REVIEW URRENT C OPINION
A practical guide to early repolarization Arnon Adler a and Michael H. Gollob b
Purpose of review Early repolarization has been associated in the past decade with idiopathic ventricular fibrillation and arrhythmic death. The purpose of this review is to clarify recent changes in the definition of early repolarization and provide a practical approach to patients with this electrocardiographic sign. Recent findings Recent population studies have associated early repolarization with arrhythmic death. Challenges remain, however, in interpreting the risk of the early repolarization electrocardiographic pattern, as it is a common finding in the general population with a prevalence of 3–13%. Early repolarization characteristics associated with an especially high risk include high-amplitude J-point elevation, horizontal/descending ST segment, and inferior lead location. In view of the association of early repolarization with sudden death, a syndrome termed ‘early repolarization syndrome’ (ERS) has been accepted as the latest ‘channelopathy’ in patients with cardiac arrest, pronounced early repolarization pattern, and an otherwise structurally normal heart. The physiological basis of early repolarization is thought to involve an electrical transmural gradient produced by the transient outward current. Recent genetic studies have associated mutations in genes contributing to this current and other ion channels with ERS, although definitive genetic data do not yet exist to confirm pathogenicity. Summary ERS patients are rare and have a high risk of recurrent cardiac events. ICD implantation and possibly quinidine are the recommended treatments in this group. Opposingly, asymptomatic individuals with early repolarization are very common and, as a group, have a good prognosis. Sudden death preventive measures in these asymptomatic patients are limited to rare and unique cases. Keywords early repolarization, idiopathic ventricular fibrillation, sudden cardiac death
INTRODUCTION The prevention of sudden death has always been one of the main goals of the cardiologist. In our quest to fulfill this goal, we have uncovered numerous risk markers facilitating the implementation of preventive measures for those at highest risk. In the last decade, early repolarization has emerged as a new possible risk marker of sudden death; however, the next step, utilization of this knowledge for effective prevention, still eludes us. One of the central obstacles standing in our path is the relatively high prevalence of early repolarization, estimated to be as high as 25% in certain populations [1]. This high prevalence spells out two conclusions: first, only a small minority of the population with early repolarization will actually succumb to sudden death and, second, every physician interpreting ECGs will stumble upon many individuals with early repolarization. In other words, each one of these physicians will face the task of sieving the www.co-cardiology.com
very few that are truly at high risk out of the masses with early repolarization who may be dismissed as low-risk patients. In this article, we will review the latest updates regarding early repolarization and suggest a practical approach to these patients.
WHAT IS EARLY REPOLARIZATION? Unlike other electrocardiographic terms (e.g., ST-segment elevation, QT interval prolongation), ‘early repolarization’ is actually a physiological a Division of Cardiology, Tel Aviv Medical Center and Tel Aviv University, Tel Aviv, Israel and bDivision of Cardiology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
Correspondence to Michael H. Gollob, MD, Division of Cardiology, Toronto General Hospital, University of Toronto, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. Tel: +1 416 340 4282; e-mail: [email protected] Curr Opin Cardiol 2015, 30:8–16 DOI:10.1097/HCO.0000000000000126 Volume 30 Number 1 January 2015
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A practical guide to early repolarization Adler and Gollob
KEY POINTS The historical early repolarization definition includes two electrocardiographic phenomena, J-point elevation and ST-segment elevation; however, contemporary studies associating early repolarization with CA/SCD use only J-point elevation in their definition. Mutations in several genes have been associated with ERS, but the clinical benefit of genetic testing in these patients is currently questionable. SCD preventive measures (e.g., ICD implantation) are limited mainly to symptomatic patients with early repolarization (i.e., patients with ERS).
concept describing an electrocardiographic phenomenon. Naturally, this is a source of confusion as the term is not self-explanatory. Moreover, some experts doubt whether the markings on the surface ECG comprising early repolarization are indeed the consequence of the physiological process, as the name implies [2–4]. It is, therefore, crucial to first of all clarify what we mean when we say ‘early repolarization’.
Electrocardiographic definition The term ‘early repolarization’ was historically used to describe two electrocardiographic phenomena:
(a)
first, an upward deflection of the J point (or terminal part of the QRS complex) termed ‘J-point elevation’ or ‘J wave’ and, second, ST-segment elevation not associated with pathological conditions such as myocardial infarction. However, a clear-cut definition of early repolarization was never endorsed by major societies, leaving considerable room for interpretation of the term. For instance, in the recommendations for ECG interpretation published by the American Heart Association/American College of Cardiology/Heart Rhythm Society in 2009, early repolarization is not clearly defined but referred to as ‘. . .a normal variant. . .commonly characterized by J-point elevation and rapidly upsloping or normal ST segment’ [5]. Since the publication of Haissaguerre et al. in 2008 [6] associating early repolarization with idiopathic ventricular fibrillation, most studies used these authors’ definition in an attempt at standardization. Their proposed definition describes elevation of the QRS–ST junction (J point) in at least two leads, excluding right precordial leads (Fig. 1), and with an amplitude of at least 1 mm (0.1 mV) above the baseline level. The morphology of the J point may be either slurring (a smooth transition from the QRS segment to the ST segment) or notching (a positive J deflection inscribed on the S wave). Importantly, in stark contrast to previous concepts of early repolarization, there is no mention
(b)
FIGURE 1. Types of early repolarization. (a) J-point elevation with notching and slurring morphologies in different leads. ST segment is horizontal. In the right precordial leads there is J-point elevation but no Brugada pattern, demonstrating limitations of current early repolarization definition and possible overlap with Brugada syndrome. (b) J-point elevation in inferior and lateral leads with a notching morphology and ascending ST segment in most leads. ST segment in lead III is horizontal, demonstrating one limitation of ECG-based risk stratification of early repolarization. 0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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of ST-segment elevation in this definition. The Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society (HRS/ EHRA/APHRS) consensus statement on the diagnosis and management of primary inherited arrhythmia syndromes [7 ] used this definition (i.e., no requirement for ST elevation) for their recommendation regarding diagnosis of early repolarization syndrome (ERS) (see below and Table 1). This definition will be used for this review from this point onward. The main reason for exclusion of right precordial leads from Haissaguerre’s definition was to differentiate early repolarization from Brugada syndrome. However, recent data pointing at similarities in postulated mechanisms [8,9 ] and overlapping genetic [10,11] and clinical findings [8,12] (see next section and Fig. 1) make this distinction less straightforward. In fact, it has been proposed that ERS (see below) and Brugada syndrome are part of a spectrum of clinical conditions coined ‘J-wave syndromes’ [8,9 ]. &&
&
&
Mechanistic insight A detailed discussion of the proposed molecular mechanisms of early repolarization is beyond the
scope of this review and may be found elsewhere [8,9 ]. The leading concept in our current understanding of J-point elevation involves transmural differences in phases 1 and 2 of the cardiac action potential. Specifically, the transient outward current (Ito) was found to be more prominent in the epicardium than the endocardium, creating a relative accentuation of the epicardial action potential notch [8]. The first data to support this hypothesis came from arterially perfused canine wedge preparations demonstrating this difference in action potential morphology in epicardial vs. endocardial myocardium and its association with J-point elevation on ECG recordings [13]. Recent studies have shown that factors augmenting Ito (e.g., Ito agonist NS5806 [14]) accentuate J-point elevation while factors decreasing this outward current (e.g., tachycardia [8,15], quinidine [16]) diminish their amplitude. The fact that quinidine (an Ito blocker) is an effective treatment for suppression and prevention of ventricular arrhythmias associated with J-point elevation [17–19] serves as a clinical correlate to the in-vitro evidence. Augmentation of the gradient created by Ito may be the result of either an increase in outward &
Table 1. HRS/EHRA/APHRS consensus recommendations for diagnosis and management of early repolarization syndrome Expert consensus recommendations on early repolarization diagnosis (1) ER syndrome is diagnosed in the presence of J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG in a patient resuscitated from otherwise unexplained VF/polymorphic VT (2) ER syndrome can be diagnosed in an SCD victim with a negative autopsy and medical chart review with a previous ECG demonstrating J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG (3) ER pattern can be diagnosed in the presence of J-point elevation 1 m in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG Expert consensus recommendations on early repolarization therapeutic interventions Class I
(1) ICD implantation is recommended in patients with a diagnosis of ER syndrome who have survived a cardiac arrest
Class IIa
(2) Isoproterenol infusion can be useful in suppression of electrical storms in patients with a diagnosis of ER syndrome (3) Quinidine in addition to an ICD can be useful for secondary prevention of VF in patients with a diagnosis of ER syndrome
Class IIb
(4) ICD implantation may be considered in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST-segment elevation >1 mm in two or more inferior or lateral leads (5) 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
(6) ICD implantation is not recommended in asymptomatic patients with an isolated ER ECG pattern
APHRS, Asia Pacific Heart Rhythm Society; EHRA, European Heart Rhythm Association; ER, early repolarization; HRS, Heart Rhythm Society; ICD, implantable cardioverter defibrillator; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia. && Reproduced with permission from [7 ].
