Long-Term Outcome Associated with Early Repolarization on Electrocardiography

Study Population

The study population consisted of subjects in the Social Insurance Institution's Coronary Heart Disease Study (CHD study) who had undergone clinical baseline examinations between 1966 and 1972 (participation rate, 89% of 12,310 invited subjects).¹⁰ The CHD study was part of the large, prospective Mobile Clinic Health Survey, which was carried out in 35 populations between 1966 and 1972 in Finland.¹⁰ This cohort consisted of 10,957 subjects between the ages of 30 and 59 years (52.3% of whom were men) who were drawn from different geographic areas of Finland and who were representative of the middle-aged Finnish population. The population groups consisted of either the whole population or a random sample of the population of a certain geographic area, with the study areas chosen from regions with varying death rates.

The procedures that were performed at the baseline examination have been described previously.¹⁰ Briefly, in addition to undergoing standard resting 12-lead electrocardiography, the subjects completed a questionnaire regarding their health habits, known diseases, and medications. A specially trained nurse checked the questionnaire to make sure all questions were answered. In addition to the questionnaire, blood pressure, body-mass index, and serum cholesterol were measured. The use of beta-blockers or other medications causing potential changes in cardiac repolarization was extremely rare at the time that the baseline examinations were performed. Risk factors that might have predisposed subjects to cardiovascular disease were documented during the examinations.

Our study was designed to assess the prevalence and prognostic significance of J-point elevation in inferior and lateral leads in this population. All electrocardiograms (ECGs) were retrospectively analyzed for the presence of J-point elevation. We excluded 93 ECGs that had missing data or otherwise unreadable traces; thus, the study group consisted of 10,864 subjects (52% of whom were men; mean age, 44.0±8.5 years) from the original cohort.

Electrocardiographic Measurement

At baseline, standard resting 12-lead ECGs were recorded at a paper speed of 50 mm per second and stored for possible further analysis. The presence or absence of left ventricular hypertrophy (according to the Sokolow–Lyon criteria) was assessed and the QT interval (corrected for heart rate according to Bazett's formula) was measured by nine trained readers at the time of the baseline examinations.¹⁰

The baseline ECGs were independently reevaluated in random order by five physicians who were unaware of the original evaluations for the presence of early repolarization in the inferior leads (II, III, and aVF) and lateral leads (I, aVL, and V₄ through V₆). The amplitude of J-point elevation from baseline was also measured. Early-repolarization patterns were stratified according to the degree of J-point elevation (≥0.1 mV or >0.2 mV) that was either notched (a positive J deflection inscribed on the S wave) or slurred (a smooth transition from QRS to ST-segment) in at least two consecutive inferior or lateral leads. A prolonged QTc interval was defined as at least 440 msec for men and at least 460 msec for women. To minimize errors in the evaluation process, we assessed 556 ECGs for interobserver and intraobserver variations (kappa value, 0.60 and 0.85, respectively).

All ECGs containing an early-repolarization pattern were double-checked and the grading was established by consensus. In addition to the original baseline examinations, the majority of subjects had undergone reexamination between 1973 and 1976, in which ECGs were recorded in a manner similar to that used at baseline. Repeated measurement data were available for 542 subjects who had J-point elevation of at least 0.1 mV at the baseline measurement.

Follow-up

The primary end point was death from cardiac causes, and the secondary end points were death from any cause and from arrhythmia before the end of 2007. The causes and rates of death were determined by examining death certificates from Statistics Finland. Less than 2% of the subjects were lost to follow-up after they had moved abroad, but even in this group, the survival status could still be determined for a majority of the subjects. Finland maintains extensive administrative registers that record every death in the country, and the quality and reliability of these registers have been validated previously.¹¹

To identify cases of sudden death from arrhythmia, we reviewed all deaths from cardiac causes, which were adjudicated by a committee of experienced cardiologists who were unaware of the data from the electrocardiographic analyses. After reviewing data available from death certificates and hospital records, we classified the deaths as either associated with arrhythmia or not associated with arrhythmia. We included definite or probable deaths from arrhythmia in the category of deaths from arrhythmia, according to the definitions described in the Cardiac Arrhythmia Pilot Study,¹² in which death from arrhythmia was defined as a spontaneous cessation of respiration and circulation with loss of consciousness in one of the following situations: witnessed and instantaneous, without new or accelerating symptoms; witnessed and preceded or accompanied by symptoms attributable to myocardial ischemia in the absence of heart failure, witnessed and preceded by symptoms attributable to cardiac arrhythmia (e.g., syncope), and unwitnessed but without evidence of another cause. In the presence of severe congestive heart failure, death was not judged to be due to arrhythmia if death from heart failure was considered to be likely within 4 months before the fatal episode.

