1737.
Keywords:

Brugada syndrome; ECG; sudden cardiac arrest; ST-segment elevation; polymorphic ventricular tachycardia; ventricular fibrillation

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