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Comparison of Inferolateral Early Repolarization and Its Electrocardiographic Phenotypes in Pre- and Postadolescent Populations
Comparison of Inferolateral Early Repolarization and Its Electrocardiographic Phenotypes in Pre- and Postadolescent Populations Solomon J. Sager, MD*, Michael Hoosien, MD, M. Juhani Junttila, MD, Tanyanan Tanawuttiwat, MD, Arlette C. Perry, PhD, and Robert J. Myerburg, MD Inferolateral early repolarization (ER) patterns on standard electrocardiogram (ECG) are associated with increased risk for cardiac and arrhythmic death in general adult population cohorts. We sought to determine the prevalence of inferolateral ER on surface ECG in multiracial pre- and postadolescent populations and to analyze its association with age, race, gender, and ST-segment patterns. A retrospective review was conducted of all ECGs recorded from preadolescent (aged 8e12 years, n [ 719) and postadolescent (aged 21e25 years, n [ 755) patients seen at a large academic medical center between January 1, 2009, and December 31, 2010. The overall prevalence of inferolateral ER was similar in the preadolescent and postadolescent populations (17% vs 16%, NS). The prevalence of ER increased after puberty in male patients (16% to 25%, p <0.001) and decreased in female patients (18% to 9%, p <0.001). Prevalence of ascending early repolarization (benign variant) also increased in males after puberty (15% to 23%, p <0.004) and decreased in females (11% to 4%, p <0.001). There were no differences in the prevalence of the riskassociated horizontal/descending pattern (3% in both groups). Subgroup analysis was performed on ECGs from the cohort of outpatients without cardiac disease, and the statistical trends remained the same. In conclusion, the overall prevalence of inferolateral ER was higher in pre- and postadolescent populations than in adult populations. However, the prevalence of the risk-associated horizontal/descending ST-segment pattern was only 3%, comparable to prevalence rates in the adult population. The variations in prevalence by gender and age suggest a possible influence of reproductive hormones. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:444e448) An inferolateral early repolarization pattern (ER) on standard 12 lead electrocardiograms (ECGs) is associated with increased risk for cardiac and arrhythmic death in general population cohorts1,2 and is more prevalent in patients with a history of unexplained (idiopathic) ventricular fibrillation than in age- and gender-matched controls.3,4 Various studies have shown a prevalence of ER ranging from 5% to 13% in the general population,1e5 and it appears even higher in specific populations, such as young athletes and black patients.6e8 However, differentiating at-risk subjects from those with a benign variation remains a clinical challenge. Recently, the pattern of a horizontal or descending ST segment after ER was identified as a marker of increased risk for arrhythmic death9 and for the development of idiopathic ventricular fibrillation,10 whereas the Division of Cardiology, University of Miami Miller School of Medicine and Jackson Memorial Hospital, Miami, Florida. Manuscript received March 5, 2013; revised manuscript received and accepted March 26, 2013. Dr. Myerburg’s participation in this study was supported in part by the Leducq Foundation, Paris, France, and the Florida Heart Research Foundation, Miami, Florida. Dr. Junttila was supported in part by the Leducq Foundation, Paris, France. Dr. Myerburg is supported in part by the American Heart Association Chair in Cardiovascular Research at the University of Miami Miller School of Medicine. See page 447 for disclosure information. *Corresponding author: Tel: (305) 469-7280; fax: (786) 664-6522. E-mail address: [email protected] (S.J. Sager). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.03.052
ascending ST-segment variant, which is more common in young athletes, appears benign.9,10 Multiple molecular studies have demonstrated that testosterone augments J-point elevation,11e13 and clinical studies suggest that testosterone may affect the incidence and prevalence of ER.14e16 We therefore analyzed the ECGs of pre- and postadolescent male and female patients in a multiracial population to determine the gender-specific prevalence and the prevalence of the higher-risk horizontal ST-segment pattern and to identify variations in prevalence associated with puberty. Methods All ECGs recorded from both inpatients and outpatients at a large, university-affiliated community hospital (Jackson Memorial Medical Center, University of Miami Miller School of Medicine, Miami, Florida) are maintained in a computerized database. We accessed all ECGs performed on patients in the age groups 8 to 12 years (preadolescent) and 21 to 25 years (postadolescent) from January 1, 2009, through December 31, 2010. Preparticipation screening ECGs among University of Miami athletes were not included in this database. We excluded all ECGs with intraventricular conduction abnormalities and paced rhythms. There were 719 ECGs in the preadolescent population (443 male patients) and 755 in the postadolescent population (351 male patients). Demographic data and ER patterns were recorded. ST-segment morphologies associated with ER were classified www.ajconline.org
Miscellaneous/Inferolateral ER Pre- and Postadolescence
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Figure 1. (A) Inferior early repolarization in a 12-year-old boy with ascending ST-segment phenotype. (B) Inferior early repolarization in a 20-year-old man with descending ST-segment phenotype.