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currents (e.g., Ito, IKATP) or decrease in opposing inward currents (e.g., ICa, INa). It was, therefore, hypothesized that mutations in genes encoding for these channels may be responsible for some cases of J-wave-associated arrhythmias. Indeed, in recent years, mutations in genes encoding for the KATP channel and its regulatory subunit [11,20,21], for the cardiac L-type calcium channel [22] and for the cardiac sodium channel [23], were described in such patients, although robust genetic evidence for disease causality in the form of familial segregation with phenotype is lacking. Recently, mutations in the genes encoding the major channel subunits of Ito, KCND2 and KCND3, have been described in Brugada syndrome and an atypical anterior J-wave syndrome associated with sudden cardiac death (SCD) [10,24]. These genetic defects produced a significant increase in Ito, consistent with inducing an exaggerated transmural gradient. Despite the evidence that mutations in Ito-encoding genes are potential causes of J-wave-associated arrhythmias, a comprehensive analysis in a cohort of patients with such arrhythmias demonstrated that major Ito-encoding genes are an uncommon cause of the phenotype [10]. Even though clinical and experimental evidence implicate Ito, the transmural gradient hypothesis is not accepted by all. Much as in Brugada syndrome [25], some hold the opinion that depolarization rather than repolarization abnormalities underlie the fundamental mechanism responsible for abnormal J waves [2,26 ,27]. &
CLINICAL IMPLICATION Patients with early repolarization may be divided into two main groups. The first includes symptomatic patients (e.g., survivors of cardiac arrest) with clear electrocardiographic evidence of early repolarization. These patients with ERS are extremely rare but have a high risk of recurrent cardiac events. In Haissaguerre’s study [6] of 64 ERS patients who were followed for a median of 51 months, 41% had arrhythmic recurrences, usually multiple (median eight arrhythmic events per patient). This recurrence rate was significantly higher than that noted in idiopathic ventricular fibrillation patients without early repolarization (hazard ratio 2.1). The second group comprises asymptomatic patients who are usually found to have an early repolarization pattern as an incidental finding. These cases are very common but, as a group, have low risk of adverse events. The challenge at hand is to discern, if possible, which of these asymptomatic patients may be at risk of a lethal event.
Patients with early repolarization and cardiac arrest (early repolarization syndrome) In essence, idiopathic ventricular fibrillation patients who are found to have early repolarization are now defined as ERS patients. Therefore, ERS patients, like idiopathic ventricular fibrillation patients, usually present at a young age (typically 1 mm elevation 100 ms post J point), is regarded as ascending. (b) Holter tracings demonstrating augmentation of J-point elevation at maximum bradycardia during early morning (top) and a short-coupled PVC (bottom). There is no consensus regarding management of this type of patients. PVC, premature ventricular complex.
found a rare variant in the KCND2 gene encoding for the Kv4.2 channel in a patient with J waves in the right precordial leads [10]. However, all of these variants were detected in single patients and only in the minority of ERS cases studied. Furthermore, a study of probands from large families with ERS failed to detect any mutations in these genes [32 ]. Therefore, genetic testing for ERS should remain a research initiative as no genetic findings have been clearly validated in large ERS cohorts with adequate control subjects. &&
Management Survivors of cardiac arrest or those with documented sustained ventricular arrhythmias and ERS should undergo ICD implantation [7 ] (Table 1). An ICD can also be considered in family members of ERS patients with a history of suspicious syncope or in asymptomatic patients with especially high-risk ECG features of early repolarization (see next section) and strong family history of SCD [7 ] (Fig. 3). In ERS cases with ventricular fibrillation storms, isoproterenol and temporary pacing [17,18] have been described to be of benefit. Quinidine has been used to prevent ventricular arrhythmias in patients with frequent ICD shocks and has been shown to ameliorate the early repolarization pattern in ERS patients [17–19] (Fig. 3). Other antiarrhythmics, including amiodarone, mexiletine, verapamil, beta blockers, and class IC drugs, have shown no or very &&
&&
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modest results in preventing arrhythmias in this patient population [18].
Asymptomatic patients with early repolarization (early repolarization pattern) The prevalence of early repolarization pattern in the middle-aged (age: 35–65 years) population is estimated to be between 3 and 13% [33–36] depending on the methods used and the population studied. In specific populations (young [1,37], male [33,37], athletes [38,39], and African-Americans [40]), it has been demonstrated to be especially high and may reach 25%. These demographics highlight the caution needed in drawing conclusions that an early repolarization ECG pattern is directly associated with a cardiac event occurring in young athletes. It is also not surprising that the study of Tikkanen et al. [33] associating early repolarization in a middle-aged population with arrhythmic death would make such a great impact in raising concern over early repolarization patterns – a huge population was now considered to be at risk. Most population studies following Tikkanen’s footsteps [34,35] found a similar association; however, major differences in population, methods, and definitions make direct comparison difficult [41]. Some studies have found no association between early repolarization and arrhythmic death but have typically been of short-term follow-up. The biggest population study to find no association between early repolarization Volume 30 Number 1 January 2015
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A practical guide to early repolarization Adler and Gollob
J-point elevation >1 mm in 2 contiguous inferior and/or lateral leads Yes
Early repolarization syndrome Class I
Yes
Cardiac arrest?* No
ICD implantation ----------------
Possible early repolarization syndrome
Strong family history of ERS/ SCD**?
Yes
Syncope$?
Yes
Class IIb
Yes
Class IIb
No No
High risk ECG#?
Syncope$?
Consider ICD implantation
No Yes
No
Follow§
Consider treatment of CV risk factors Consider follow-up in unique cases§†
Quinidine
Yes
Arrhythmic storm?
Class IIa
Follow§. Consider ILR and possibly ICD in unique high risk cases
Early repolarization pattern
Class IIa
Possible early repolarization syndrome
Yes
Recurrent shocks?
