J wave syndromes as a cause of sudden arrhythmic death

Accentuated J waves have been associated with idiopathic ventricular tachycardia and fibrillation (VT/VF) for nearly three decades. Prominent J waves characterize both Brugada and early repolarization syndromes leading to their designation as J wave syndromes. An early repolarization (ER) pattern, characterized by J point elevation, slurring of the terminal part of the QRS and ST segment elevation was considered to be a totally benign electrocardiographic manifestation until a decade ago. Recent case-control and population-based association studies have advanced evidence that an ER pattern in the inferior or infero-lateral leads is associated with increased risk for life-threatening arrhythmias, named early repolarization syndrome (ERS). ERS and Brugada syndrome (BrS) share similar electrocardiogram features, clinical outcomes, risk factors as well as a common arrhythmic platform related to amplification of I to -mediated J waves. Although 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. A classification scheme for ERS has been proposed: type 1, displaying an ER pattern predominantly in the lateral precordial leads, is considered to be largely benign; type 2, displaying an ER pattern predominantly in inferior or infero-lateral leads, is associated with a higher level of risk; whereas type 3, displaying an ER pattern globally in inferior, lateral and right precordial leads, is associated with the highest level of risk for development of malignant arrhythmias and is often associated with VF storms.

their designation as J wave syndromes. An early repolarization (ER) pattern, characterized by J point elevation, slurring of the terminal part of the QRS and ST segment elevation was considered to be a totally benign electrocardiographic manifestation until a decade ago. Recent casecontrol and population-based association studies have advanced evidence that an ER pattern in the inferior or infero-lateral leads is associated with increased risk for life-threatening arrhythmias, named early repolarization syndrome (ERS). ERS and Brugada syndrome (BrS) share similar electrocardiogram features, clinical outcomes, risk factors as well as a common arrhythmic platform related to amplification of I to -mediated J waves. Although 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. A classification scheme for ERS has been proposed: type 1, displaying an ER pattern predominantly in the lateral precordial leads, is considered to be largely benign; type 2, displaying an ER pattern predominantly in inferior or infero-lateral leads, is associated with a higher level of risk; whereas type 3, displaying an ER pattern globally in inferior, lateral and right precordial leads, is associated with the highest level of risk for development of malignant arrhythmias and is often associated with VF storms.

Evolution of the J wave syndromes
Early repolarization syndrome (ERS) and Brugada syndrome (BrS) share similar electrocardiogram (ECG) features, clinical outcomes, risk factors as well as a common arrhythmic platform related to amplification of I to -mediated J waves. 1 Also referred to as the Osborn wave, the J wave or elevated J point has been described in the ECG of animals and humans for over six decades, 2 since Osborn's observation in the early 1950s. 3 In humans, the appearance of a prominent J wave in the ECG is considered pathognomonic of hypothermia, 4-6 hypercalcemia 7,8 and more recently as a marker for a substrate capable of generating life-threatening ventricular arrhythmias. 9 A distinct J wave has been described in subjects completely recovered from hypothermia 10,11 or those predisposed to idiopathic ventricular fibrillation (IVF), but is otherwise rarely observed in humans under normal conditions. In animals, a distinct J wave is commonly observed in the ECG of some species, including Baboons and dogs, under baseline conditions and is greatly amplified under hypothermic conditions. [12][13][14] An elevated J point is commonly encountered in humans and some animal species under normal conditions. An early repolarization (ER) pattern in the ECG has in recent years been shown to be associated with life-threatening arrhythmias, earning the designation of ERS. Although BrS and ERS differ with respect to lead location and magnitude of abnormal J wave manifestation, they have been proposed to represent a continuous spectrum of phenotypic expression termed J wave syndromes. 9 An ER pattern, consisting of J point elevation or a distinct J wave, a notch or slur of the terminal part of the QRS and an ST segment elevation, is commonly found in healthy young males and has long been considered to be benign. 