Genetics and Cellular Mechanisms of the J Wave Syndromes

Definition and Clinical Characteristics of the J Wave Syndromes

The J wave is a positive deflection in the electrocardiogram (ECG) that occurs at the junction between the QRS complex and the ST segment, also known as the J point. Because much of the J wave is typically hidden inside the QRS, it may manifest as a J point elevation, a slurring of the terminal part of the QRS, or a late delta wave following the QRS. When it becomes more accentuated, it may appear as a small secondary R wave (R′) or ST segment elevation (Figure 52-1).

Figure 52-1 Cellular Basis for Diversity in the Manifestation of the Early Repolarization Pattern in the ECG
Each panel shows transmembrane action potentials recorded from the epicardial and endocardial regions of an arterially perfused canine ventricular wedge preparation and a transmural electrocardiogram (ECG) simultaneously recorded. Under the conditions indicated, 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 and ST-segment elevation, and a very prominent J wave appearing as an ST-segment elevation and giving rise to a brief episode of polymorphic ventricular tachycardia (VT).

The J wave or elevated J point has been recognized in the ECG of humans and animals since the early 1930s. It was first described by Tomaszewski ¹ in 1938 in an accidentally frozen human. The J wave has also been termed an Osborn wave after Osborn’s description of the wave in hypothermic dogs.²

In both humans and animals, the appearance of a prominent J wave in the ECG is pathognomonic of hypothermia 3–5 and hypercalcemia^6,7 and, more recently, as a marker for a substrate capable of generating life-threatening ventricular arrhythmias.⁸ A distinct J wave has been described in the ECG of subjects completely recovered from hypothermia^9,10 and those predisposed to idiopathic ventricular fibrillation, but is otherwise rarely observed in humans under normal conditions. A distinct J wave is commonly observed under baseline conditions in the ECG of some animal species, such as dogs and baboons, and is greatly accentuated under hypothermic conditions.^11–13 An elevated J point, on the other hand, is commonly encountered in humans and in some animal species under normal conditions.

The term early repolarization (ER) to the best of our knowledge was coined by Grant et al ¹⁴ to describe ST-segment deviations and associated T wave changes and was thought to result from premature repolarization. The ER pattern in the ECG in recent years has been shown to be associated with life-threatening arrhythmias, describing an entity that we termed early repolarization syndrome (ERS). Although Brugada syndrome (BrS) and ERS differ with respect to the magnitude and lead location of abnormal J wave manifestation, they are thought to represent a continuous spectrum of phenotypic expression termed J wave syndromes.⁸ In this chapter, we discuss the genetic basis for and the cellular and ionic mechanisms underlying J wave syndromes. The clinical aspects are discussed in Chapter 96.

An ER pattern in the ECG, consisting of a distinct J wave or J point elevation, a notch or slur of the terminal part of the QRS, and an ST-segment elevation, is commonly seen in healthy young males and until recent years had been viewed as benign.15,16 Our observation in 2000 that an ER pattern in the canine coronary-perfused wedge preparation can readily convert to one in which phase 2 reentry gives rise to polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF) prompted us to suggest that ER in some cases may predispose to malignant arrhythmias in the clinic.^8,17,18

A number of case reports and experimental studies have suggested a critical role for the J wave in the pathogenesis of idiopathic ventricular fibrillation (IVF).19–28 A definitive association between ER pattern and IVF was reported in two studies published in New England Journal of Medicine in 2008.^29,30 These publications were followed by another study from Viskin and coworkers³¹ that same year and by large population association studies in 2009 and 2010.^32–36 As is discussed in Chapter 96, a number of case-control and population-based studies appeared between 2010 and 2012, confirming the association between ER and IVF. It is interesting to note that recent studies have reported that the prevalence of inferior and anterior, but not lateral, ER is significantly greater among patients who developed VT/VF within 72 h after an acute myocardial infarction.^37–40

A strong male predominance is observed with all of the J wave syndromes,⁸ including BrS.⁴¹ Experimental and clinical studies have provided evidence in support of the hypothesis that testosterone plays an important role in ventricular repolarization. Ezaki and coworkers⁴² demonstrated that ST-segment elevation is relatively small and is similar in males and females before puberty. After puberty, ST-segment elevation in males, but not in females, increases sharply, more so in the right precordial leads, subsequently decreasing gradually with advancing age. The effect of androgen-deprivation therapy on the ST segment was evaluated in 21 prostate cancer patients. Androgen-deprivation therapy significantly decreased ST-segment elevation. These results suggest that testosterone modulates the early phase of ventricular repolarization and thus ST-segment elevation.

