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Early repolarization and short QT interval in healthy subjects
Early repolarization and short QT interval in healthy subjects Gopi Krishna Panicker, BHMS, PGDCR,* Deepak Manohar, MSc,* Dilip R. Karnad, MD, FACP, FRCP, FCP,† Vaibhav Salvi, MBBS, PGDCR,* Snehal Kothari, MD, DM, FACC,* Yash Lokhandwala, MD, DM, FACC* From *Research Section, Quintiles Cardiac Safety Services, Mumbai, India, and †Seven Hills Hospital, Mumbai, India. BACKGROUND An early repolarization (ER) pattern is common in ECGs from patients with ventricular fibrillation (VF). These patients with ER have shorter QT intervals. Morphological variants of the ER pattern also have been associated with idiopathic VF, but their prevalence in healthy subjects is unclear. OBJECTIVE The purpose of this study was to study the prevalence of ER and its morphological variants, and its association with the QTc interval in healthy subjects. METHODS Digital ECGs from 1886 healthy subjects from Phase I clinical trials were analyzed by a central ECG laboratory.
common in inferior/lateral leads, and slurring was common in anterior leads. A non-ascending ST segment was seen in 71% of ECGs with a notched pattern but in only 12.3% of ECGs with a slurred pattern. The ER group had slower heart rates (9.3 ⫾ 13.3 bpm [mean difference ⫾ SD], P ⬍.001) and shorter QTc intervals (QTcB ⫽ 20.2 ⫾ 25.6 ms, QTcF ⫽ 11.0 ⫾ 21.9 ms; P ⬍.001). Four subjects in each group had a short QT interval (QTcF ⬍350 ms). CONCLUSION ER and all of its variants are common in healthy young males with slower heart rates and slightly shorter QTc intervals. A short QT interval (QTcF ⬍350 ms) is rare.
RESULTS ER, defined as J-point elevation ⱖ0.1 mV in ⱖ2 contiguous leads, was present in 514 subjects (27.3%), of whom 505 (98.2%) were males. The prevalence of ER declined progressively with increasing age. ER pattern was seen in lateral leads (I, aVL, V4–V6) in 26.1%, in inferior (II, III, aVF) or inferolateral leads in 8%, and was global in 1.9%. The terminal portion of the QRS complex was notched in 43.1% and slurred in 56.9%. Notching was
KEYWORDS Arrhythmia; Cardiac repolarization; Early repolarization; Electrocardiography; Short QT interval; Sudden cardiac death
Introduction
probably results from transmural repolarization heterogeneity from endocardium to epicardium resulting from a longer duration of action potentials in subendocardial cells than in subepicardial cells,3,4 which in turn could predispose to cardiac arrhythmias. More recently, subtypes of the ER pattern have been described based on leads showing ER, morphology of the terminal part of QRS complex (notching or slurring), and shape of the ST segment (horizontal/ downsloping and ascending/concave) in an attempt to differentiate between malignant and benign variants of ER.8,9 Interestingly, the studies by Tikkanen et al6 and Haïssaguerre et al5 found that the QTc interval was shorter in patients with ER. In 2004, Viskin et al10 reported that the QTc interval is shorter in survivors of idiopathic VF than in healthy controls. However, the extent of QT shortening in these studies was small, and whether shorter QT interval itself contributes to the development of ventricular arrhythmias in individuals with ER is being debated.2,11–13 Watanabe et al14 studied patients with short QT syndrome and found ER in 65% of patients with ventricular arrhythmias compared to 10% of healthy controls. However, Gross13 suggested that the shorter mean QTc interval found in some of the ER cohort studies5,6 may have resulted from the inclusion of a few unrecognized patients with familial short QT syndrome.10 Although several studies have reported on the prevalence of ER in the healthy population, most of
Early repolarization (ER) is a widely recognized ECG pattern characterized by J-point elevation in the ST segment, usually in the inferior or lateral leads of a 12-lead ECG.1 Until recently, it was generally regarded as a normal variant2 of limited clinical significance that could be mistaken for conditions such as acute myocardial infarction, pericarditis, or intraventricular conduction defects.3 Recent studies have now identified a possible link between ER and the risk of malignant ventricular arrhythmias.4 –7 Haïssaguerre et al5 found ER in 31% of survivors of idiopathic ventricular fibrillation (VF) compared to 5% of healthy controls. Tikkanen et al6 prospectively studied a cohort of middle-aged Finnish individuals and observed higher mortality from cardiac causes in subjects with ER at baseline. The ER pattern
G.K. Panicker, D. Manohar, V. Salvi, and S. Kothari are employees of Quintiles Cardiac Safety Services, Mumbai. Y. Lokhandwala is a consultant to Quintiles Cardiac Safety Services. D. Karnad is a consultant to Quintiles Cardiac Safety Services, Abbott Nutrition (India), and Bharat Serum and Vaccines Limited. A portion of the results from this study was published as a research abstract in the abstract supplement issue (ESC Congress, Paris, France, August 2011) of the European Heart Journal. Address reprint requests and correspondence: Dr. Gopi Krishna Panicker, Quintiles Cardiac Safety Services, 502 A, Leela Business Park, M.V. Road, Andheri (East), Mumbai 400 059, India. E-mail address: gopi. [email protected].
