Brugada syndrome mimicking acute coronary syndrome.

Abstract: This report describes a 42-year-old man with Brugada syndrome (BRS) mimicking acute coronary syndrome. Chest pain, near-syncope, and electrocardiographic changes were thought initially to be due to ischemia. Cardiac catheterization was performed. The coronary arteries and left ventricular function were normal. Careful review of his electrocardiogram suggested a diagnosis of BRS. BRS may be confused with acute coronary syndrome; early recognition of this syndrome is essential, as implantable cardioverter-defibrillator therapy may be life-saving.

Key Words: Brugada syndrome, implantable cardioverter-defibrillator, ST-segment elevation, sudden cardiac death, ventricular tachycardia/fibrillation (1)

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Brugada syndrome (BRS) is characterized by a history of syncope or sudden cardiac death (SCD) and a characteristic electrocardiographic (ECG) pattern. It is associated with a high incidence of SCD secondary to ventricular arrhythmias. It is therefore imperative that all practicing physicians be familiar with the typical ECG manifestations of BRS and prompt referral for an implantable cardioverter-defibrillator (ICD) placement. (1,3)

The following case report illustrates some of the problems associated with the diagnosis of BRS in a patient who presents with syncope and ST-segment elevation (ST-SE) in the right precordial leads ([V.sub.1]-[V.sub.3]).

Case Report

A 42-year-old white male presented with syncope. He had a family history positive for premature coronary disease but not for sudden death. His medical history is significant for severe hypercholesterolemia and hypertriglyceridemia; there was no history of chest pain or syncope. On the day of admission, he had a sudden onset of chest tightness and diaphoresis associated with syncope. He was brought to the emergency department after receiving nitroglycerin and aspirin, with no improvement. He was given morphine and became pain free. The physical examination was normal. The ECG revealed greater than 2 mm downsloping ST-SE on leads [V.sub.1]-[V.sub.3]. Serum electrolytes and cardiac enzymes were normal. The cause of the chest pain remained obscure.

In light of his chest pain and ECG changes, emergent cardiac catheterization was performed. The coronary arteriogram revealed normal left ventricular function and normal coronary arteries. Review of his ECG suggested a diagnosis of BRS. Electroencephalogram, magnetic resonance imaging, and magnetic resonance angiography were normal. When other causes of syncope were excluded, he was referred for an ICD. His family members were referred for complete cardiology evaluation.

Discussion

Mechanism

Brugada syndrome is a primary cardiac electrophysiologic disease of the right ventricular epicardium and was described by Pedro and Josep Brugada in 1992. BRS is a familial disease that displays an autosomal dominant mode of transmission and has been linked to mutations in SCN5A, a gene located on chromosome 3 encoding the [alpha]-subunit of the sodium channel that leads to sodium channelopathy and causes a reduction in the density of the fast sodium current. This results in a less opposed and therefore more prominent transient outward potassium current ([I.sub.to]) and loss of the action potential dome in the right ventricular epicardium but not endocardium. The net effect is a transmural voltage gradient that sets the stage for both the ECG abnormality and the propensity for the malignant reentrant ventricular tachyarrhythmias (VT/VF). (1) In support of this theory, sodium channel blocking agents such as procainamide unmask the ECG phenotype and are used clinically as a drug challenge for the diagnosis of BRS. (2) Also, the polymorphic VT can often be induced in these patients by programmed electrical stimulation of the heart, suggesting a reentrant mechanism. (3)

Clinical presentation

Syncope or SCD is the only symptom in patients with BRS. In some cases, SCD caused by rapid polymorphic VT is the first symptom of the disease. Self-terminating episodes lead to repeated episodes of syncope. (4) Cardiac events typically occur during sleep (vagal stimulation is believed to trigger the arrhythmia in some patients) or at rest. (5) Patients with history of syncope or aborted sudden death are at high risk and deserve aggressive treatment. (1)

[FIGURE 1 OMITTED]

The mean age at which symptoms first appear in affected individuals (both male and female) is in the third to the fourth decade, although they may occur in both infancy and old age. (1,4) BRS is rare in the United States, although the exact prevalence is unknown. It is more common in Southeast Asia. (2)

ECG and differential diagnosis

Brugada syndrome is characterized by complete or incomplete right bundle branch block, transient (concealed BRS) or persistent (overt BRS) ST-SE in the right pericardial leads ([V.sub.1]-[V.sub.3]), SCD caused by polymorphic VT or VF, (1,5) and the absence of prolongation of the QT interval during sinus rhythm. (5) The ECG findings are not explainable by other conditions such as a serum electrolyte abnormality, structural heart disease, or ischemia. (6)

