Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects

Abstract

Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome first described as a new clinical entity in 1992. Electrocardiographically characterized by distinct coved type ST segment elevation in the right-precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young adults, and less frequently in infants and children. The electrocardiographic manifestations of BrS are often concealed and may be unmasked or aggravated by sodium channel blockers, a febrile state, vagotonic agents, as well as by tricyclic and tetracyclic antidepressants. An implantable cardioverter defibrillator is the most widely accepted approach to therapy. Pharmacologic therapy is designed to produce an inward shift in the balance of currents active during the early phases of the right ventricular action potential (AP) and can be used to abort electrical storms or as an adjunct or alternative to device therapy when use of an implantable cardioverter defibrillator is not possible. Isoproterenol, cilostazol, and milrinone boost calcium channel current and drugs like quinidine, bepridil, and the Chinese herb extract Wenxin Keli inhibit the transient outward current, acting to diminish the AP notch and thus to suppress the substrate and trigger for ventricular tachycardia or fibrillation. Radiofrequency ablation of the right ventricular outflow tract epicardium of patients with BrS has recently been shown to reduce arrhythmia vulnerability and the electrocardiographic manifestation of the disease, presumably by destroying the cells with more prominent AP notch. This review provides an overview of the clinical, genetic, molecular, and cellular aspects of BrS as well as the approach to therapy.

Figure 1

Three Types of ST segment elevation generally observed in patients with the Brugada syndrome. Shown are precordial leads recorded from a patient diagnosed with the Brugada syndrome. Note the dynamic ECG changes occurring over a period of a week. The left panel shows a clear Type 1 ECG, which is diagnostic of the Brugada syndrome. A saddleback ST segment elevation (Type 2) is observed a day later. The ST segment is further normalized a week later, showing a Type 3 ECG. Modified from , with permission.

Figure 2

Cellular basis for electrocardiographic and arrhythmic manifestation of BrS. Each panel shows transmembrane action potentials from one endocardial (top) and two epicardial sites together with a transmural ECG recorded from a canine coronary-perfused right ventricular wedge preparation. A: Control (Basic cycle length (BCL) 400 msec). B: Combined sodium and calcium channel block with terfenadine (5 μM) accentuates the epicardial action potential notch creating a transmural voltage gradient that manifests as an ST segment elevation or exaggerated J wave in the ECG. C: Continued exposure to terfenadine results in all-or-none repolarization at the end of phase 1 at some epicardial sites but not others, creating a local epicardial dispersion of repolarization (EDR) as well as a transmural dispersion of repolarization (TDR). D: Phase 2 reentry occurs when the epicardial action potential dome propagates from a site where it is maintained to regions where it has been lost giving rise to a closely coupled extrasystole. E: Extrastimulus (S1–S2 = 250 msec) applied to epicardium triggers a polymorphic VT. F: Phase 2 reentrant extrasystole triggers a brief episode of polymorphic VT. (Modified from reference, with permission)

Figure 3

Proposed mechanism for the Brugada syndrome. An outward shift in the balance of currents serves to amplify existing heterogeneities by causing loss of the action potential dome at some epicardial, but not endocardial sites. A vulnerable window develops as a result of the dispersion of repolarization and refractoriness within epicardium as well as across the wall. Epicardial dispersion leads to the development of phase 2 reentry, which provides the extrasystole that captures the vulnerable window and initiates VT/VF via a circus movement reentry mechanism. Modified from , with permission.

Figure 4

Heterogeneities in the appearance of the epicardial action potential second upstroke gives rise to fractionated epicardial electrogram (EG) activity in the setting of Brugada syndrome (BrS). Left panel: Shown are right precordial lead recordings and unipolar and bipolar EGs recorded form the right ventricular outflow tract of a BrS patient (from Nademanee et al. ). Right panel: ECG, action potentials from endocardium (Endo) and two epicardial (Epi) sites, and a bipolar epicardial EG (Bipolar EG) all simultaneously recorded from a coronary-perfused right ventricular wedge preparation treated with the I_to agonist NS5806 (5 μM) and the calcium channel blocker verapamil (2 μM) to induce the Brugada phenotype. Basic cycle length=1000 ms. Reproduced from, with permission.

Figure 5

Concealed phase 2 reentry as the basis for late potential and fractionated bipolar epicardial (Epi) electrogram (Bipolar EG) activity in an experimental model of Brugada syndrome. Each panel shows (from top to bottom) a Bipolar EG, action potentials recorded from endocardium (Endo) and two Epi sites and an ECG all simultaneously recorded from a coronary-perfused right ventricular wedge preparation exposed to NS5806 (5 μM) and verapamil (2 μM) to induce the Brugada phenotype. Heterogeneous loss of the dome at epicardium caused local re-excitation via a ‘concealed’ phase 2 re-entry mechanism, leading to the development of late potentials and fractionated bipolar epicardial EG activity. No major delays in conduction of the primary beat were ever observed. Each panel shows results from a different preparation. Basic cycle length=1000 ms. Reproduced from , with permission.

Figure 6

Epicardial radiofrequency ablation abolishes the electrographic and arrhythmic manifestations of Brugada syndrome (BrS) in coronary-perfused canine right ventricular wedge-model. Transmembrane action potentials (AP) were simultaneously recorded from one endocardial (Endo) and two epicardial (Epi) sites together with a transmural pseudo-ECG. (The model is schematically illustrated in the top panels). Stimulus marker (pacing) is indicated in the 4^th row. All recordings were obtained at 1000 ms basic cycle length. Column 1: Control. Column 2: Recorded 20 min after the addition of the I_to-agonist NS5806 (10μM) to the coronary perfusate. The much greater accentuation of the Epicardial (Epi) vs. Endocardial (Endo) AP notch was associated with accentuation of the J wave in the ECG. Column 3: Recorded 15 min after increasing the concentration of NS5806 to 12.5 μM. A stimulated premature beat induced VT (later VF) via a phase 2 reentry (P2R) mechanism. The abbreviated cycle length caused loss of the AP dome in Epi1 due to use-dependent block of I_Na by NS5806. In the Endo and Epi2 sites the dome is maintained and the notch is slightly reduced because slow recovery of I_to overwhelmed the use-dependent inhibition of I_Na. The pronounced epicardial and transmural dispersion of repolarization created the substrate for P2R and VT/VF. Column 4: Recorded after washout of NS5806 and 70 min after RF ablation of the epicardial surface. APs were recorded from the subepicardial layer (Subepi) just below the ablation border and from the midmyocardium (Mid) because the Epi layer was destroyed. Column 5: Recorded 45 min after re-introduction of NS5806 (12.5μM) to the coronary perfusate. After ablation of epicardium, NS5806 was no longer able to induce the ECG or arrhythmic manifestations of BrS.