as upsloping or horizontal/downsloping. Medical records were reviewed for inpatient and outpatient status, medical history, and indications for ECGs. Indications were divided into 5 general categories: suspected cardiac symptoms; cardiac arrhythmia; structural heart disease; screening, including prechemotherapy, preoperative, and prestimulant therapy for attention-deficit disorder; and noncardiac illness. To determine if the results could be applied to the general population, subgroup analyses were performed on outpatients who did not have underlying structural or arrhythmic cardiac disease (including hypertension and echocardiographic evidence of left ventricular hypertrophy). Subjects who had ECGs performed for suspected cardiac symptoms and who were subsequently diagnosed with cardiac disease were also excluded. In this cohort, there were 418 subjects in the preadolescent population and 496 in the postadolescent. This study was approved by the Institutional Review Board of the University of Miami. All ECG analyses were performed visually by physicians trained in ECG interpretation. ER was defined based on previously reported criteria1,3: a slow deflection (“slurring”) of the downslope of the R wave 0.1 mV or a notched J point 0.1 mV in 2 contiguous inferior (II, III, aVF) or lateral leads (I, aVL, V4e6), or both. Using criteria introduced by Tikkanen et al,7 we classified ST-segment morphology after ER as ascending if the ST segment was 0.1 mV at 100 milliseconds after the J point and as horizontal/descending if the ST segment was 0.1 mV at 100 milliseconds after J-point elevation (Figure 1). All readers were blinded to ECG indications, initial clinical interpretations, and computerized interpretations of the ECGs. Because of the possibility of inter-reader variation, the first 800 ECGs were analyzed by 2 readers blinded to age, gender, and race as a pilot to test diagnostic
Table 1 Demographics, electrocardiogram indications, and prevalence of early repolarization in the 2 populations Variable
Preadolescent Postadolescent p Value (Ages 8e12 Yrs, (Ages 21e25 Yrs, n ¼ 719) n ¼ 755)
Male 443 (62%) 351 Black 375 (52%) 350 Inpatients 202 (28%) 244 ECG indications Suspected cardiac 342 (48%) 312 symptoms Arrhythmia 43 (6%) 12 Structural heart disease 96 (13%) 19 Screening 162 (23%) 137 Noncardiac condition 76 (11%) 275 Prevalence of ER in overall population Total ER 121 (17%) 123 Inferior ER 38 (5%) 19 Lateral ER 51 (7%) 45 Inferolateral ER 32 (4%) 59 Ascending 99 (14%) 98 Descending 22 (3%) 25 Lead-specific distribution of ER in ER population Inferior ER 38/121 (31%) 19/123 Lateral ER 51/121 (42%) 45/123 Inferolateral ER 32/121 (26%) 59/123 Ascending 99/121 (82%) 98/123 Descending 22/121 (18%) 25/123
(47%) (46%) (32%)
<0.001 0.04 NS
(41%)
<0.02
(2%) (3%) (18%) (36%)
<0.001 <0.001 <0.04 <0.001
(16%) (3%) (6%) (8%) (13%) (3%)
NS NS NS <0.01 NS NS
(15%) (37%) (48%) (80%) (20%)
<0.02 NS <0.001 NS NS
accuracy. Kappa score for ER diagnosis was .63, which was considered a statistically acceptable value. Therefore, the remainder of the ECGs were interpreted by a single blinded reader.
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Figure 3. Prevalence of early repolarization in black and white subjects. Figure 2. Change in prevalence of early repolarization and ST-segment patterns after puberty in male and female subjects.
