Primary Arrhythmogenic Cardiomyopathies. Channelopathies  

The QRS complex of the ECG represents the ventricular depolarization and the ST segment the final phase of ventricular depolarization. The J wave represents the junction of the QRS complex with the beginning of the ST segment of the ECG, which normally must be isoelectric and corresponds to the transition of ventricular depolarization toward the repolarization in the surface ECG. J-point elevation is felt to reflect the transmural differ­ences in the early phases of the action potential (Antzelevitch et al., 2013).

Following the recent consensus report on ERP (MacFarlane et al., 2015), ERS is recognized if: (1) there is an end QRS notch (J wave) or slur on the downslope of a prominent R wave with and without ST-segment elevation; (2) the peak of the notch or J wave (Jp) ≥0.1 mV in ≥2 contiguous leads of the 12-lead ECG, excluding leads V1−V3; and (3) QRS duration (measured in leads in which a notch or slur is absent) < 120 ms. 

An early repolarization (ER) ECG pattern, 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 in inferior leads appears frequently in the ECG of healthy young individuals (20-40 years) with slow heart rates. Thus, for years ER was a marker of "good health". The ER pattern on ECG has been reported to have a prevalence of between 1% and 24 % in cohort studies, idiopathic VF is rare (Tikkanen et al., 2009; Sinner et al., 2010; Wu et al., 2013). The incidence of idiopathic VF due to ER in an individual younger than 45 years is estimated to be 3:100,000 (Rosso et al., 2008, 2012). Its prevalence is 1%–13% in the general population along with a higher incidence in children, males, athletes, and African-Americans.

In a community-based general population of 10.864 middle-aged subjects (mean 44 years) the early-repolarization pattern of 0.1 mV or more was present in 630 subjects (5.8%) (Tikkanen et al., 2009). However, in an study performed in young healthy athletes from Finland and the United States early repolarization was present in 44% of the Finnish athletes and 30% of the US athletes (Tikkanene et al., 2011; Rosso et al., 2008). The high prevalence of ER in athletes does not imply an increased risk of arrhythmic events; thus, it is not reasonable to recommend the suspension of sport in asymptomatic athletes. The high prevalence of ER in athletes does not imply an increased risk of arrhythmic events; thus, it is not reasonable to recommend the suspension of sport in asymptomatic athletes. Indeed, the probability of arrhythmic death is approximately 0.35:100,000 in competitive athletes (Cappato et al., 2010).

The prevalence of the ERS was much greater among young males compared with females, suggesting a potential influence of testosterone as a modifier of J wave or ER manifestation. The male predominance is observed with all of the J wave syndromes. Testosterone testosterone modulates the early phase of ventricular repolarization and thus ST-segment elevation. Indeed, ST-segment elevation is similar in males and females before puberty, but after puberty, ST-segment elevation increased markedly in males (but not females) in the right precordial leads; these differences decreased gradually with advancing age (Ezaki et al., 2010). ER is also observed in patients with hypothermia, hypercalcemia, hypervagotonía, spinal injuries leading to loss of sympathetic tone or vasospastic angina. However, recent evidence suggests a critical role for the J wave in the pathogenesis of idiopathic VF (IVF).


1. Correlation between the J point and ERS

Recent evidence indicates that in 1-5% of the general population and 15-70% of patients with idiopathic VF the ECG displays an elevation of the ST interval not secondary to ischemic events, that starts at the end of QRS and the beginning of the ST (J point = 0.1 mV), associated with a notch at the end of the QRS and high and asymmetric T waves in leads V2-V4. In fact, the presence of ER increases 2-6 times the risk of SCD due to cardiovascular causes in individuals between 35 and 54 years old (Haissaguerre et al., 2008; Haruta et al., 2011; Nam et al., 2008; Rosso et al., 2008, 2011; Sinner et al., 2010). Furthermore, in patients with a ventricular electrical storm the only premonitory signal in the ECG is the presence of an ER and an accentuation of J waves in the inferolateral leads and the development of marked J waves or ST segment elevation in the right precordial leads just before the onset of VT/VF and the arrhythmia is triggered by a short-coupled premature ventricular beat. ER is also more common in patients with idiopathic VF that in the control group (31% vs 5%, P <0.001) and in men with a history of syncope or sudden death during sleep, even after ruling out the existence of ischemic events (Lellouche et al., 2011).