Isoproterenol‡ Quinidine
FIGURE 3. Proposed algorithm for approach to patients with early repolarization. CV, cardiovascular; ERS, early repolarization syndrome; ILR, implantable loop recorder; PVC, premature ventricular complex; SCD, sudden cardiac death; VT, ventricular tachycardia. After exclusion of other causes – see text. Patients with documented polymorphic VT triggered by short-coupled ventricular premature complexes, especially if preceded by augmentation of J-waves, should also be included in this group. There is no accepted definition for strong family history. We propose either one family member diagnosed with ERS or at least two family members with SCD of unknown cause under the age of 45. $Thought to be of arrhythmic cause. § Follow-up should include evaluation of new symptoms (e.g., syncope) in patient and family and analysis of changes in ECG. It may include Holter tests in specific cases. Our policy is to see patients every 1–3 years but follow-up approach needs to be tailored to each patient individually. #Horizontal/descending ST-segment, J-point elevation more than 2 mm, inferior leads location and, possibly, short-coupled PVCs. yFollow-up should probably be limited to unique patients with very high-risk ECGs. z For acute treatment class recommendations based on consensus statement [7 ]. &&
and mortality [40] relied on evaluation of ST-segment elevation rather than J-point elevation in the majority of the population studied. Furthermore, it has been criticized for having a follow-up time of less than 8 years [42 ]. As the Kaplan–Meier curves in Tikkanen’s study began to diverge only after 13 years of follow-up, this is of major significance. The late divergence of the Kaplan–Meier curves has another significant implication – as the mean age at the time of inclusion in Tikkanen’s study was 44 years (range 30–59), cardiac mortality significance became evident only after the age of 55 years. Because idiopathic ventricular fibrillation patients (and the subset with early repolarization now referred to as ERS) rarely become symptomatic after &
the age of 40 years, it is evident that Tikkanen’s patients succumbing to arrhythmic death were of a different type. It was, therefore, hypothesized that these patients have an electrical substrate predisposing them to sudden death in the event of a second trigger coming into play [43]. In a middle-aged population, the most obvious trigger is ischemia. Support for this hypothesis was soon to come from case–control studies demonstrating increased prevalence of early repolarization in patients with ventricular fibrillation complicating myocardial infarction [44–46]. These studies, by associating early repolarization with ventricular fibrillation rather than mortality, also serve to substantiate the assumption that
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sudden death in patients with early repolarization is of arrhythmic cause. This is important as the population studies rely on retrospective analysis of records for death categorization, which is inherently inaccurate. The most direct and substantial support for this hypothesis, however, comes from a recent study specifically analyzing the association between early repolarization and ventricular tachycardia/ ventricular fibrillation events [42 ]. It demonstrated that early repolarization in inferior leads predicts ventricular tachycardia/ventricular fibrillation with a hazard ratio of 2.2 but is not associated with nonarrhythmic mortality. Unfortunately, implementation of this new data in the clinical setting is problematic. As the prevalence of early repolarization is so high, it is obvious that only very few of these individuals will actually die suddenly. In an attempt to improve the specificity of attempted risk stratification of the early repolarization pattern, various early repolarization characteristics were analyzed. Those found to infer an especially high risk include high-amplitude J-point elevation (>0.2 mV) and location of early repolarization in inferior leads [33,35,47]. It has also been suggested by some studies [17] that global early repolarization (in both inferior and lateral leads) is a marker of even higher risk. Most important, however, is the finding that only J-point elevation followed by a horizontal or descending ST segment (Fig. 1) is associated with arrhythmic mortality [38,48]. Individuals with J-point elevation and an ascending ST segment (like the classic ‘high-takeoff’ pattern) had no such association. J-point elevation morphology (notch vs. slur) was not consistently found to be of significance. This is perhaps not surprising taking into account that both morphologies may be found in the same patient at different times and even in different leads on the same ECG recording (Fig. 1). Analysis of Tikkanen’s data has shown that the subset at highest risk (those with high-amplitude J-point elevation on inferior leads and a horizontal ST segment) comprises only 0.3% of the population studied and that 24% of these suffered arrhythmic death during the 30 years of follow-up (adjusted hazard ratio 3.1) [38]. Nevertheless, data supporting preventive measures in this relatively high-risk middle-aged population, such as more aggressive screening and management of ischemic heart disease, are lacking. The clinical implication for young individuals (i.e., younger than 35) with early repolarization is also far from straightforward. As these patients are still at an age typical of idiopathic ventricular fibrillation/ERS presentation and are not yet at significant risk of ischemia, their risk stratification is different from their middle-aged counterparts. &
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However, the only population study to actually examine the association of early repolarization and mortality in the young [49] used a definition including ST-segment elevation rather than J-point elevation alone. Perhaps not surprisingly, the study was negative. Thus, the evidence supporting an increased risk of mortality in the young is based mainly on extrapolation from middle-aged population studies, idiopathic ventricular fibrillation case–control studies [6,17,50], and case reports. The prevalence of idiopathic ventricular fibrillation is estimated to be 3.4 : 100 000 [50] but only 30–40% of these have early repolarization [6,50]. Therefore, only around 1 : 100 000 may be expected to suffer SCD attributed to ERS. In young individuals (ages 21–25 years), the prevalence of early repolarization was recently found to be 16% but only 3% had the horizontal ST-segment type [1]. Although it is tempting to focus only on those with the horizontal ST segment, it is important to remember that, unlike suggested by Tikkanen’s middle-aged population study, more than 30% of idiopathic ventricular fibrillation patients with an observed ER ECG pattern were found to have an ascending ST segment [51]. Thus, the population at risk is too large and the risk too low to be practical for implementation of preventive measures. As currently there are no methods to increase the specificity further, asymptomatic patients with no family history of SCD and early repolarization do not require any further workup. Management of rare cases of asymptomatic patients with extreme highrisk features (e.g., dynamic high-amplitude J-point elevation) (Fig. 2) needs to be considered on a caseby-case basis. A special problem is presented by patients with no family history but an early repolarization pattern and syncope. As both early repolarization pattern and syncope are common, the majority of these patients will still have a very good prognosis. In patients without typical vagal syncope, implantable loop recorders may be of aid; however, there are no data supporting this approach specifically in patients with early repolarization. In rare and unique cases with extremely high-risk early repolarization ECG characteristics and/or symptoms highly supportive of syncope from arrhythmic cause, ICD implantation may be discussed. A proposed algorithm for approach to patients with early repolarization is shown in Fig. 3.
CONCLUSION As in many other fields in medicine, the key aspect in management of patients with early repolarization is the presence or absence of symptoms. Those with clear symptoms (i.e., polymorphic ventricular Volume 30 Number 1 January 2015
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A practical guide to early repolarization Adler and Gollob
tachycardia/ventricular fibrillation survivors) are diagnosed with ERS and have a clear indication for ICD implantation. Quinidine therapy may also be of benefit in certain cases. On the other end of the spectrum are asymptomatic patients. Although in recent years a small but significant association with sudden death has been demonstrated in these patients, no preventive measures are currently recommended. In fact, in most cases, reassurance is in place. Patients with pronounced early repolarization and equivocal symptoms (e.g., syncope of uncertain cause) and asymptomatic patients with very high-risk early repolarization features (e.g., high-amplitude dynamic J waves) remain a challenge and should be managed in specialized referral centers. Finally, although genetic testing holds promise for diagnosis of those at high risk, it is probably still too early to recommend its use in the routine clinical setting. Acknowledgements Dr M.H.G’s research is supported by the Heart and Stroke Foundation of Ontario and the Canadian Institute for Health Research. Conflicts of interest Dr M.H.G. is the Peter Munk Chair in Cardiovascular Molecular Medicine (Toronto General Hospital). There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Sager SJ, Hoosien M, Junttila MJ, et al. Comparison of inferolateral early repolarization and its electrocardiographic phenotypes in pre and postadolescent populations. Am J Cardiol 2013; 112:444–448. 2. Surawicz B, Macfarlane PW. Inappropriate and confusing electrocardiographic terms: J-wave syndromes and early repolarization. J Am Coll Cardiol 2011; 57:1584–1586. 3. Hoogendijk MG, Potse M, Coronel R. Critical appraisal of the mechanism underlying J waves. J Electrocardiol 2013; 46:390–394. 4. Wellens HJ. Early repolarization revisited. N Engl J Med 2008; 358:2063– 2065. 5. Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol 2009; 53:982–991. 6. Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008; 358:2016–2023. 7. 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; 10:1932–1963. Includes the most recent recommendations regarding diagnosis and management of ERS endorsed by major heart rhythm associations. 8. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010; 7:549–558.