Categorical variables are expressed as number and percentages. Continuous variables are presented as mean SD. The chi-square test was used to compare dichotomized variables, and a 2-sample t test was used for continuous variables; p value <0.05 was considered statistically significant. The analysis was performed using PASW 17.0 (SPSS, Chicago, Illinois) software. Results Demographics, ECG indications, and prevalence of ER in the overall population are presented in Table 1. There was a higher percentage of ECGs recorded from black and from male patients in the preadolescent population. The increase in the proportion of ECGs recorded from female patients in the postadolescent population may be attributable to the proportion of patients in the postadolescent age group on the obstetrics services. The prevalence of ER in the male population increased after puberty, from 16% in preadolescents (71 of 443) to 25% in postadolescents (88 of 351; p <0.001). In contrast, the overall prevalence in female patients decreased from 18% in preadolescents to 9% after puberty (p <0.001; Figure 2). There was no difference in mean heart rate between male pre- and postadolescents (78.0 vs 79.5, p ¼ 0.4) or between female pre- and postadolescents (83.6 vs 83.4, p ¼ 0.9). Similar to the overall prevalence of ER, the overall prevalence of ascending ST-segment pattern increased in male patients after puberty (15% to 23%, p <0.004) and decreased in females (11% to 4%, p <0.001; Figure 2). The prevalence of the risk-associated horizontal/descending STsegment pattern was low in both age groups (3% in each) and there was no difference in the prevalence when stratified by gender (male, 1% to 2%, p ¼ 0.10; females, 7% to 5%, p ¼ 0.19). The prevalence of both ascending and horizontal/ descending patterns within the subset of patients with early repolarization was also similar in both groups (Table 1). Black patients had a higher prevalence of ER than white patients in both age groups. The prevalence was 22% in black preadolescents compared with 11% in white preadolescents, and 22% versus 11% in the respective postadolescent subgroups (p <0.001 for both; Figure 3). Black patients had a higher prevalence of ER than white patients in
Table 2 Demographics and electrocardiogram indications in cohort of outpatients without cardiac disease Variable
Male Black Chronic medical condition (noncardiac) ECG Indication Suspected cardiac symptoms* Screening Noncardiac condition
Preadolescent Postadolescent p Value (Ages 8e12 Yrs, (Ages 21e25 Yrs, n ¼ 418) n ¼ 496) 254 (61%) 230 (55%) 148 (35%)
229 (46%) 222 (45%) 130 (26%)
<0.001 <0.002 <0.003
295 (71%)
268 (54%)
<0.001
73 (17%) 50 (12%)
75 (15%) 153 (31%)
NS <0.001
* In subjects not subsequently diagnosed with cardiac disease.
both age groups (23% vs 9% for preadolescent boys and 35% vs 18% for postadolescent men, p <0.0001 for both). In the preadolescent female population, there was no difference in prevalence between black and white girls (20% vs 16%, p <0.39); however, in the postadolescents, black women had a higher prevalence of ER (12% vs 5%, p <0.008), although this remained lower than in black male patients. In the subanalysis of outpatients without cardiac disease, the results were similar. Table 2 lists demographics and ECG indications for this cohort. There were more male and black patients in the preadolescent population, as well as more patients with a chronic medical condition, primarily asthma, attention-deficit/hyperactivity disorder, hypertension, or sickle cell disease. There were 77 patients with ER in the preadolescent population (18%) and 92 in the postadolescent population (19%, NS). There was a similar change in the prevalence of ER in the male population, from 18% in preadolescent population to 28% in postadolescents (p <0.01) and in the prevalence of ascending phenotypes in male patients, from 18% to 26% (p <0.03). In the female population, prevalence of ER decreased from 19% to 11% (p <0.02), and the ascending phenotype exhibited a similar pattern (12% to 5%, p <0.01). There was no significant change in the prevalence of the descending phenotype. Preadolescent black outpatients without cardiac disease had a higher prevalence of inferolateral ER (24% vs 12%,
Miscellaneous/Inferolateral ER Pre- and Postadolescence
p <0.001) and ascending phenotype (21% vs 9%, p <0.001) than white subjects. The same pattern persisted in the postadolescent population (25% vs 14% for ER, p <0.001; 20% vs 10% for ascending, p <0.002). Discussion In this study, we have for the first time evaluated the prevalence of both the “benign” ascending and high-risk descending inferolateral early repolarization variants in a large pre- and young postadolescent population, analyzed for age, gender, and race. The cumulative inferolateral ER prevalence of approximately 17% in both populations is slightly higher than the 5% to 13% range for adult populations. Although a large majority of inferolateral ER patterns in the young population is likely to represent normal variants, the possibility of a novel marker for sudden cardiac death that will identify a subset of patients who warrant further clinical evaluation and long-term tracking is promising. Only 3% of the pediatric and young adult populations in our study demonstrated the pattern of horizontal/descending ST segments with inferolateral ER. In the study by Tikkanen et al in which this pattern was first reported to associate with risk, the overall prevalence was 