Early repolarization with a constant ST-segment elevation in leads II, III, and AVF: Heritability and follow-up results

Egle Kalinauskiene; Jonas Jucevicius; Jone Vencloviene; Antanas Jankauskas; Inesa Navickaite; Albinas Naudziunas

doi:10.4103/hm.hm_6_19

ORIGINAL ARTICLE

Year : 2018 | Volume : 2 | Issue : 3 | Page : 85-91

Early repolarization with a constant ST-segment elevation in leads II, III, and AVF: Heritability and follow-up results

Egle Kalinauskiene¹, Jonas Jucevicius¹, Jone Vencloviene², Antanas Jankauskas³, Inesa Navickaite¹, Albinas Naudziunas¹
¹ Department of Internal Medicine, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
² Department of Clinical Cardiology, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
³ Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania

Date of Submission	11-Jul-2019
Date of Decision	04-Sep-2019
Date of Acceptance	10-Sep-2019
Date of Web Publication	27-Sep-2019

Correspondence Address:
Egle Kalinauskiene
Department of Internal Medicine, Medical Academy, Lithuanian University of Health Sciences, Josvainiu 2, LT-47144 Kaunas
Lithuania

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/hm.hm_6_19

Abstract

Background: A recent scientific statement from the American Heart Association included ST-segment elevation in the absence of chest pain in the definition of early repolarization (ER). ST-elevation at J-point termination (Jt)-point was not taken into account in previous heritability studies. The relevance of ST-elevation at Jt point (especially in inferior leads) is not evident enough. Our aim was to assess the heritability of ER with ST-elevation in inferior leads among offspring of such patients and patients' follow-up results. Materials and Methods: A prospective study of 16 consecutive patients with inferior ST-elevation at Jt ≥0.1 mV, who have arrived to outpatient department most often due to chest pain not associated with coronary stenosis according to multislice computed tomography angiography, started in 2013. Repeated cardiologist evaluation included their 12 children in 2017. Comparisons were made with 16 age- and gender-matched control patients' rest 12-lead electrocardiograms (ECGs) from the outpatient department of year 2018. Impact of ST-elevation's localization and sex on heritability were assessed by odds ratio (OR) with 95% confidence interval (CI). Results: There were no significant changes of patients' (all men) health and ECGs during follow-up. Eight (66.7%) of their children were ECG-positive versus 1 (6.2%) control patient,P = 0.001. All siblings (from the same father) of 5 (62.5%) ECG-positive children were ECG-positive. Two of the 5 (male and female) underwent detailed evaluation, including cardiac magnetic resonance, without abnormalities. In cases of only inferior father's ST-elevation, OR, 3.00; 95%CI, 0.24-37.7, and for male children, OR, 7.00; 95%CI, 0.400-23, for presenting with this pattern. Conclusions: Constant inferior ST-elevation, even in cases of chest pain, maybe ER, heritable without structural abnormalities. Heritability may be greater for male offspring and in cases of only inferior father's ST-elevation. Longer studies are necessary to confirm that it is benign. We suggest the term “a constant ST-segment elevation (at Jt)” instead of “ST-segment elevation in the absence of chest pain,” with adding that it is possible latent, depending on the heart rate.

Keywords: Chest pain, constant ST-segment elevation, early repolarization, inherited electrocardiographic disorders

How to cite this article:
Kalinauskiene E, Jucevicius J, Vencloviene J, Jankauskas A, Navickaite I, Naudziunas A. Early repolarization with a constant ST-segment elevation in leads II, III, and AVF: Heritability and follow-up results. Heart Mind 2018;2:85-91

How to cite this URL:
Kalinauskiene E, Jucevicius J, Vencloviene J, Jankauskas A, Navickaite I, Naudziunas A. Early repolarization with a constant ST-segment elevation in leads II, III, and AVF: Heritability and follow-up results. Heart Mind [serial online] 2018 [cited 2023 Mar 27];2:85-91. Available from: http://www.heartmindjournal.org/text.asp?2018/2/3/85/268095

