J wave syndromes: molecular and cellular mechanisms

Abstract

An early repolarization (ER) pattern in the ECG, consisting of J point elevation, distinct J wave with or without ST segment elevation or slurring of the terminal part of the QRS, was long considered a benign electrocardiographic manifestation. Experimental studies a dozen years ago suggested that an ER is not always benign, but may be associated with malignant arrhythmias. Validation of this hypothesis derives from recent case-control and population-based studies showing that an ER pattern in inferior or infero-lateral leads is associated with increased risk for life-threatening arrhythmias, termed early repolarization syndrome (ERS). Because accentuated J waves characterize both Brugada syndrome (BrS) and ERS, these syndromes have been grouped under the heading of J wave syndromes. BrS and ERS appear to share common ECG characteristics, clinical outcomes, risk factors as well as a common arrhythmic platform related to amplification of Ito-mediated J waves. However, they differ with respect to the magnitude and lead location of abnormal J waves and can be considered to represent a continuous spectrum of phenotypic expression. Recent studies support the hypothesis that BrS and ERS are caused by a preferential accentuation of the AP notch in right or left ventricular epicardium, respectively, and that this repolarization defect is accentuated by cholinergic agonists. Quinidine, cilostazol and isoproterenol exert ameliorative effects by reversing these repolarization abnormalities. Identifying subjects truly at risk is the challenge ahead. Our goal here is to review the clinical and genetic aspects as well as the cellular and molecular mechanisms underlying the J wave syndromes.

Keywords: Brugada syndrome; Cardiac arrhythmias; Early repolarization syndrome; Idiopathic ventricular fibrillation; Sudden cardiac death.

Figure 1

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 , with permission.

Figure 2

Diverse manifestations of early repolarization pattern. Each panel shows transmembrane action potentials recorded from the epicardial and endocardial regions of arterially-perfused canine left ventricular wedge preparations and a transmural ECG simultaneously recorded. Under the conditions indicated, early repolarization of the epicardial action potential result in different configurations of the action potential notch giving rise to diverse electrocardiographic manifestations of ERP. The six panels illustrate the cellular basis for a J point elevation, a distinct J wave, slurring of the terminal part of the QRS, combined J wave, J point and ST segment elevation, and a gigantic J wave appearing as an ST segment elevation, which gives rise to polymorphic VT. Modified from , with permission.

Figure 3

Ionic and Cellular basis for the early repolarization syndrome. Left panel: A: Schematic of Coronary-perfused wedge preparation B: Simultaneous recording of transmembrane action potentials (APs) from epicardial (Epi) and endocardial (Endo) regions and a transmural ECG in an isolated arterially perfused canine ventricular wedge. A J wave in the transmural ECG is manifest due to the presence of an AP notch in epicardium but not endocardium. Pinacidil (2 μM), an ATP-sensitive potassium channel opener, causes depression of the AP dome in epicardium, resulting in ST segment elevation in the ECG resembling the ERS. C: I_K-ATP activation in the canine right ventricular wedge preparation using 2.5 uM pinacidil produces heterogeneous loss of the AP dome in epicardium, resulting in ST segment elevation, phase 2 reentry and ventricular tachycardia or ventricular fibrillation (VT/VF) (BrS phenotype). D: The I_to blocker, 4-aminopyridine (4-AP), restored the Epi AP dome, reduced both transmural and Epi dispersion of repolarization, normalized the ST segment and prevented phase 2 reentry and VT/VF in the continued presence of pinacidil. (Modified from , with permission). Right panel: Schematic depicting our working hypothesis of the ionic mechanism underlying the J wave syndromes. An outward shift in repolarizing current due to a decrease in sodium or calcium channel currents or an increase in I_to, I_K-ATP or I_K-ACh, or other outward currents gives rise to accentuated J waves associated with the Brugada syndrome and early repolarization syndrome. Both are thought to be triggered by closely-coupled phase 2 reentrant extrasystoles, but in the case of ERS a Purkinje source of ectopic activity is also suspected. (Modified from , with permission)