3.8% in a middle-aged Finnish population.9 Importantly, although the majority of the observed early repolarization in that study was of the descending phenotype (71.5%), the majority of observed ER in our study was of the ascending phenotype (82% of ER in preadolescents and 80% of ER in postadolescents). Rosso et al corroborated the prevalence of horizontal/descending ER, demonstrating that 3.3% of healthy control subjects (mean age 38 years) and 3.3% of young noncompetitive athletes (aged 17 to 19) carry J waves with a horizontal/ descending ST-segment.10 Because it appears that the prevalence of the horizontal/descending ST-segment remains stable through puberty and beyond, the question of whether it implies sudden cardiac death risk in the younger group requires exploration. However, the risk in Tikkanen’s data did not manifest until approximately 10 years of follow-up, when a majority of the patients were older than 50 years. The pattern, therefore, may represent a risk-modifying substrate rather than a primary arrhythmogenic disease. Both Tikkanen et al and Rosso et al also demonstrated that the ascending pattern does not suggest an increased risk for arrhythmic death or for the development of idiopathic ventricular fibrillation.9,10 Our demonstration that a majority of the ER in younger patients associates with ascending ST segment should alleviate some of the pressure on clinicians regarding the question of a general risk of inferolateral ER patterns in younger populations. In contrast to the stable frequency of the potentially high-risk pattern, the frequencies of the low-risk ER patterns appear to vary with age. There is evidence suggesting that distribution of ER in multiple leads influences risk, with ER involving the lateral, inferior, and right precordial leads (“global ER”) conferring an extremely high risk of malignant arrhythmias.17 As can be seen in Table 1, the prevalence of ER involving both the lateral and inferior leads increases from 26% (32 of 121 cases of ER) in the preadolescent population to 48% (59 of 123 cases of ER) in the postadolescent population. The
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significance of this finding in these populations is unclear, and further studies are warranted with long-term outcomes data in populations of patients with ECGs from adolescence. There is not enough evidence at the current time to suggest further testing in young asymptomatic patients with this ECG pattern. There was no significant difference in gender-specific prevalence of ER in the preadolescent population of our study. However, in the young adults, male patients had significantly more ER than female patients. A previous study demonstrated that there was no gender-related difference in ST-segment elevation in anterior and lateral leads (V2 to V5) before puberty, but levels in males significantly increase after puberty, peaking at 29 years of age and then gradually declining in the third decade of life.16 On the basis of our clinical findings and those of others,15,16 it is possible that changes in reproductive hormone levels at puberty contribute to the higher prevalence of inferolateral ER seen in male young adults and young athletes. It is these patients who more frequently have the benign, ascending ST-segment phenotype, and thus this pattern may partly reflect the impact of testosterone. We found a higher prevalence of ER in black patients in both pre- and postadolescent populations. Similar findings have been described in young athletes and in older populations, and this may be related to larger-amplitude R waves in the lateral leads.6,8 Black men have an especially high prevalence of inferolateral ER; however, in postadolescent patients, black women also have greater prevalence of inferolateral ER. The clinical relevance of this finding is unclear, and further studies investigating the possibility of genetically based variants are warranted. There are important limitations to consider when interpreting our results. This was a retrospective study of ER prevalence in prespecified cohorts of inpatients and outpatients seen at an academic medical center, and therefore the data should not be interpreted as conclusive for the presence of these findings in a general preadolescent or young adult population. However, the statistical patterns persisted in the cohort of outpatients without cardiac disease, and so the results are likely similar in the general population. The cross-sectional nature of the study prohibited any assessment of prognosis. Finally, although a kappa value of .63 is statistically reasonable, it also suggests that there will be some degree of interobserver variability. Disclosures The authors have no conflicts of interest to disclose. 1. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361: 2529e2537. 2. Sinner MF, Reinhard W, Muller M, Beckmann BM, Martens E, Perz S, Pfeufer A, Winogradow J, Stark K, Meisinger C, Wichmann HE, Peters A, Riegger GA, Steinbeck G, Hengstenberg C, Kaab S. Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA). PLoS Med 2010;7:e1000314. 3. Haissaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, de Roy L, Pasquie JL, Nogami A, Babuty D, Yli-Mayry S, De Chillou C, Scanu P, Mabo P, Matsuo S, Probst V, Le Scouarnec S, Defaye P, Schlaepfer J, Rostock T, Lacroix D, Lamaison D, Lavergne T, Aizawa Y, Englund A, Anselme F, O’neill M, Hocini M, Lim KT, Knecht S, Veenhuyzen GD,
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4.
