Author + information
- Received August 28, 2012
- Revision received October 21, 2012
- Accepted November 6, 2012
- Published online February 26, 2013.
- Joseph A. Walsh III, MD⁎,
- Leonard Ilkhanoff, MD, MS⁎,
- Elsayed Z. Soliman, MD, MSc, MS†,
- Ronald Prineas, MD, PhD†,
- Kiang Liu, PhD‡,
- Hongyan Ning, MD, MS‡ and
- Donald M. Lloyd-Jones, MD, ScM⁎,‡,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Donald M. Lloyd-Jones, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, Illinois 60611
Objectives The objective of this analysis was to determine the natural history and prospective association of cardiovascular risk factors with early repolarization (ER).
Background ER is common and has been suggested to increase risk for cardiovascular mortality in middle-aged adults. Data are sparse regarding the natural history of ER from young adulthood to middle age.
Methods We examined 5,069 participants (mean age 25 years at baseline; 40% black) from the CARDIA (Coronary Artery Risk Development in Young Adults) cohort over 20 years. Electrocardiograms were recorded at years 0 (Y0), 7 (Y7), and 20 (Y20) and coded as either definite, probable, possible, or no ER. Logistic regression was used to determine the association of cardiovascular risk factors with the presence of ER cross-sectionally and prospectively.
Results A total of 941 of the 5,069 participants (18.6%) had definite ER at baseline, and only 119 of 2,505 participants (4.8%) at the Y20 examination still demonstrated the presence of ER. Younger age, black race, male sex, longer exercise duration and QRS duration, and lower body mass index (BMI), heart rate, QT index, and Cornell voltage were associated cross-sectionally with the presence of ER. Predictors of maintenance of ER from Y0 to Y20 were black race (odds ratio [OR]: 2.62; 95% CI; 1.61 to 4.25), BMI (OR: 0.62 per 1 SD; 95% CI: 0.40 to 0.94), serum triglyceride levels (OR: 0.66 per 1 SD; 95% CI: 0.45 to 0.98), and QRS duration (OR: 1.68 per 1 SD; 95% CI: 1.37 to 2.06) at baseline.
Conclusions The prevalence of ER was significantly higher than previous estimates among asymptomatic young adults, and the majority of ER regressed by middle age. Black race, lower BMI, lower serum triglyceride levels, and longer QRS duration were independently associated with maintenance of ER over time.
Early repolarization (ER) on the resting 12-lead electrocardiogram (ECG), first described by Shipley and Hallaran (1) in 1936 as ST-segment elevation in the absence of coronary artery disease, has typically been viewed as a benign ECG finding. Previous analyses (2–4), using diverse definitions, have examined the prevalence and prognosis of ER and observed that ER tends to be associated with younger age, male sex, and black race and does not appear to be associated with an increased risk for mortality. Recently, there has been renewed interest in ER on the basis of data from Haissaguerre et al. (5) and Tikkanen et al. (6) that have suggested that certain subtypes of ER may be associated with a predisposition for malignant arrhythmias and sudden cardiac death (SCD). These studies, however, used unconventional definitions for ER (isolated ST-segment elevation in the inferior and lateral leads) and were conducted in primarily middle-aged white men and women. Subsequent analyses by our group (7), Tikkanen et al. (8), and Uberoi et al. (9) showed that varying phenotypes exist with varying prognostic implications. These recent data warrant further investigation into the contemporary prevalence, natural course, and factors associated with ER in all of its manifestations.