Accordingly, the coronary arteriogram, echocardiogram, magnetic resonance imaging, and right ventricular endomyocardial biopsy must be normal. (7) These peculiar ECG abnormalities are often more prominent in the right chest leads placed at or above the third intercostal space--a higher-than-usual placement. (8) On electrophysiologic study, there is frequently prolongation of the H-V interval, which supports an abnormality of the conduction system, probably the right bundle branch (Fig. 1). (5)

In BRS there are two ST-SE morphologies (Table 2 and Fig. 3): coved ST-SE (dome shape or convex upward) with negative T-wave (type 1 BRS), and saddleback ST-SE (concave upward) with positive or biphasic T-wave (type 2) or with positive T-wave (type 3). (4) Acute anteroseptal myocardial infarction may also give rise to ST-SE on the ECG and sometimes cause confusion, as seen in this case. Although the ECG featured in acute anteroseptal myocardial infarction may mimic those found in BRS, there are several means for differentiating the two conditions (Table 1 and Fig. 2). (9)

The differential diagnosis for ST-SE in the right precordial leads in conditions other than BRS includes anteroseptal myocardial infarction or ischemia, right ventricular ischemia or infarction, early repolarization syndrome, acute pulmonary embolism, dissecting aortic aneurysm, right bundle branch block, left bundle branch block, left ventricular hypertrophy, hyperkalemia, hypercalcemia, arrhythmogenic right ventricular dysplasia/cardiomyopathy, acute myocarditis and pericarditis, tricyclic antidepressants, cocaine intoxication, hypothermia, mediastinal tumors compressing right ventricular outflow tract, right ventricular outflow tract obstruction, various central and autonomic nervous system abnormalities, and Friedreich ataxia. (2,4,5,6,10) Structural heart disease must therefore be excluded before making the diagnosis of BRS (Fig. 3).

The ECG abnormalities are precipitated by or unmasked by drugs such as flecainide, procainamide, ajmaline, disopyramide, propafenone, pilsicainide, [beta]-blockers, [alpha]-adrenergic agonists, first-generation antihistamines (dimenhydrinate), cocaine toxicity, tricyclic antidepressants, and vagotonic agents, as well as conditions such as febrile states, vagotonia, and alcohol consumption. (7) Consequently, avoidance of such "unmaskers" is critical in patients with BRS.

One of the intriguing aspects of BRS is that despite equal genetic transmission of the disease, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this sex-related distinction was recently shown to be due to a more prominent [I.sub.to]-mediated (transient outward potassium current) action potential notch in the right ventricular epicardium of males versus females. (10) The prognosis is poor, whether the patient is symptomatic or asymptomatic, with a 10% annual mortality rate.

Antiarrhythmic drugs including [beta]-blockers and amiodarone have not shown benefit in prolonging survival. Only patients with an ICD are protected from SCD. When provided with an ICD, total mortality rate in patients with BRS has been 0%, with up to 10 years of follow-up. (3,5)

Conclusion

BRS should be considered in the differential diagnosis in patients with unexplained syncope or SCD, especially if they have a positive family history of unexplained syncope or SCD. Also, it should be considered in patients with right precordial leads ([V.sub.1]-[V.sub.3]) ST-SE that are unexplainable by any other condition such as ischemia, serum electrolyte abnormality, or structural heart disease.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Patients presenting with syncope or presyncope should have a 12-lead resting ECG with shift [V.sub.1], [V.sub.2] above the third intercostal space to reveal BRS changes on ECG. (10)

Individuals with asymptomatic BRS with a family history of SCD should be examined for mutations of the SCN5A gene and possible electrophysiologic study (EPS). Family members should be referred for complete evaluation.

Cardiac EPS in patients with the BRS may or may not be needed: When the patient has classic Brugada waves in the ECG after VT has returned to normal, there is the clear need for an ICD, though not necessarily for an EPS. (7)

Some clinicians believe that asymptomatic patients with ECG criteria for BRS should have an EPS, and, if VT is inducible, then an ICD should be subsequently implanted. (7)

Rapid referral and placement of an ICD is associated with excellent prognosis, whereas failure to diagnose this condition is associated with a high risk of SCD. As such, it is imperative that all practicing physicians be familiar with the typical ECG manifestations of BRS. It is hoped that such familiarity will lead to a sizable increase in the identification and treatment of patients with this syndrome and therefore at risk of SCD. (5)

References

1. Littman L, Honroe MH, Kerns WP, et al Brugada syndrome and Brugada sign: clinical spectrum with a guide for the clinician. Am Heart J 2003;145:768-778.