9. Antzelevitch CJ. Wave syndromes: molecular and cellular mechanisms. & J Electrocardiol 2013; 46:510–518. Comprehensive review of J-wave syndromes’ pathophysiology. 10. 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. [Epub ahead of print] 11. Hu D, Barajas-Martinez H, Terzic A, et al. ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. Int J Cardiol 2014; 171:431– 442. 12. Viskin S. Is there anyone left with a normal electrocardiogram? J Am Coll Cardiol 2013; 62:1619–1620. 13. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation 1996; 93:372–379. 14. Koncz I, Gurabi Z, Patocskai B, et al. Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome. J Mol Cell Cardiol 2014; 68:20–28. 15. Gussak I, Antzelevitch C. Early repolarization syndrome: clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol 2000; 33:299–309. 16. Gurabi Z, Koncz I, Patocskai B, et al. Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine, cilostazol, and milrinone. Circ Arrhythm Electrophysiol 2014; 7:134–142. 17. 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. 18. Haissaguerre M, Sacher F, Nogami A, et al. Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization role of drug therapy. J Am Coll Cardiol 2009; 53:612–619. 19. Sacher F, Derval N, Horlitz M, Haissaguerre M. J wave elevation to monitor quinidine efficacy in early repolarization syndrome. J Electrocardiol 2013; 47:223–225. 20. 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. 21. Medeiros-Domingo A, Tan BH, Crotti L, et al. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm 2010; 7:1466–1471. 22. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm 2010; 7:1872–1882. 23. 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. 24. Giudicessi JR, Ye D, Tester DJ, et al. Transient outward current (I(to)) gain-offunction mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm 2011; 8:1024–1032. 25. Wilde AA, Postema PG, Di Diego JM, et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J Mol Cell Cardiol 2010; 49:543–553. 26. Derval N, Sacher F, Shah A, et al. Gussak I, Antzelevitch C, editors. Early & repolarization syndrome: epidemiology, genetics, and risk stratification. In: Electrical diseases of the heart. London: Springer-Verlag; 2013. pp. 537– 550. There is a nice discussion on the relevant topic in this reference, which may be interesting for the reader interested in further information. 27. Antzelevitch C, Yan GX, Viskin S. Rationale for the use of the terms J-wave syndromes and early repolarization. J Am Coll Cardiol 2011; 57:1587–1590. 28. Yagihara N, Sato A, Furushima H, et al. Ischemia-induced prominent J waves in a patient with Brugada syndrome. Intern Med 2010; 49:1979–1982. 29. Myojo T, Sato N, Nimura A, et al. Recurrent ventricular fibrillation related to hypokalemia in early repolarization syndrome. Pacing Clin Electrophysiol 2012; 35:e234–e238. 30. Otero J, Lenihan DJ. The ‘normothermic’ Osborn wave induced by severe hypercalcemia. Tex Heart Inst J 2000; 27:316–317. 31. Osborn JJ. Experimental hypothermia; respiratory and blood pH changes in relation to cardiac function. Am J Physiol 1953; 175:389–398. 32. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large && families in early repolarization syndrome. J Am Coll Cardiol 2013; 61:164–172. First comprehensive study on large families with ERS. Its findings suggest an autosomal dominant pattern of inheritance in some ERS families. 33. 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. 34. Sinner MF, Reinhard W, Muller M, et al. Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a populationbased prospective cohort study (MONICA/KORA). PLoS Med 2010; 7:e1000314. 35. Rollin A, Maury P, Bongard V, et al. Prevalence, prognosis, and identification of the malignant form of early repolarization pattern in a population-based study. Am J Cardiol 2012; 110:1302–1308.
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Arrhythmias 36. Olson KA, Viera AJ, Soliman EZ, et al. Long-term prognosis associated with J-point elevation in a large middle-aged biracial cohort: the ARIC study. Eur Heart J 2011; 32:3098–3106. 37. Panicker GK, Manohar D, Karnad DR, et al. Early repolarization and short QT interval in healthy subjects. Heart Rhythm 2012; 9:1265–1271. 38. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011; 123:2666–2673. 39. Noseworthy PA, Weiner R, Kim J, et al. Early repolarization pattern in competitive athletes: clinical correlates and the effects of exercise training. Circ Arrhythm Electrophysiol 2011; 4:432–440. 40. Uberoi A, Jain NA, Perez M, et al. Early repolarization in an ambulatory clinical population. Circulation 2011; 124:2208–2214. 41. Yong CM, Perez M, Froelicher V. Prognostic implications of the J wave ECG patterns. J Electrocardiol 2013; 46:408–410. 42. Junttila MJ, Tikkanen JT, Kentta T, et al. Early repolarization as a predictor of & arrhythmic and nonarrhythmic cardiac events in middle-aged subjects. Heart Rhythm 2014; 11:1701–1706. First study to focus on the association between early repolarization and ventricular tachycardia/ventricular fibrillation rather than mortality in the general population. Its results support the indirect data from previous population studies suggesting that excess mortality in patients with early repolarization is due to arrhythmias. 43. Rosso R, Adler A, Halkin A, Viskin S. Risk of sudden death among young individuals with J waves and early repolarization: putting the evidence into perspective. Heart Rhythm 2011; 8:923–929.
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44. Tikkanen JT, Wichmann V, Junttila MJ, et al. Association of early repolarization and sudden cardiac death during an acute coronary event. Circ Arrhythm Electrophysiol 2012; 5:714–718. 45. Naruse Y, Tada H, Harimura Y, et al. Early repolarization is an independent predictor of occurrences of ventricular fibrillation in the very early phase of acute myocardial infarction. Circ Arrhythm Electrophysiol 2012; 5:506–513. 46. Rudic B, Veltmann C, Kuntz E, et al. Early repolarization pattern is associated with ventricular fibrillation in patients with acute myocardial infarction. Heart Rhythm 2012; 9:1295–1300. 47. Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011; 123:2931–2937. 48. Adler A, Rosso R, Viskin D, et al. What do we know about the ‘malignant form’ of early repolarization? J Am Coll Cardiol 2013; 62:863–868. 49. Ilkhanoff L, Soliman EZ, Prineas RJ, et al. Clinical characteristics and outcomes associated with the natural history of early repolarization in a young, biracial cohort followed to middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Circ Arrhythm Electrophysiol 2014; 7:392–399. 50. 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. 51. Rosso R, Glikson E, Belhassen B, et al. Distinguishing ‘benign’ from ‘malignant early repolarization’: the value of the ST-segment morphology. Heart Rhythm 2012; 9:225–229.