We recently suggested a classification scheme for ER based on the data available in the literature in 2010 (Table 52-1).⁸ An ER pattern manifest exclusively in the lateral precordial leads was designated as Type 1; this form is prevalent among healthy male athletes and is thought to be associated with a relatively low level of risk for arrhythmic events. The ER pattern in the inferior or inferolateral leads was designated as Type 2; this form is thought to be associated with a moderate level of risk. Finally, an ER pattern appearing globally in the inferior, lateral, and right precordial leads was labeled Type 3; this form is associated with the highest level of risk and in some cases has been associated with electrical storms.⁸ Type 3 ER patterns may be very similar to those of Type 2, exhibiting inferolateral ER, except for brief periods just before the development of VT/VF, when pronounced J waves are also observed in the right precordial leads.⁴³ BrS represents a fourth variant in which ER is limited to the right precordial leads. Within each category, the level of risk appears to increase in accordance with the presence of additional electrocardiographic signatures, including a horizontal or declining ST segment following the J wave or J point elevation,^35,44,45 relatively short QT intervals,⁴⁶ and very prominent J waves or J point elevation, which may appear as a coved-type ST-segment elevation (Box 52-1). Risk stratification strategies for BrS and ERS are discussed more fully in Chapter 96.

Box 52-1 Risk Stratification of Patients With Early Repolarization (ER) Pattern

Who Is at Risk?

1. Association of ER pattern with sudden cardiac death (SCD), unexplained syncope, or unexplained family history of SCD.

2. J point or ST-segment elevation of 0.2 mV or greater in inferior and inferolateral or global leads.

3. Transient J wave augmentation portends a high risk for ventricular fibrillation in patients with ER.

4. Appearance of distinct and prominent J waves.

5. Association of ER pattern with abbreviated QT intervals.

6. Association with horizontal or descending ST segment.

7. Appearance of closely coupled extrasystoles.

8. Hyperpnea-induced ventricular tachycardia (VT)/ventricular fibrillation (VF).

Table 52-1

J Wave Syndromes: Similarities and Differences

ER, Early repolarization; ERS, early repolarization syndrome; N/A, not available; VF, ventricular fibrillation; VT, ventricular tachycardia.

Modified from Antzelevitch C, Yan GX: J wave syndromes. Heart Rhythm 7:549–558, 2010.

Cellular Basis for the J Wave and Associated Arrhythmogenesis

Transmural differences in the magnitude of the action potential notch have long been recognized as the basis for inscription of the electrocardiographic J wave.47,48 The ventricular epicardial (Epi) action potential (AP), particularly in the right ventricle outflow tract, displays a prominent transient outward current (I_to)-mediated action potential notch or spike and dome morphology. The presence of a prominent I_to-mediated action potential notch in ventricular epicardium but not endocardium leads to the development of a transmural voltage gradient that manifests as a J wave or J point elevation on the ECG. Direct evidence in support of this hypothesis was first acquired in the arterially perfused canine ventricular wedge preparation,²⁰ as illustrated in Figures 52-1 and 52-2. Modulation of the notch amplitude, whether due to hypothermia (Figure 52-2, C and D) or due to changes in activation rate or to prematurity (Figure 52-3), gives rise to parallel changes in the amplitude of the J wave. Factors that influence I_to kinetics or ventricular activation sequence (Figure 52-2, A, B) can modify the manifestation of the J wave on the ECG. Whether reduced by I_to blockers such as 4-aminopyridine, quinidine, or premature activation; or augmented by exposure to hypothermia, I_Ca and I_Na blockers, or I_to agonists such as NS5806 or I_K-ATP agonists, changes in the magnitude of the epicardial action potential notch parallel those of the J wave or J point elevation (see Figure 52-1).^49–52