In a community-based general population a J-point elevation of at least 0.1 mV in inferior leads was associated with an increased risk of death from cardiac causes (RR 1.28; 95% CI, 1.04 to 1.59) and from arrhythmia (RR 1.43; 95% CI, 1.06 to 1.94) than did those without this abnormality; however, these subjects did not have a significantly higher rate of death from any cause (RR 1.10; 95% CI, 0.97 to 1.26) (Tikkanen et al., 2009). Subjects with J-point elevation of more than 0.2 mV on inferior leads had an increased risk of death from any cause (RR 1.54; 95% CI, 1.06 to 2.24), death from cardiac causes (RR 2.98; 95% CI, 1.85 to 4.92), and death from arrhythmia (RR.92; 95% CI, 1.45 to 5.89). J-point elevation in the lateral leads was of borderline significance in predicting death from cardiac causes and death from any cause, but it did not predict death from arrhythmia. This Finish group found that ST-segment morphology variants associated with ER separates subjects with and without an increased risk of arrhythmic death in middle-aged subjects (Tikkanen et al., 2011). Subjects with early repolarization ≥0.1 mV and horizontal/descending ST variant had an increased hazard ratio of arrhythmic death (RR 1.43; 95% CI, 1.05 to 1.94). An early repolarization ≥0.2 mV in inferior leads and horizontal/ descending ST-segment variant increases the risk of arrhythmic death (RR 3.14, 95% CI 1.56 to 6.30), while in subjects with ascending ST variant, the relative risk for arrhythmic death was not increased (0.89; 95% confidence interval 0.52 to 1.55) (Tikkanen et al., 2009). These results were confirmed by Rosso et al (2012) who found that the presence of J waves is associated with idiopathic VF with an odds ratio of 4.0, but that having both J waves and horizontal/descending ST-segment yielded an odds ratio of 13.8 for having idiopathic VF. However, the current risk stratification scheme is still in its infancy.

At present, it would be safe to say that patients with ST-segment elevation only (without J waves) or patients with a J wave and rapidly ascending ST-segment have a favourable prognosis (Uberoi et al., 2011; Tikkanen et al., 2011). VF episodes in patients with ERS are typically initiated by premature beats with short coupling intervals and a short-long-short sequence of activation, which is not commonly observed in patients with BS (72.4% vs. 15.1%). A prominent augmentation of the J wave [typically wide (>2 mm) in the right precordial leads, or tall (>4–5 mm) in the left precordial leads] heralds each VF episode.
Heart rate and autonomic tone modulate ER. Thus, the increase of the J wave and the incidence of idiopathic VF increase when there is a predominance of vagal tone (postprandial, sleep) and at slow heart rates. On the contrary, an increase in sympathetic tone suppresses ERS and arrhythmogenic events, while ß-blocker increase the ST elevation.


2. Genetic basis

ERS are associated with mutations in several genes leading to an increase in the net repolarizing currents, either by decreasing the INa or the ICa or and increase in IKATP and IKACh (Antzelevitch 2012). Gain-of-function mutations in the KCNJ8 gene encoding a subunit of the inward rectifier KATP channels increases outward potassium current that is associated with ERS and idiopathic VF (Medeiros-Domingo et al., 2010; Haisseguerre et al., 2009, Watanabe et al., 2011; Barajas-Martínez et al., 2012). The increase in KATP mutated channels in the ventricular epicardium produce the J point in the ECG. The ERS is also associated with loss-of-function mutations in CACNA1C, CACNB2 and CACNA2D1 genes encoding the α, β2 and δ subunits of the L-type Ca2+ channels (Burashnikov et al., 2010) and in the SCN5A and SCN10A genes encoding the α subunit of the Na+ channels (Watanabe et al., 2011). Recently, a rare variant [substitution of aspartic acid (D) for glutamine acid (E) at position 5 in exon 1b in the N-terminal of DPP10] was found in the KCND2 gene encoding for the Kv4.2 channel in a patient with J waves in the right precordial leads (Perrin et al., 2014). A KCNE5 mutation (and rare polymorphism in DPP10) slows the inactivation and the recovery from inactivation of Ito, increasing the transient outward current (Ito) (Barajas-Martínez et al., 2012).

Table. Genetic loci and genes associated with Early Repolarization Syndrome (autosomal dominant)




Gene product






α subunit Kir6.1



ERS2 (4,2%)



α1 subunit Cav1.2



ERS3 (10,3%)



β2 subunit Cav1.2



ERS4 (4,1%)



δ subunit Cav1.2






β subunit SUR2A






α subunit Nav1.5






α subunit Nav1.8






β subunit MiRP4






Dipeptidyl Peptidase Like 10




3. Clasification of ERS

Antzelevichand Yan (2010) suggested a classification scheme for ER:
Type 1: the ER pattern manifest predominantly in the lateral precordial leads. This form is very prevalent among healthy male athletes and is thought to be associated with a relatively low level of risk for arrhythmic events.
Type 2: the ER pattern manifest in the inferior or infero-lateral leads; this form is associated with a moderate level of risk.
Type 3: the ER pattern appears globally in the inferior, lateral and right precordial leads and is associated with the highest level of risk and in some cases is associated with electrical storms.