ABBREVIATIONS ER ⫽ early repolarization; VF ⫽ ventricular fibrillation (Heart Rhythm 2012;9:1265–1271) © 2012 Heart Rhythm Society. All rights reserved.
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2012.03.046
1266 those studies preceded the reports that drew attention to this association. Because the prevalence of ER and its various morphological patterns and their association with the length of the QTc interval in healthy subjects are not clear, we studied ECGs from volunteers participating in Phase I clinical trials who had been screened to exclude comorbid conditions.
Methods Subjects We retrospectively studied ECGs from 1886 healthy subjects (1433 males and 453 females, age 18 –92 years) participating in 41 Phase I clinical trials for which Quintiles Cardiac Safety Services was the central ECG laboratory. For each subject, a single drug-free ECG that served as a baseline for the trial was included in the present study. All ECGs were recorded using digital ECGs (ELI 250, Mortara Inc, Milwaukee, WI) with 1000-Hz sampling rate, 25 mm/s speed, and 10 mm/mV amplitude. All subjects were screened by history, physical examination, and laboratory tests for abnormalities. Tests included hemoglobin; total, differential leukocyte, and platelet counts; and urine examination. Blood chemistry included serum bilirubin, transaminases, alkaline phosphatase, sodium, potassium, chloride, calcium, bicarbonate, blood urea nitrogen, creatinine, albumin, and glucose. Appropriate tests for viral hepatitis (hepatitis A, B, and C) and HIV were performed. Subjects with a history of clinically significant cardiac disease were excluded from the study. Only normotensive subjects with resting blood pressure ⱖ90 mm Hg and ⱕ140 mm Hg systolic and ⱖ60 mm Hg and ⱕ90 mm Hg diastolic and normal resting heart rate (ⱖ50 bpm and ⱕ100 bpm) on screening were included. ECGs with bundle branch block or intraventricular conduction defects were excluded because of the difficulty in reliably identifying J-point elevation in these ECGs. Female subjects were included only if they were not pregnant or lactating. Individuals with body mass index ⬍18 or ⬎30 kg/m2, clinically significant abnormality at the screen-
Heart Rhythm, Vol 9, No 8, August 2012 ing medical assessment, history of drug/alcohol abuse, or use of tobacco/nicotine products in the 6-month period preceding the screening visit were excluded. All studies were approved by the respective institutional review boards, and all subjects consented to participate in the studies.
ECG analysis All ECGs were analyzed manually by trained readers in a central ECG laboratory using onscreen analysis software (CalECG version 2.7, AMPS_LLC, New York, NY). ER was defined as J-point elevation ⱖ0.1 mV, visually determined onscreen using mouse-driven digital calipers, present in at least 2 contiguous leads.5,15,16 ECGs with ER were further classified based on leads showing ER pattern: inferior (II, III, aVF), lateral (I, aVL, V4–V6), and anterior (V1–V3) leads, or global (anterior, lateral, and inferior leads).12 ER was further classified as notched if there was a definite notch followed by a small rounded positive deflection at the junction of the QRS complex and the ST segment, or slurred if the transition occurred gradually without a notch5 (Figure 1). ER pattern was also classified based on the shape of the ST segment as concave/rapidly ascending (defined as ⬎0.1 mV elevation of the ST segment within 100 ms after the J point or persistent elevation ⬎0.1 mV throughout) or horizontal/descending (defined as ⱕ0.1 mV elevation of the ST segment within 100 ms after the J point).8,9 QT interval was measured between QRS onset and the point where the T wave met the isoelectric baseline in 5 consecutive complexes in lead II. If the amplitude of the T wave in lead II was ⬍1 mV, then QT interval was measured in lead V5. R-R intervals were measured between the complex in which QT was measured and the preceding complex. QT interval was corrected for the effect of heart rate using the Bazett formula (QTcB ⫽ QT/公RR) and the Fridericia formula (QTcF ⫽ QT/3公RR). In the absence of a universal definition for a short QTc interval, 3 cutoff values (330,14 340,17 and 35018 ms) from previous studies were used. Long QTc interval was defined as QTc ⬎450 ms.19
Figure 1 Single lead from ECGs from different healthy individuals showing notched (A) and slurred (B) patterns of the terminal portion of the QRS complex (arrows). The shape of the ST segment is ascending (defined as ⬎0.1 mV elevation of ST segment within 100 ms after the J point) in A and is non-ascending (defined as ⱕ0.1 mV elevation of the ST segment within 100 ms after the J point) in B.
