7/6/23, 3:25 PM Early repolarization - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Early repolarization : Andrew Krahn, MD, Manoj Obeyesekere, MBBS, MD : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2022. INTRODUCTION The term early repolarization (ER), also known as "J waves" or "J-point elevation," has long been used to characterize a QRS-T variant on the electrocardiogram (ECG). Most literature defines ER as being present on the ECG when there is J-point elevation of 0.1 mV in two adjacent leads with either a slurred or notched morphology. Historically, ER has been considered a marker of good health because it is more prevalent in athletes, younger persons, and at slower heart rates. However, contemporary reports, largely based on data from resuscitated sudden cardiac arrest (SCA) patients, suggest an association between ER and an increased risk for arrhythmic death and idiopathic ventricular fibrillation (VF). While some level of increased risk of sudden cardiac death (SCD) has been reported in persons with ER, the relatively high prevalence of the ER pattern in the general population (5 to 13 percent) in comparison with the incidence of idiopathic VF (approximately 10 cases per 100,000 population) means that the ER pattern will nearly always be an incidental ECG finding with no clinical implications. However, a primary arrhythmic disorder such as idiopathic VF due to ER is far more likely when associated with resuscitated SCD in the absence of other etiologies. (See 'ER syndrome' below.) This topic will review the genetics, prevalence, clinical manifestations, and diagnosis of ER and will present an approach to the management of patients with ER and idiopathic VF. DEFINITION https://www.uptodate.com/contents/early-repolarization/print 1/37 7/6/23, 3:25 PM Early repolarization - UpToDate The definition of ER on an ECG is based on well-defined ECG findings ( table 1) [1]. Although the 2013 Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society presented a definition ( table 1), the 2016 American Heart Association (AHA) Scientific Statement [2] highlights the lack of agreement across published studies pertaining to definition. A 2015 consensus document suggested reporting more detailed amplitudes of the J-wave including amplitudes corresponding to J-wave onset (Jo), J-wave peak (Jp), and J-wave termination (Jt), as well as durations D1 (Jo to Jp) and D2 (Jp to Jt), in relation to an end-QRS notch, and of Jp, Jt, and D2, in relation to an end-QRS slur [3]. The majority of publications at the present time merely adopt the amplitude of Jp as the reference point for measuring J-point elevation. The ST segment should be regarded as horizontal or downward sloping if the amplitude of the ST-segment 100 ms after the Jt (interval M) is equal to or less than the amplitude at Jt. The ST segment should be regarded as upward sloping if the amplitude of the ST segment 100 ms after Jt (interval M) is greater than the amplitude at Jt. However, duration measurements K, L, and M, each 100 ms, from Jo, Jp and Jt could be used in the measurement of the ST slope in the presence of a notch or duration measurements L or M, each 100 ms, used in the presence of an end-QRS slur with onset from Jp or Jt to measure slope, respectively ( figure 1). ECG findings On the ECG, ER is defined as either: A sharp well-defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST segment; correspondingly, in negative QRS complexes, J waves may also be negative. The presence of slurring at the terminal part of the QRS complex (since the J-wave or J- point elevation may be hidden in the terminal part of the QRS complex, resulting in the slurring of the terminal QRS complex) ( waveform 1). Most literature defines ER as being present on the ECG when there is J-point elevation of 0.1 mV in two adjacent leads with either a slurred or notched morphology [2,4,5]. The AHA scientific statement proposed the use of ER qualified with descriptive terms such as with ST-segment elevation, the magnitude, ER with terminal slur/notch and also noting the distribution on the ECG and any concomitant ECG findings (eg, J-wave augmentation or short coupled ventricular ectopy). ECG classification Based on data associating arrhythmic risk with spatial distribution of ER, a classification scheme has been proposed [6,7] (see 'Prognosis of ER pattern' below): Type 1 is associated with ER in the lateral precordial leads. This form is common among healthy male athletes and is thought to be largely benign. https://www.uptodate.com/contents/early-repolarization/print 2/37 7/6/23, 3:25 PM Early repolarization - UpToDate Type 2 is associated with ER in the inferior or inferolateral leads and is associated with a moderate level of risk. Type 3 is associated with ER globally in the inferior, lateral, and right precordial leads, and appears to be associated with the highest relative risk, though the absolute risk of sudden death remains small [8]. Type 4, or Brugada syndrome, is marked by J-wave/point elevation in the right precordial leads. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) While this classification system would seem to simplify categorization of the ECG patterns, it has been criticized due to the controversial presumed common pathophysiological substrate across the four types [9,10]. Concealed ER The ER pattern is not always identified on routine ECG due to the intermittent nature of ER [11]. As an example, among 542 persons with baseline ER who underwent repeat ECG examination five years later, ER ( 0.1 mV) was not observed in approximately 20 percent [5]. No systematic evaluation has been undertaken reporting the prevalence of concealed ER in the general population, and the clinical importance, if any, of concealed ER remains unclear. ER pattern versus ER syndrome As noted above, ER is an ECG finding. 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 ER syndrome can have identical findings on surface ECG. However, the mere presence of ER pattern on ECG should not lead to a classification of ER syndrome in the absence of symptoms or documented ventricular fibrillation (VF) [12]. Rarely, ER may be associated with the primary arrhythmic disorder idiopathic VF in the absence of structural heart disease [4,11]. Given the prevalence of 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. (See 'ER syndrome' below.) PREVALENCE OF ER AND INCIDENCE OF IDIOPATHIC VF https://www.uptodate.com/contents/early-repolarization/print 3/37 7/6/23, 3:25 PM Early repolarization - UpToDate Prevalence Several population studies have estimated that the prevalence of ER ranges from 5 to 18 percent of persons, with higher prevalence in younger patients [5,13-15]. In a multiethnic population, ER pattern was independently associated with greater LV mass [16]. Arrhythmic risk The perception that ER was a benign finding devoid of clinical significance changed as case reports, case-control studies, and population studies established a link between the presence of ER and an increased risk for arrhythmic death, in particular idiopathic ventricular fibrillation (VF) [4,5,8,13-15,17-23]. Even though ER is fairly common in the general population, idiopathic VF is rare. In one report which estimated the incidence of idiopathic VF, the estimated risk of developing idiopathic VF in an individual younger than 45 years was 3 in 100,000 [13,24]. The risk increased to 11 in 100,000 when J waves ( waveform 2) were present. Although ER increased the relative risk of SCD, the absolute risk was very low. In a meta-analysis, the relative risk of arrhythmic death in persons with the ER pattern was 1.70 (95% CI 1.19-2.42), and the estimated absolute risk for arrhythmic death was 70 per 100,000 person-years [25]. Therefore, the incidental identification of ER should not be interpreted as a high-risk marker for arrhythmic death due to the relatively low odds of SCD based on ER alone. Athletes with early repolarization The prevalence of J-point elevation among 121 young athletes was reported at 22 percent, a prevalence rate higher than seen in the general population [13]. However, higher ER prevalence rates ranging as high as 44 percent have also been reported in athletes [26,27]. The reported higher prevalence of ER in athletes likely is related to the physiological balance in autonomic tone favoring the parasympathetic tone and its regulation of the action potential [28]. Notably, the association of ER with arrhythmic risk is typically at rest or during sleep and not during physical activity when J-point elevation is typically markedly reduced or eliminated. In a study of 704 athletes (14 percent with ER) with six years follow-up, there were no arrhythmic events [29]. PROGNOSIS OF ER PATTERN Certain ECG characteristics may distinguish the benign ER pattern from patterns associated with an arrhythmic prognosis. Additionally, ER pattern may be modified by physiological variables with subsequent effect on prognosis. The coexistence of ER with other cardiac pathologies also likely influences prognosis/arrhythmic risk. Reports suggest that ER may be viewed as an https://www.uptodate.com/contents/early-repolarization/print 4/37 7/6/23, 3:25 PM Early repolarization - UpToDate adjunctive prognostic variable in the presence of other cardiac pathologies (ie, ER may incrementally worsen the prognosis of other more common conditions such as ischemic heart disease). Prognosis in the general population While the ER pattern