5. 6. 7. 8. 9.
The American Journal of Cardiology (www.ajconline.org) Bordachar P, Chauvin M, Jais P, Coureau G, Chene G, Klein GJ, Clementy J. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016e2023. Rosso R, Kogan E, Belhassen B, Rozovski U, Scheinman MM, Zeltser D, Halkin A, Stinvil A, Heller K, Glikson M, Katz A, Viskin S. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol 2008;52:1231e1238. Klatsky AL, Oehm R, Cooper RA, Udaltsova N, Armstrong MA. The early repolarization normal variant electrocardiogram: correlates and consequences. Am J Med 2003;115:171e177. Junttila MJ, Sager SJ, Freiser M, McGonagle S, Castellanos A, Myerburg RJ. Inferolateral early repolarization in athletes. J Interv Card Electrophysiol 2011;31:33e38. Uberoi A, Jain NA, Perez M, Weinkopff A, Ashley E, Hadley D, Turakhia MP, Froelicher V. Early repolarization in an ambulatory clinical population. Circulation 2011;124:2208e2214. Perez MV, Uberoi A, Jain NA, Ashley E, Turakhia MP, Froelicher V. The prognostic value of early repolarization with ST-segment elevation in African Americans. Heart Rhythm 2012;9:558e565. Tikkanen JT, Junttila MJ, Anttonen O, Aro AL, Luttinen S, Kerola T, Sager SJ, Rissanen HA, Myerburg RJ, Reunanen A, Huikuri HV. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666e2673.
10. Rosso R, Glikson E, Belhassen B, Katz A, Halkin A, Steinvil A, Viskin S. Distinguishing “benign” from “malignant early repolarization”: the value of the ST-segment morphology. Heart Rhythm 2012;9:225e229. 11. Pham TV, Rosen MR. Sex, hormones, and repolarization. Cardiovasc Res 2002;53:740e751. 12. Bai CX, Kurosawa J, Tamagawa M, Nakaya H, Fukukawa T. Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation 2005;112:1701e1710. 13. Niwa N, Nerbonne JM. Molecular determinants of cardiac transient outward potassium current (Ito) expression and regulation. J Mol Cell Cardiol 2010;48:12e25. 14. Haruta D, Matsuo K, Tsuneto A, Ichimaru S, Hida A, Sera N, Imaizumi M, Nakashima E, Maemura K, Akahoshi M. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011;123:2931e2937. 15. Surawicz B, Parikh SR. Prevalence of male and female patterns of early ventricular repolarization in the normal ECG of males and females from childhood to old age. J Am Coll Cardiol 2002;40:1870e1876. 16. Ezaki K, Nakagawa M, Taniguchi Y, Nagano Y, Teshima Y, Yufu K, Takahashi N, Nomura T, Satoh F, Mimata H, Saikawa T. Gender differences in the ST segment: effect of androgen-deprivation therapy and possible role of testosterone. Circ J 2010;74:2448e2454. 17. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010;7: 549e558.
ascending ST-segment variant, which is more common in young athletes, appears benign.9,10 Multiple molecular studies have demonstrated that testosterone augments J-point elevation,11e13 and clinical studies suggest that testosterone may affect the incidence and prevalence of ER.14e16 We therefore analyzed the ECGs of pre- and postadolescent male and female patients in a multiracial population to determine the gender-specific prevalence and the prevalence of the higher-risk horizontal ST-segment pattern and to identify variations in prevalence associated with puberty. Methods All ECGs recorded from both inpatients and outpatients at a large, university-affiliated community hospital (Jackson Memorial Medical Center, University of Miami Miller School of Medicine, Miami, Florida) are maintained in a computerized database. We accessed all ECGs performed on patients in the age groups 8 to 12 years (preadolescent) and 21 to 25 years (postadolescent) from January 1, 2009, through December 31, 2010. Preparticipation screening ECGs among University of Miami athletes were not included in this database. We excluded all ECGs with intraventricular conduction abnormalities and paced rhythms. There were 719 ECGs in the preadolescent population (443 male patients) and 755 in the postadolescent population (351 male patients). Demographic data and ER patterns were recorded. ST-segment morphologies associated with ER were classified www.ajconline.org
Miscellaneous/Inferolateral ER Pre- and Postadolescence
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Figure 1. (A) Inferior early repolarization in a 12-year-old boy with ascending ST-segment phenotype. (B) Inferior early repolarization in a 20-year-old man with descending ST-segment phenotype.
