Early Repolarization – Is it really a benign entity?

The term early repolarization (ER) is defined electrocardiographically by either

• a sharp well-defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST-segment, or
• slurring at the terminal part of the QRS complex (also termed J-waves or J-point elevation).

Specifically, the ER pattern is present when J-point elevation of ≥0.1 mV is seen in 2 adjacent leads with either a slurred or notched morphology.1,2
The J point deflection occurring at the QRS-ST junction (known as Osborn wave or J wave) was first described in 1938, and is seen in both extracardiac and cardiac disorders like hypothermia, hypercalcemia, brain injury, hypervagotonia, or spinal cord injury leading to loss of sympathetic tone and vasospastic angina. Besides the recently described early repolarization syndrome,3–5 ER has generally been considered a normal ECG variant with good long-term prognosis. It is more prevalent in males, African-Americans, and in young trained athletes especially those engaged in endurance disciplines.6,7 However, emerging case-control 8,9 and prospective cohort 10 studies suggested that the early repolarization pattern in the inferior ECG leads is associated with an increased risk of sudden cardiac death.
Antzelevitch et al described early repolarization syndrome into three subtypes:11

Type 1: Early repolarization pattern predominantly in the lateral precordial leads. This form is very prevalent among healthy male athletes and is rarely seen in VF survivors.
Type 2: Early repolarization pattern predominantly in the inferior or inferolateral leads. Numerous cases of otherwise idiopathic VF have this ECG pattern, this is also prevalent in healthy young males.
Type 3: Early repolarization pattern globally in the inferior, lateral, and right precordial leads and is associated with the highest level of risk for development of malignant arrhythmia. It is often associated with VT/VF storms.

Tikkanen et al 11 proposed another classification. ER is J-point and ST segment elevation >1 mm in 2 or more contiguous leads. Two types of J-point elevation are described:

• J-point with a rapidly ascending ST segment, considered a Benign form.
• J-point with a horizontal or descending ST segment, considered a Malignant form.

ER is most often an incidental ECG finding that may be present intermittently.12 Given the relatively high prevalence of the ER pattern in the general population (5 to 13 percent) in comparison to the incidence of idiopathic VF (approximately 10 cases per 100,000 population), the ER pattern is nearly always a benign incidental ECG finding. There are no specific signs or symptoms attributed to the ER pattern, which is identified through the use of a standard ECG. In the absence of syncope or sudden cardiac arrest, no additional testing is required in persons with the ER pattern. Asking patients to perform the Valsalva manoeuvre may unmask or accentuate the ER pattern. While performing this manoeuvre has been shown to aid in the identification of the ER pattern in high-risk familial ER, the report of this has not been validated and its applicability to broad populations of asymptomatic persons has not been evaluated.13

The diagnosis of ER syndrome is most commonly considered in a survivor of sudden cardiac death (SCD) with ECG evidence of ventricular fibrillation (VF) and an apparently structurally normal heart following extensive testing. A systematic assessment of the survivors of sudden cardiac death without evidence of infarction or left ventricular dysfunction is reported to establish a causative diagnosis in the majority of cases.14,15

Following clinical patterns are now known:16,11

• Asymptomatic and incidentally detected ER is very common in young athletes. The prevalence and magnitude of ER increase as their training intensifies.
• Malignant variety with Idiopathic VF and Sudden cardiac death (SCD).
• ER with Coronary artery disease (CAD) with increased risk of having ischemic VF. ER pattern recorded during an ischemic event is the strongest predictor of VF occurrence.
• ER has been linked to high cardiac death and arrhythmic death rates in vasospastic angina.
• Idiopathic VF is reported with horizontal or down-sloping ST following J-point elevation

ER pattern and ER syndrome — These two terms, distinguished by the presence or absence of symptomatic arrhythmias, have been used to describe patients with this ECG finding:

• The ER pattern describes the patient with appropriate ECG findings in the absence of symptomatic arrhythmias.
• The ER syndrome applies to the patient with both appropriate ECG findings and symptomatic arrhythmias.

Persons with either the ER pattern or the ER syndrome can have identical findings on surface ECG. However, the mere presence of the ER pattern on the ECG should not lead to a classification of ER syndrome in the absence of symptoms or documented VF.

Rarely, ER may be associated with the primary arrhythmic disorder idiopathic ventricular fibrillation (VF) in the absence of structural heart disease.14,17 Given the prevalence of the ER pattern in the general population and the exceedingly low incidence of idiopathic VF, the diagnosis of idiopathic VF due to malignant ER is a diagnosis of exclusion.

The ER pattern may be sporadic or inherited, although first-degree relatives of a person with the ER pattern appear to have a two to three-fold higher likelihood of also having the ER pattern on ECG. While the vast majority of ER is likely sporadic, familial ER appears to be transmitted in an autosomal dominant fashion.

Following are recommendations from latest Consensus document of HRS/ACC/ESC: 18

Class I

• ICD implantation is recommended in patients with a diagnosis of ER syndrome who have survived a cardiac arrest.