15,16 Our observation in 2000 that an early repolarization pattern in the canine coronary-perfused wedge preparation can convert to one in which phase 2 reentry gives rise to polymorphic ventricular tachycardia and fibrillation (VT/VF), prompted the suggestion that ER may in some cases predispose to malignant arrhythmias in the clinic. 9,17,18 A growing number of case control and population-based studies as well asexperimental studies have suggested a critical role for the J wave in the pathogenesis of IVF. [19][20][21][22][23][24][25][26][27] A conclusive association between ER and IVF was presented in the form of two studies published in the New England Journal of Medicine in 2008. 28,29 These were followed by another study from Viskin and co-workers 30 that same year and large population-based association studies in 2009 and 2010. [31][32][33][34][35] In a case-control study of 206 patients who survived an episode of IVF and 412 matched control subjects, Haissaguerre and co-workers demonstrated that 31% of the IVF group, compared to 5% of the controls displayed an early repolarization pattern consisting of a J point elevation (>0.1 mV), slurring of the terminal part of the QRS and ST segment elevation in the inferior and/or lateral ECG leads. 31 In the same issue of the New England Journal of Medicine, Nam and co-workers reported that 60% of their IVF patients displayed an ER pattern. 29 Four of their patients presented with electrical storm (four or more episodes of ventricular fibrillation in one day). Continuous electrocardiographic monitoring of the patients with electrical storm revealed a unique electrocardiographic signature consisting of an early repolarization pattern in the infero-lateral leads at baseline and dramatic transient accentuation of the J waves in the infero-lateral leads and the development of a marked J wave in the right precordial leads, where it had not appeared before, just before the development of electrical storm, which was precipitated by relatively short-coupled premature ventricular beat. 29 The accentuated J waves and VF could be suppressed with quinidine and isoproterenol or with pacing at increasingly rapid rates. Interestingly, unlike in patients BrS, the electrocardiographic and arrhythmic abnormalities could not be provoked with intravenous flecainide in these type 3 ERS patients.
Several case-control studies followed confirming the association between ER and IVF. 30,[36][37][38][39][40] A recent case-control study explored the prognostic significance of ER among chronic coronary disease patients with implantable cardioverterdefibrillator (ICD). 41 The prevalence of inferior ER was significantly greater among patients who had appropriate ICD therapy for ventricular arrhythmias than in patients who were arrhythmia-free (28% vs 8%, P=0.011), irrespective of their ejection fraction. Rgwy noted that ER prevalence was much greater among young males compared to females and that the higher prevalence in males declines rapidly with age, suggesting a potential influence of testosterone as a modifier of J-wave or ER manifestation. This male predominance is observed with all of the J wave syndromes, 9 including Brugada syndrome. 42 The prevalence and prognosis of inferior or infero-lateral ER have also been studied in several general population studies. 31,32,34,35,40 In a study of 10,864 middle-aged Fins enrolled in a population-based study of coronary heart disease between (1966-1972) with a mean followup of 30±11 years, the prevalence of inferolateral ER at entry was 5.8%. Inferior ER was associated with increased risk of cardiac mortality [relative risk (RR) 1.28, P=0.03], and inferior ER patterns with J-point elevations greater than 0.2 mV was associated with cardiac mortality (RR 2.98, P<0.001) and sudden arrhythmic death (RR 2.92, P=0.01). Interestingly, QTc durations >440 ms in males and 460 ms in females were associated with a smaller magnitude of increased risk for cardiac mortality (RR 1.20, P=0.03).
This was followed by a population-based study reported by Sinner and co-workers examining the ER prevalence and prognosis in a German population of 1945 subjects from the KORA/MONICA cohort. 32 Inferolateral ER was observed in 13.1% of the cohort, whereas inferior ER prevalence was 7.6%, both higher than those observed in the Finnish study. The risk of death from cardiac causes was greater in relatively young males with inferior ER, ER pattern was associated with a 2-to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 years.
