Therapy for the Brugada syndrome

Abstract

The Brugada syndrome is a congenital syndrome of sudden cardiac death first described as a new clinical entity in 1992. Electrocardiographically characterized by a 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 and otherwise healthy adults, and less frequently in infants and children. The ECG manifestations of the Brugada syndrome are often dynamic or concealed and may be revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, and hypokalemia, as well as by alcohol and cocaine toxicity. An implantable cardioverter-defibrillator (ICD) is the most widely accepted approach to therapy. Pharmacological therapy aimed at rebalancing the currents active during phase 1 of the right ventricular action potential is used to abort electrical storms, as an adjunct to device therapy, and as an alternative to device therapy when use of an ICD is not possible. Isoproterenol and cilostazol boost calcium channel current, and drugs like quinidine inhibit the transient outward current, acting to diminish the action potential notch and thus suppress the substrate and trigger for ventricular tachycardia/fibrillation (VT/VF).

Fig. 1

Twelve-lead electrocardiogram (EGG) tracings in an asymptomatic 26-year-old man with the Brugada syndrome. Left: Baseline: type 2 EGG (not diagnostic) displaying a “saddleback-type” ST segment elevation is observed in V₂,. Center: After intravenous administration of 750 mg procainamide, the type 2 EGG is converted to the diagnostic type 1 EGG consisting of a “coved-type” ST segment elevation. Right: A few days after oral administration of quinidine bisulfate (1,500 mg/day, serum quinidine level 2.6 mg/l), ST segment elevation is attenuated, displaying a nonspecific abnormal pattern in the right precordilal leads. VF could be induced during control and procainamide infusion, but not after quinidline. (Modified from Beihassen et al. 2002, with permission)

Fig. 2a-d

Terfenadine-induced ST segment elevation, T wave inversion, transmural and epicardial dispersion of repolarization, and phase 2 reentry. Each panel shows transmembrane action potentials from one endocardial (top) and two epicardial sites together with a transmural ECG recorded from a canine arterially perfused right ventricular wedge preparation. a Control (BCL 400 ms). b Terfenadine (5μ pM) accentuated the epicardial action potential notch creating a transmural voltage gradient that manifests as an ST segment elevation or exaggerated J wave in the ECG. First beat recorded after changing from BCL 800 ms to BCL 400 ms. c Continued pacing at BCL 400 ms 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. (Note: d was recorded from a different preparation.) (From Fish and Antzelevitch 2004, with permission)

Fig. 3a-d

Spontaneous and programmed electrical stimulation-induced polymorphic VT in RV wedge preparations pretreated with terfenadine (5-10μpM).a Phase 2 reentry in epicardium gives rise to a closely coupled extrasystole. b Phase 2 reentrant extrasystole triggers a brief episode of polymorphic VT. c Phase 2 reentrant extrasystole triggers reentry d Same impalements and pacing conditions as c, however an extra stimulus = 250 ms) applied to epicardium (S1-S2 = 250 ms) applied to epicardium triggers a polymorphic VT. (From Fish and Antzelevitch 2004, with permission)

Fig. 4

Proposed mechanism for the Brugada syndrome. A 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 Antzelevitch 2001b, with permission)

Fig. 5

Indications for ICD implantation in patients with the Brugada syndrome

Fig. 6a,b

Effects of I_to blockers 4-AP and quinidine on pinacidil-induced phase 2 reentry and VT in the arterially perfused RV wedge preparation. In both examples, 2.5 mmol/l pinacidil produced heterogeneous loss ofAP dome in epicardium, resulting in ST segment elevation, phase 2 reentry, and VT (left); 4-AP (a) and quinidine (b) restored epicardial AP dome, reduced both transmural and epicardial dispersion of repolarization, normalized the ST segment, and prevented phase 2 reentry and VT in continued presence of pinacidil. (From Yan and Antzelevitch 1999, with permission)

Fig. 7

Precordial leads recorded from a Brugada syndrome patient before and after quinidine (1,500 mg/day). (Modified from Alings et al. 2001, with permission)

Fig. 8a-c

Effects of I_to block with tedisamil to suppress phase 2 reentry induced by terfenadine in an arterially perfused canine RV wedge preparation. a Control, BCL 800 ms. b Terfenadine (5μ M) induces ST segment elevation as a result of heterogeneous loss of the epicardial action potential dome, leading to phase 2 reentry, which triggers an episode of poly VT (BCL 800 ms). c Addition of tedisamil (2μM) normalizes the ST segment and prevents loss of the epicardial action potential dome and suppresses phase 2 reentry induced polymorphic VT(BCL 800 ms)

Fig. 9a-c

Effects of I_to blockade with AVE0118 to suppress phase 2 reentry induced by terfenadine in an arterially perfased canine RV wedge preparation. a Control, BCL 800 ms. b Terfenadine (5 μM) induces ST segment elevation as a result of heterogeneous loss of the epicardial action potential dome, leading to phase 2 reentry3 which triggers a closely coupled extrasystole (BCL = 800 ms). c Addition of AVEO 118 (7 μM) prevents loss of the epicardial action potential dome and phase 2 reentry-induced arrhythmias (BCL = 800 ms)