M

Fig. 5. Twelve-lead electrocardiogram with early repolarization pattern. Note the upward concavity of the ST segment in leads V3-V5, positive T-wave polarity, and notched J point.

Table 5

Abnormalities That Can Lead to ST Segment Elevation in the Right Precordial Leads

Right or left bundle-branch block, left ventricular hypertrophy Acute MI

Left ventricular aneurysm

Exercise test-induced

Acute myocarditis

Right ventricular infarction

Aortic dissection

Acute pulmonary thromboemboli

Central nervous system and autonomic nervous system abnormalities

Heterocyclic antidepressant overdose

Duchenne muscular dystrophy

Friedrich ataxia

Thiamine deficiency

Hypercalcemia

Hyperkalemia

Compression of RVOT by metastatic tumor Cocaine intoxication

Adapted with permission from: the American College of Cardiology (Gussak et al. The Brugada syndrome: clinical, electrophysiologic and genetic aspects. JACC 33[1]:8.)

to occur in the right precordial leads, because of the greater concentration of Ito in the right ventricular epicardium.

Candidate genes for the Brugada syndrome include mutations that increase Ito or Ik-atp, decrease ICa or INa, or autonomic receptors that modulate the activity of these channels. The first gene linked to the Brugada syndrome was SCN5A, the same sodium-channel gene that is abnormal in the LQT3 form of congenital LQTS (73). The mutations epicardium endocardium

"spike and dome" + epicardium epicardium endocardium

"spike and dome" + epicardium baseline

Fig. 6. Stylized epicardial (left) and epicardial + endocardial action potentials at baseline (top) and with sodium-channel block (bottom). The end of phase I (indicated by *) is determined by the balance between repolarizing Ito and depolarizing INa and ICa-L. With a decrease in INa (e.g. with flecainide), the resulting predominance of Lto moves the end of phase I sufficiently negative that Ica_L will not generate the phase 2 dome. Since this loss of the dome does not occur in the endocardium, there is a marked increase in heterogeneity of action-potential durations across the wall of the heart, which is believed to account for ST segment elevation and for reentrant excitation. (Reproduced with permission from: Roden et al. Drug-induced J point elevation: a marker for genetic risk of sudden death or ECG curiosity? JCE 1999;10:220.)

â– large potential difference -> ST segment elevation

Fig. 6. Stylized epicardial (left) and epicardial + endocardial action potentials at baseline (top) and with sodium-channel block (bottom). The end of phase I (indicated by *) is determined by the balance between repolarizing Ito and depolarizing INa and ICa-L. With a decrease in INa (e.g. with flecainide), the resulting predominance of Lto moves the end of phase I sufficiently negative that Ica_L will not generate the phase 2 dome. Since this loss of the dome does not occur in the endocardium, there is a marked increase in heterogeneity of action-potential durations across the wall of the heart, which is believed to account for ST segment elevation and for reentrant excitation. (Reproduced with permission from: Roden et al. Drug-induced J point elevation: a marker for genetic risk of sudden death or ECG curiosity? JCE 1999;10:220.)

that were identified in the Brugada patients were at different loci than the LQT3 mutations and produce different functional consequences (reduced sodium current rather than the persistent leakage of sodium current that is characteristic of LQT3). SCN5A was excluded as a candidate gene in at least one family, indicating that significant genetic heterogeneity is likely to exist in Brugada syndrome as well.

The reported effects of various pharmacologic interventions on the magnitude of ST-segment elevation in experimental models and in Brugada syndrome patients are consistent with the ionic specificity of the individual agents. Autonomic neurotransmit-ters like acetylcholine facilitate loss of the action-potential dome by suppressing calcium current and augmenting potassium current, and beta-adrenergic agonists restore the dome by augmenting ICa (78,79). Class I agents that block INa to a much greater extent than Ito (procainamide, ajmaline, flecainide) accentuate or unmask the syndrome (Fig. 7), but agents that block both channels (quinidine) diminish the ST segment elevation (78,80).

Experimental models have yielded new insights into potential mechanisms of arrhythmogenesis in the Brugada syndrome. It appears that Ito is distributed heteroge-neously throughout the epicardium, in addition to the transmural and regional differences that were previously described (75). Conditions that favor loss of the action-potential dome are therefore likely to create dispersion of repolarization within the epicardium, as well as transmural and regional dispersion of repolarization. Local dispersion of repolarization within the epicardium gives rise to current fluxes that can cause local re-excitation of the areas that lack the action-potential dome, a phenomenon that has

Mechanisms of Arrhythmogenesis in Brugada Syndrome

Fig. 7. (A) ECG tracing showing transient normalization of ST segments in a patient with Brugada syndrome. (B) ECG from the same patient after flecainide administration. (Reproduced with permission from: Alings et al. "Brugada" syndrome. Clinical data and suggested pathophysiologic mechanism. Circulation 1999;99:671.)