In a subsequent publication from Tikkanen and co-workers based on the Finnish population, the authors subgrouped the inferior ER patterns into notched or slurred J-wave patterns and into ascending or horizontal/descending ST-segments following the J-wave. 34 The risk for arrhythmic death did not differ between notched and slurred J-wave ER patterns, but they reported a higher risk for in subjects with horizontal or descending ST-segments in the inferior leads [RR 1.62, 95% confifence interval (CI) 1.19-2.21] when compared to subjects with rapidly ascending ST segments [RR 1.01, P=not significant (NS)]. Rapidly ascending ST segments after the J-wave was the most prevalent pattern observed in athletes. A horizontal/ascending ST segment combined with a 2 mm J-point elevation was associated with a still higher risk for arrhythmic death (RR 3.37, 95% CI 1.75-6.51). Rosso and co-workers reported similar results showing that a horizontal/descending ST segment following the J-point is associated with a higher level of risk for VT/VF. 39 Another population-based study of atomic bomb survivors in the Nagasaki region of Japan 40 reported that in subjects followed over a period of 46 years, a stable ER pattern was found in 650 subjects resulting in a prevalence of 29.3%. Mortality rates in subjects with ER did not show an increased risk for all-cause mortality or cardiac death, but the risk for sudden unexpected death was significantly higher among ER subjects, as in the other studies.
Based on a review of published clinical data, we recently suggested a classification scheme for ER. 9 An ER pattern appearing 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. ER pattern in the inferior or infero-lateral leads was designated as type 2; this form appears to be associated with a moderate level of risk. Finally, an ER pattern manifest globally in the inferior, lateral and right precordial leads was labeled type 3; this form is associated with the highest level of risk and has been associated with electrical storms. 9 Of note, type 3 ER may often be similar to that of type 2, exhibiting infero-lateral ER, except for brief periods just before the development of VT/VF when pronounced J waves are also observed in the right precordial leads (see Nam et al. 43 for an exam-ple). BrS represents a fourth variant in which ER is limited to the right precordial leads.

Mechanisms underlying the inscription of the electrocardiogram J wave and associated arrhythmogenesis
The cellular basis for the J wave was first identified in 1996. 20 Transmural distribution of the transient outward current (I to )-mediated action potential notch was shown to be responsible for the inscription of the electrocardiographic J wave. 20,44,45 The ventricular epicardial action potential, particularly in the right ventricle, displays a prominent I to -mediated 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. 46 Direct evidence in support of this hypothesis was first obtained in the arterially-perfused canine ventricular wedge preparation, 20 as illustrated in currents contributing to the early phases of the action potential or ventricular activation sequence can modify the manifestation of the J wave on the ECG. Whether reduced by I to blockers such as quinidine, 4-aminopyridine, premature activation or augmented by exposure to hypothermia, I Ca and I Na blockers or I to agonists such as NS5806, changes in the magnitude of the epicardial action potential notch parallel those of the J wave. [47][48][49][50] An outward shift in the balance of currents during phases 1 and 2 of the action potential, whether secondary to a decrease of inward currents or an increase of outward current, accentuates the action potential notch leading to augmentation of the J wave or appearance of ST segment elevation. Further augmentation of net repolarizing current can result in partial or complete loss of the action potential dome, leading to a transmural voltage gradient that manifests as accentuation of the J wave or an ST segment elevation. 18,47,48 In regions of the myocardium exhibiting a prominent I to , such as the right ventricular epicardium, marked accentuation of the action potential notch gives rise to a prominent J wave, often characterized as a coved-type ST segment elevation, which is diagnostic of BrS ( Figure 2B). Additional outward shift of the balance of current active during the early phase of the action potential leads to loss of the action potential dome, thus creating a dispersion of repolarization between epicardium and endocardium as well as within epicardium, between regions that lost the dome and regions at which the dome is maintained ( Figure 2C). Sodium channel blockers like ajmaline, flecainide, procainamide, pilsicainide, propafenone and disopyramide cause a further outward shift of current flowing during the early phases of the action potential and therefore effective in inducing or unmasking ST segment elevation in patients with concealed J-wave syndromes. [51][52][53] Some sodium channel blockers like quinidine, which also inhibits I to , reduce the magnitude of the J wave and normalize ST segment elevation. 18,54 Loss of the action potential dome is usually heterogeneous, resulting in marked abbreviation of action potential at some sites but not others. The dome is then able to propagate from regions at which it is maintained to regions at which it is lost, giving rise to a very closely coupled extrasystole via phase 2 reentry ( Figure 2D). 55 The phase 2 reentrant beat is capable of initiating polymorphic VT or VF ( Figure 2E and F).