Introduction

A recent scientific statement from the American Heart Association ^[1] submits that a concerted effort to understand the epidemiology, prognostic associations, genetic underpinning, and biological basis of early repolarization (ER) is warranted. An umbrella term that can refer to ST-segment elevation in the absence of chest pain, terminal QRS slur, or terminal QRS notch was proposed in this document for the definition of ER pattern (ERP), that refers to an electrocardiographic characteristic, whereas ER syndrome (ERS) is a collection of clinical findings (which may include certain electrocardiographic characteristics) that share a pathophysiological mechanism. ERS was defined as occurring in patients with ERP who have survived idiopathic ventricular fibrillation with clinical evaluation unrevealing for other explanations.^[1]

Terminal QRS notching or slurring plus J-point termination (Jt) elevation with Jt ≥0.1 mV occurred in 2.1% of 1496 apparently healthy, White adults (mean age 37.4 ± 12.6 years), whereas the prevalence was 29.3% if only notching or slurring was present without Jt elevation.^[2] Jt equates with ST-segment amplitude in relation to the definition of ST-segment elevation myocardial infarction. The different definitions of the ERP were reviewed in a consensus paper to delineate the electrocardiographic measures to be used when defining this pattern.^[3] One condition for ER to be present is Jp ≥0.1 mV (at the peak of the notch or at the onset of the slur), while ST-segment elevation is not a required criterion in this document.

Gussak and Antzelevitch raised the possibility that ER may not be as benign as generally thought, and that under certain conditions known to predispose to ST-segment elevation, patients with ER may be at greater risk.^[4] Their definition of the pattern included the presence of prominent J-waves, or QRS notching or slurring, together with ST-segment elevation.

The results from recent meta-analysis suggest that ERP was associated with increased risk of sudden cardiac arrest, cardiac death, and death from any cause; independent of conventional cardiovascular risk factors, especially ERP with J-point elevation in inferior leads, in both inferior and lateral leads; notching configuration; and horizontal or descending ST-segment (its elevation was not required).^[5]

Reinhard et al., studying the British general population, found that offspring of ER-positive parents (at least one) have a 2.5-fold increased risk of presenting with ER on their electrocardiogram (ECG).^[6] ER was defined by the criteria proposed by Haïssaguerre et al., that is, the presence of J-point elevation ≥0.1 mV in at least 2 adjacent leads in inferior (II, III, and AVF) or anterolateral leads (I, AVL, and V4 through V6).^[7] In the study of Noseworthy et al., there was evidence for a heritable basis in the general population.^[8] A study of Nunn et al. found a higher prevalence of J-point elevation in sudden arrhythmic death syndrome families.^[9] Study of Gourraud et al. also suggested that ER should be considered a real inherited arrhythmia syndrome.^[10] However, patients were only included in this study after experiencing sudden cardiac arrest associated with an ER and results should not be extrapolated to the general population. The presence or absence of ST-segment elevation in addition to J-point elevation was not taken into account in any of these studies.

In clinical practice, we noticed that children of outpatient department patients with a constant ST-segment elevation often also have this ECG pattern. Thus, our aim was to establish its frequency between the children of such patients and to assess follow-up results of the parents. ST-segment elevation (at Jt) was a required criterion in our study. It is a novelty of our study.

Materials And Methods

This is a follow-up of a prospective study of cardiologist's patients in the Kaunas Clinical Hospital Outpatient Department with a constant ST-segment elevation ≥0.1 mV in at least two of electrocardiographic leads II, III, and AVF, started in 2013 and described in our previous publication.^[11] In 2017, we invited these patients to come for cardiologist's examination, and this time with their children who agreed to be included in this study.

Criteria for inclusion in our study (for offspring) was known constant ST-segment elevation ≥0.1 mV in at least two of electrocardiographic leads II, III, and AVF in parent's ECG. Exclusion criteria were (in both offspring and control groups) ventricular pacemaker, intraventricular conduction defects, and myocardial infarction.

Patients' and their children's demographic characteristics, complaints during an interview, medical history during the follow-up period, data of physical examination, such as arterial blood pressure (BP), heart rate during heart auscultation and any pathology, revealed by heart and lung auscultation or general inspection and palpation (leg edema), were collected. In cases of patient hospitalization during the follow-up period, medical records were analyzed.

