Sudden cardiac death (SCD) is the most common cause of death worldwide and accounts for greater than half of all mortality of cardiovascular origin.^1,2 Despite robust effort to elucidate underlying mechanism and predisposition to SCD, the overwhelming majority of SCD occurs in subjects devoid of currently recognized “high risk” features.³ Accordingly, identification and screening for SCD markers is of extreme importance in the general population in which, despite low relative risk, a high number of SCD events occur. Although the majority of SCD likely involves coronary artery disease and ischemia, events without cardiac structural abnormalities are also appreciable.⁴ Several primary electrical disorders have been identified, including long-QT syndrome, short-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.⁵ Historically, early repolarization pattern (ERP) on electrocardiogram (ECG) has been considered a pattern without relevant clinical consequence and is relatively common, with an estimated prevalence of approximately 5% in the general population.^6-8

The J point on an ECG identifies the junction of the QRS complex and the ST segment and designates the end of ventricular depolarization and the beginning of ventricular repolarization. ERP on ECG is defined as J point elevation that is either notching (a positive deflection on terminal QRS complex) or slurring (on the downslope portion of the QRS complex), is typically associated with concave upward ST-segment elevation and prominent T waves, and is present in at least two contiguous leads.⁹

As recently as 2003, Klatsky et al reported following 2000 patients, 670 of whom exhibited ERP on ECG, for over 12 years and concluded the prognosis of ERP to be benign with a reduced arrhythmia burden.¹⁰ The reported innocent nature of this ECG  manifestation, however, has been recently called into question. Case reports from the year 2000 suggested a relationship between ERP and idiopathic ventricular fibrillation (IVF),^11,12 noted as ventricular fibrillation in the absence of structural and/or ischemic heart disease.^13,14 Canine wedge preparations provided cellular and ionic support for potential arrythmogenicity of ERP.¹⁵ A landmark case-control study in 2008, however, truly challenged the innocuous nature of ERP.⁶ Haïssaguerreet al reviewed data from 206 case subjects resuscitated after cardiac arrest due to IVF compared to data from 412 subjects without heart disease matched for age, gender, race, and level of physical activity. Baseline ECGs, obtained at the time of ICD implantation for case patients, revealed that ERP in the inferior (II, III, and aVF) or lateral (I, aVL, and V4 to V6) ECG leads was six times more frequent in cases than in controls. Furthermore, ICD monitoring exhibited higher incidence of recurrent VF in case patients with ERP than case patients without ERP.⁶

Haïssaguerre et al as well as other independent case control studies associated ERP on ECG with vulnerability to ventricular fibrillation,^6,16,17 and catalyzed the current “revisitation” of ERP. As such, studies to help clarify a theorized predisposition to IVF and investigate the natural history of ERP ensued. In one study, the prevalence and prognostic significance of ERP over a mean follow up of 30±11 years was evaluated in a community-based general population of over 10,000 subjects, of which ERP was present in 5.8%. Of the non-ERP cohort, 18% died from cardiac causes over the follow up period. ERP with J point elevation in the inferior leads of at least 0.1mV and greater than 0.2mV was associated with an increased risk of cardiac death, with 24% and 47% dying from cardiac causes during follow up with adjusted relative risks of 1.28 and 2.98, respectively.⁷ Additional investigation by another group also implicated ERP as a marker of increased long-term cardiac mortality.¹⁸ Evaluation of these studies in sum led to the suggestion that ERP may exist on a continuous spectrum of disease, ranging from a truly benign early repolarization “pattern” on ECG to an IVF predisposed early repolarization “syndrome.”¹⁹

It may seem puzzling that an ECG pattern, for decades considered entirely benign, confers ventricular arrhythmic risk. Certainly, exact mechanisms that potentially predispose patients with ERP to ventricular tachyarrhythmia are not clear. Exploration of proposed ionic and cellular mechanisms may, however, provide insight into possible arrhythmogenesis.^8,19 Resting ventricular myocardial cell membrane potentials are very negative until reaching a certain threshold. At this critical point, sodium channels open and allow for rapid sodium entry into cells to quickly depolarize the myocyte (Phase 0 of action potential), rendering the depolarized potential much more positive than the resting potential. In the broadest of terms, myocyte repolarization is a complex interplay of activated and deactivated ion channels. Repolarization (Phases 1-3 of action potential) is the process in which the cell membrane potential return to a negative resting state, and can be simplistically seen as the net effect of potassium out of the cell and sodium and calcium into the cell. Ion channel abnormalities may increase net repolarization current by either increasing outward potassium and/or decreasing inward sodium and calcium to cause an “earlier” repolarization pattern, which can be transcribed on ECG.^8,19