as upsloping or horizontal/downsloping. Medical records were reviewed for inpatient and outpatient status, medical history, and indications for ECGs. Indications were divided into 5 general categories: suspected cardiac symptoms; cardiac arrhythmia; structural heart disease; screening, including prechemotherapy, preoperative, and prestimulant therapy for attention-deficit disorder; and noncardiac illness. To determine if the results could be applied to the general population, subgroup analyses were performed on outpatients who did not have underlying structural or arrhythmic cardiac disease (including hypertension and echocardiographic evidence of left ventricular hypertrophy). Subjects who had ECGs performed for suspected cardiac symptoms and who were subsequently diagnosed with cardiac disease were also excluded. In this cohort, there were 418 subjects in the preadolescent population and 496 in the postadolescent. This study was approved by the Institutional Review Board of the University of Miami. All ECG analyses were performed visually by physicians trained in ECG interpretation. ER was defined based on previously reported criteria1,3: a slow deflection (“slurring”) of the downslope of the R wave 0.1 mV or a notched J point 0.1 mV in 2 contiguous inferior (II, III, aVF) or lateral leads (I, aVL, V4e6), or both. Using criteria introduced by Tikkanen et al,7 we classified ST-segment morphology after ER as ascending if the ST segment was 0.1 mV at 100 milliseconds after the J point and as horizontal/descending if the ST segment was 0.1 mV at 100 milliseconds after J-point elevation (Figure 1). All readers were blinded to ECG indications, initial clinical interpretations, and computerized interpretations of the ECGs. Because of the possibility of inter-reader variation, the first 800 ECGs were analyzed by 2 readers blinded to age, gender, and race as a pilot to test diagnostic
Table 1 Demographics, electrocardiogram indications, and prevalence of early repolarization in the 2 populations Variable
Preadolescent Postadolescent p Value (Ages 8e12 Yrs, (Ages 21e25 Yrs, n ¼ 719) n ¼ 755)
Male 443 (62%) 351 Black 375 (52%) 350 Inpatients 202 (28%) 244 ECG indications Suspected cardiac 342 (48%) 312 symptoms Arrhythmia 43 (6%) 12 Structural heart disease 96 (13%) 19 Screening 162 (23%) 137 Noncardiac condition 76 (11%) 275 Prevalence of ER in overall population Total ER 121 (17%) 123 Inferior ER 38 (5%) 19 Lateral ER 51 (7%) 45 Inferolateral ER 32 (4%) 59 Ascending 99 (14%) 98 Descending 22 (3%) 25 Lead-specific distribution of ER in ER population Inferior ER 38/121 (31%) 19/123 Lateral ER 51/121 (42%) 45/123 Inferolateral ER 32/121 (26%) 59/123 Ascending 99/121 (82%) 98/123 Descending 22/121 (18%) 25/123
(47%) (46%) (32%)
<0.001 0.04 NS
(41%)
<0.02
(2%) (3%) (18%) (36%)
<0.001 <0.001 <0.04 <0.001
(16%) (3%) (6%) (8%) (13%) (3%)
NS NS NS <0.01 NS NS
(15%) (37%) (48%) (80%) (20%)
<0.02 NS <0.001 NS NS
accuracy. Kappa score for ER diagnosis was .63, which was considered a statistically acceptable value. Therefore, the remainder of the ECGs were interpreted by a single blinded reader.
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Figure 3. Prevalence of early repolarization in black and white subjects. Figure 2. Change in prevalence of early repolarization and ST-segment patterns after puberty in male and female subjects.