is associated with an increased relative risk of adverse events, the prognostic implications described in this section should be viewed in the context of the overall very low risk of SCD in those with this asymptomatic ECG finding. Thus, even with a twofold increase in relative risk of SCD, the absolute risk remains exceedingly low. Additionally, in spite of the data discussed in this section, there is no current risk stratification strategy for asymptomatic patients with ER pattern in the general population and within families with ER pattern that would allow for the identification of higher risk individuals with the ER pattern who might be candidates for treatment. (See 'Prevalence' above and 'Arrhythmic risk' above and 'Treatment of ER pattern' below.) The presence of the ER pattern has generally been associated with adverse outcomes in numerous cohort and case-control studies, although some studies have suggested no overall impact on mortality after adjusting for comorbidities including coronary risk factors [4,5,13- 15,17,25,30-33]. Prognostic variables Variables thought to affect prognosis that have been investigated include: Distribution and amplitude of ER Morphology of the J wave, ST segment, T wave, T T interval peak end Age and sex Family history Slurring versus notching Ethnicity Association with other cardiac pathology Distribution and amplitude of early repolarization The inferior location of ER, in addition to higher J-point amplitude, have been described as variables associated with increased arrhythmic risk in both the general population and in patients with idiopathic ventricular fibrillation (VF), although some conflicting data have been reported in the general population. J-point elevation greater than 0.1 mV in the inferior leads in the large Finnish cohort study of 10,864 persons was weakly associated with an increased risk for death from cardiac causes (adjusted RR 1.28, 95% CI 1.04-1.59) [5]. While observed in only 0.3 percent of the cohort, J-point elevation greater than 0.2 mV in inferior leads ( waveform 3) was https://www.uptodate.com/contents/early-repolarization/print 5/37 7/6/23, 3:25 PM Early repolarization - UpToDate associated with a three times greater risk of death from cardiac causes (adjusted RR 2.98, 95% CI 1.85-4.92) [5]. In a population-based case-cohort study of 6213 persons (1945 persons with ECGs) with a mean follow-up of 19 years, ER was associated with higher cardiac mortality (hazard ratio 1.96, 95% CI 1.05-3.68) [14]. An inferior localization of ER further increased ER-attributable cardiac mortality (hazard ratio 3.15, 95% CI 1.58-6.28. However, these findings were not replicated in a cohort of 20,661 patients (90.5 percent male) with a median follow-up of 17.5 years, among whom the findings of ER were not associated with an increased risk of cardiovascular death [34]. Morphology of the ST segment The morphology of the ST segment may also determine the risk associated with ER, with a horizontal or downsloping ST segment following ER portending a higher risk in both the general population and in patients with idiopathic VF [24,26,31]. However, despite the increased risk of arrhythmia associated with the horizontal/downsloping ER pattern, the prevalence of this pattern in controls (approximately 3 percent) compared with the exceedingly low incidence of idiopathic VF renders this variable alone devoid of meaningful test accuracy [24,26]. In one study that compared 92 patients with ER and VF with 247 control patients with asymptomatic ER pattern, patients with ER and VF had a higher prevalence of low- amplitude T waves, lower T/R ratio (lead II or V5), and longer QTc interval [35]. The authors suggested the combination of these parameters with J-wave amplitude and distribution of J waves may further allow for improved identification of malignant ER. T to T interval has been reported to predict malignant ventricular arrhythmias in an ER peak end syndrome model [36], which is prolonged in patients with VF attributed to ER syndrome (86.7 14 ms versus 68 13.2 ms, p<0.001) [37]. J-wave duration (interval from Jo and the intersection of the tangent to the J wave with the isoelectric line >60 ms) and slope/j-angle (angle between an ideal line drawn from Jo perpendicular to the isoelectric line and the tangent to the J wave >30 ) have been reported to identify the malignant form of ER from the benign form [38]. Age and sex Although the data are conflicting, males with ER in the inferior leads may be at greater risk of cardiac mortality than males without ER or females with or without ER [14]. However in a conflicting study reporting on 6631 Finnish general population subjects (age 30 years) with ER ( 0.1 mV in 2 inferior/lateral