Early repolarization occurring uniformly throughout ventricular myocardial cells would cause a general “early” repolarization by uniformly shortening QT-intervals. Non-uniform early repolarization would establish an appreciable delta in repolarization activity and creation of voltage gradients. It is proposed that in ERP, compared to ventricular endocardial cells, ventricular epicardial cells are richly innervated with specific outward potassium currents (i.e., Ito). This renders repolarization in epicardial cells that is “earlier” than in endocardial cells, establishing transmural gradients that may initiate arrhythmia. This heterogeneity in repolarization between epicardial and endocarial sites largely occurs at the onset of repolarization (i.e., J wave) and is transcribed on ECG as J point elevation, which has become a hallmark for the classification of ERP.^19,20

Should we overturn decades of ideology and no longer consider ERP a benign entity? Does convincing data suggesting a definitive link between ERP and IVF exist?  What should the medical community advise asymptomatic patients with clear evidence of ERP on routine ECG? A plethora of questions remain unanswered, several with complex, far-reaching ramifications. Not surprisingly, the evolving theory of ERP as a potentially dangerous entity is controversial. A few studies have emerged challenging the recent association between ERP and IVF and question the existence of a bone fide early repolarization “syndrome.” One group evaluated the association of ERP in over 29,000 subjects in an ambulatory population followed for a median of 7.6 years, and concluded that ERP is not associated with an increase in cardiovascular mortality.²¹

It remains a challenge to reconcile these diametrically opposed conclusions. One very simple, yet plausible explanation may exclusively involve semantics. The exact electrocardiographic definition and subsequent recognition of ERP has been subject to some degree of variation. Klatsky et al. reported a benign nature of ERP after a decade of follow up, but ERP was simply defined as “≥1.0-mm ST elevation,” could also have included an anterior location (V1 and V3 available for analysis), and did not specify the number of leads needed for ERP designation.10 The seminal case-control study by Haïssaguerre et al defined ERP as ≥0.1mV J-point elevation requiring either QRS slurring or notching in two contiguous leads. Haïssaguerre et al excluded anterior precordial leads (V1 through V3) to avoid inclusion of subjects with right ventricular dysplasia or the Brugada Syndrome.6 Several groups have espoused this specific definition in their ERP investigation. Uberoi et al utilized computer-read analysis to prescreen for subjects with ST elevation and ultimately concluded that ERP is not associated with an increase in cardiovascular mortality. These ECGs were not specifically interpreted for J point elevation, although ECGs from a subset of subjects (14% of total population) were manually read utilizing an ERP definition similar to one offered by Haïssaguerre et al.²¹ The exact definition of ERP utilized in each study should be assessed for critical data interpretation. To the authors’ knowledge, all published studies suggesting an associated between ERP and IVF or cardiac mortality have defined ERP as the presence of J point elevation associated with either QRS notching or slurring, irrespective of ST-segment elevation.²²

Without question, ERP investigation presents an area of intense interest because of its relatively common prevalence and potential impact on a myriad of issues. Once considered benign, ERP on ECG has been associated with IVF and cardiac mortality, although considerable debate exists. Ionic and cellular investigation provides mechanisms that may possibly describe arrhythmic potential. Transmural electrical heterogeneity is likely inscribed as J point elevation on ECG, which is an integral component of ERP definition. Variation in the exact definition of ERP in the reviewed literature may, in part, explain conclusive differences. While individuals with ERP may have an increased risk of SCD, the absolute risk remains low. Management of asymptomatic individuals demonstrating this pattern is an important clinical question. Methods to stratify SCD risk present an area of future investigation, as ramifications may include prophylactic treatment for individuals currently without indication for therapy.

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References

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Keywords: Action Potentials, Arrhythmias, Cardiac, Brugada Syndrome, Case-Control Studies, Coronary Artery Disease, Death, Sudden, Cardiac, Electrocardiography, Follow-Up Studies, Heart Conduction System, Potassium, Prevalence, Risk, Sodium, Tachycardia, Ventricular, Ventricular Fibrillation

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