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A practical guide to early repolarization Arnon Adler a and Michael H. Gollob b
Purpose of review Early repolarization has been associated in the past decade with idiopathic ventricular fibrillation and arrhythmic death. The purpose of this review is to clarify recent changes in the definition of early repolarization and provide a practical approach to patients with this electrocardiographic sign. Recent findings Recent population studies have associated early repolarization with arrhythmic death. Challenges remain, however, in interpreting the risk of the early repolarization electrocardiographic pattern, as it is a common finding in the general population with a prevalence of 3–13%. Early repolarization characteristics associated with an especially high risk include high-amplitude J-point elevation, horizontal/descending ST segment, and inferior lead location. In view of the association of early repolarization with sudden death, a syndrome termed ‘early repolarization syndrome’ (ERS) has been accepted as the latest ‘channelopathy’ in patients with cardiac arrest, pronounced early repolarization pattern, and an otherwise structurally normal heart. The physiological basis of early repolarization is thought to involve an electrical transmural gradient produced by the transient outward current. Recent genetic studies have associated mutations in genes contributing to this current and other ion channels with ERS, although definitive genetic data do not yet exist to confirm pathogenicity. Summary ERS patients are rare and have a high risk of recurrent cardiac events. ICD implantation and possibly quinidine are the recommended treatments in this group. Opposingly, asymptomatic individuals with early repolarization are very common and, as a group, have a good prognosis. Sudden death preventive measures in these asymptomatic patients are limited to rare and unique cases. Keywords early repolarization, idiopathic ventricular fibrillation, sudden cardiac death
INTRODUCTION The prevention of sudden death has always been one of the main goals of the cardiologist. In our quest to fulfill this goal, we have uncovered numerous risk markers facilitating the implementation of preventive measures for those at highest risk. In the last decade, early repolarization has emerged as a new possible risk marker of sudden death; however, the next step, utilization of this knowledge for effective prevention, still eludes us. One of the central obstacles standing in our path is the relatively high prevalence of early repolarization, estimated to be as high as 25% in certain populations [1]. This high prevalence spells out two conclusions: first, only a small minority of the population with early repolarization will actually succumb to sudden death and, second, every physician interpreting ECGs will stumble upon many individuals with early repolarization. In other words, each one of these physicians will face the task of sieving the www.co-cardiology.com
very few that are truly at high risk out of the masses with early repolarization who may be dismissed as low-risk patients. In this article, we will review the latest updates regarding early repolarization and suggest a practical approach to these patients.
WHAT IS EARLY REPOLARIZATION? Unlike other electrocardiographic terms (e.g., ST-segment elevation, QT interval prolongation), ‘early repolarization’ is actually a physiological a Division of Cardiology, Tel Aviv Medical Center and Tel Aviv University, Tel Aviv, Israel and bDivision of Cardiology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
Correspondence to Michael H. Gollob, MD, Division of Cardiology, Toronto General Hospital, University of Toronto, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. Tel: +1 416 340 4282; e-mail: [email protected] Curr Opin Cardiol 2015, 30:8–16 DOI:10.1097/HCO.0000000000000126 Volume 30 Number 1 January 2015
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A practical guide to early repolarization Adler and Gollob
KEY POINTS The historical early repolarization definition includes two electrocardiographic phenomena, J-point elevation and ST-segment elevation; however, contemporary studies associating early repolarization with CA/SCD use only J-point elevation in their definition. Mutations in several genes have been associated with ERS, but the clinical benefit of genetic testing in these patients is currently questionable. SCD preventive measures (e.g., ICD implantation) are limited mainly to symptomatic patients with early repolarization (i.e., patients with ERS).
concept describing an electrocardiographic phenomenon. Naturally, this is a source of confusion as the term is not self-explanatory. Moreover, some experts doubt whether the markings on the surface ECG comprising early repolarization are indeed the consequence of the physiological process, as the name implies [2–4]. It is, therefore, crucial to first of all clarify what we mean when we say ‘early repolarization’.
Electrocardiographic definition The term ‘early repolarization’ was historically used to describe two electrocardiographic phenomena:
(a)
first, an upward deflection of the J point (or terminal part of the QRS complex) termed ‘J-point elevation’ or ‘J wave’ and, second, ST-segment elevation not associated with pathological conditions such as myocardial infarction. However, a clear-cut definition of early repolarization was never endorsed by major societies, leaving considerable room for interpretation of the term. For instance, in the recommendations for ECG interpretation published by the American Heart Association/American College of Cardiology/Heart Rhythm Society in 2009, early repolarization is not clearly defined but referred to as ‘. . .a normal variant. . .commonly characterized by J-point elevation and rapidly upsloping or normal ST segment’ [5]. Since the publication of Haissaguerre et al. in 2008 [6] associating early repolarization with idiopathic ventricular fibrillation, most studies used these authors’ definition in an attempt at standardization. Their proposed definition describes elevation of the QRS–ST junction (J point) in at least two leads, excluding right precordial leads (Fig. 1), and with an amplitude of at least 1 mm (0.1 mV) above the baseline level. The morphology of the J point may be either slurring (a smooth transition from the QRS segment to the ST segment) or notching (a positive J deflection inscribed on the S wave). Importantly, in stark contrast to previous concepts of early repolarization, there is no mention
(b)
FIGURE 1. Types of early repolarization. (a) J-point elevation with notching and slurring morphologies in different leads. ST segment is horizontal. In the right precordial leads there is J-point elevation but no Brugada pattern, demonstrating limitations of current early repolarization definition and possible overlap with Brugada syndrome. (b) J-point elevation in inferior and lateral leads with a notching morphology and ascending ST segment in most leads. ST segment in lead III is horizontal, demonstrating one limitation of ECG-based risk stratification of early repolarization. 0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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of ST-segment elevation in this definition. The Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society (HRS/ EHRA/APHRS) consensus statement on the diagnosis and management of primary inherited arrhythmia syndromes [7 ] used this definition (i.e., no requirement for ST elevation) for their recommendation regarding diagnosis of early repolarization syndrome (ERS) (see below and Table 1). This definition will be used for this review from this point onward. The main reason for exclusion of right precordial leads from Haissaguerre’s definition was to differentiate early repolarization from Brugada syndrome. However, recent data pointing at similarities in postulated mechanisms [8,9 ] and overlapping genetic [10,11] and clinical findings [8,12] (see next section and Fig. 1) make this distinction less straightforward. In fact, it has been proposed that ERS (see below) and Brugada syndrome are part of a spectrum of clinical conditions coined ‘J-wave syndromes’ [8,9 ]. &&
&
&
Mechanistic insight A detailed discussion of the proposed molecular mechanisms of early repolarization is beyond the
scope of this review and may be found elsewhere [8,9 ]. The leading concept in our current understanding of J-point elevation involves transmural differences in phases 1 and 2 of the cardiac action potential. Specifically, the transient outward current (Ito) was found to be more prominent in the epicardium than the endocardium, creating a relative accentuation of the epicardial action potential notch [8]. The first data to support this hypothesis came from arterially perfused canine wedge preparations demonstrating this difference in action potential morphology in epicardial vs. endocardial myocardium and its association with J-point elevation on ECG recordings [13]. Recent studies have shown that factors augmenting Ito (e.g., Ito agonist NS5806 [14]) accentuate J-point elevation while factors decreasing this outward current (e.g., tachycardia [8,15], quinidine [16]) diminish their amplitude. The fact that quinidine (an Ito blocker) is an effective treatment for suppression and prevention of ventricular arrhythmias associated with J-point elevation [17–19] serves as a clinical correlate to the in-vitro evidence. Augmentation of the gradient created by Ito may be the result of either an increase in outward &
Table 1. HRS/EHRA/APHRS consensus recommendations for diagnosis and management of early repolarization syndrome Expert consensus recommendations on early repolarization diagnosis (1) ER syndrome is diagnosed in the presence of J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG in a patient resuscitated from otherwise unexplained VF/polymorphic VT (2) ER syndrome can be diagnosed in an SCD victim with a negative autopsy and medical chart review with a previous ECG demonstrating J-point elevation 1 mm in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG (3) ER pattern can be diagnosed in the presence of J-point elevation 1 m in 2 contiguous inferior and/or lateral leads of a standard 12-lead ECG Expert consensus recommendations on early repolarization therapeutic interventions Class I
(1) ICD implantation is recommended in patients with a diagnosis of ER syndrome who have survived a cardiac arrest
Class IIa
(2) Isoproterenol infusion can be useful in suppression of electrical storms in patients with a diagnosis of ER syndrome (3) Quinidine in addition to an ICD can be useful for secondary prevention of VF in patients with a diagnosis of ER syndrome
Class IIb
(4) ICD implantation may be considered in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST-segment elevation >1 mm in two or more inferior or lateral leads (5) 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
(6) ICD implantation is not recommended in asymptomatic patients with an isolated ER ECG pattern
APHRS, Asia Pacific Heart Rhythm Society; EHRA, European Heart Rhythm Association; ER, early repolarization; HRS, Heart Rhythm Society; ICD, implantable cardioverter defibrillator; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia. && Reproduced with permission from [7 ].