Statistical Analysis

Continuous variables are presented as means ±SD, and categorical variables are presented as percentages in each J-point group. The general linear model was used to compare the age- and sex-adjusted mean values for continuous variables and the prevalence of categorical variables between the groups. The hazard ratios and 95% confidence intervals for death were calculated with Cox proportional-hazards models. The primary adjustments in these models were for age and sex, with further adjustments for covariates that were selected on the basis of previous evidence of an association with death from cardiovascular causes or from any cause. We added age, systolic blood pressure, body-mass index, and heart rate as continuous variables in the multivariate model. The categorical variables that we added were sex, smoking status, and presence or absence of signs of left ventricular hypertrophy or coronary artery disease on electrocardiography (classified according to Minnesota codes). Kaplan–Meier survival curves were plotted for J-point elevation of more than 0.2 mV in the inferior leads and were compared by means of the log-rank test. The statistical analyses were performed with SAS software, version 9.1.3 (SAS Institute) and with the Statistical Package for Social Studies, version 14.0 (SPSS). All reported P values are two-sided, with a P value of less than 0.05 considered to indicate statistical significance.

Early-Repolarization Pattern

J-point elevation of at least 0.1 mV was present in 630 of 10,864 subjects (5.8%). Among these subjects, the elevation was in the inferior leads in 384 subjects (3.5%), of whom 70% were men, and in the lateral leads in 262 subjects (2.4%), of whom 58% were men; 16 subjects (0.1%) had an elevation in both inferior and lateral leads. J-point elevation of more than 0.2 mV occurred in inferior leads in 36 subjects (0.3%) and in lateral leads in 31 subjects (0.3%). Among the 542 subjects with J-point elevation on the baseline ECG who underwent a repeat electrocardiographic examination (an average of 5 years after baseline), the early-repolarization pattern (≥0.1 mV) was again observed in 443 of the subjects (81.7%).

Table 1. Table 1. Characteristics of the Subjects at Baseline.

The baseline characteristics of subjects with and those without the early-repolarization pattern are shown in Table 1. There were some differences in the characteristics between those with early repolarization and those without the abnormality. Subjects with J-point elevation in inferior leads were more often men and smokers, had a lower average resting heart rate, had a lower body-mass index, had lower blood pressure, had a shorter QTc interval and a longer QRS duration, and were more likely to have electrocardiographic signs of coronary artery disease than those without a J-point elevation. J-point elevation in the lateral leads was also associated with evidence of left ventricular hypertrophy on electrocardiography.

Risk of Death

Table 2. Table 2. Unadjusted and Adjusted Relative Risk of Death, According to J-Point Elevation.

During the mean follow-up of 30±11 years, 6133 subjects (56.5%) died. Of these deaths, 1969 were from cardiac causes (32.1% of all deaths), and 795 of these deaths were from sudden arrhythmia (40.4%). Table 2 shows the unadjusted and adjusted relative risks of death from any cause, from cardiac causes, and from arrhythmia. Subjects with J-point elevation of at least 0.1 mV in the inferior leads had a higher risk of death from cardiac causes (adjusted relative risk, 1.28; 95% confidence interval [CI], 1.04 to 1.59; P=0.03) and from arrhythmia (adjusted relative risk, 1.43; 95% CI, 1.06 to 1.94; P=0.03) than did those without this abnormality; however, these subjects did not have a significantly higher rate of death from any cause (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.26; P=0.15).

Subjects with J-point elevation of more than 0.2 mV on inferior leads had an increased risk of death from any cause (adjusted relative risk, 1.54; 95% CI, 1.06 to 2.24; P=0.03), a markedly elevated risk of death from cardiac causes (adjusted relative risk, 2.98; 95% CI, 1.85 to 4.92; P<0.001), and a markedly elevated risk of death from arrhythmia (unadjusted relative risk, 3.94; 95% CI, 1.96 to 7.90; P<0.001; adjusted relative risk, 2.92; 95% CI, 1.45 to 5.89; P=0.01). J-point elevation in the lateral leads was of borderline significance in predicting death from cardiac causes and death from any cause, but it did not predict death from arrhythmia.

Figure 1. Figure 1. Kaplan–Meier Curves for Death from Cardiac Causes and from Arrhythmia in Subjects with J-Point Elevation.

Subjects with J-point elevation of more than 0.2 mV in the inferior leads on standard 12-lead electrocardiography had a markedly elevated risk of death from cardiac causes, as compared with those without an early-repolarization pattern (<0.1 mV), with an unadjusted relative risk of 3.52 (95% confidence interval [CI], 2.18 to 5.68; P<0.001) (Panel A). The same subjects had an unadjusted relative risk of death from arrhythmia of 3.94 (95% CI, 1.96 to 7.90; P<0.001) (Panel B).

Figure 1 shows the Kaplan–Meier curves for death from cardiac causes and death from arrhythmia in subjects with J-point elevation of more than 0.2 mV in the inferior leads. Almost half of these subjects (47.2%) died from cardiac causes, whereas less than one in five (17.2%) of those without J-point elevation died from cardiac causes during follow-up.

Figure 2. Figure 2. Baseline Electrocardiograms of Two Male Subjects with J-Point Elevation of More Than 0.2 mV in the Inferior Leads.

In two subjects with J-point elevation of more than 0.2 mV in the inferior leads, Subject 1 has a slurred elevation (arrows) and Subject 2 has a notched elevation (arrows). Both subjects died from arrhythmia during the follow-up period.

