Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome

Abstract

Background Early repolarization pattern in the ECG has been associated with increased risk for ventricular tachycardia/fibrillation (VT/VF), particularly when manifest in inferior leads. This study examines the mechanisms underlying VT/VF in the early repolarization syndrome (ERS). Method Transmembrane action potentials (AP) were simultaneously recorded from 2 epicardial and 1 endocardial site of coronary-perfused canine left-ventricular (LV) wedge preparations, together with a pseudo-ECG. Transient outward current (Ito) was recorded from epicardial myocytes isolated from inferior and lateral LV of the same heart. Results J wave area (pseudo-ECG), epicardial AP notch magnitude and index were larger in inferior vs. lateral wall preparations at baseline and after exposure to provocative agents (NS5806+verapamil+acetylcholine (ACh)). Ito density was greater in myocytes from inferior vs. lateral wall (18.4±2.3pA/pF vs. 11.6±2.0pA/pF;p<0.05). A combination of NS5806 (7μM) and verapamil (3μM) or pinacidil (4μM), used to pharmacologically model the genetic defects responsible for ERS, resulted in prominent J-point and ST-segment elevation. ACh (3μM), simulating increased vagal tone, precipitated phase-2-reentry-induced polymorphic VT/VF. Using identical protocols, inducibility of arrhythmias was 3-fold higher in inferior vs. lateral wedges. Quinidine (10μM) or isoproterenol (1μM) restored homogeneity and suppressed VT/VF. Conclusion Our data support the hypothesis that 1) ERS is caused by a preferential accentuation of the AP notch in LV epicardium; 2) this repolarization defect is accentuated by elevated vagal tone; 3) higher intrinsic levels of Ito account for the greater sensitivity of the inferior LV wall to development of VT/VF; 4) quinidine and isoproterenol exert ameliorative effects by reversing the repolarization abnormality.

Electrocardiographic Early Repolarization

“…16,23,[33][34][35] Some controversy exists as to whether the electrocardiographic findings represent ER, late depolarization, or neither. 36,37 The repolarization hypothesis suggests that the presence of the ERP reflects regional heterogeneity in the dispersion gradient of myocardial refractoriness prompted by a net outward shift in repolarizing current.…”

“…23 Meticulous studies of canine left ventricular wedge preparations have shown accentuation of the action potential notch in the epicardium enhanced by vagal tone, associated with increased level of I to current, and reversed by quinidine and isoproterenol, supporting the repolarization hypothesis. 35 The depolarization hypothesis proposes that slowed conduction in the right ventricular outflow tract with fractionated and late potentials contributes to arrhythmogenicity. 38 Several observations have raised speculation that a genetic basis for ERP exists.…”

J-Wave in Patients With Syncope

“…5 They suggested that vagal activity contributes to the arrhythmogenicity in ER and J-wave syndrome patients.…”

Management of Ventricular Arrhythmias in Suspected Channelopathies

“…50 Recent studies have provided insight into how the repolarization gradients in ER translate into arrhythmogenesis. 51 The study by Koncz et al 51 suggest that the AP dome of cells within LV epicardium become accentuated giving rise to phase 2 reentry and PMVT. This study showed that repolarization defects can be accentuated by acetylcholine, explaining the deleterious influence of elevated vagal tone, and that relatively high intrinsic levels of I to account for the greater sensitivity of the inferior LV wall to development of VT/VF.…”