leads), ER was associated with SCD in subjects younger than 50 years, particularly in women, but not in subjects 50 years and older [39]. Family history Conflicting data exist regarding the prognostic significance of a family history of SCD in persons with ER, such that no clear recommendations regarding risk https://www.uptodate.com/contents/early-repolarization/print 6/37 7/6/23, 3:25 PM Early repolarization - UpToDate assessment or treatment can be made [4,40]. Further studies are required to define the risk contribution of a family history of SCD to the prognosis of a patient with ER since no clear mechanism for inheritance of risk has been identified. Society guidelines support a possible role for an implantable cardioverter-defibrillator (ICD) in symptomatic family members of ER syndrome patients with a history of syncope in the presence of ST-segment elevation, or asymptomatic individuals with a high-risk ER pattern in the presence of a family history of early sudden death. The latter should be exceptional, in discussion with an expert versed in assessment of familial sudden death syndromes [41]. Slurring versus notching Although both slurring and notching type ER are observed and may exist in the same patient, the prognostic value of one compared with the other has not been clearly established ( waveform 1 and figure 2) [11,15,24,31,34,42]. However, a meta- analysis of 19 observational studies (7268 patients with 1127 cases of ventricular arrhythmias or SCD) demonstrated a higher risk with J waves in the inferior leads, with notching, and horizontal or descending ST segment [43]. Ethnicity Although ER pattern is more common in African Americans [44], there is no clear attributable risk associated with ethnicity, and African Americans are not specifically over represented in idiopathic VF cohorts compared with White Americans [45]. Thus, no clinically relevant risk stratification can be undertaken to identify the small subset at high risk for primary prevention. Modifying risk of underlying cardiac pathology In the context of structural heart disease or primary electrical disorders, the ER pattern may be a modifier of underlying arrhythmic risk associated with heterogeneous cardiac conditions (myocardial infarction [46,47], coronary disease [48], heart failure [49], SQTS [50,51], LVNC [52], LQTS [53,54], CPVT [55], Brugada [56]), in addition to the rare association with idiopathic VF (ie, in the absence of other cardiac conditions). Thus, the ER pattern is potentially a marker for increased arrhythmic mortality due to a vulnerable repolarization substrate when combined across a number of heterogeneous clinical conditions (eg, short QT syndrome, Brugada syndrome, or ischemic heart disease) in the general population, in addition to rarely being a primary arrhythmogenic disorder. Early repolarization may also indicate an underlying atrial electrical substrate for atrial fibrillation; however, studies are conflicting [57,58]. Risk stratification with invasive EP studies Invasive electrophysiologic studies (EPS) do not appear to improve the risk stratification of patients with the ER syndrome and prior VF arrest [59]. (See 'Chronic treatment of ER syndrome' below and "Invasive diagnostic cardiac electrophysiology studies".) https://www.uptodate.com/contents/early-repolarization/print 7/37 7/6/23, 3:25 PM Early repolarization - UpToDate GENETIC BASIS AND INHERITANCE OF ER The genetic basis of ER syndrome continues to be elucidated, with the evidence restricted to either case reports or preliminary studies that have not identified an accepted genetic basis of ER [60,61]. The reported implicated gene mutations involve the KCNJ8 gene (responsible for the ATP-sensitive potassium channel Kir6.1 - I current); CACNA1C, CACNB2, CACNA2D1 genes KATP (responsible for the cardiac L-type calcium channel - I current); and the SCN5A gene Ca.L (responsible for the sodium channel - I current) ( figure 3) [60-64]. First-degree relatives of Na patients with the ER pattern are more likely to also demonstrate the pattern, but this weak association has not been associated with clinical implications [65,66]. Inheritance of ER pattern 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 threefold higher likelihood of also having the ER pattern on ECG [65,66]. While the vast majority of ER is likely sporadic, familial ER appears to be transmitted in an autosomal dominant fashion [67]. Gain of function mutations Consistent with the reports that I activation (KCNJ8 and KATP ABCC9) or I (KCNE5 mutation and rare polymorphism in DPP10) can generate an ER pattern on to the surface ECG, several investigators have detected a rare missense mutation, S422L in KCNJ8, to be associated with ER and idiopathic