For these patients and their offspring (12 persons), 12-lead computerized ECG was recorded in 2017. The data of patients were compared with ECG data of their first examination and ECG data of their children. Frequency of syndrome in offspring was compared with frequency in 16 age- and gender-matched control patients. Control group patients were consecutive patients from the outpatient department of the year 2018 and their parents ECG status was unknown.

The subgroups of inferior ST-segment elevation (only in leads II, III, and AVF) and inferior-anterior ST-segment elevation (in standard leads II, III, and AVF and precordial leads, excluding leads V1 to V3) were analyzed according to the terms of leads in the universal definition of myocardial infarction.^[12] ECG analysis was made manually by the same cardiologist as in the previous study ^[11] who was experienced and blinded to other results. QRS notching and slurring was considered to be present if the peak of an end-QRS notch and/or the onset of an end-QRS slur was ≥0.1 mV.^[3] The ST-segment elevation was measured at Jt. The ST-segment was regarded as upward or downward if the amplitude of the ST-segment 100 ms after Jt was, respectively, greater or less than the amplitude at Jt, horizontal, if equal to the amplitude at Jt. In cases when the point of 100 ms after Jt was on T-wave, the measurement of the ST-segment slope was made at the point of an angle between ST-segment and T-wave (the beginning of the T-wave).

Patient's, whose ECG was presented as an example in our previous publication,^[11] both children, male and female, and had the same ST-segment elevation in leads II, III, and AVF as their father. Hence, their examination included additional data: height, weight, blood tests, and bicycle exercise test, performed by single observer who was experienced and blinded to the other results. Furthermore, the male had cardiac magnetic resonance imaging (MRI) performed by single radiologist who was experienced and blinded to other results. Female had transthoracic echocardiography and chest X-ray, performed by single observer and single radiologist, both were experienced and blinded to other results. Patients provided written informed consent for the exercise test, chest X-ray, and MRI.

This study was approved by the Ethics Committee of the Lithuanian University of Health Sciences and was conducted in full accordance with the Declaration of Helsinki.

Statistical analysis

To compare the proportions, the exact binomial test was used. To calculate frequencies in control versus test group and female versus male, and depending on ST-elevation location, data were put in contingency tables. To detect the association between categorized variables, the Fisher's exact test was used. To compare proportions, 95% exact confidence intervals (CIs) were calculated. The continuous variables were evaluated by the mean and standard deviation (SD). To compare mean values, the Mann–Whitney U-test was used.

The impact of gender and ER localization on the heritability was assessed by odds ratio (OR) with 95% CI. Statistical analysis was performed using the Statistical Package for the Social Sciences 20 for Windows (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp). Differences were assumed statistically significant if P < 0.05 for all the tests and if CI did not include 1 for OR.

Results

In 2017, 11 patients of 16 that were described in our previous publication ^[11] arrived for the examination, 4 patients were interviewed by telephone, and 1 patient was not contacted. There were no significant changes of their health. Only one hypertonic patient was hospitalized during the follow-up period due to paroxysmal cerebral ischemia with the BP 193/97 mmHg and one patient had short recurrences of paroxysmal atrial fibrillation. Both these patients had ST-segment elevation in inferior-anterior leads (higher in anterior leads); the first patient in leads V4 to V6 had a slur on the downslope of a prominent R wave, but in leads V4, V5 without ST-segment elevation; the second patient had an end-QRS notch in leads V3, V4 and a slur on the downslope of a prominent R wave. Patients who came for examination had ST-segment elevation with a slur or notch only in inferior leads. There were no differences between their previous and repeated in 2017 ECGs. Their constant ST-segment elevation was not associated with coronary stenosis.^[11]

Three of those 16 patients did not have children, one had single female baby, one was not able to be reached, so it is unclear if he had any children. One patient had one son and two daughters, but only the son arrived for the examination. Hence, we analyzed data of 12 children – 9 males and 3 females of the rest of 8 patients [Table 1]. One 12-year-old boy with inferior ST-segment elevation is not included in this table due to differences in BP and heart rate limits by age. His BP was 100/65 mmHg and heart rate – 83 beats per minute (bpm) on ECG. The QTc on his ECG was 371 ms. His father was only patient in our group from fathers who had abnormal, a little shorter than 360 ms QTc (359 ms). He had horizontal-downward sloping ST-segment elevation in inferior leads only. Other fathers in subgroup of only inferior ST-segment elevation had upward sloping ST-segment in 2 cases, horizontal in 2 cases, and upward sloping and horizontal in different leads in 1 case. In inferior-anterior subgroup, an upward sloping ST-segment was in 1 case and horizontal-downward sloping ST-segment elevation was in the other case. All patients and their children and persons in control group were White and not athletes.