We therefore sought to conduct one of the first longitudinal studies to document the natural course of ER from young adulthood to middle age (years when this ECG abnormality is most likely to be manifest) in the CARDIA (Coronary Artery Risk Development in Young Adults) study, using a standardized definition of ER. The CARDIA cohort, with its similar numbers of black and white men and women followed from young adulthood (mean age 25 years at baseline) to middle age (mean age 45 years at year 20 [Y20]), as well as extensive repeated phenotyping, provides a unique opportunity to study the associations of ER with long-term cardiovascular (CV) risk factors, ECG abnormalities, and ECG left ventricular (LV) structure over 20 years' follow-up. The coding algorithm used in the CARDIA study to define ER as “definite, probable, or possible” make this one of the first cohorts to date to describe ER using a standardized visually confirmed definition. As opposed to the previously described definitions used by Haissaguerre et al. (5) and Tikkanen et al. (6), our study used multiple criteria for confirming the “syndrome” or ER using the presence of J point, T-wave amplitude, and morphology of the ST segment. We believe that although previous studies linking ER to cardiac death have unmasked a more ominous phenotype, the everyday clinician is more concerned with understanding the natural history and association of risk factors with the conventionally identified ECG syndrome of ER (concave ST-segment elevation with J point typically in the precordial leads). Such knowledge will expand understanding of the mechanisms and natural history of this important ECG finding and may help to elucidate the process by which certain phenotypes may be associated with an increased risk for mortality and SCD.
The CARDIA cohort was initiated to investigate the development of heart disease risk factors beginning in young adulthood. Details of the study design and procedures have previously been published (10). Briefly, 5,115 men and women ages 18 to 30 years with approximate balance in distribution of sex, race (black and white), and education were enrolled in 1985 and 1986 at 4 field centers: Birmingham, Alabama (University of Alabama at Birmingham); Chicago, Illinois (Northwestern University); Minneapolis, Minnesota (University of Minnesota); and Oakland, California (Kaiser Permanente Northern California). Participants were examined at baseline (Y0) and at follow-up examinations in Y2, Y5, Y7, Y10, Y15, Y20, and Y25. With the addition of telephone contact with participants who did not attend examinations, follow-up has been maintained on 91% of all baseline participants. For the present analysis, we used data from participants attending the Y0, Y7, and Y20 examinations, when resting 12-lead ECGs were obtained. Of the initial 5,115 participants, there were 34 participants with missing baseline ECGs and 12 with ECG abnormalities that precluded diagnosis of ER. Therefore, the total number of participants included in the present analysis was 5,069 for Y0. With hierarchical exclusion procedures for participants with missing ECGs (n = 1,393 for Y7; n = 2,546 for Y20), ECGs with abnormalities precluding the diagnosis of ER (n = 2 for Y7; n = 10 for Y20), or medications affecting ST segment (n = 5 for Y7; n = 8 for Y20), there were 3,669 participants available for the Y7 analysis and 2,505 for Y20. All participants signed informed consent at each examination, and the institutional review boards at each site approved study protocols.
Clinical assessment and measurement
Demographic, anthropometric, physiological, and serological measurements for each participant were obtained according to previously published standardized protocols (10). Current medication data were also obtained at serial examinations. Resting ECGs were obtained in conjunction with the CARDIA Fitness Study, an ancillary study of the main CARDIA cohort during examinations at Y0, Y7, and Y20 (10).
ECGs were recorded immediately before the exercise portion of examination visits at Y0, Y7, and Y20. For resting ECGs, all participants had standard limb and precordial ECG leads placed, with use of the Heartsquare device (11) for the Y20 exam to determine appropriate placement of the precordial leads (V1 to V6). Identical ECGs (at Y20; MAC1200, GE Healthcare, Milwaukee, Wisconsin) were used in all clinical centers. For the Y0 and Y7 ECGs, hard copies of the tracings were sent to the central ECG laboratory at the Epidemiological Cardiology Research Center (EPICARE; Wake Forest University, Winston-Salem, North Carolina) and visually read for the ECG definitions of ER shown below. ECGs were obtained in conjunction with the CARDIA Fitness Study during examination at Y20. Participants who declined or were ineligible to participate in the CARDIA Fitness Study, therefore, did not undergo routine ECG ascertainment. As a result, 2,505 of the 3,548 participants attending the Y20 examination had codeable ECGs available for analysis. At Y20, ECG recordings were transmitted via modem to EPICARE for reading using Marquette 12SL analysis program (GE Healthcare). All ECGs received were inspected visually to detect technical errors, missing leads, and inadequate quality, and such records were rejected from ECG data files.