ventricular fibrillation (VF) [60,62,63,68]. The first report on this variant was a case report of a 14-year-old female who experienced numerous episodes of recurrent idiopathic VF unresponsive to beta-blockers, multiple anti- arrhythmic medications and verapamil [60]. Recurrences of VF were associated with a marked accentuation of ER. In a study of 87 patients with Brugada syndrome and 14 patients with ER syndrome, one Brugada syndrome case and one ER syndrome case hosted the identical missense mutation S422L. Investigators demonstrated that I was increased significantly in the KATP S422L variant compared with Kir6.1 wild type channels [62]. A separate study of 204 patients and family members with Brugada syndrome or ER syndrome also demonstrated a similar gain of function of the Kir6.1 channel (identified in three Brugada syndrome and one ER syndrome proband) [63]. KCNJ8-S422L is highly conserved across species and was absent in the reference alleles in these three studies [60,62,63]. This gain of function variant appears to be pathogenic in ER and idiopathic VF. https://www.uptodate.com/contents/early-repolarization/print 8/37 7/6/23, 3:25 PM Early repolarization - UpToDate Gain of function of I by missense variant (c.2240T > C/p. L747P) in DPP6 in four families with to SCA due to ER syndrome has been reported [69]. A heterozygous gain of function missense mutation in a highly conserved (K801T) residue in the hERG (KCNH2 gene) in a single Chinese family with ER syndrome involving four nocturnal SCD events has been reported involving the proband with ER syndrome and affected family members and was not present in a control population of 150 individuals [70]. Whole-cell patch-clamp methods were used to characterize the gain of function. A heterozygous gain of function mutation of KCND3 encoding Kv4.3, an -subunit (I ), Gly306Ala to (c.917g>c) was reported to be associated with ER syndrome in a 12-year-old male SCA survivor [71]. Isoproterenol and quinidine were effective in preventing VF recurrence with restoration of the J-point elevation. Furthermore, a genome wide association with ER on chromosome 1 in the KCND3 gene with rs1545300 as the lead polymorphism has been reported [72]. A total KCND3 duplication (with likely increase in I current) has been reported in a patient with to nonfatal nocturnal SCA and intermittent ER [73], responding to quinidine. Segregation analysis of available family members identified the proband's asymptomatic daughter as a carrier also demonstrating J-point elevation. Loss of function mutations Loss of function mutations of the inward sodium channel gene and cardiac L-type calcium channel gene have also been implicated in patients with ER (CACNA1C, CACNB2, and CACNA2D1 genes) ( figure 3). Two small studies (three and four patients with ER, respectively) have reported that mutations in these highly conserved residues were associated with ER, suggesting linkage of these genes with ER [61,64]. The complex genetic basis continues to be explored. Highlighting the complexity, a study indicated that the c.4297 G>C missense mutation in the SCN5A gene caused a "loss-of-function" of sodium channels accounting for the ER syndrome in a single case [74]. The reduction in INa density was due to a decreased number of sodium channels caused by abnormal translation processes. However, the synonymous T5457C polymorphism on the same allele partially restored the INa density of the mutant channels by the upregulation of mRNA levels. Furthermore, KCNE1 (and others) may be modulatory genes associated to ER syndrome [75]. A genome-wide association study was not able to reliably identify genetic variants predisposing to ER, presumably due to insufficient statistical power and phenotype heterogeneity [76]. This does however suggest that the genetic mechanisms may be multifactorial and that an ER gene or family of genes is an unlikely outcome of further ascertainment. Furthermore, a small proportion of reported genetic variants have undergone functional studies, and none has been https://www.uptodate.com/contents/early-repolarization/print 9/37 7/6/23, 3:25 PM Early repolarization - UpToDate studied in genetically engineered animal models. The poverty of validation of mutation effects remains a significant limitation when interpreting genetic test results. MECHANISM OF ER AND IDIOPATHIC VENTRICULAR FIBRILLATION There is controversy regarding whether the ER pattern represents abnormal repolarization or depolarization. The repolarization theory is based on the presence of a prominent action potential notch in the epicardium but not endocardium, which has been demonstrated to result in a voltage gradient that manifests as ER on the ECG ( figure 3 and figure 