Fig. 7. (A) ECG tracing showing transient normalization of ST segments in a patient with Brugada syndrome. (B) ECG from the same patient after flecainide administration. (Reproduced with permission from: Alings et al. "Brugada" syndrome. Clinical data and suggested pathophysiologic mechanism. Circulation 1999;99:671.)

been called phase 2 reentry (81). Phase 2 reentry produces the closely coupled premature ventricular beats that initiate ventricular arrhythmias. When these premature beats propagate to other regions of the myocardium, the transmural and regional dispersion of repolarization creates the substrate for circus movement reentry, which is believed to be the mechanism by which polymorphic ventricular tachycardia (PVT)/VF are perpetuated.

Diagnostic Workup and Treatment

When a patient presents with a clinical history of syncope/pre-syncope or aborted cardiac arrest and ECG findings that suggest Brugada syndrome, several additional diagnostic measures are required. Conditions that can mimic the ECG manifestations of the disorder should be excluded (Table 5). Occult coronary-artery disease (CAD) should be ruled out by cardiac catheterization or exercise stress testing with adjunctive imaging. Echocardiography is usually sufficient to exclude cardiomyopathy with second ary ECG changes, although magnetic resonance imaging (MRI) may be required in some instances to distinguish between Brugada syndrome and subtle presentations of right ventricular dysplasia. It is now well-recognized that the ECG findings in Brugada syndrome can be dynamic (82). In some instances, ST-segment elevation may completely resolve, which can contribute to underdiagnosis of the disorder. For this reason, when symptomatic individuals with nondiagnostic ECG findings are encountered, pharmacologic challenge with procainamide or flecainide may reveal the typical ECG findings (80) (Fig. 7). All first-degree relatives of patients with proven Brugada syndrome should undergo ECG screening, with pharmacologic provocation if the resting ECG is nondiagnostic.

EPS reveals a prolonged HV interval in the majority of instances (74). VF is inducible in 66% of patients, and an additional 11% of patients have induced nonsustained PVT (74). The inducibility rates appear to be similar in symptomatic and asymptomatic patients. At present, the value of the EPS for risk-stratification of patients with Brugada syndrome is unclear. Specifically, insufficient information is available regarding the comparative prognosis of patients with sustained VF, nonsustained VT (NSVT), or no inducible arrhythmias. In the absence of definitive evidence that noninducible patients have a favorable prognosis, a "negative" study cannot be currently used to justify withholding therapy, considering the high incidence of serious arrhythmias during follow-up.

The available data indicate that the risk of serious arrhythmic events during follow-up is similar in symptomatic patients (14 of 41, or 34%) and asymptomatic patients (6 of 22, or 27%) (83). Although no randomized comparative trials have been performed, it appears that the risk of arrhythmia recurrence is similar in patients treated with ICDs, antiarrhythmic drugs, or no therapy; however, these events are almost always fatal in drug-treated or untreated patients, and no patients treated with ICDs have died during follow-up (83). In this study, treatment with beta-blockers, amiodarone, or both agents were all ineffective. In fact, there is some evidence that beta-blockers may actually be contraindicated (78). At present, the preferred treatment for symptomatic patients with Brugada syndrome as well as asymptomatic relatives with definite evidence of the disorder is ICD implantation—the only treatment with demonstrated efficacy (83). Quinidine, which has some activity against Ito, may be useful in some patients who sustain frequent ICD shocks. Anecdotal reports indicate that quinidine or other drugs guided by electrophysiology testing may be efficacious for patients with idiopathic VF, although it is unclear whether these patients in fact had Brugada syndrome (84,85). At present, no drugs are clinically available that possess selective activity against Ito. There have been occasional reports of patients who developed the Brugada ECG pattern during treatment with class IC drugs for atrial arrhythmias (86). As these patients do not appear to have an adverse prognosis, the most prudent approach is to simply discontinue the drug. It is possible that these patients have mutations in ion-channel genes that do not have severe functional consequences in the absence of class IC drugs; a similar phenomenon has been described in the case of LQTS. It is presently unclear whether treatment is warranted for asymptomatic individuals who have the Brugada ECG pattern noted incidentally on a screening ECG and have no family history of syncope or sudden cardiac death, although avoidance of class IC drugs would also be prudent in this situation.

Fig. 8. ECG during VT in a patient with arrhythmogenic right ventricular dysplasia. Note the left bundle-branch-block (LBBB) configuration. (Reproduced with permission from: Marcus et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. PACE 1995;18:1300.)

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