Specific Therapy Based on the Genotype and Cellular Mechanism in Inherited Cardiac Arrhythmias. Long QT Syndrome and Brugada Syndrome

Wataru      Shimizu; Takeshi      Aiba; Charles      Antzelevitch

Abstract

Seven forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes have been identified. Genotype-phenotype correlation in clinical and experimental studies involving arterially-perfused canine left ventricular wedges suggest that β-blockers are protective in LQT1, less so in LQT2, but not protective in LQT3. A class IB sodium channel blocker, mexiletine, is most effective in abbreviating QT interval in LQT3, but effectively reduces transmural dispersion of repolarization (TDR) and prevents the development of Torsade de Pointes (TdP) in all 3 models, suggesting its potential as an adjunctive therapy in LQT1 and LQT2. High concentrations of intravenous nicorandil, a potassium channel opener, have been shown to be capable of decreasing QT and TDR, and preventing TdP in LQT1 and LQT2 but not in LQT3. The calcium channel blocker, verapamil, has also been suggested as adjunctive therapy for LQT1, LQT2 and possibly LQT3. Experimental data using right ventricular wedge preparations suggest that a prominent transient outward current (Ito )-mediated action potential (AP) notch and a loss of AP dome in epicardium, but not in endocardium, give rise to a transmural voltage gradient, resulting in ST segment elevation and the induction of ventricular fibrillation (VF), characteristics of the Brugada syndrome. Since the maintenance of the AP dome is determined by the balance of currents active at the end of phase 1 of the AP, any intervention that reduces the outward current or boosts inward current at the end of phase 1 may normalize the ST segment elevation and suppress VF. Such interventions are candidates for pharmacological therapy of the Brugada syndrome. The infusion of isoproterenol, a β-adrenergic stimulant, strongly augments L-type calcium current (ICa-L), and is the first choice for suppressing electrical storms associated with Brugada syndrome. Quinidine, by virtue of its actions to block Ito, has been proposed as adjunctive therapy, with an implantable cardioverter defibrillator as backup. Oral denopamine, atropine or cilostazol all increase ICa-L, and for this reason may be effective in reducing episodes of VF.

Keywords: electrocardiogram (ecg), lqt syndrome, epinephrine, genotype-specific therapy, sodium channel blockers, implantable cardioverter-defibrillator (icd), potassium channel openers, pacemaker therapy, endocardium, cardiac arrest