Table 1: Patient and their children characteristics

Click here to view

Control group consisted of 16 age (mean 24 years ± SD 5.08 vs. mean 26.1 years ± SD 3.36, P = 0.4)- and gender (male 75% vs. 50%, P = 0.172)-matched patients.

Eight children (66.7%) had ST-segment elevation on resting ECG-same as their fathers versus 1 male person (6.2%) in control group (P = 0.001). In affected parents' children group, 77.8% of males and 33.3% of females had ST elevation [Table 2].

Table 2: Early repolarization with ST-segment elevation between the children of fathers with such electrocardiogram pattern

Click here to view

The risk for presenting with this pattern (in group whose parents had ST elevation) was 0.667; 95% CI, 0.349–0.891; in case of male children, respectively 0.778; 95% CI, 0.400–0.972. OR for presenting with this pattern for male children (vs. female in the same group) was 7.00 and 95% CI was 0.40–23. All children with ST-segment elevation had only inferior ST-segment elevation, five of them had a slur, two had a notch, and one had both of these changes of the QRS complex. There were no abnormal Q-waves or negative T-waves. The ST-segment elevation was not big – 0.1–0.15 mV, as in cases of their fathers. In a half of cases, it was upward sloping (4 children), upward sloping and horizontal in different leads in 3 cases, and horizontal in 1 case. Looking at subgroups of fathers, in cases of only inferior ST-segment elevation on father's ECG, 75% of children (83.3% of males and 50% of females) had ST-segment elevation, in cases of inferior-anterior ST-segment elevation on father's ECG 50% of children (66.7% of males and no one of females, but there was only one female in this subgroup) had ST-segment elevation, P > 0.05. OR for presenting with this pattern in cases of inferior only ST-segment elevation on father's ECG (compared to inferior-anterior in the same group) was 3.00; 95% CI, 0.24–37.7.

In 41.7% of all children, ST-segment elevation was not only on their ECG, but all children of the same father had it [Table 2]. In cases of the ST-segment elevation in children, in 62.5% of cases all children and in 37.5% of cases, half of children of the same father had it. In subgroup of only inferior ST-segment elevation, 80% of males and 100% of females with the ST-segment elevation had this ECG sign as all sons or daughters of the same father. However, it was only one female in this case and another one female in this subgroup did not have this sign, in both cases, it was only one daughter of the same father.

One patient with the constant ST-segment elevation in leads II, III, and AVF on ECG, presented in our previous publication ^[11] had two children: a son and a daughter. Both had very similar ECG changes as their father. Computerized ECG conclusion was “Inferior ST elevation, consider acute ischemia” [Figure 1]. The boy was 21 years of age, had a normal physique (height 185 cm, weight 75 kg), BP was 120/80 mmHg, heart rate was 83 bpm on physical examination, and 68 bpm on ECG. He had no complains, and there were no pathological changes on physical examination: normal heart and lung auscultation data and no edemas. He had few cases of tonsillitis in his medical history. Troponin I test was negative (0.001 mkg/l). Furthermore, his blood test showed no others abnormalities: potassium was 4.6 mmol/l, magnesium – 0.8 mmol/l, calcium – 2.5 mmol/l, glycemia – 4.0 mmol/l, creatinine – 91.6 mkmol/l, C-reactive protein – 0.1 mg/l, white cell count (WBC) – 5.5 10*9/l (NE 51.20%, LY 35.72%), red blood count – 5.08 10*12/l, hemoglobin – 157 g/l, and thrombocytes – 209 10*9/l. Immunological antistreptolysin O titer test in blood was negative, and a throat culture test showed no infection. The exercise test [Figure 2] showed that his ECG changes disappeared during peak exercise, but again were seen at rest after the exercise test, however, less than in [Figure 1] with less heart rate. Cardiac MRI showed no pathology.