2) [77]. The depolarization theory is based on epicardial structural elements with conduction disturbances/delays in the epicardium [78-80]. The cause for this abnormal conduction leading to delayed and fractionated local epicardial electrograms remains unknown. A repolarization disparity secondary to the depolarization abnormality may also accentuate this mechanism. It is more likely that two mechanisms are contributing to ER. Clinical mapping data suggest two distinct substrates, delayed depolarization (with evident delayed local epicardial electrograms) and early repolarization abnormality (with absence of local delayed electrograms), underlie the J wave [78,79]. The term "J-wave syndromes" has been proposed in light of the heterogenous mechanisms to eliminate the implied mechanism in the term ER. Clinical studies also suggest the likelihood of two different substrates: In a study of 206 persons with idiopathic VF and the ER pattern, only a minority of cases (11 percent) had late potentials on signal-averaged ECG, with a prevalence similar to the control group who did not have the ER pattern (13 percent), suggesting that ER is not a depolarization phenomenon ( figure 4) [4]. However, in a smaller study of 22 patients with apparently idiopathic VF who were monitored using a signal-averaging system to record depolarization markers, repolarization markers, and autonomic modulation, the incidence of late potentials in persons with VF was significantly higher in those with the ER pattern (86 versus 27 percent in those without ER pattern) [18]. In contrast, repolarization markers did not differ between the two groups. These investigators concluded that ER might be more closely associated with a depolarization abnormality and autonomic modulation than with repolarization. https://www.uptodate.com/contents/early-repolarization/print 10/37 7/6/23, 3:25 PM Early repolarization - UpToDate Given that the mechanism for ER is likely heterogenous, the precise mechanism for ER- related idiopathic ventricular fibrillation (VF) is also likely heterogenous. The repolarization theory holds to endo-epicardial action potential gradients caused by gain or loss of function mutations by outward or inward currents respectively, causing phase 2 reentry and polymorphic VT/VF [81]. The depolarization theory holds to unidentified micro- structural abnormalities in the right ventricular (RV) epicardium, causing conduction delay and local triggers and reentry [78]. The two different mechanisms will likely have implications for therapy, with varied response to pharmacotherapy. The response to isoproterenol has been reported to be variable, with inferior J waves persisting in 35 percent, suggestive of a depolarization substrate, and normalizing (or decreasing) in 65 percent, suggestive of an early repolarization substrate [82]. Quinidine and isoproterenol have been demonstrated to restore electrical homogeneity by restoring the epicardial action potential dome, thus preventing VT/VF [82]. In contrast, those who fail to respond to quinidine tend to display depolarization abnormalities [78]. Furthermore, late depolarization may be associated with gene variants in the Na channel, connexins, and structural proteins, whereas mutations in I , IK-ATP, or ICa may be associated to with early repolarization [79]. Sodium channel blockers have been demonstrated to accentuate the ER in those with depolarization substrates and not in those devoid of depolarization substrate, further highlighting the heterogenous mechanism [78]. ER mechanistically demonstrates some similarities to Brugada syndrome and short QT syndrome (SQTS). (See "Short QT syndrome" and "Brugada syndrome: Epidemiology and pathogenesis", section on 'Pathogenesis'.) CLINICAL MANIFESTATIONS AND DIAGNOSIS ER pattern Given the relatively high prevalence of the ER pattern in the general population (5 to 13 percent) in comparison with the incidence of idiopathic ventricular fibrillation (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. In the absence of SCA, no additional testing is required in persons with the ER pattern. Asking patients to perform the Valsalva maneuver may unmask or accentuate the ER pattern. While performing this maneuver has been shown to aid in the identification of the ER pattern in high-risk familial ER, this has not been validated, and its applicability to broad populations of asymptomatic persons has not been evaluated [67]. The Valsalva maneuver is discussed in greater detail separately. (See "Vagal maneuvers".) https://www.uptodate.com/contents/early-repolarization/print 11/37 7/6/23, 3:25 PM Early repolarization - UpToDate ER syndrome Patients with ER syndrome typically present with SCA due to VF. Syncope has not been shown