History

Early repolarization (ER) was first described in 1936 by Shipley and Hallaran when they performed four-lead electrocardiograms (ECGs) on 200 healthy 20 to 35-year-old individuals and noticed an elevated ST segment in lead II in 25% of males and 16% of females.¹ In 1938, Tomaszewski described this variant in a man who died from hypothermia.² The term "early repolarization" was coined by Grant in 1951 in his study on spatial vector electrocardiography.³ In 1953, Osborn described the J wave,which also became known as Osborn wave in hypothermic dogs.⁴ The Osborn wave can be seen in both cardiac and non-cardiac disorders including neural/brain injury, increased vagal tone, hypercalcemia, and hypothermia.⁵

ER has historically been considered a normal variant, but it is becoming more evident through numerous case controls and population based studies that it is associated with an increased incidence of arrhythmic sudden cardiac arrest. Its link to malignant potential was suggested in 1984, when Otto et al. discussed idiopathic ventricular fibrillation (VF) that occurred in the sleep of three young Southeast Asian males with J waves and no structural heart disease.⁶ Among patients with a history of idiopathic VF, Haïssaguerre et al. found an increased prevalence of ER in 2008.⁷

Epidemiology

Multiple cohort studies have estimated that the prevalence of ER occurs in up to 13% of the general population.^8-12 Over 75% of ER occurs in men who also have a higher degree of J point elevation.¹² This is thought to be related to an increase in outward potassium current in men caused by higher levels of testosterone, which also increases the J wave.^13-14 Men also represent 75% of ER malignant cases.^7,12 J point elevation is found more frequently among patients with idiopathic VF than among healthy subjects.¹⁰ The frequency of J point elevation among young athletes was higher than among healthy adults but lower than among patients with idiopathic VF.¹¹ African Americans also tend to have the ER pattern more often, but the arrhythmic risk in this population is uncertain.¹⁵ In a case-control study, subjects with idiopathic VF have higher prevalence of ER (31%) than healthy control subjects (5%).⁷

While ER is relatively prevalent in the general population, the incidence of idiopathic VF is low. The arrhythmic events usually occur at higher age (>55 years). In asymptomatic individuals before age of 45 years, the risk of sudden cardiac death (SCD) is three per 100,000 and the SCD risk is 11 per 100,000 with J waves and 30 per 100,000 with horizontal ST segment elevation. In a meta-analysis by Wu et al., the estimated absolute risk for arrhythmic death in patients with ER was 70 per 100,000.¹⁶

Molecular Basis and Genetics

The J wave can be augmented by factors that increase the net repolarization current (decreased inward sodium and calcium currents, or increased outward potassium currents).¹³ This explains how sodium channel blockers can augment or unmask ST segment elevation in concealed J waves and quinidine, which also inhibits the Ito, reduces the amplitude of the J wave and ST segment.¹⁴ Individuals with ER do have some degree of voltage gradients due to depolarization/repolarization currents imbalance and it manifests on the ECG as a J wave or ST elevation. This currents imbalance is heterogeneous, causes a dispersion of repolarization that could be regional or transmural, and leads to local transmural Phase 2 reentry and closely coupled premature ventricular complexes, leading to polymorphic ventricular tachycardia and VF when R-on-T phenomenon occurs, especially in the presence of additional proarrhythmic factors or triggers.¹⁷

ER is more common in relatives of unexplained arrhythmic SCD, suggesting possible pro-arrhythmic inherited mutations.¹⁸ Reported responsible genetic mutations include the KCNJ8 and the ABCC9 genes (ATP-sensitive potassium channel),^19,21,22 KCNE5 mutation (and rare polymorphism in DPP10)²³ affecting the transient outward current (I_to), CACNA1C, CACNB2B, CACNA2D1 genes (cardiac L-type calcium channels),²⁴ and SCN5A and SCN10A genes (sodium channels). Gain of function mutation in the KCNJ8 results in increased outward potassium current that is associated with ER and idiopathic VF, while loss of function mutations in the genes responsible for cardiac L-type calcium channels and sodium channels have been linked to ER (Table 1).

Table 1: Genes Linked to Early Repolarization

Gene	Protein	Effect of Mutation on Current	Chromosome
KCNJ8	Kir6.1	↑ IKATP	12p11.23
ABCC9	SUR2	↑ IKATP	12p12.1
KCNE5	MiRP4	↑ Ito	Xq22.3
DPP10	DPL2	↑ Ito (due to E5D polymorphism)	2q14.1
CACNA1C	CaV1.2 α1c	↓ ICa.L	12p13.33
CACNB2B	Cav1.2β2b	↓ ICa.L	10p12.33-p12.31
CACNA2D1	Cav1.2 α2δ1	↓ ICa.L	7q21.11
SCN5A	Nav1.5 α	↓ INa	3p21
SCN10A	Nav1.8	↓ INa	3p22.2