2. Weiss R, Barmada MM, Nguyen Tuduy, et al. Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3. Circulation 2002;105:707.

3. Naccarelli GV, Antzelevitch CT. Brugada syndrome: clinical, genetic, cellular, and molecular abnormalities. Am J Med 2001;110:573-581.

4. Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002;106:2514-2519.

5. Antzelevitch C, Brugada P, Brugada R. The Brugada syndrome. Armonk, NY: Futura Publishing Co; 1999: 4,7,30-32,49,73.

6. Gussak I, Antzelevitch C, Bjerregaard P, et al. The Brugada syndrome: clinical, electrophysiologic and genetic aspects Am Coll Cardiol 1999;33:5-51.

7. Ahn J, Wills Hurst J. Worrisome thoughts about the diagnosis and treatment of patients with Brugada waves and the Brugada syndrome. Circulation 2004;109:1465.

8. Takagi M, Toda I, Takeuchi K, et al. Utility of right precordial leads at higher intercostal space positions to diagnose Brugada syndrome. Pacing Clin Electrophysiol 2002;25:241-242.

9. Wang K, Astinger RW, Marriott HJL. ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med 2003;349:2128-2135.

10. Antzelevitch C, Brugada P, Brugada J. Brugada syndrome: 1992-2002: a historical perspective J Am Coll Cardiol 2003;41:1668.

That is what learning is. You suddenly understand something you've
understood all your life, but in a new way.
--Doris Lessing

Samir Edward Yousef, MD, and John M. Herre, MD, FACC 

From the Department of Medicine and the Department of Cardiology, Eastern Virginia Medical School, Norfolk, VA.

Reprint requests to Samir Edward Yousef, MD, 600-F Fairfax Avenue, Norfolk, VA 23507. Email: [e-mail]

The authors have no commercial or proprietary interest in any drug, device, or equipment mentioned in this article.

Accepted February 8, 2005.

RELATED ARTICLE: Key Points

* Brugada syndrome (BRS) is a primary cardiac electrophysiologic disease of the right ventricular epicardium.

* BRS should be considered as a differential diagnosis in patients with unexplained syncope or sudden cardiac death.

* BRS should be considered in the differential diagnosis of ST-segment elevation in the right precordial leads not explainable by other conditions such as ischemia, electrolyte abnormality, or structural heart disease.

* The only effective gold standard therapy to date is an implantable cardiac defibrillator, which should be considered in symptomatic individuals and in asymptomatic patients with positive electrophysiologic testing.

Table 1. Differential diagnosis

Features          Brugada syndrome           Acute myocardial infarction

RBBB              RS[bar.R] in [V.sub.1]-    Uncommon feature
                    [V.sub.2]
ST-SE             Typically downsloping,     Upsloping, plateau, or
                    coved type or              shoulder
                    saddleback type
                    due to J-point
                    elevation
Reciprocal ST-SE  N/A                        Reciprocal ST-segment
  depression                                   depression in opposite
                                               leads
T-wave            Inverted in coved type,    Inverted
                    positive or biphasic in
                    saddleback ST-SE
Pathological Qs   N/A                        Develop as time progresses
Serial ECGs       No changes                 Development of pathological
                                               Q waves, T-wave
                                               inversion, and
                                               attenuation of ST-SE as
                                               time progresses

RBBB, right bundle branch block; ST-SE, ST-segment elevation; ECG,
electrocardiogram.

Table 2. ST-segment abnormalities in leads [V.sup.1] to [V.sup.3]

                            Type 1                   Type 2

J-wave amplitude      [less than or equal to]  [less than or equal to]
                        2 mm                     2 mm
T wave                Negative                 Positive or biphasic
ST-T configuration    Coved type               Saddleback
ST segment (terminal  Gradually descending     Elevated
  portion)                                       [less than or equal to]
                                                 1 mm

                              Type 3

J-wave amplitude      [less than or equal to] 2 mm
T wave                Positive
ST-T configuration    Saddleback
ST segment (terminal  Elevated > 1 mm
  portion)

1 mm = 0.1 mV. The terminal portion of the ST segment refers to the
latter have of the ST segment.