to be more common in patients with ER pattern [65,83]. The diagnosis of ER syndrome is most commonly considered in a survivor of SCD with ECG evidence of VF and an apparently structurally normal heart following extensive testing ( table 1). A systematic assessment of the survivors of SCD without evidence of infarction or left ventricular dysfunction is reported to establish a causative diagnosis in the majority of cases [11,84]. Systematic evaluation includes: Cardiac monitoring. Signal-averaged ECG. Exercise testing. Echocardiogram. Cardiac magnetic resonance imaging. Exclusion of coronary artery disease or anomalies. Intravenous sodium channel blocker challenge (discretionary epinephrine challenge). Targeted genetic testing should also be considered when a heritable phenotype is suggested. (See "Congenital long QT syndrome: Diagnosis" and "Catecholaminergic polymorphic ventricular tachycardia" and "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) In patients whose evaluation revealed no identifiable cardiac pathology, idiopathic VF and the ER syndrome should be considered. A careful review of all available ECGs for evidence of ER is warranted, particularly around the time of the cardiac arrest [11]. ECGs often show variable and at times absent ER, so thorough review is important. VF storms in the idiopathic VF patients attributed to ER syndrome were highly associated with J wave augmentation prior to the VF onset [85]. ER syndrome causing VF may be diagnosed when: Other etiologies have been systematically excluded When J-point elevation is augmented immediately preceding VF ER syndrome causing VF is probable when: Other etiologies have been systematically excluded https://www.uptodate.com/contents/early-repolarization/print 12/37 7/6/23, 3:25 PM Early repolarization - UpToDate ER pattern exists or increased parasympathetic tone provokes ER Cardiac arrest occurs at rest or during sleep These patients may also display a high-risk ER pattern (J-point elevation >2 mm in the inferior or inferolateral leads or globally and/or horizontal or down sloping ST segment. (See 'Prognosis of ER pattern' above.) The ER pattern is not always identified on routine ECG due to the intermittent nature of ER. Bradycardia dependent and vagally dependent augmentation of ER has been reported [86]. However, no provocative test, such as pharmacologic augmentation of parasympathetic tone, is currently available and validated in this setting. Although the utility has not been studied systematically, tilt table testing may be of assistance to establish if vagal stimulation is associated with VF/syncope and/or if high-risk ER features are provoked. However, the diagnostic accuracy of this approach is unknown, and vasovagal syncope is far more common in comparison with VF due to ER syndrome. (See 'Prognostic variables' above and "Upright tilt table testing in the evaluation of syncope".) DIFFERENTIAL DIAGNOSIS ER versus Brugada syndrome Some individuals with Brugada syndrome (ECG findings of ST- segment elevation in leads V1 to V2 associated with SCD or sustained ventricular arrhythmia) also have ER (approximately 12 percent) as variants in genes encoding the L-type calcium channel, ATP-sensitive potassium channel, and sodium channels have been associated with both of these conditions [61,62,64,87-90]. Additionally, some ECG characteristics of ER resemble features of the Brugada ECG, including J waves, pause and bradycardia dependent accentuation, the dynamic nature of the ECG manifestations, short-coupled extra-systole-induced polymorphic ventricular tachycardia/ventricular fibrillation, and suppression of the ECG features and arrhythmia with isoproterenol and quinidine [8,82]. However, the provocation of the Brugada pattern by sodium channel blocker is not observed in ER [91]. In fact, sodium channel blockers in most patients with ER attenuate the J-point, whereas the J-point is augmented by sodium-channel blockers in the right precordial leads in patients with a Brugada ECG. Furthermore, a positive signal-averaged ECG and structural abnormalities in the RV outflow tract are not consistently observed and have not been reported in patients with ER, respectively [92-94]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) ER versus acute pericarditis As is seen in ER, there is J-point elevation with resultant ST segment elevation in patients with acute pericarditis. Symptom presentation is markedly https://www.uptodate.com/contents/early-repolarization/print 13/37 7/6/23, 3:25 PM Early repolarization - UpToDate different in the two conditions. Unlike ER, most patients with acute pericarditis have ST elevations diffusely in most or all limb and precordial leads. Additionally, patients with acute pericarditis often have deviation of the PR segment, which is not present in ER. