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 maybe revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic ortetracyclic 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). KeywordsBrugada syndrome; Phase 2 reentry; ST segment elevation; I Na ; I to ; Implantable cardioverterdefibrillator (ICD); VT; SCN5A mutations; Sudden death; Bradycardia Clinical Characteristics and Diagnostic CriteriaThe Brugada syndrome typically manifests in the third or fourth decade of life (average age of 41±15 years), although patients have been diagnosed with the syndrome at an age as young as 2 days and as old as 84 years. The prevalence of the disease is estimated to be at least 5 per 10,000 inhabitants in Southeast Asia, where the syndrome is endemic (Nademanee et al. 1997). In Japan, a Brugada syndrome ECG (type 1) is observed in 12 per 10,000 inhabitants; type 2 and type 3 ECGs, which are not diagnostic of Brugada syndrome, are much more prevalent, appearing in 58 per 10,000 inhabitants (Miyasaka et al. 2001). The true prevalence of the disease in the general population is difficult to estimate because the ECG pattern is often concealed (Brugada et al. 2003). Sudden unexplained nocturnal death syndrome (SUNDS also known as SUDS) and Brugada syndrome have been shown to be phenotypically, genetically, and functionally the same disorder (Vatta et al. 2002).Although syncope and sudden death are a consequence of ventricular tachycardia/fibrillation (VT/VF), approximately 20% of Brugada syndrome patients also develop supraventricular arrhythmias (Morita et al. 2002). Atrial fibrillation (AF) is reported in approximately 10%-20% of cases. Atrio-ventricular (AV) nodal reentrant tachycardia (AVNRT) and Wolf-ParkinsonWhite (WPW) syndrome have been described as well (Eckardt et al. 2001 et al. 2004)...

Dimethyl Lithospermate B, an Extract of Danshen, Suppresses Arrhythmogenesis Associated With the Brugada Syndrome

“…A pharmacological solution is desirable as an alternative to device therapy in these cases as well as in minimizing the firing of the ICD in patients with frequent events. 1,10,16 Our data suggest that dmLSB is effective in eliminating the arrhythmogenic substrate responsible for the Brugada syndrome and that it deserves further study as a pharmacological adjunct to ICD usage.…”

“…Previous studies from our laboratory suggest block of I to as a therapeutic strategy for the Brugada syndrome (for review, see Antzelevitch and Fish 10 ). Both I to block and delay in the inactivation of I Na with dmLSB result in a positive shift in the balance of currents active at the end of epicardial AP phase 1, making loss of the epicardial AP dome and phase 2 reentry unlikely.…”

Inherited Arrhythmias

“…However, pharmacotherapy with quinidine has been tried. 169,170 Other pharmacological approaches use ranolazine or derivatives that selectively inhibit late I Na , reduce [Na ϩ ] i -dependent intracellular Ca 2ϩ overload, and attenuate the abnormalities of ventricular repolarization and contractility that are associated with ischemia/reperfusion injury and/or HF. Future studies will have to determine whether inhibition of late I Na reduces proarrhythmogenic Ca 2ϩ overload.…”

From syncope to ICD: clinical paths of the Brugada syndrome

“…3. La conversione farmacologica del tipo 2 o 3 al tipo 1, associata a uno degli altri criteri, è considerata positiva ai fini diagnostici Approssimativamente il 20% (range: 6-38%) dei pazienti con SB sviluppa un'aritmia sopraventricolare: nel 10-20% di questi casi si tratta di fibrillazione atriale 33,34,50 . La fibrillazione atriale è la più comune aritmia atriale riscontrata nei pazienti affetti da SB, mentre più rare sono le aritmie da rientro intranodale e quelle da rientro atrio-ventricolare su via anomala 59 .…”

“…• nei soggetti con anamnesi per precedente arresto cardiaco che hanno una aspettativa di vita maggiore di 1 anno e un normale stato funzionale (Classe I, Livello di evidenza C) 43,45 ; • nei soggetti con sopraslivellamento ST in V1-V3 spontaneo e storia di sincope, indipendentemente dalla presenza di una mutazione sul gene SCN5A (Classe IIa, Livello di evidenza C) 33,42,43 ; • nei pazienti con SB nei quali sia documentata una TV che non abbia causato arresto cardiaco (Classe IIa, Livello di evidenza C) 42,43,45 . Per quanto riguarda la gran parte di soggetti con rischio intermedio e basso, tuttora l'evidenza utilizzata per fornire le raccomandazioni proposte clinica e terapia è in gran parte basata sull'opinione degli esperti.…”