Diagnosis

ER is diagnosed on ECG as a sharp, well-defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST segment, or the presence of slurring at the terminal part of the QRS complex (since the J point elevation may be hidden in the terminal part of the QRS complex, resulting in slurring of the terminal QRS complex). It is present when J point elevation is ≥0.1 mV in two adjacent leads. The notch or the onset of the slur should be entirely above the baseline, and the angle between the tangent to the slur and the initial R downslope exceeds 10 degrees.²⁵ ER can occur with ST segment elevation (with or without a J wave) or without ST segment elevation (with a J wave or a slurred QRS downstroke). The ST elevation is defined by ≥1 mm in at least two adjacent leads. The ST changes seen in early repolarization are different than the ST changes seen with acute ischemia/infarction that are due to current flow, called "injury current," across the area between ischemic and non-ischemic myocardium.²⁶

"ER pattern" describes ECG findings of ER in the absence of symptomatic arrhythmias. If ER pattern is accompanied with a history of resuscitated idiopathic VF and/or polymorphic ventricular tachycardia (VT), "early repolarization syndrome" (ERS) is diagnosed.²⁷ ER falls under the category of "J wave syndromes," which are a phenotypic spectrum of J wave disorders, including ERS, the Brugada Syndrome, and arrhythmias linked to ST-segment elevation myocardial infarction and hypothermia.²⁸

Scope of the Problem

ER is associated with increased risk of idiopathic VF in the absence of pre-existing heart conditions, and there is also an increased risk of VT and VF in patients with acute coronary events who have baseline ER pattern.^29,37 ER has not been associated with non-arrhythmic cardiac diseases.³² As the evidence associating ER with sudden arrhythmic death is increasing, research has been focusing on ways to distinguish between benign and malignant patterns of ER in attempts to risk stratify patients for optimal management.

Risk Stratification

Various ECG parameters have been studied as prognostic indicators in patients with ER (Table 2). Tikkanen et al. studied the ST-segment morphology in Finnish and American young healthy athletes. ST segments were classified as either horizontal/descending (≤0.1 mV within 100 ms after the J point; downsloping ST segment elevation is characterized by a STJ [J point]/ST80 [the point 80 ms after the J point] ratio >1) or rapidly ascending/upsloping (>0.1 mV elevation throughout the ST segment). The majority of these athletes (>85%) with ER pattern had the ascending ST variant. When comparing these athletes to ECGs from a large population, it was shown that the horizontal/descending variant of ST segments were more strongly associated with sudden arrhythmic death as compared to patients without ER, and the upsloping pattern did not show significant association with sudden arrhythmic death.³³ However, the horizontal/descending variant is commonly seen in healthy adults and this may result in over-diagnosis of malignant pattern of ER.³²

Roten et al. compared ECGs of patients with ER and VF with those of asymptomatic patients with ER pattern and found that patients with VF had significantly longer QTc intervals, had J wave and with higher J wave amplitudes, higher frequency of low-amplitude T waves, and lower T/R ratio (leads II or V₅).³³ Among these parameters, low T/R ratio was most strongly associated with malignant ER. Cristoforetti et al. analyzed the slope of the J wave in ERS patients (the J wave slope is the angle between an ideal line drawn from J point perpendicular to isoelectric line and tangent to the J wave, resulting in a J angle) and the J wave duration (interval between the onset of J point [or J₀] and intersection of tangent to Jwave with isoelectric line or the change in slope of the J wave into the ST/T wave, depending on which comes first), and compared these parameters to healthy athletes with ER pattern. ER syndrome patients had longer duration of J waves (>60 ms) and had significantly wider J angle (>30 degree angle) than ER pattern patients. Longer J wave duration with wider J angle was shown to be associated with higher arrhythmic risk.³⁴ Other ECG parameters associated with malignant ER are the presence of ER in inferior/inferolateral leads (ERS type 2) or global ER (ERS type 3), and shifting of ER into a Brugada Syndrome pattern (involvement of the anterior precordial lead or ERS type 4).³⁵ Aizawa et al. studied J waves occurring after sudden RR-interval prolongations (pauses) caused by benign arrhythmias, and found that "pause-dependent augmentation" of J waves was associated with idiopathic VF with 100% positive predictive value and specificity.³⁸ Thus, the dynamicity of the J wave (instantaneous J/ST changes or the accentuation of ER by arrhythmias) is associated with SCD.