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Electrocardiogram'.) ER versus acute myocardial injury While patients with acute myocardial injury due to ST- elevation myocardial infarction (STEMI) can initially have elevation of the J point with concave ST- segment elevation, the ST-segment elevation typically becomes more pronounced and convex (rounded upward) as the infarction persists. However, the primary distinguishing factor between ER and acute myocardial injury is the presence of clinical symptoms such as chest pain or dyspnea. The distinction between the ECG findings of ER and acute MI are discussed in greater detail elsewhere. (See "Electrocardiogram in the diagnosis of myocardial ischemia and infarction", section on 'Early repolarization'.) TREATMENT Treatment of ER pattern As discussed above, the ER pattern is nearly always a benign incidental ECG finding, with no specific signs or symptoms attributed to it. In addition, there is no current risk stratification strategy for asymptomatic patients with ER pattern in the general population and within families with ER pattern that would allow for the identification of higher risk individuals with the ER pattern who might be candidates for treatment. The 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline for management of patients with ventricular arrhythmias and the prevention of SCD recommends observation with no treatment, and the 2015 European Society of Cardiology guidelines on the treatment of ventricular arrhythmias and prevention of SCD found that there was "insufficient evidence" to make a recommendation on the management of the ER pattern without associated symptomatic ventricular arrhythmias [12,95]. As such, for patients with the incidental finding of the ER pattern on their ECG, we recommend observation without therapy ( table 1). Treatment of ER syndrome with idiopathic VF Among survivors of SCD due to idiopathic ventricular fibrillation (VF), the reported rate of recurrent VF ranges between 22 and 37 percent at two to four years [96-98]. Because these patients have no demonstrated structural heart disease, they have an excellent prognosis for long-term survival if VF is treated ( algorithm 1). As a result, such patients are best treated with an ICD [12,95-100]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) https://www.uptodate.com/contents/early-repolarization/print 14/37 7/6/23, 3:25 PM Early repolarization - UpToDate In patients with idiopathic VF, substrate and/or trigger ablation is feasible, safe, and effective in specialized centers [78,79]. In 43 patients undergoing ablation for recurrent VF episodes due to ER syndrome, two phenotypes were identified; one with late depolarization abnormalities predominantly in the epicardium of the RV outflow tract and RV inferolateral epicardium (group 1), and the other with VF triggers associated with Purkinje sites but without abnormal epicardial/endocardial depolarization substrates (group 2) [78]. Epicardial anterior RV, RV outflow tract, inferior RV, posterior and posterolateral LV and apical ablation guided by location of abnormal depolarization substrates +/- premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) triggers in group 1 and Purkinje PVC ablation in group 2 were effective with no VF recurrence in 91 percent at 31 +/- 26 months follow-up. Single procedure success was 67 percent. Ablation resulted in the disappearance of the ER pattern in 82 percent. Acute treatment of ER syndrome with VF storm For patients with ER syndrome and ongoing acute VF requiring frequent defibrillation, we suggest intravenous isoproterenol ( table 1). In a multicenter observational cohort study of 122 patients (90 males, mean age 37 12 years) with ER in the inferolateral leads and more than three episodes of idiopathic VF (including those with electrical storm), isoproterenol was effective for the acute suppression of VF, immediately suppressing electrical storms in seven of seven patients [101]. Theophylline has been described in a case report as eliminating ongoing malignant ventricular arrhythmias in spite of treatment with quinidine and high-rate ventricular pacing [102]. High-dose flecainide has also been reported to be effective at suppressing VF in ER syndrome in a case report [103]. In an experimental canine model of ER, quinidine, cilostazol, and milrinone, each administered individually, have been shown to suppress hypothermia-induced ventricular arrhythmias [104]. Furthermore in an ER syndrome wedge preparation, cilostazol and milrinone or isoproterenol were demonstrated to reverse the repolarization defects underlying the development of phase 2