Definition and coding of ER
ER was diagnosed using a definition developed (7,12) at EPICARE that is determined on the basis of the application of strict criteria selected from previous publications as follows (see Fig. 1 for an illustration): 1) definite ER: ST-segment J elevation >1 mm in ≥50% of beats, T-wave amplitude ≥5 mm, prominent J point, upward concavity of the ST segment, and distinct notch or slur on the downstroke of the R wave in any of leads V3 to V6; or ST-segment J elevation >2 mm in ≥50% of beats, T-wave amplitude ≥5 mm, prominent J point, and upward concavity of the ST segment in any of leads V3 to V6; 2) probable ER: ST-segment J elevation >1 mm in ≥50% of beats, prominent J point, upward concavity of the ST segment in any of leads V3 to V6, and T-wave amplitude ≥8 mm in any of the chest leads; and 3) possible ER: presence of Minnesota code 9-2 (ST-segment elevation >1 mm in any of leads I, II, III, aVL, aVF, V5, and V6 or ST-segment elevation >2 mm in any of leads V1 to V4) or Minnesota code 9-5 (T-wave amplitude >12 mm in any of leads I, II, III, aVL, aVF, V1, V2, V3, V4, V5, and V6) (12) (Fig. 1). All ECGs were read for ER by a single reader.
In a separate, non-CARDIA validation analysis (7), a random sample of 50 ECGs was reread blindly by the same reader. There was very high repeatability; the kappa statistic and 95% CI were 0.93 (0.84 to 1.00). We also validated the comparability of detecting ER using this method with the clinical diagnosis by a trained cardiologist in 60 randomly selected ECGs. For this purpose, possible and probable in our results were collapsed into 1 group (possible/probable) and the cardiologist (who was blinded to the results) was asked to classify the ECGs as definite, possible/probable, or no ER. As reflected by the high kappa statistic (kappa 0.84; 95% CI: 0.70 to 0.98), detection of ER using the strict criteria that we used in this analysis showed a high degree of agreement with the clinical diagnosis of ER (as determined by visual overreading by a cardiologist) (7).
All analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina). Baseline characteristics were described, after stratification by definition of ER, using means and SDs or percentages. Differences in means or percentages were compared between subgroups using general linear models and Student t tests for continuous variables and chi-square tests for categorical variables, as appropriate. For determination of the cross-sectional association of ER with CV risk factors, logistic regression models were fitted with age, sex, race, and common CV risk factors as independent covariates and the presence of definite ER as the dependent variable. For determination of the association of CV risk factors with maintenance of ER over time, logistic regression models were fitted with age, sex, race, and CV risk factors as independent covariates and maintenance of ER (presence at both Y0 and Y7 or Y0 and Y20) as the outcome: p < 0.05 was considered statistically significant.
Baseline characteristics of the study sample, stratified by type of ER, are shown in Table 1. The study sample consisted of 5,069 participants at Y0, of whom 941 (18.6%) had definite ER, 314 (6.2%) had probable ER, and 265 (5.2%) had possible ER. Compared with participants without ER at baseline, participants with definite ER were more likely to be black, be male, and smoke; have lower body mass index (BMI), heart rate, and QT index; and have higher Cornell voltage, systolic blood pressure, and ECG LV mass. Participants with definite ER at baseline also had longer exercise duration and QRS duration.
Cross-sectional association of CV risk factors with presence of ER
As shown in Table 2, multivariate-adjusted regression analyses at each examination indicated that participants with ER were more likely to be young (Y7 and Y20), black, and male; have longer exercise duration (Y7 and Y20) and QRS duration (Y0 and Y7); and have lower BMI, heart rate, QT index, and Cornell voltage.