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currents (e.g., Ito, IKATP) or decrease in opposing inward currents (e.g., ICa, INa). It was, therefore, hypothesized that mutations in genes encoding for these channels may be responsible for some cases of J-wave-associated arrhythmias. Indeed, in recent years, mutations in genes encoding for the KATP channel and its regulatory subunit [11,20,21], for the cardiac L-type calcium channel [22] and for the cardiac sodium channel [23], were described in such patients, although robust genetic evidence for disease causality in the form of familial segregation with phenotype is lacking. Recently, mutations in the genes encoding the major channel subunits of Ito, KCND2 and KCND3, have been described in Brugada syndrome and an atypical anterior J-wave syndrome associated with sudden cardiac death (SCD) [10,24]. These genetic defects produced a significant increase in Ito, consistent with inducing an exaggerated transmural gradient. Despite the evidence that mutations in Ito-encoding genes are potential causes of J-wave-associated arrhythmias, a comprehensive analysis in a cohort of patients with such arrhythmias demonstrated that major Ito-encoding genes are an uncommon cause of the phenotype [10]. Even though clinical and experimental evidence implicate Ito, the transmural gradient hypothesis is not accepted by all. Much as in Brugada syndrome [25], some hold the opinion that depolarization rather than repolarization abnormalities underlie the fundamental mechanism responsible for abnormal J waves [2,26 ,27]. &
CLINICAL IMPLICATION Patients with early repolarization may be divided into two main groups. The first includes symptomatic patients (e.g., survivors of cardiac arrest) with clear electrocardiographic evidence of early repolarization. These patients with ERS are extremely rare but have a high risk of recurrent cardiac events. In Haissaguerre’s study [6] of 64 ERS patients who were followed for a median of 51 months, 41% had arrhythmic recurrences, usually multiple (median eight arrhythmic events per patient). This recurrence rate was significantly higher than that noted in idiopathic ventricular fibrillation patients without early repolarization (hazard ratio 2.1). The second group comprises asymptomatic patients who are usually found to have an early repolarization pattern as an incidental finding. These cases are very common but, as a group, have low risk of adverse events. The challenge at hand is to discern, if possible, which of these asymptomatic patients may be at risk of a lethal event.
Patients with early repolarization and cardiac arrest (early repolarization syndrome) In essence, idiopathic ventricular fibrillation patients who are found to have early repolarization are now defined as ERS patients. Therefore, ERS patients, like idiopathic ventricular fibrillation patients, usually present at a young age (typically 1 mm elevation 100 ms post J point), is regarded as ascending. (b) Holter tracings demonstrating augmentation of J-point elevation at maximum bradycardia during early morning (top) and a short-coupled PVC (bottom). There is no consensus regarding management of this type of patients. PVC, premature ventricular complex.
found a rare variant in the KCND2 gene encoding for the Kv4.2 channel in a patient with J waves in the right precordial leads [10]. However, all of these variants were detected in single patients and only in the minority of ERS cases studied. Furthermore, a study of probands from large families with ERS failed to detect any mutations in these genes [32 ]. Therefore, genetic testing for ERS should remain a research initiative as no genetic findings have been clearly validated in large ERS cohorts with adequate control subjects. &&
Management Survivors of cardiac arrest or those with documented sustained ventricular arrhythmias and ERS should undergo ICD implantation [7 ] (Table 1). An ICD can also be considered in family members of ERS patients with a history of suspicious syncope or in asymptomatic patients with especially high-risk ECG features of early repolarization (see next section) and strong family history of SCD [7 ] (Fig. 3). In ERS cases with ventricular fibrillation storms, isoproterenol and temporary pacing [17,18] have been described to be of benefit. Quinidine has been used to prevent ventricular arrhythmias in patients with frequent ICD shocks and has been shown to ameliorate the early repolarization pattern in ERS patients [17–19] (Fig. 3). Other antiarrhythmics, including amiodarone, mexiletine, verapamil, beta blockers, and class IC drugs, have shown no or very &&
&&
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modest results in preventing arrhythmias in this patient population [18].
Asymptomatic patients with early repolarization (early repolarization pattern) The prevalence of early repolarization pattern in the middle-aged (age: 35–65 years) population is estimated to be between 3 and 13% [33–36] depending on the methods used and the population studied. In specific populations (young [1,37], male [33,37], athletes [38,39], and African-Americans [40]), it has been demonstrated to be especially high and may reach 25%. These demographics highlight the caution needed in drawing conclusions that an early repolarization ECG pattern is directly associated with a cardiac event occurring in young athletes. It is also not surprising that the study of Tikkanen et al. [33] associating early repolarization in a middle-aged population with arrhythmic death would make such a great impact in raising concern over early repolarization patterns – a huge population was now considered to be at risk. Most population studies following Tikkanen’s footsteps [34,35] found a similar association; however, major differences in population, methods, and definitions make direct comparison difficult [41]. Some studies have found no association between early repolarization and arrhythmic death but have typically been of short-term follow-up. The biggest population study to find no association between early repolarization Volume 30 Number 1 January 2015
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A practical guide to early repolarization Adler and Gollob
J-point elevation >1 mm in 2 contiguous inferior and/or lateral leads Yes
Early repolarization syndrome Class I
Yes
Cardiac arrest?* No
ICD implantation ----------------
Possible early repolarization syndrome
Strong family history of ERS/ SCD**?
Yes
Syncope$?
Yes
Class IIb
Yes
Class IIb
No No
High risk ECG#?
Syncope$?
Consider ICD implantation
No Yes
No
Follow§
Consider treatment of CV risk factors Consider follow-up in unique cases§†
Quinidine
Yes
Arrhythmic storm?
Class IIa
Follow§. Consider ILR and possibly ICD in unique high risk cases
Early repolarization pattern
Class IIa
Possible early repolarization syndrome
Yes
Recurrent shocks?