While most investigators consider the pathophysiology of Brugada syndrome to be due to repolarization abnormalities, several studies have suggested the possibility that delayed depolarization in the right ventricular outflow tract underlies the development of ST segment elevation or J waves associated with BrS. 56,57 The repolarization vs depolarization hypotheses controversy has been documented as a published debate. 58 The net outward shift of current may extend beyond the action potential notch and thus lead to depression of the dome in addition to accentuating the J wave. Activation of the ATP-sensitive potassium current (I K-ATP ) or depression of inward calcium channel current (I Ca ) can effect such a change ( Figure 3A and B). This is more likely to manifest in the ECG as an ER pattern consisting of a J point elevation, slurring of the terminal part of the QRS and mild ST segment elevation. The ER pattern facilitates loss of the dome secondary to agents or conditions that produce a further outward shift of net current, leading to the development of ST segment elevation, phase 2 reentry and VT/VF ( Figure 3C). Inhibition of I to shifts net current in the inward direction, thus normalizing the ST segment and suppressing the J wave and arrhythmic manifestation.

Clinical manifestations of J wave syndromes
In both BrS and ERS, the manifestation of the J wave or ER is dynamic, 27,59,60 with the most prominent ECG changes appearing just before the onset of VT/VF. 20-27, 43,59,60 Other ECG characteristics of ERS also closely match those of BrS, including the presence of accentuated J waves, ST segment elevation, pause and bradycardia-dependence, short coupled extrasystoleinduced polymorphic VT/VF. Suppression of the ECG features by isoproterenol or pacing in ER patients further supports the notion that they share common underlying electrophysiologic abnormalities with BrS patients. 43 However, salient diagnostic features of BrS such as provocation by sodium channel blockers or positive signal averaged ECG are rarely observed in these ERS patients. 29,43 An exception to this rule appears to apply to ERS associated with SCN5A mutations. 61 Kawata and coworkers recently showed that sodium channel blockers attenuate ER in patients with both ERS apparently due to slowing of transmural conduction so that J point shifts to a lower position on the terminal part of the QRS. 62 Table 1 lists the various features common to BrS and ERS and possible underlying mechanisms. The table highlights the fact that the two syndromes display a strong male predominance and are similar with respect to the age at which the first event is documented. Both show great dynamicity as far as manifestations of the ECG phenotype and in both cases VT/VF is often precipitated by a very closely coupled premature beat. BrS and ERS respond similarly to I to blockers such as quinidine, adrenergic agonists such as isoproterenol, and rapid heart rates or pacing rates; these intervention all produce an ameliorative effect. The ECG and arrhythmic manifestation of both BrS and ERS are exacerbated by increased vagal tone.

Genetics of J wave syndromes
BrS has been associated with mutations in twelve different genes ( Table 2). Greater than 300 mutations in SCN5A (Na v 1.5, BrS1) have been reported in 11-28% of BrS probands. [63][64][65] Mutations in CACNA1C (Ca v 1.2, BrS3), CACNB2b (Ca v β2b, BrS4) and CACNA2D1 (Ca v a2 , BrS9) are found in approximately 13% of probands. 66  in these genes lead to loss of function in I Na and I Ca , as well as to a gain of function in I to or I K-ATP .