Figure 1: Representative electrocardiogram from a 21-year-old male: early repolarization with a constant ST-segment elevation in the inferior leads. Very similar electrocardiogram from his father was presented in our previous publication (Kalinauskiene et al., 2016)

Click here to view

Figure 2: Electrocardiogram changes of the same 21-year-old male during the exercise test: ST-segment elevation disappeared during peak exercise, but again was seen at rest after the exercise test, however, less than in Figure 1 with less heart rate

Click here to view

The daughter was 19 years of age, also had a normal physique (height 167 cm, weight 55 kg) and no complaints. She had one case of bronchitis in her medical history. Her BP was 115/60 mmHg, heart rate was 69 bpm on physical examination and 71 bpm on ECG. Heart and lung auscultation data revealed no pathology, and there were no edemas. Her blood test showed no abnormalities: WBC 6.94 10*9/l (NE 59.3%, LY 29.1%), hemoglobin 132 g/l. Echocardiographic examination and chest X-ray showed no pathology. There was only minimal mitral regurgitation, but insignificant. The exercise test was not pathological. Inferior ST-segment elevation in leads II, III, and AVF disappeared during the exercise, but again was seen at rest after the exercise test as in a case of her brother.

The decreasing of ST-segment elevation with increasing heart rate was noted in other children too: three children with changing heart rate on resting ECG had this difference between the resting ECG at a heart rate more than 80 bpm and <70 bpm. However, one patient had a very clear inferior ST-segment elevation on resting ECG at a heart rate of 87 bpm.

Discussion

There were no significant changes in patients' health and ECG during follow-up. Their constant ST-segment elevation was not associated with coronary stenosis, despite the fact that they arrived to outpatient department most often due to chest pain.^[11] Furthermore, in clinical practice, there are cases of myocardial infarction with the absence of chest pain, for example, in cases of diabetic patients. Hence, the recent definition of ER as an umbrella term that can mean any of the following: ST-segment elevation in the absence of chest pain, terminal QRS slurring, or terminal QRS notching,^[1] should be corrected in our opinion. Maybe, the term “a constant ST-segment elevation” should be used instead of “ST-segment elevation in the absence of chest pain.” However, there was the decreasing of ST-segment elevation with increasing heart rate in our study and manifestation of latent ER with decreasing heart rate using the Valsalva maneuver in the study of Gourraud et al.^[10] Thus, we suggest the term “a constant ST-segment elevation” instead of “ST-segment elevation in the absence of chest pain,” with adding that it is possible latent, for example, depending on the heart rate.

Pargaonkar et al. showed that J-waves and QRS slurs did not exhibit a clinically meaningful increased risk for cardiovascular death in long-term follow-up.^[13] However, other studies found that QRS slurring or notching was more frequent in case patients with idiopathic ventricular fibrillation than in controls,^[7] and appropriate implantable cardioverter-defibrillator interventions were observed more often and earlier in patients with ERP.^[14] ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 years and an inferior localization of ERP was associated with a particularly increased risk.^[15],[16] ER with rapidly ascending ST-segment in inferior or lateral leads was a benign variant, in contrast, ER in inferior leads with a horizontal/descending ST-segment was associated with an increased risk of arrhythmic death, and a high amplitude of J-point elevation increased the risk even further.^[17],[18] However, ST-segment elevation was not taken into account in all the studies, as well as in the studies of ER heritability, while it was a required criterion in our study. The slope of ST-segment was only taken into account evaluating ST-segment in other studies. We also assessed the ST-segment slope at 100 ms after Jt, as it was recommended in a consensus paper.^[3] However, we have noticed that sometimes the point of 100 ms after Jt was on T-wave. In such cases, measurement of the ST-segment slope was made at the point of an angle between ST-segment and T-wave (the beginning of the T-wave) in our study. Maybe the measurement at 80 ms after Jt could be suggested and furthermore it would be easier to use in cases of visual assessment of ECG recorded at a paper speed of 25 mm/s (1 mm = 40 ms). We also suggest another possible point for the measurement of ST-segment slope: a visible angle between the ST-segment and upward slope of T-wave, the beginning of T-wave.