Categorical variables are expressed as number and percentages. Continuous variables are presented as mean SD. The chi-square test was used to compare dichotomized variables, and a 2-sample t test was used for continuous variables; p value <0.05 was considered statistically significant. The analysis was performed using PASW 17.0 (SPSS, Chicago, Illinois) software. Results Demographics, ECG indications, and prevalence of ER in the overall population are presented in Table 1. There was a higher percentage of ECGs recorded from black and from male patients in the preadolescent population. The increase in the proportion of ECGs recorded from female patients in the postadolescent population may be attributable to the proportion of patients in the postadolescent age group on the obstetrics services. The prevalence of ER in the male population increased after puberty, from 16% in preadolescents (71 of 443) to 25% in postadolescents (88 of 351; p <0.001). In contrast, the overall prevalence in female patients decreased from 18% in preadolescents to 9% after puberty (p <0.001; Figure 2). There was no difference in mean heart rate between male pre- and postadolescents (78.0 vs 79.5, p ¼ 0.4) or between female pre- and postadolescents (83.6 vs 83.4, p ¼ 0.9). Similar to the overall prevalence of ER, the overall prevalence of ascending ST-segment pattern increased in male patients after puberty (15% to 23%, p <0.004) and decreased in females (11% to 4%, p <0.001; Figure 2). The prevalence of the risk-associated horizontal/descending STsegment pattern was low in both age groups (3% in each) and there was no difference in the prevalence when stratified by gender (male, 1% to 2%, p ¼ 0.10; females, 7% to 5%, p ¼ 0.19). The prevalence of both ascending and horizontal/ descending patterns within the subset of patients with early repolarization was also similar in both groups (Table 1). Black patients had a higher prevalence of ER than white patients in both age groups. The prevalence was 22% in black preadolescents compared with 11% in white preadolescents, and 22% versus 11% in the respective postadolescent subgroups (p <0.001 for both; Figure 3). Black patients had a higher prevalence of ER than white patients in
Table 2 Demographics and electrocardiogram indications in cohort of outpatients without cardiac disease Variable
Male Black Chronic medical condition (noncardiac) ECG Indication Suspected cardiac symptoms* Screening Noncardiac condition
Preadolescent Postadolescent p Value (Ages 8e12 Yrs, (Ages 21e25 Yrs, n ¼ 418) n ¼ 496) 254 (61%) 230 (55%) 148 (35%)
229 (46%) 222 (45%) 130 (26%)
<0.001 <0.002 <0.003
295 (71%)
268 (54%)
<0.001
73 (17%) 50 (12%)
75 (15%) 153 (31%)
NS <0.001
* In subjects not subsequently diagnosed with cardiac disease.
both age groups (23% vs 9% for preadolescent boys and 35% vs 18% for postadolescent men, p <0.0001 for both). In the preadolescent female population, there was no difference in prevalence between black and white girls (20% vs 16%, p <0.39); however, in the postadolescents, black women had a higher prevalence of ER (12% vs 5%, p <0.008), although this remained lower than in black male patients. In the subanalysis of outpatients without cardiac disease, the results were similar. Table 2 lists demographics and ECG indications for this cohort. There were more male and black patients in the preadolescent population, as well as more patients with a chronic medical condition, primarily asthma, attention-deficit/hyperactivity disorder, hypertension, or sickle cell disease. There were 77 patients with ER in the preadolescent population (18%) and 92 in the postadolescent population (19%, NS). There was a similar change in the prevalence of ER in the male population, from 18% in preadolescent population to 28% in postadolescents (p <0.01) and in the prevalence of ascending phenotypes in male patients, from 18% to 26% (p <0.03). In the female population, prevalence of ER decreased from 19% to 11% (p <0.02), and the ascending phenotype exhibited a similar pattern (12% to 5%, p <0.01). There was no significant change in the prevalence of the descending phenotype. Preadolescent black outpatients without cardiac disease had a higher prevalence of inferolateral ER (24% vs 12%,
Miscellaneous/Inferolateral ER Pre- and Postadolescence
p <0.001) and ascending phenotype (21% vs 9%, p <0.001) than white subjects. The same pattern persisted in the postadolescent population (25% vs 14% for ER, p <0.001; 20% vs 10% for ascending, p <0.002). Discussion In this study, we have for the first time evaluated the prevalence of both the “benign” ascending and high-risk descending inferolateral early repolarization variants in a large pre- and young postadolescent population, analyzed for age, gender, and race. The cumulative inferolateral ER prevalence of approximately 17% in both populations is slightly higher than the 5% to 13% range for adult populations. Although a large majority of inferolateral ER patterns in the young population is likely to represent normal variants, the possibility of a novel marker for sudden cardiac death that will identify a subset of patients who warrant further clinical evaluation and long-term tracking is promising. Only 3% of the pediatric and young adult populations in our study demonstrated the pattern of horizontal/descending ST segments with inferolateral ER. In the study by Tikkanen et al in which this pattern was first reported to associate with risk, the overall prevalence was 