Figure 3. Cellular basis for the early repolarization syndrome. A) Surface electrocardiogram (ECG) (lead V5) recorded from a 17-year-old healthy African American male. Note the presence of a small J wave and marked ST segment elevation. B) Simultaneous recording of transmembrane action potentials from epicardial (Epi) and endocardial (Endo) regions and a transmural ECG in an isolated arterially perfused canine left ventricular wedge. A J wave in the transmural ECG is manifest due to the presence of an action potential notch in epi-
The genetic basis for ERS is gradually coming into better focus. The familial nature of ER pattern has been demonstrated in a number of studies. 33,76,77 The Framingham Heart Study reported that siblings of ER subjects are twice as likely to have ER than non-ER subjects [odds ratio (OR) 2.22, P<0.05]. In another study of over 500 British families, ER was over two times more likely to occur in children (OR 2.54, P=0.005) if one of the parents had an ER ECG pattern. 33,76 ERS has been associated with mutations in 6 genes (Table 3). Consistent with the findings that I K-ATP activation can generate an ER pattern in canine ventricular wedge preparations, a rare variant in KCNJ8, responsible for the pore forming subunit of the I K-ATP channel, has recently been reported in a patients with ERS as well as BrS. 71,78,79 Recent studies have identified loss of function mutations in the α and β and α2δ1 subunits of the cardiac L-type calcium channel (CACNA1C, CACNB2, and CACNA2D1) and as well as loss-of-function mutations in SCN5A in patients with ERS. 61,67    Our working hypothesis is that an outward shift in repolarizing current secondary to a decrease in sodium or calcium channel currents or an increase in I to , I K-ATP , I K-ACh , or other outward currents gives rise to the J wave syndromes ( Figure 4). The particular phenotype depends on what part of the heart is principally affected and which ion channels are involved. We regard the J wave syndromes as a spectrum of disorders that involve accentuation of the epicardial action potential notch in different regions of heart, leading to the development of prominent J waves that predispose to the development of VT/VF. 9 In the case of patients with BrS, the appearance of prominent J waves is limited to the leads facing the right ventricular outflow tract where I to is thought to be most intense. The more prominent I to in right ventricular epicardium provides for an outward shift in the balance of current, which promotes the appearance of the J wave in this region of the ventricular myocardium. In the case of ERS, the appearance of prominent J waves may be limited to other regions of the ventricular myocardium because of the presence of heterogeneities in the distribution of other currents such as I K-ATP .

Risk stratification
As in most cases of BrS, bradycardia accentuates ST segment elevation, and tachycardia tends to normalize the ST segment in ERS. VF often occurs near midnight or in the early morning hours when heart rate is slower and parasympathetic tone is augmented. 23,80 In BrS, the manifestation of spontaneous ST segment elevation has been associated with a higher risk for development of arrhythmic events. Risk stratification of asymptomatic patients remains a challenge. Indeed, the most debated issue has to do with risk stratification of asymptomatic BrS patients. Brugada et al. 81,82 reported that the risk for developing VT/VF is much greater in patients who are inducible during electrophysiological study (EPS), whether or not a type 1 ST-segment elevation is spontaneously present and whether or not they are symptomatic. In asymptomatic spontaneous type 1 ECG patients, multivariate analysis showed that the only predictor of arrhythmic events is inducibility during EPS.