The frequency of ER with ST-segment elevation on resting ECG between the children of fathers with such ECG pattern was much greater than in control group. Results of the prevalence in control group are similar to those found in other studies of the ER prevalence – 2.1% of 1496 apparently healthy, White adults.^[2] This supports our hypothesis that ER with constant ST elevation might be heritable.

Reinhard et al. presented the first study examining the heritability of the ER pattern in a large family-based British cohort. They concluded that ER is a highly heritable trait, and about 50% of the variation in the presence of ER can be attributed to genetic factors. Presence of the trait in the mother increased the risk in children 3.8-fold, whereas the presence of ER in the father was associated with a nonsignificant 1.8-fold risk increase.^[6] However, the observed difference in paternal versus maternal ER transmission was not statistically significant in that study. Reinhard et al. showed a strong heritability in families with ER in the inferior leads, whereas the anterolateral occurrence of ER had a lesser genetic contribution.^[6] Our study showed that heritability may be greater in cases of father with this pattern only in inferior leads than in both inferior and anterior; however, results were not statistically significant (CI including 1), which may be due to that last localization (inferior and anterior) in our study had only two fathers. All patients, except their children, were male in our study. Heritability tended to be bigger for male children, but again the results were not statistically significant (CI including 1) and there were only three female children in our study.

Gourraud et al. showed that ERS can be inherited through autosomal dominant transmission and concluded that it should be considered a real inherited arrhythmia syndrome.^[10] We found ER with ST-segment elevation in males and females and a father-to-son transmission of this ER pattern in our study too. Our patients were different from probands of Gourraud et al.; they were ordinary cardiologist's patients of outpatient department, usually hypertonic, while the families studied by Gourraud et al. represented a rare cohort because the probands were included in the study after experiencing sudden cardiac death associated with an ER pattern. We agree with the opinion of Krahn and Obeyesekere that findings of Gourraud et al. can provide invaluable mechanistic clues but should not be extrapolated to the general population.^[19]

Mechanisms of ER can be genetically determined channelopathies or structural heart diseases since ER has been linked to both electrophysiological vulnerability and cardiomyopathies.^[20] Hence, ER syndrome is not monogenic. It is likely to be a complex disorder influenced by multiple genetic as well as environmental factors.^[21] ER is often associated with shorter-than-normal QT interval and is more pronounced at slower heart rates or following long pauses.^[22] In many cases, a clear distinction between ERS and short QT syndrome cannot always be made on the basis of an ECG alone and genetic tests could be helpful in these cases.^{[23],[24],[25]} In our study, we had only one patient with a little shorter-than-normal QT interval. We had no genetic tests in our study. It can be a limitation of our study. Other limitations are a small sample size of our study and just few females.

Conclusions

There were no significant changes in patients' health and ECGs during follow-up. 66.7% of their children had ER with ST-segment elevation as fathers. ER with ST elevation might be heritable as its frequency in patients whose parents had the same ECG changes were much higher than in control group or in general population. In 62.5% of ECG-positive cases it had all children of the same father.

Heritability may be greater for male children and in cases of inferior only father's ST-elevation than in cases of both inferior and other localization. Larger sample size studies are needed to confirm this tendency. Longer studies are necessary to confirm that the heritable constant ST-segment elevation is benign.