4. Pathophysiological basis

The J wave has been shown to originate from the heterogeneous distribution of a transient outward current-mediated spike-and-dome morphology of the AP across the ventricular wall. The epicardial AP, particularly in the right ventricle, presents a marked notch due to the activation of Ito, which gives the typical peak-dome morphology. The notch is no present in the ventricular endocardium, creating a transmural voltage gradient which results in a J wave or ST segment elevation in the ECG (Antzelevitch, 2012). An increase in net repolarizant current, either due to a reduction of inward currents or an increase in outward currents accentuates the notch, increases the J wave or elevates the J point in the ECG (Yan and Antzelevitch, 1999). Similarly, INa blockers (class I antiarrhythmic drugs) produce a predominance of repolarizing currents during the phase 1 of the AP, shorten the APD in some areas of the ventricles and facilitate a phase 2 reentry due to spread of the dome of the PA from the areas where it persist elevated to those where the dome was abolished and are already repolarized. As a result, they induce and unmask the elevation of the ST segment (type 1 pattern) in patients with concealed J wave syndromes (Yan and Antzelevitch, 1999). However, sodium-channel blockers such as quinidine, which also inhibits Ito, reduce the magnitude of the J wave and normalize ST-segment elevation (Antzelevitch, 2012).

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5. Diagnosis

Although there are no defined and validated criteria for the diagnosis of ERS in the ECG of these patients it is possible to see a J point elevation ≥ 1 mV in precordial leads (V1-V3), positive T waves, asymmetric, high and with increased amplitude and depression and/or shortening of the PR segment. If the ER are associated with history of syncope or familial history of VT or SCD an echocardiography should be performed to rule out the presence of a structural heart disease and non-invasive electrophysiological studies (Holter ECG, exercise ECG) to stratify the arrhythmic risk of the patient. However, and in contrast to the BS, the ECG and arrhythmic abnormalities can not be provoked with intravenous flecainide. Thus, a test with a Na+ channel blocker should be performed to unmask a BrS.
Risk factors for ERS include: a) the presence of ERS associated to syncope, SCD or a familial history of SCD; b) the appearance of prominent J waves, the transient increase of J waves or the elevation of the J > 0.2 mV in inferior or inferolateral leads; c) a transient increase of the J wave; d) the occurrence of ERS associated with an horizontal or downwards ST segment or a short QT interval, and e) the occurrence of extrasystoles with short coupling interval (Antzelevitch, 2012).


Proposed Shanghai Score System for diagnosis of an ERS (Taken from Antzelevitch et al., 2016)



I. Clinical History

A. Unexplained cardiac arrest, documented VF or polymorphic VT


B. Suspected arrhythmic syncope


C. Syncope of unclear mechanism/unclear etiology


**Only award points once for highest score within this category.

II. Twelve-Lead ECG


A. ER =0.2 mV in =2 inferior and/or lateral ECG leads with horizontal/descending ST segmentT


B. Dynamic changes in J-point elevation (=0.1 mV) in =2 inferior and/ or lateral ECG leads


C. =0.1 mV J-point elevation in at least 2 inferior and/or lateral ECG leads


*Only award points once for highest score within this category.

III. Ambulatory ECG Monitoring


A. Short-coupled PVCs with R on ascending limb or peak of T wave


IV. Family History


A. Relative with definite ERS


B. =2 first-degree relatives with a II.A. ECG pattern


C. First-degree relative with a II.A. ECG pattern


D. Unexplained sudden cardiac death o45 years in a first- or second degree relative


*Only award points once for highest score within this category.

V. Genetic Test Result


A. Probable pathogenic ERS susceptibility mutation


Score (requires at least 1 ECG finding)

5 points: Probable/definite ERS
3-4.5 points: Possible ERS
<3 points: Nondiagnostic

ER: early repolarization; ERS: early repolarization syndrome; PVC: premature ventricular contraction; VF: ventricular fibrillation; VT: ventricular tachycardia.

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6. Treatment

Implantation of an ICD is first-line therapy for JWS patients presenting with aborted SCD or documented VT/VF with or without syncope (Class I recommendation) (Haissaguerre  et al., 2009). Quinidine is effective for suppression of VF related to ER syndrome, with acute use of isoproterenol in patients who are unstable (Haissaguerre  et al., 2009). However, there are no studies with appropriate design to establish their use as the standard treatment.

