Novel therapeutic strategies for the management of ventricular arrhythmias associated with the Brugada syndrome

Abstract

Introduction Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome characterized by prominent J waves appearing as distinct coved type ST segment elevation in the right precordial leads of the ECG. It is associated with a high risk for sudden cardiac death. Areas Covered We discuss 1) ECG manifestations of BrS which can be unmasked or aggravated by sodium channel blockers, febrile states, vagotonic agents, as well as tricyclic and tetracyclic antidepressants; 2) Genetic basis of BrS; 3) Ionic and cellular mechanisms underlying BrS; 4) Therapy involving devices including an implantable cardioverter defibrillator (ICD); 5) Therapy involving radiofrequency ablation; and 6) Therapy involving pharmacological therapy which is aimed at producing an inward shift in the balance of the currents active during phase 1 of the right ventricular action potential either by boosting calcium channel current (isoproterenol, cilostazol and milrinone) or by inhibition of transient outward current Ito (quinidine, bepridil and the Chinese herb extract Wenxin Keli). Expert Opinion This review provides an overview of the clinical and molecular aspects of BrS with a focus on approaches to therapy. Available data suggest that agents capable of inhibiting the transient outward current Ito can exert an ameliorative effect regardless of the underlying cause.

Pharmacological Therapy in Brugada Syndrome

“…When phase one is repolarised beyond the voltage range at which L-type Ca 2+ channels activate, the Ca 2+ channels fail to activate, resulting in loss of the action potential dome. 7 Beta adrenergic agents, such as isoproterenol, denopamine or orciprenaline, augment L-type calcium channels, and this is the basis for their usefulness in controlling VF storms in BrS. 29,33,63 Isoproterenol has been shown to be effective in controlling VF storm either as a lone agent or in combination with quinidine.…”

“…29,70,77,[81][82][83] In a study of seven patients with repetitive VF episodes, Murakami et al 84 This effect of bepridil may be due to its effect to block I f 86 as well as its I Ca -blocking effect. 7 Currently, bepridil is available only in Japan.…”

“…Both result in an outward shift in the net transmembrane current active at the end of phase one of the right ventricular epicardial action potential (where I to is most prominent). [6][7][8] The guidelines recommend ICD implantation in patients with BrS who have survived a cardiac arrest, or have documented spontaneous sustained VT (class I). 3,4 ICD implantation should also be considered in patients with BrS who have had a syncopal episode suspected to be caused by VT or VF (class IIa).…”

Should theophylline be added to the J wave syndrome therapeutic armamentarium?

“…The principal goal of therapy in both cases is therefore to effect an inward shift in the balance of currents. This can be accomplished either by boosting inward calcium channel current using β‐adrenergic agent or phosphodiesterase III inhibitors or by reducing outward currents, particularly I to , using agents such as quinidine …”

Cellular mechanisms underlying the effects of cilostazol, milrinone, isoproterenol and ajmaline on electrographic and arrhythmic manifestations of early repolarization syndrome, and comparative analysis of the cardiac electrophysiological effects of the optical isomers of mexiletine

“…Although overlap-phenotypes are also frequent, ERS mainly involves the LV, whilst BrS preferentially affects the right ventricular outflow tract (RVOT), so thus its ECG-sign is depicted in right precordial leads [Patocskai 2015CPC, Antzelevitch 2016. Lately, clinical studies tested the effect of ajmaline on early repolarization pattern [Roten 2012, Bastiaenen 2013.…”