We suggest the term “a constant ST-segment elevation (at Jt)” instead of “ST-segment elevation in the absence of chest pain” in the definition of ER with ST-segment elevation, with adding that it is possible latent, for example, depending on the heart rate. We suggest the point at 80 ms after Jt for the measurement of ST-segment slope or a visible angle between the ST-segment and upward slope of T-wave, the beginning of T-wave. Further studies are necessary to confirm our suggested solutions of the problems in measurement of ST-segment slope.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Patton KK, Ellinor PT, Ezekowitz M, Kowey P, Lubitz SA, Perez M, et al. Electrocardiographic early repolarization: A scientific statement from the american heart association. Circulation 2016;133:1520-9.
2.	Heng SJ, Clark EN, Macfarlane PW. End QRS notching or slurring in the electrocardiogram: Influence on the definition of “early repolarization”. J Am Coll Cardiol 2012;60:947-8.
3.	Macfarlane PW, Antzelevitch C, Haissaguerre M, Huikuri HV, Potse M, Rosso R, et al. The early repolarization pattern: A consensus paper. J Am Coll Cardiol 2015;66:470-7.
4.	Gussak I, Antzelevitch C. Early repolarization syndrome: Clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol 2000;33:299-309.
5.	Cheng YJ, Lin XX, Ji CC, Chen XM, Liu LJ, Tang K, et al. Role of early repolarization pattern in increasing risk of death. J Am Heart Assoc 2016;5:e3375.
6.	Reinhard W, Kaess BM, Debiec R, Nelson CP, Stark K, Tobin MD, et al. Heritability of early repolarization: A population-based study. Circ Cardiovasc Genet 2011;4:134-8.
7.	Haïssaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, de Roy L, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016-23.
8.	Noseworthy PA, Tikkanen JT, Porthan K, Oikarinen L, Pietilä A, Harald K, et al. The early repolarization pattern in the general population: Clinical correlates and heritability. J Am Coll Cardiol 2011;57:2284-9.
9.	Nunn LM, Bhar-Amato J, Lowe MD, Macfarlane PW, Rogers P, McKenna WJ, et al. Prevalence of J-point elevation in sudden arrhythmic death syndrome families. J Am Coll Cardiol 2011;58:286-90.
10.	Gourraud JB, Le Scouarnec S, Sacher F, Chatel S, Derval N, Portero V, et al. Identification of large families in early repolarization syndrome. J Am Coll Cardiol 2013;61:164-72.
11.	Kalinauskiene E, Balnyte R, Naudziunas A. A constant ST segment elevation in leads II, III, AVF: An electrocardiographic, echocardiographic, clinical, exercise test, laboratory and multi-slice computed tomography angiographic study. J Electrocardiol 2016;49:610-3.
12.	Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Circulation 2012;126:2020-35.
13.	Pargaonkar VS, Perez MV, Jindal A, Mathur MB, Myers J, Froelicher VF, et al. Long-term prognosis of early repolarization with J-wave and QRS slur patterns on the resting electrocardiogram: A cohort study. Ann Intern Med 2015;163:747-55.
14.	Siebermair J, Sinner MF, Beckmann BM, Laubender RP, Martens E, Sattler S, et al. Early repolarization pattern is the strongest predictor of arrhythmia recurrence in patients with idiopathic ventricular fibrillation: Results from a single centre long-term follow-up over 20 years. Europace 2016;18:718-25.
15.	Sinner MF, Reinhard W, Müller 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.
16.	Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529-37.
17.	Tikkanen JT, Junttila MJ, Anttonen O, Aro AL, Luttinen S, Kerola T, et al. Early repolarization: Electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666-73.
18.	Rosso R, Glikson E, Belhassen B, Katz A, Halkin A, Steinvil A, et al. Distinguishing “benign” from “malignant early repolarization”: The value of the ST-segment morphology. Heart Rhythm 2012;9:225-9.
19.	Krahn AD, Obeyesekere MN. Inheritance of early repolarization and familial malignant forms. J Am Coll Cardiol 2013;61:173-5.
20.	Boineau JP. The early repolarization variant normal or a marker of heart disease in certain subjects. J Electrocardiol 2007;40:3.e11-6.
21.	Mizusawa Y, Bezzina CR. Early repolarization pattern: Its ECG characteristics, arrhythmogeneity and heritability. J Interv Card Electrophysiol 2014;39:185-92.
22.	Watanabe H, Makiyama T, Koyama T, Kannankeril PJ, Seto S, Okamura K, et al. High prevalence of early repolarization in short QT syndrome. Heart Rhythm 2010;7:647-52.
23.	Gussak I, Antzelevitch C. Early repolarization syndrome: A decade of progress. J Electrocardiol 2013;46:110-3.
24.	Antzelevitch C. Genetic, molecular and cellular mechanisms underlying the J wave syndromes. Circ J 2012;76:1054-65.
25.	Haïssaguerre M, Chatel S, Sacher F, Weerasooriya R, Probst V, Loussouarn G, et al. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol 2009;20:93-8.