Genetic, Ionic, and Cellular Mechanisms Underlying the J Wave Syndromes

Introduction

The J wave syndromes, consisting of Brugada syndrome (BrS) and early repolarization syndromes (ERS), have intrigued the cardiology community since the initial delineation of BrS as a clinical entity in 1992. The clinical impact of ERS was not fully realized until 2008, when publication of the now classic studies of Haïssaguerre et al., Nam et al., and Rosso et al. appeared. The genetic basis for BrS and ERS has progressed, but the Mendelian nature of their inheritance has been questioned by recent studies. The cellular mechanisms underlying the J wave syndromes have also been a matter of debate. This chapter provides a critical review of the genetic, ionic, and cellular mechanisms underlying the J wave syndromes.

The appearance of prominent J waves in the electrocardiogram (ECG) have long been reported in clinical cases of hypothermia and hypercalcemia. ^, Accentuation of the J wave has been associated with life-threatening ventricular arrhythmias. Under these circumstances, the accentuated J wave typically may be so broad that it appears as an ST segment elevation, as in BrS cases. The normal J wave in humans often appears as a J-point elevation, with part of the J wave buried inside the QRS. An ER pattern (ERP) in the ECG, characterized by a distinct J wave, J-point elevation, or a notch or slur of the terminal part of the QRS with and without an ST segment elevation has traditionally been viewed as benign. ^, In 2000, Gussak and Antzelevitch challenged this view on the basis of experimental data and showed that this ECG manifestation predisposes to the development of polymorphic ventricular tachycardia and fibrillation (VT/VF) in coronary-perfused wedge preparations. ^, This hypothesis was validated 8 years later by Haïssaguerre et al., Nam et al., and Rosso et al. These formative studies, coupled with many additional case control and population-based studies, have provided clinical evidence for an increased risk for development of life-threatening arrhythmic events and sudden cardiac death (SCD) among patients presenting with an ER pattern, particularly in inferior and inferolateral leads. This field has been marred by inconsistent reporting of data because of lack of agreement regarding terminology relative to ER. An expert consensus statement recently published by MacFarlane et al. has provided recommendations of measurement and reporting of ER and J waves. The task force recommends that the peak of an end QRS notch and/or the onset of an end QRS slur be designated as J _p and that J _p should exceed 0.1 mV in two or more contiguous inferior and/or lateral leads of a standard 12-lead ECG for ER to be present. It was further recommended that the start of the end QRS notch or J wave should be designated as J _o and the termination as J _t .

Both BrS and ERS have been associated with vulnerability to development of polymorphic VT and VF leading to SCD ^, in young adults and occasionally to sudden infant death syndrome (SIDS). The region generally most affected in ERS is the inferior region of the left ventricle (LV); in BrS, it is the anterior right ventricular outflow tract (RVOT). ^{, ,} BrS is characterized by accentuated J waves, appearing as a coved-type ST segment elevation in the right precordial leads V ₁ to V ₃ , whereas ERS is characterized by J waves, J _o elevation, and notch or slur of the terminal part of the QRS and ST- segment or J _t elevation in the lateral (type I), inferolateral (type II), or inferolateral and anterior or right ventricular (RV) leads (type III). ERP is often encountered in healthy individuals, particularly in young Black individuals and athletes. ERP is also observed in acquired conditions, including hypothermia and ischemia. ^{, ,} When associated with VT/VF, ERP is referred to as ERS.

The prevalence of type 1 BrS ECG is higher in Asian countries, such as Japan (0.15%–0.27%), ^, the Philippines (0.18%), and among Japanese Americans in North America (0.15%), than in Western countries, including Europe (0%–0.017%) and North America (0.005%–0.1%). ^, The prevalence of an ERP in the inferior and/or lateral leads with a J _o elevation of at least 0.1 mV ranges between 1% and 24%; for J _o of at least 0.2 mV, it ranges between 0.6% to 6.4%. An ERP is significantly more common in Blacks than in whites. ER appears to be more common in Aborigine Australians than in white Australians.