Isoproterenol‡ Quinidine
FIGURE 3. Proposed algorithm for approach to patients with early repolarization. CV, cardiovascular; ERS, early repolarization syndrome; ILR, implantable loop recorder; PVC, premature ventricular complex; SCD, sudden cardiac death; VT, ventricular tachycardia. After exclusion of other causes – see text. Patients with documented polymorphic VT triggered by short-coupled ventricular premature complexes, especially if preceded by augmentation of J-waves, should also be included in this group. There is no accepted definition for strong family history. We propose either one family member diagnosed with ERS or at least two family members with SCD of unknown cause under the age of 45. $Thought to be of arrhythmic cause. § Follow-up should include evaluation of new symptoms (e.g., syncope) in patient and family and analysis of changes in ECG. It may include Holter tests in specific cases. Our policy is to see patients every 1–3 years but follow-up approach needs to be tailored to each patient individually. #Horizontal/descending ST-segment, J-point elevation more than 2 mm, inferior leads location and, possibly, short-coupled PVCs. yFollow-up should probably be limited to unique patients with very high-risk ECGs. z For acute treatment class recommendations based on consensus statement [7 ]. &&
and mortality [40] relied on evaluation of ST-segment elevation rather than J-point elevation in the majority of the population studied. Furthermore, it has been criticized for having a follow-up time of less than 8 years [42 ]. As the Kaplan–Meier curves in Tikkanen’s study began to diverge only after 13 years of follow-up, this is of major significance. The late divergence of the Kaplan–Meier curves has another significant implication – as the mean age at the time of inclusion in Tikkanen’s study was 44 years (range 30–59), cardiac mortality significance became evident only after the age of 55 years. Because idiopathic ventricular fibrillation patients (and the subset with early repolarization now referred to as ERS) rarely become symptomatic after &
the age of 40 years, it is evident that Tikkanen’s patients succumbing to arrhythmic death were of a different type. It was, therefore, hypothesized that these patients have an electrical substrate predisposing them to sudden death in the event of a second trigger coming into play [43]. In a middle-aged population, the most obvious trigger is ischemia. Support for this hypothesis was soon to come from case–control studies demonstrating increased prevalence of early repolarization in patients with ventricular fibrillation complicating myocardial infarction [44–46]. These studies, by associating early repolarization with ventricular fibrillation rather than mortality, also serve to substantiate the assumption that
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sudden death in patients with early repolarization is of arrhythmic cause. This is important as the population studies rely on retrospective analysis of records for death categorization, which is inherently inaccurate. The most direct and substantial support for this hypothesis, however, comes from a recent study specifically analyzing the association between early repolarization and ventricular tachycardia/ ventricular fibrillation events [42 ]. It demonstrated that early repolarization in inferior leads predicts ventricular tachycardia/ventricular fibrillation with a hazard ratio of 2.2 but is not associated with nonarrhythmic mortality. Unfortunately, implementation of this new data in the clinical setting is problematic. As the prevalence of early repolarization is so high, it is obvious that only very few of these individuals will actually die suddenly. In an attempt to improve the specificity of attempted risk stratification of the early repolarization pattern, various early repolarization characteristics were analyzed. Those found to infer an especially high risk include high-amplitude J-point elevation (>0.2 mV) and location of early repolarization in inferior leads [33,35,47]. It has also been suggested by some studies [17] that global early repolarization (in both inferior and lateral leads) is a marker of even higher risk. Most important, however, is the finding that only J-point elevation followed by a horizontal or descending ST segment (Fig. 1) is associated with arrhythmic mortality [38,48]. Individuals with J-point elevation and an ascending ST segment (like the classic ‘high-takeoff’ pattern) had no such association. J-point elevation morphology (notch vs. slur) was not consistently found to be of significance. This is perhaps not surprising taking into account that both morphologies may be found in the same patient at different times and even in different leads on the same ECG recording (Fig. 1). Analysis of Tikkanen’s data has shown that the subset at highest risk (those with high-amplitude J-point elevation on inferior leads and a horizontal ST segment) comprises only 0.3% of the population studied and that 24% of these suffered arrhythmic death during the 30 years of follow-up (adjusted hazard ratio 3.1) [38]. Nevertheless, data supporting preventive measures in this relatively high-risk middle-aged population, such as more aggressive screening and management of ischemic heart disease, are lacking. The clinical implication for young individuals (i.e., younger than 35) with early repolarization is also far from straightforward. As these patients are still at an age typical of idiopathic ventricular fibrillation/ERS presentation and are not yet at significant risk of ischemia, their risk stratification is different from their middle-aged counterparts. &
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However, the only population study to actually examine the association of early repolarization and mortality in the young [49] used a definition including ST-segment elevation rather than J-point elevation alone. Perhaps not surprisingly, the study was negative. Thus, the evidence supporting an increased risk of mortality in the young is based mainly on extrapolation from middle-aged population studies, idiopathic ventricular fibrillation case–control studies [6,17,50], and case reports. The prevalence of idiopathic ventricular fibrillation is estimated to be 3.4 : 100 000 [50] but only 30–40% of these have early repolarization [6,50]. Therefore, only around 1 : 100 000 may be expected to suffer SCD attributed to ERS. In young individuals (ages 21–25 years), the prevalence of early repolarization was recently found to be 16% but only 3% had the horizontal ST-segment type [1]. Although it is tempting to focus only on those with the horizontal ST segment, it is important to remember that, unlike suggested by Tikkanen’s middle-aged population study, more than 30% of idiopathic ventricular fibrillation patients with an observed ER ECG pattern were found to have an ascending ST segment [51]. Thus, the population at risk is too large and the risk too low to be practical for implementation of preventive measures. As currently there are no methods to increase the specificity further, asymptomatic patients with no family history of SCD and early repolarization do not require any further workup. Management of rare cases of asymptomatic patients with extreme highrisk features (e.g., dynamic high-amplitude J-point elevation) (Fig. 2) needs to be considered on a caseby-case basis. A special problem is presented by patients with no family history but an early repolarization pattern and syncope. As both early repolarization pattern and syncope are common, the majority of these patients will still have a very good prognosis. In patients without typical vagal syncope, implantable loop recorders may be of aid; however, there are no data supporting this approach specifically in patients with early repolarization. In rare and unique cases with extremely high-risk early repolarization ECG characteristics and/or symptoms highly supportive of syncope from arrhythmic cause, ICD implantation may be discussed. A proposed algorithm for approach to patients with early repolarization is shown in Fig. 3.
CONCLUSION As in many other fields in medicine, the key aspect in management of patients with early repolarization is the presence or absence of symptoms. Those with clear symptoms (i.e., polymorphic ventricular Volume 30 Number 1 January 2015
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tachycardia/ventricular fibrillation survivors) are diagnosed with ERS and have a clear indication for ICD implantation. Quinidine therapy may also be of benefit in certain cases. On the other end of the spectrum are asymptomatic patients. Although in recent years a small but significant association with sudden death has been demonstrated in these patients, no preventive measures are currently recommended. In fact, in most cases, reassurance is in place. Patients with pronounced early repolarization and equivocal symptoms (e.g., syncope of uncertain cause) and asymptomatic patients with very high-risk early repolarization features (e.g., high-amplitude dynamic J waves) remain a challenge and should be managed in specialized referral centers. Finally, although genetic testing holds promise for diagnosis of those at high risk, it is probably still too early to recommend its use in the routine clinical setting. Acknowledgements Dr M.H.G’s research is supported by the Heart and Stroke Foundation of Ontario and the Canadian Institute for Health Research. Conflicts of interest Dr M.H.G. is the Peter Munk Chair in Cardiovascular Molecular Medicine (Toronto General Hospital). There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Sager SJ, Hoosien M, Junttila MJ, et al. Comparison of inferolateral early repolarization and its electrocardiographic phenotypes in pre and postadolescent populations. Am J Cardiol 2013; 112:444–448. 2. Surawicz B, Macfarlane PW. Inappropriate and confusing electrocardiographic terms: J-wave syndromes and early repolarization. J Am Coll Cardiol 2011; 57:1584–1586. 3. Hoogendijk MG, Potse M, Coronel R. Critical appraisal of the mechanism underlying J waves. J Electrocardiol 2013; 46:390–394. 4. Wellens HJ. Early repolarization revisited. N Engl J Med 2008; 358:2063– 2065. 5. Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol 2009; 53:982–991. 6. Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008; 358:2016–2023. 7. 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; 10:1932–1963. Includes the most recent recommendations regarding diagnosis and management of ERS endorsed by major heart rhythm associations. 8. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010; 7:549–558.