Typical examples of ECGs from subjects with either a slurred or notched J-point elevation in the inferior leads are shown in Figure 2. Both subjects whose ECGs are shown died from cardiac causes associated with arrhythmia during follow-up.

Other Risk Markers

Table 3. Table 3. Adjusted Relative Risk of Death from Cardiac Causes in the Secondary Analysis.

The secondary analysis showed an increased risk of death from cardiac causes among subjects with a prolonged QTc interval (adjusted relative risk, 1.20; 95% CI, 1.02 to 1.42; P=0.03) and among those with electrocardiographic evidence of left ventricular hypertrophy (adjusted relative risk, 1.16; 95% CI, 1.05 to 1.27; P=0.004) (Table 3).

The presence of J-point elevation on standard 12-lead electrocardiography has generally been viewed as an innocuous finding in healthy persons.¹ The data from our study challenge this concept, since J-point elevation in inferior leads was a marker of an increased risk of death from cardiac causes among middle-aged subjects. These data are partly consistent with the recent reports of a higher incidence of the early-repolarization pattern in leads other than V₁ through V₃ among subjects with idiopathic ventricular fibrillation.^2-4 In our study, J-point elevation of more than 0.2 mV in inferior leads was a stronger predictor of death from cardiac causes than other well-known electrocardiographic risk markers, such as the QTc interval and signs of left ventricular hypertrophy. Furthermore, the early-repolarization pattern remained an independent prognostic marker even after adjustment for several other risk factors.

The overall prevalence of J-point elevation of at least 0.1 mV in the inferior or lateral leads (5.8%) was in the same range as or somewhat lower than the prevalences reported in previous studies involving younger populations.^2,4 In agreement with the results of previous smaller studies,^4,13 the early-repolarization pattern was associated with several demographic and other characteristics, such as male sex and lower heart rate. In addition, the QRS duration was longer, the QTc interval was shorter, and electrocardiographic signs of coronary artery disease were more prevalent among subjects with J-point elevation in the inferior leads than among those without this abnormality.

The early-repolarization pattern in the inferior leads was a stronger predictor of death from cardiac causes or from arrhythmia than J-point elevation in the lateral leads. Similarly, previous studies have reported that the J wave is present in inferior leads among many patients with idiopathic ventricular fibrillation.^4,13 In addition to the location of the early-repolarization pattern, the amplitude of the J-point elevation had some prognostic value: there was a higher risk of death from cardiac causes among subjects with a markedly elevated J point (>0.2 mV) than among those with a more moderate elevation (≥0.1 mV). A similar phenomenon was previously observed in survivors of primary ventricular fibrillation.⁴

How the early-repolarization pattern in inferior leads increases the risk of death from cardiac causes remains unclear. The presence of this pattern in repeated electrocardiographic recordings shows that J-point elevation is a stable rather than a transient phenomenon, suggesting a permanent electrophysiological disorder. More than three of four subjects with J-point elevation on baseline measurement had the same pattern several years later. The current experimental data support the concept that J-point elevation is a marker of increased transmural heterogeneity of ventricular repolarization, which increases the vulnerability to ventricular tachyarrhythmias.^14-16

Concordant with case–control studies,^2,4 it is possible that primary ventricular fibrillation was the cause of death in the subjects with J-point elevation in our study. The survival curves for death from cardiac causes started to diverge 15 years after baseline electrocardiographic recordings (in the early 1980s) and continued to diverge at a constant rate throughout the follow-up period, even though the treatment and prognosis for patients with cardiac disease have substantially changed during the past two decades. This finding underscores the long-standing established link between abnormal ventricular repolarization and the risk of death from arrhythmia, regardless of the cause and treatment of underlying cardiac disease. This concept is also supported by the observation that J-point elevation in the inferior leads predicted the occurrence of sudden death from arrhythmia. However, this hypothesis remains to be confirmed because of our limited ability in a retrospective analysis of death certificates to determine whether death was specifically associated with arrhythmia.

It is also possible that transmural heterogeneity in the ventricular repolarization, which is manifested as J-point elevation, increases the vulnerability to fatal arrhythmias during a cardiac ischemic event, which was the most common cause of death in the Finnish population.^17,18 This hypothesis is supported by the observation that the deaths from cardiac causes occurred relatively late after the baseline electrocardiographic recording in subjects with the early-repolarization pattern, whereas primary ventricular fibrillation is more commonly observed in younger age groups. Prospective studies, with a predefined and more precise definition of the cause of death, are needed to clarify the mechanistic link between an increased risk of death from cardiac causes and J-point elevation in the inferior leads. It is also important to determine whether the early-repolarization pattern in inferior leads is a sign of a genetic ion-channel disorder or a marker for a structural cardiac abnormality, since a previous report suggested that the early-repolarization pattern may be related to both electrophysiological instability and cardiomyopathies.¹⁹

In conclusion, our community-based study shows that J-point elevation in the inferior leads on standard electrocardiography is not an innocuous finding in middle-aged subjects. Future clinical and experimental studies should focus on understanding the exact mechanisms and reasons for this pattern and ultimately on devising strategies to prevent premature death from cardiac causes in subjects with this pattern.