Class II a

• Isoproterenol infusion can be useful in suppressing electrical/VT storms in patients with diagnosis of ER syndrome.
• Quinidine in addition to an ICD can be useful for secondary prevention and suppression of VT/VF in patients with a diagnosis of ER syndrome.

Class II b

• ICD implantation may be considered in symptomatic family members of ER syndrome, with a history of syncope in the presence of ST segment elevation >1 mm in 2 or more inferior or lateral leads.
• ICD implantation may be considered in asymptomatic individuals who demonstrate a high-risk ER ECG pattern (high J-wave amplitude, horizontal/descending ST) in the infero-posterior leads and 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 in asymptomatic patients with an isolated ER pattern on ECG.

There is no recommendation to do ECG screening of the families of individuals with asymptomatic ER pattern or individuals with strong family history of ER or ER with VF. No established provocative tests are present to diagnose concealed ER in family members of ER syndrome patients, although preliminary observation suggest that the Valsalva maneouvre may assist in identifying concealed ER cases.18,19

Conclusions:

ER which was thought to be benign previously is not always benign. However, the ER syndrome as a primary arrhythmogenic disorder causing VF is very rare. Currently, there are no clinically useful risk stratifying tools or an established provocative test for identifying malignant ER, despite some ECG features that are associated with a higher risk. There are no current recommendations to perform ECG screening in the families with a strong history of ER or ER with VF.

References

1. Michel Haïssaguerre, M.D., Nicolas Derval, M.D., Frederic Sacher, M.D., Laurence Jesel, M.D., Isabel Deisenhofer, M.D., Luc de Roy, M.D., Jean-Luc Pasquié, M.D., Ph.D., Akihiko Nogami, M.D., Dominique Babuty, M.D., Sinikka Yli-Mayry, M.D., Christian De Chillou, M.D., Patrice Scanu, M.D., Philippe Mabo, M.D., Seiichiro Matsuo, M.D., Vincent Probst, M.D., Ph.D., Solena Le Scouarnec, Ph.D., Pascal Defaye, M.D., Juerg Schlaepfer, M.D., Thomas Rostock, M.D., Dominique Lacroix, M.D., Dominique Lamaison, M.D., Thomas Lavergne, M.D., Yoshifusa Aizawa, M.D., Anders Englund, M.D., Frederic Anselme, M.D., Mark O'Neill, M.D., Meleze Hocini, M.D., Kang Teng Lim, M.B., B.S., Sebastien Knecht, M.D., George D. Veenhuyzen, M.D., Pierre Bordachar, M.D., Michel Chauvin, M.D., Pierre Jais, M.D., Gaelle Coureau, Ph.D., Genevieve Chene, Ph.D., George J. Klein, M.D., and Jacques Clémenty, M.D. Sudden Cardiac Arrest Associated with Early Repolarization. N Engl J Med 2008; 358:2016-2023.

2. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med. 2009;361:2529–2537.

3. Mehta M, Jain AC, Mehta A. Early repolarization. Clin Cardiol. 1999;22:59–65.

4. Klatsky AL, Oehm R, Cooper RA, Udaltsova N, Armstrong MA. The early repolarization normal variant electrocardiogram: correlates and consequences. Am J Med. 2003;15:171–177.

5. Tomaszewski W. Changement electrocardiographiques observes chez un homme mort de froid. Arch Mal CoeurVaiss. 1938;31:525–528.

6. Junttila MJ, Sager SJ, Freiser M, et al. Inferolateral early repolarization in athletes. J Interv Card Electrophysiol. 2011; 31: 33-38.

7. Higgins, J.P. Normal resting electrocardiographic variants in young athletes. Phys Sportsmed. 2008; 36: 69–75.

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

9. 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.

10. Tikkanen, J.T., Anttonen, O., Junttila, M.J. et al. Long-term outcome associated with early repolarization on electrocardiography. N Eng J Med. 2009; 361: 2529–2537.

11. Junttila M.J., Sager S.J., Tikkanen J.T. Clinical significance of variants of J-points and J-waves: early repolarization patterns and risk. Eur Heart J. 2012 Nov;33:2639–2643

12. Derval N, Simpson CS, Birnie DH, Healey JS, Chauhan V, Champagne J, Gardner M, Sanatani S, Yee R, Skanes AC, Gula LJ, Leong-Sit P, Ahmad K, Gollob MH, Haissaguerre M, Klein GJ, Krahn AD. Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol. 2011;58:722–728.

13. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large families in early repolarization syndrome. J Am Coll Cardiol 2013; 61:164.

14. Derval N, Simpson CS, Birnie DH, et al. Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. J Am Coll Cardiol 2011; 58:722.

15. Krahn AD, Healey JS, Chauhan V, et al. Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER). Circulation 2009; 120:278.

16. Antzelevitch C. Yan GX.J wave syndromes – contemporary review. Heart Rhythm. 2010;7:549–559.

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

18. HRS/EHRA/APHRS Expert Consensus Statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. Oct 2013; 10: 10.

19. Ackerman M.J., Priori S.G., Willems S. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) Heart Rhythm. 2011 Aug;8:1308–1339.