Natural history of ER
As shown in Figures 2 and 3,⇓⇓ 941 of the 5,069 baseline (Y0) participants (18.6%) had definite ER compared with only 398 of the 3,669 Y7 participants (10.8%) and only 119 of the 2,505 Y20 participants (4.8%). Moreover, there were only 31 participants who developed ER between Y0 and Y20. Of these 31 participants, 22 started with no evidence of ER at their baseline examination and 9 of them started with possible ER. The proportion of white participants with definite ER at Y20 was much lower than at Y0, suggesting that black men and women were more likely to maintain presence of ER.
Association of baseline CV risk factors with maintenance (vs. loss) of ER
As shown in Table 3, participants who maintained ER from Y0 to Y7 and Y0 to 20 (as compared with those who lost ER) were more likely to be black, be male, and have lower BMI, heart rate, waist:hip ratio, LV mass index, and LV mass by ECG (the last 3 characteristics are not shown in Table 3). Longer QRS duration was also a strong predictor of maintenance of ER over time.
Participants lost to follow-up
Of the 941 participants with definite ER at the baseline examination (Y0), there were only 672 participants with ECGs recorded at Y7 and 429 participants with ECGs recorded at Y20. This dropout rate among ER-positive participants may have contributed to attrition bias and affected findings among the Y7 and Y20 participants with ER. Indeed, as shown in Online Table 1 (comparing all ER-positive baseline participants vs. those who were ER positive at baseline and lost to follow-up), those participants lost to follow-up were somewhat more likely to be black and have slightly lower exercise duration.
ER is a very common ECG finding that recent epidemiological studies have suggested is associated with increased CV mortality among middle-aged adults. However, there have been no prospective studies to examine the natural history of ER from young adulthood to middle age. In this prospective study of 5,069 participants from the CARDIA cohort, the prevalence of ER was 18.6% at a mean age of 25 years, and it was more common in blacks than whites. The majority of participants who had ER at baseline no longer had it in middle age, at Y20. In general, participants with ER were more likely to be black, male, and leaner, with longer exercise duration and QRS duration and lower heart rate and QT index. The strongest predictors of maintaining (vs. losing) ER were black race, male sex, lower BMI, and longer QRS duration. Our findings suggest that although this ECG abnormality is extremely common among young adults, the majority of participants who have evidence of ER during their mid-20s tend not to manifest it in middle age.
Current study in context and potential mechanisms
Previous analyses from the Charleston Heart Study (2), ARIC (Atherosclerosis Risk in Communities) study (3), and Kaiser Permanente (4) examined the prevalence and prognosis of ER in middle-age black and white men and women free of CV disease (CVD). These studies, using various definitions, estimated the prevalence of ER in the general population to be 1% to 5%. Our data obtained at a mean age of 45 years are consistent with these prior reports. However, in the CARDIA study, the prevalence of definite ER at a mean age of 25 years was substantially higher (18.6%). Given that this is the youngest cohort to date for which the prevalence and natural course of ER has been described with a standardized definition, this likely represents a strong inverse relationship between age and prevalence of ER. Indeed, very few of the participants developed ER de novo during follow-up, and likewise, few of those with ER at baseline maintained presence of ER by Y20. Clinicians are commonly faced with asymptomatic young adults with ER on routine ECGs, and our data suggest that the majority of their patients' ER will regress over time.
The mechanism by which younger age is associated with presence of ER is poorly understood. It is hypothesized that increased vagal tone, lower heart rate, and higher CV fitness (13) contribute to the increased prevalence of ER in younger adults (because they tend to be more physically fit than their older counterparts). In the CARDIA study, lower heart rate and longer exercise duration were indeed associated with presence of ER cross-sectionally, but they were not predictors of maintenance (vs. loss) over time. We hypothesize that increased vagal tone and better CV fitness are factors that contribute to a less ominous phenotype of ER that may wane over time, whereas a more lethal inherited phenotype may be related to arrhythmic substrate and persist over time. In a recent analysis of middle-aged Framingham participants by Noseworthy et al. (14), it was suggested that ER shows a heritability basis in Framingham offspring (recurrence risk ratio 1.89). This evidence suggests that there is both a heritable as well as an environmental contribution to the presence and specific phenotypes of ER that may determine its arrhythmic potential. In fact, all of the studies to date suggesting a relationship between ER and SCD have been conducted in middle-age populations and not in young adults. Further investigation is warranted to explore the mechanisms and genetic basis for ER and its prognostic role in both young and middle-aged adults.