In sharp contrast, other studies [83][84][85][86][87][88][89] failed to find an association between inducibility and cardiac arrhythmic events. The incidence of VT/VF events during follow-up was too low (annual event rate of 0.8-1%) 83,84 to demonstrate value for risk stratification based on EPS inducibility. Of note, the last consensus conference published in 2005 90 recommended that asymptomatic patients displaying a type 1 ST segment elevation (either spontaneously or after sodium channel blockade) undergo EPS if a family history of sudden cardiac death is suspected to be the result of BrS. EPS was also considered justified with a negative family history but a spontaneous type 1 ST segment elevation. If inducible for ventricular arrhythmia, implantation of an ICD was recommended either as a class IIa or IIb indication, meaning that conflicting evidence exists concerning usefulness and that the weight of evidence is either in favor of usefulness (class IIa) or usefulness is not well established (class IIb). The report also recommended that asymptomatic patients with no family history who develop a type 1 ST segment elevation only after sodium channel blockade should be closely followed up. The large number of studies conducted since the appearance of the last consensuses statement that have failed to demonstrate and association between inducibility and risk, call into question the value or need for EPS in asymptomatic Brugada patients. The reason for the large disparity between the results of the Brugada brothers and those from other centers is not clearly evident.
A recent study by Makimoto and coworkers reported that the number of extrastimuli that induced VT/VF serves as a prognostic indicator of risk in Brugada patients with type 1 ST segment elevation. They reported that single or double extrastimuli were adequate for programmed electrical stimulation in patients with BrS. 91 Asymptomatic BrS patients with type I ST segment elevation are also at increased risk compared to those manifesting a saddleback or type II ST segment elevation. Some electrocardiographic patterns are associated with higher risk of symptoms or lifethreatening events in BrS, including higher Jpoint elevations, QRS durations >100 ms, and a prominent r' in lead aVR. 92 Athletes do not appear to have a higher prevalence of Brugada ECG patterns, despite the fact that many athletes display an early repolarization patterns. 93 In the case of ERS, it is clear that the vast majority of individuals with ER are at no or minimal risk for arrhythmic events and sudden cardiac arrest. Our great challenge moving forward is to develop better risk stratification strategies and effective treatments for the J wave syndromes. Incidental discovery of a J wave on routine screening should not be interpreted as a marker of high risk for sudden cardiac death (SCD) since the odds for this leading to a fatal outcome is relatively low. 39 However, mounting evidence suggests that careful attention should be paid to subjects with high risk ER. Who is at high risk?
Although we are still on a very steep learning curve, available data suggest a number of guidelines for risk stratification ( Table 4). As with other inherited cardiac arrhythmia syndromes, Figure 4. J wave syndromes. Schematic depicting our working hypothesis that 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 can give rise to accentuated J waves associated with the Brugada syndrome and early repolarization syndrome (ERS). 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 Antzelevitch and Yan, 2010 9 with permission). association of ER with syncope, aborted SCD or family history of SCD is a marker of risk. Appearance of prominent and distinct J waves, 94 transient augmentation of J waves or J point elevation of >0.2 mV in the inferior or inferolateral ECG leads should raise a red flag. 31,33,95 Association of ER with horizontal or descending ST segment or short QT intervals. 34,35,96 Finally, the appearance of very short-coupled extrasystoles are thought to be a marker of risk in that they likely reflect phase 2 reentry, the presumed trigger for the development of polymorphic VT in the J wave syndromes. 9 Interestingly, recent studies have reported a higher prevalence of ER in victims of SCD than in survivors among subjects with acute coronary events, suggesting that the presence of ER increases the vulnerability to fatal arrhythmia during acute myocardial ischemia. [97][98][99] The ion channel current most important in development of arrhythmogenesis associated with ischemia is I K-ATP . These findings are consistent with the discovery that gain-of-function mutations in the genes that encode the I K-ATP underlie many cases of I K-ATP . 71,78,79,100 These results provide a possible mechanistic link to increased arrhythmic risk in patients displaying an ER pattern on their ECG.  Association of ER pattern with 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 infero-lateral or global leads 3 Transient J wave augmentation portends a high risk for VF in patients with ER 4 Appearance of distinct and prominent J waves 5

Review
Association of ER pattern with abbreviated QT intervals 6 Association with horizontal or descending ST segment 7 Appearance of closely coupled extrasystoles 8 Pause-dependent augmentation of J waves ER, early repolarization; SCD, sudden cardiac death; VF, ventricular fibrillation.