Expert consensus recommendations on early repolarization therapeutic interventions include (Priori et al., 2013): 1) Class I: ICD implantation is recommended in patients with a diagnosis of ERS who have survived a cardiac arrest. 2) Class II. a) Isoproterenol infusion can be useful in suppression of electrical storms in patients with a diagnosis of ERS; b) quinidine in addition to an ICD can be useful for secondary prevention of VF in patients with a diagnosis of ERS. 3) Class IIb. a) ICD implantation may be considered in symptomatic family members of ERS patients with a history of syncope in the presence of ST-segment elevation >1 mm in two or more inferior or lateral leads; b) ICD implantation may be considered in asymptomatic individuals who demonstrate a high-risk ER ECG pattern (high J wave amplitude, horizontal/descending ST segment) in the presence of a strong family history of juvenile unexplained sudden death with or without a pathogenic mutation. Class III: ICD implantation is not recommended for asymptomatic patients with an isolated ER ECG pattern.

Arrhythmic events and SCD in ERS generally occur during sleep or at rest and are associated with slow heart rates, which arises a potential therapeutic role for cardiac pacing. Because malignant ventricular arrhythmias are infrequent in asymptomatic patients with ERP (Tikkanen et al., 2009) and usually are unrelated to physical activity, the presence of the ECG patterns does not contraindicate participation in sports, but there are no data currently available to make definitive recommendations for participation in sports.

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7. References

Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010;7:549-558.

Antzelevitch C. Genetic, molecular and cellular mechanisms underlying the J wave syndromes. Circ J 2012;76:1054-1065.

Antzelevitch C. J wave syndromes: molecular and cellular mechanisms. J Electrocardiol. 2013;46:510–518.

Antzelevitch C, Yan GX, Ackerman MJ, et al. J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. J Arrhythm. 2016;32:315-339.

Barajas-Martínez H, Hu D, Ferrer T, et al. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm 2012;9:548-55.

Barajas-Martinez H, Hu D, Pfeiffer R, et al. A Genetic Variant in DPP10 Linked to Inherited J-Wave Syndrome Associated with Sudden Cardiac Death by Augmentation of Kv4.3 Channel Current. Heart Rhythm 2012;9:1919-20.

Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated J wave sydnrome and sudden cardiac death. Heart Rhythm 2010;7:1872-1882.

Cappato R, Furlanello F, Giovinazzo V, et al. J-wave, QRS slurring, and ST elevation in athletes with cardiac arrest in the absence of heart disease: marker of risk or innocent bystander? Circ Arrhythm Electrophysiol 2010;3:305–11.

Haissaguerre M, Chatel S, Sacher F, et al. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol 2009;20:93-98.

Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016-2023.

Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation. 2011;123:2931-2397.

Lellouche N, Sacher F, Jorrot P, et al. Sudden cardiac arrest: ECG repolarization after resuscitation. J Cardiovasc Electrophysiol. 2011;22:131-136.

Macfarlane P., Antzelevitch C., Haissaguerre M. The early repolarization pattern: consensus paper. J Am Coll Cardiol. 2015;66:470–477.

Medeiros-Domingo A, Tan BH, Crotti L et al. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac KATP channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm 2010;7:1466-1471.

Nam GB, Kim YH, Antzelevitch C. Augmentation of J waves and electrical storms in patients with early repolarization. N Engl J Med 2008;358:2078-2079.

Perrin MJ, Adler A, Green S, et al. Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J wave syndrome associated with sudden cardiac death. Circ Cardiovasc Genet. 2014;7:782–789.

Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;15:1389– 406.

Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–63.

Rosso R, Adler A, Halkin A, et al. Risk of sudden death among young individuals with J waves and early repolarization: Putting the evidence into perspective. Heart Rhythm 2011;8:923-929.

Rosso R, Glikson E, Belhassen B, et al. Distinguishing “benign” from “malignant” early repolarization: The value of the ST-segment morphology. Heart Rhythm 2012; 9:225-233.

Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: Incidence and clinical significance. J Am Coll Cardiol 2008;52:1231-1238.

Sinner MF, Reinhard W, Muller M, Beckmann BM, Martens E, Perz S, et al. Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: A population-based prospective cohort study (MONICA/KORA). PLoS Med 2010;7:e1000314.

Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529-2537.

Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: Electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011; 123:2666-2673.

Uberoi A, Jain NA, Perez M, et al. Early repolarization in an ambulatory clinical population. Circulation 2011;124:2208-2214.

Watanabe H, Nogami A, Ohkubo K, et al. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. Circ Arrhythm Electrophysiol 2011;4:874-881.

Wu SH, Lin XX, Cheng YJ, Qiang CC, Zhang J. Early repolarisation pattern and risk for arrhythmia death: a metaanalysis. J Am Coll Cardiol 2013;61:645–50.

Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 1999;100:1660-1666.

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