3.8% in a middle-aged Finnish population.9 Importantly, although the majority of the observed early repolarization in that study was of the descending phenotype (71.5%), the majority of observed ER in our study was of the ascending phenotype (82% of ER in preadolescents and 80% of ER in postadolescents). Rosso et al corroborated the prevalence of horizontal/descending ER, demonstrating that 3.3% of healthy control subjects (mean age 38 years) and 3.3% of young noncompetitive athletes (aged 17 to 19) carry J waves with a horizontal/ descending ST-segment.10 Because it appears that the prevalence of the horizontal/descending ST-segment remains stable through puberty and beyond, the question of whether it implies sudden cardiac death risk in the younger group requires exploration. However, the risk in Tikkanen’s data did not manifest until approximately 10 years of follow-up, when a majority of the patients were older than 50 years. The pattern, therefore, may represent a risk-modifying substrate rather than a primary arrhythmogenic disease. Both Tikkanen et al and Rosso et al also demonstrated that the ascending pattern does not suggest an increased risk for arrhythmic death or for the development of idiopathic ventricular fibrillation.9,10 Our demonstration that a majority of the ER in younger patients associates with ascending ST segment should alleviate some of the pressure on clinicians regarding the question of a general risk of inferolateral ER patterns in younger populations. In contrast to the stable frequency of the potentially high-risk pattern, the frequencies of the low-risk ER patterns appear to vary with age. There is evidence suggesting that distribution of ER in multiple leads influences risk, with ER involving the lateral, inferior, and right precordial leads (“global ER”) conferring an extremely high risk of malignant arrhythmias.17 As can be seen in Table 1, the prevalence of ER involving both the lateral and inferior leads increases from 26% (32 of 121 cases of ER) in the preadolescent population to 48% (59 of 123 cases of ER) in the postadolescent population. The
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significance of this finding in these populations is unclear, and further studies are warranted with long-term outcomes data in populations of patients with ECGs from adolescence. There is not enough evidence at the current time to suggest further testing in young asymptomatic patients with this ECG pattern. There was no significant difference in gender-specific prevalence of ER in the preadolescent population of our study. However, in the young adults, male patients had significantly more ER than female patients. A previous study demonstrated that there was no gender-related difference in ST-segment elevation in anterior and lateral leads (V2 to V5) before puberty, but levels in males significantly increase after puberty, peaking at 29 years of age and then gradually declining in the third decade of life.16 On the basis of our clinical findings and those of others,15,16 it is possible that changes in reproductive hormone levels at puberty contribute to the higher prevalence of inferolateral ER seen in male young adults and young athletes. It is these patients who more frequently have the benign, ascending ST-segment phenotype, and thus this pattern may partly reflect the impact of testosterone. We found a higher prevalence of ER in black patients in both pre- and postadolescent populations. Similar findings have been described in young athletes and in older populations, and this may be related to larger-amplitude R waves in the lateral leads.6,8 Black men have an especially high prevalence of inferolateral ER; however, in postadolescent patients, black women also have greater prevalence of inferolateral ER. The clinical relevance of this finding is unclear, and further studies investigating the possibility of genetically based variants are warranted. There are important limitations to consider when interpreting our results. This was a retrospective study of ER prevalence in prespecified cohorts of inpatients and outpatients seen at an academic medical center, and therefore the data should not be interpreted as conclusive for the presence of these findings in a general preadolescent or young adult population. However, the statistical patterns persisted in the cohort of outpatients without cardiac disease, and so the results are likely similar in the general population. The cross-sectional nature of the study prohibited any assessment of prognosis. Finally, although a kappa value of .63 is statistically reasonable, it also suggests that there will be some degree of interobserver variability. Disclosures The authors have no conflicts of interest to disclose. 1. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361: 2529e2537. 2. Sinner MF, Reinhard W, Muller M, Beckmann BM, Martens E, Perz S, Pfeufer A, Winogradow J, Stark K, Meisinger C, Wichmann HE, Peters A, Riegger GA, Steinbeck G, Hengstenberg C, Kaab S. Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA). PLoS Med 2010;7:e1000314. 3. Haissaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, de Roy L, Pasquie JL, Nogami A, Babuty D, Yli-Mayry S, De Chillou C, Scanu P, Mabo P, Matsuo S, Probst V, Le Scouarnec S, Defaye P, Schlaepfer J, Rostock T, Lacroix D, Lamaison D, Lavergne T, Aizawa Y, Englund A, Anselme F, O’neill M, Hocini M, Lim KT, Knecht S, Veenhuyzen GD,
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