This is the first study to date to explore the prospective predictors of maintenance (vs. loss) of ER over time in a young adult cohort. Identifying which clinical factors predict persistence of ER over time may inform future research efforts and aid clinicians in identifying patients on whom to focus preventive efforts. In the CARDIA study, race and lower BMI and QRS duration were the strongest predictors of persistence (vs. loss) of ER over time. As shown in Figure 2, the proportion of black men and women with persistent ER was far greater than that of their white counterparts. The association of black race with the presence of ER has been known for decades, but there have been no prospective studies of ER over time to suggest that black race also predicts persistence of ER over time. Whether this is due to a different phenotype of ER in blacks or that they simply start out with a greater degree of J-point elevation and hence are less likely to fully regress over time is unknown. Moreover, the prognostic implications of ER in blacks are unknown because most of the recent data linking ER with SCD have been in all-white cohorts. Recent data have suggested that J-point elevation is only predictive of SCD risk in whites but not blacks (15).
The association of longer QRS duration with persistence (vs. loss) of ER is a novel finding that has not been previously described. It may be mediated by a greater degree of notching or slurring in the J point that prolongs the QRS and makes these participants less likely to regress over time. This strong association provides clinicians with an easy to identify marker of ER persistence and warrants further mechanistic and prognostic investigation.
Although the definition of ER used in our analysis is highly accurate in defining the syndrome of ER, it varies somewhat from the recent epidemiological data that have suggested a link between ER and SCD that primarily focused on ST-segment elevation in the inferior leads. This may limit the external validity of our sample to the SCD population of interest; however, our analysis remains clinically important and generalizable to the everyday clinician because this is the commonly accepted ECG syndrome of ER. Further analyses regarding prognosis of the varying patterns of ER among CARDIA participants are underway but are difficult given the young age of the cohort and limited number of CVD events to date (only 21 total deaths attributable to CVD during the 20-year follow-up).
The higher dropout rate among black participants may have contributed migration bias to our finding of a decreasing prevalence of ER over time in CARDIA participants. However, as shown in Online Table 1, the differences are minimal in baseline characteristics between participants with ER who did not return for the Y20 ECG examination and those included in the sample, with the exception of being slightly more likely to be black and having somewhat longer exercise duration. In separate analyses (not shown), multinomial logistic regression analyses using loss to follow-up at Y20 as an outcome demonstrated that black race and longer QRS duration were both associated with loss to follow-up and maintenance of ER. Likewise, it is unlikely that the declining prevalence of definite ER over time was due to those participants with definite ER being downgraded to “probable” or “possible” ER given that the proportions of all manifestations of ER declined similarly over time, as shown in Figure 3.
For a supplemental table, please see the online version of this article.
Work on this manuscript was supported (or partially supported) by grants from the National Heart, Lung and Blood Institute to the University of Alabama at Birmingham, Coordinating Center (N01-HC-95095); University of Alabama at Birmingham, Field Center (N01-HC-48047); University of Minnesota, Field Center and Diet Reading Center (year 20 examination) (N01-HC-48048); Northwestern University, Field Center (N01-HC-48049); and Kaiser Foundation Research Institute (N01-HC-48050). Work was also supported by grant RO1 HL086792-01 to Dr. Lloyd-Jones. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body mass index
- cardiovascular disease
- Epidemiological Cardiology Research Center
- early repolarization
- left ventricular
- sudden cardiac death
- Received August 28, 2012.
- Revision received October 21, 2012.
- Accepted November 6, 2012.
- American College of Cardiology Foundation
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