9. Antzelevitch CJ. Wave syndromes: molecular and cellular mechanisms. & J Electrocardiol 2013; 46:510–518. Comprehensive review of J-wave syndromes’ pathophysiology. 10. 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. [Epub ahead of print] 11. Hu D, Barajas-Martinez H, Terzic A, et al. ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. Int J Cardiol 2014; 171:431– 442. 12. Viskin S. Is there anyone left with a normal electrocardiogram? J Am Coll Cardiol 2013; 62:1619–1620. 13. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation 1996; 93:372–379. 14. Koncz I, Gurabi Z, Patocskai B, et al. Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome. J Mol Cell Cardiol 2014; 68:20–28. 15. Gussak I, Antzelevitch C. Early repolarization syndrome: clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol 2000; 33:299–309. 16. Gurabi Z, Koncz I, Patocskai B, et al. Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine, cilostazol, and milrinone. Circ Arrhythm Electrophysiol 2014; 7:134–142. 17. 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. 18. Haissaguerre M, Sacher F, Nogami A, et al. Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization role of drug therapy. J Am Coll Cardiol 2009; 53:612–619. 19. Sacher F, Derval N, Horlitz M, Haissaguerre M. J wave elevation to monitor quinidine efficacy in early repolarization syndrome. J Electrocardiol 2013; 47:223–225. 20. 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. 21. Medeiros-Domingo A, Tan BH, Crotti L, et al. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm 2010; 7:1466–1471. 22. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm 2010; 7:1872–1882. 23. 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. 24. Giudicessi JR, Ye D, Tester DJ, et al. Transient outward current (I(to)) gain-offunction mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm 2011; 8:1024–1032. 25. Wilde AA, Postema PG, Di Diego JM, et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J Mol Cell Cardiol 2010; 49:543–553. 26. Derval N, Sacher F, Shah A, et al. Gussak I, Antzelevitch C, editors. Early & repolarization syndrome: epidemiology, genetics, and risk stratification. In: Electrical diseases of the heart. London: Springer-Verlag; 2013. pp. 537– 550. There is a nice discussion on the relevant topic in this reference, which may be interesting for the reader interested in further information. 27. Antzelevitch C, Yan GX, Viskin S. Rationale for the use of the terms J-wave syndromes and early repolarization. J Am Coll Cardiol 2011; 57:1587–1590. 28. Yagihara N, Sato A, Furushima H, et al. Ischemia-induced prominent J waves in a patient with Brugada syndrome. Intern Med 2010; 49:1979–1982. 29. Myojo T, Sato N, Nimura A, et al. Recurrent ventricular fibrillation related to hypokalemia in early repolarization syndrome. Pacing Clin Electrophysiol 2012; 35:e234–e238. 30. Otero J, Lenihan DJ. The ‘normothermic’ Osborn wave induced by severe hypercalcemia. Tex Heart Inst J 2000; 27:316–317. 31. Osborn JJ. Experimental hypothermia; respiratory and blood pH changes in relation to cardiac function. Am J Physiol 1953; 175:389–398. 32. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large && families in early repolarization syndrome. J Am Coll Cardiol 2013; 61:164–172. First comprehensive study on large families with ERS. Its findings suggest an autosomal dominant pattern of inheritance in some ERS families. 33. 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. 34. Sinner MF, Reinhard W, Muller M, et al. Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a populationbased prospective cohort study (MONICA/KORA). PLoS Med 2010; 7:e1000314. 35. Rollin A, Maury P, Bongard V, et al. Prevalence, prognosis, and identification of the malignant form of early repolarization pattern in a population-based study. Am J Cardiol 2012; 110:1302–1308.
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Arrhythmias 36. Olson KA, Viera AJ, Soliman EZ, et al. Long-term prognosis associated with J-point elevation in a large middle-aged biracial cohort: the ARIC study. Eur Heart J 2011; 32:3098–3106. 37. Panicker GK, Manohar D, Karnad DR, et al. Early repolarization and short QT interval in healthy subjects. Heart Rhythm 2012; 9:1265–1271. 38. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011; 123:2666–2673. 39. Noseworthy PA, Weiner R, Kim J, et al. Early repolarization pattern in competitive athletes: clinical correlates and the effects of exercise training. Circ Arrhythm Electrophysiol 2011; 4:432–440. 40. Uberoi A, Jain NA, Perez M, et al. Early repolarization in an ambulatory clinical population. Circulation 2011; 124:2208–2214. 41. Yong CM, Perez M, Froelicher V. Prognostic implications of the J wave ECG patterns. J Electrocardiol 2013; 46:408–410. 42. Junttila MJ, Tikkanen JT, Kentta T, et al. Early repolarization as a predictor of & arrhythmic and nonarrhythmic cardiac events in middle-aged subjects. Heart Rhythm 2014; 11:1701–1706. First study to focus on the association between early repolarization and ventricular tachycardia/ventricular fibrillation rather than mortality in the general population. Its results support the indirect data from previous population studies suggesting that excess mortality in patients with early repolarization is due to arrhythmias. 43. Rosso R, Adler A, Halkin A, Viskin S. Risk of sudden death among young individuals with J waves and early repolarization: putting the evidence into perspective. Heart Rhythm 2011; 8:923–929.
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44. Tikkanen JT, Wichmann V, Junttila MJ, et al. Association of early repolarization and sudden cardiac death during an acute coronary event. Circ Arrhythm Electrophysiol 2012; 5:714–718. 45. Naruse Y, Tada H, Harimura Y, et al. Early repolarization is an independent predictor of occurrences of ventricular fibrillation in the very early phase of acute myocardial infarction. Circ Arrhythm Electrophysiol 2012; 5:506–513. 46. Rudic B, Veltmann C, Kuntz E, et al. Early repolarization pattern is associated with ventricular fibrillation in patients with acute myocardial infarction. Heart Rhythm 2012; 9:1295–1300. 47. Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011; 123:2931–2937. 48. Adler A, Rosso R, Viskin D, et al. What do we know about the ‘malignant form’ of early repolarization? J Am Coll Cardiol 2013; 62:863–868. 49. Ilkhanoff L, Soliman EZ, Prineas RJ, et al. Clinical characteristics and outcomes associated with the natural history of early repolarization in a young, biracial cohort followed to middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Circ Arrhythm Electrophysiol 2014; 7:392–399. 50. 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. 51. Rosso R, Glikson E, Belhassen B, et al. Distinguishing ‘benign’ from ‘malignant early repolarization’: the value of the ST-segment morphology. Heart Rhythm 2012; 9:225–229.
Volume 30 Number 1 January 2015
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