Exercise ECG testing has been shown to unmask high-risk ER patterns. In a study conducted by Bastiaenen et al., exercise tolerance testing (ETT) and ajmaline provocation testing on 229 patients with history of aborted sudden cardiac death (SCD), sustained ventricular arrhythmia, unexplained syncope, and/or a positive family history of SCD with no definitive cardiac etiology. 26 of these patients had baseline ER pattern, and of these, ajmaline provocation and ETT led to the disappearance of all lateral ER patterns and rapidly ascending ST segment patterns. In patients with horizontal/descending ST segment patterns, 40% of ER persisted in ajmaline provocation and 75% of ER persisted in ETT. Inferior ER persisted in 44% during ajmaline provocation and 40% during ETT. Patients with persistent ER had in increased likelihood of symptoms (mainly unexplained syncope) than patients with diminished ER during exercise tolerance testing.^39,40

Table 2: Summary of ECG Parameters in Early Repolarization

ECG Parameter	Description	Results	Study
J wave amplitude & STsegment morphology	≥0.1 mV, horizontal/descending ST segment ≥0.2 mV, horizontal/descending ST segment, inferior leads ≥0.1 mV, ascending ST segment	RR = 1.43 [1.05 – 1.94] RR = 3.14 [1.56 – 6.30] RR = 0.89 [ 0.52 – 1.55]	Tikkanen et al31
QTc Interval	Per 10 ms QTc > 420 ms QTc > 400 ms	OR = 1.15 [1.02 – 1.30] OR = 11.77 [4.23 – 32.79] OR = 3.5 [1.96 – 6.25]	Roten et al33
T waves	Low amplitude (<0.1 mV and <10% of R-wave amplitude in lead I, II, or V4 – V6	OR = 12.41 [5.38 – 28.61]	Roten et al33
T/R ratio (lead II or V5)	<0.25 <0.20 <0.15 <0.10	OR = 6.93 [3.98 – 12.07] OR = 6.45 [3.82 – 10.89] OR = 5.73 [3.22 – 10.20] OR = 11.15 [4.81 – 25.85]	Roten et al33
J wave duration	>60 ms Average	Controls = 0% Cases = 55.6% Controls = 35.05 ± 10.33 ms < Cases = 69.48 ± 27.93 ms (p < 0.001)	Cristoforetti et al34
J wave slope	>300 Average	Controls = 8.3% Cases = 55.6% Controls = 20.00° ± 6.84° < Cases = 32.59° ± 10.4° (p < 0.001)	Cristoforetti et al34

Management

The ER pattern is relatively prevalent in the general population with a rare incidence of idiopathic VF. The ER pattern usually remains asymptomatic and patients with ER pattern require no intervention.²⁷ However, for patients with ER syndrome who have survived cardiac arrest, an implantable cardioverter defibrillator (ICD) implantation is indicated.²⁷ The challenge is in the management of patients with ER pattern who have family members with ER syndrome or unexplained sudden cardiac death, have history of syncope, or have high-risk ER ECG pattern. Isoproterenol infusion can be useful in suppressing electrical storms in patients with a diagnosis of ER syndrome. Quinidine in addition to an ICD can be useful for secondary prevention of VF in patients with a diagnosis of ER syndrome. In the setting of resuscitated SCA, cascade/familial screening is needed.

Gaps in Knowledge and Future Implications

While ECG parameters have been suggested for risk stratification, the absolute risk of arrhythmia related to these variants is still very small, and the value of these ECG markers are still uncertain in clinical practice, especially in asymptomatic patients. On one hand, the very low probability of sudden cardiac arrhythmia in a patient with high risk ER ECG parameters warrants observation alone, but the consequence of sudden cardiac arrhythmia in a patient, no matter how rare, is still a grave consequence. Exercise tolerance testing can characterize ER (during ajmaline provocation) and might unmask ER pattern at high risk for SCD.⁴¹

Electrophysiology Studies (EPS) have not been shown to have a role in risk stratification, as J point elevation may be augmented right before a VF episode and may not be seen at the time of the EPS.³⁸ Non-invasive electrocardiographic imaging (ECGI) and invasive monophasic action potential (MAP) are used to study ventricular substrate for reentry.³⁵ The association of ECGI and MAP with novel genetic sequencing methods (next generation sequencing) may help in the management of asymptomatic or intermediate-risk ER patients in the near future.

References

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Keywords: Adenosine Triphosphate, Ajmaline, Arrhythmias, Cardiac, Brain Injuries, Brugada Syndrome, Calcium Channels, L-Type, Chromosomes, Cohort Studies, Death, Sudden, Cardiac, Defibrillators, Implantable, Electrophysiology, Heart Arrest, Heart Conduction System, High-Throughput Nucleotide Sequencing, Hypercalcemia, Hypothermia, Infarction, Isoproterenol, KATP Channels, Mutation, Myocardial Infarction, Myocardium, Potassium, Potassium Channels, Quinidine, Secondary Prevention, Sodium, Sodium Channels, Sodium Channel Blockers, Syncope, Syndrome, Tachycardia, Ventricular, Testosterone, Vectorcardiography, Ventricular Fibrillation

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