Panicker et al
Early Repolarization and Short QT Interval in Healthy Subjects
JT interval was calculated as the difference between the QT interval and QRS duration. The heart rate-corrected JT interval (JTcF) was obtained as the difference between QTcF and QRS duration.20
Statistical analysis SAS version 9 (SAS Institute, Cary, NC) was used for statistical analysis. Differences between groups were compared using the unpaired t test or 2 test, as appropriate. A two-sided ␣ of 0.05 was considered the cutoff for statistical significance. The uncorrected QT interval, QTcB, and QTcF from each ECG was plotted versus heart rate, and simple linear regression was used to determine the correction method that performed better (ie, gave a slope that was most horizontal).
Results Of the 1886 subjects included in the study, ER was present in 514 subjects (27.3%), of whom 505 (98%) were males; thus, 35.2% of 1433 males and 1.9% of 453 females had ER. The prevalence of ER was highest (57.0%) among subjects in the 18- to 29-year age group (Table 1) and declined progressively thereafter in males. A similar trend was seen in females (Table 1). The age-related trend persisted even after excluding subjects with ER pattern in anterior leads: 18.9% in the age group 18 –29 years, 11.1% in the fourth decade, 4.2% in the fifth decade, and 1.3% after the fifth decade. Subjects with ER had a significantly lower heart rate than did subjects without ER (mean difference 9.3 ⫾ 13.3 bpm; P ⬍.001; Table 1); 49.6% of subjects with ER and 23.4% of subjects without ER had heart rates ⬍60 bpm. This difference in heart rate was present in all age groups (Table 1). Of the 514 subjects with ER pattern, the pattern was seen in anterior leads in 362, inferior leads in 41, and lateral leads in 134; 34 subjects had ER in inferior and lateral leads, and 10 had ER in all leads. Slurring of the terminal portion of the QRS complex was more common in anterior leads, whereas notching was more common in inferior leads (Figure 2). In 60% to 80% of ECGs with notched pattern, a non-ascending (horizontal/descending) ST segment was present, regardless of the lead in which it was seen. An ascending (concave/ascending) ST segment was more common in ECGs with slurring of the terminal portion of the QRS complex. An ascending pattern was seen in 75% of Table 1
1267
ECGs with ER in the anterior leads vs 31% in inferior and/or lateral leads. Subjects with ER also had shorter mean QTc (QTcB difference 20.2 ⫾ 25.6 ms, QTcF difference 11.0 ⫾ 21.9 ms) and JTcF (11.8 ⫾ 21.5 ms) values, but QRS duration was similar in the two groups (Table 2). Because the proportion of female subjects was grossly different in the two groups (9 females with ER, 444 without ER), we repeated the analysis including only male subjects. In the male subgroup, heart rate also was significantly lower in those with ER (mean ⫾ SD 60.8 ⫾ 9.6 bpm) than in those without ER (68.6 ⫾ 13.9 bpm). Mean QTcB was shorter by 15.0 ⫾ 25.0 ms and QTcF by 7.3 ⫾ 21.4 ms, respectively (Table 3). Compared to subjects without ER, QTcB and QTcF values were lower in all subgroups of ER based on leads showing ER pattern, notching or slurring of the terminal portion of the QRS complex, and morphology of the ST segment (Table 4). There were no differences between the subgroups of individuals with ER (Table 4). Simple linear regression analysis showed that QTcF was better than QTcB in correcting for the effect of heart rate on QT interval in the present study (Figure 3). QTc prolongation, defined as interval ⬎450 ms, was more common in subjects without ER [131 subjects (9.5%) vs 4 subjects (0.8%) with ER; P ⬍.001] for QTcB. The proportion of subjects with QTcF interval ⬎450 ms in the two groups was similar. In contrast, QTcB interval ⬍350 ms was observed in only 6 of 1439 males, of whom 5 subjects had ER [1.0% vs 1 subject (0.1%) without ER; P ⬍.0069]. Only 1 subject (in the ER group) had QTcB interval ⬍340 ms, and none had QTcB ⬍330 ms. Four subjects with ER and 4 without ER had a short QTcF interval using a cutoff value of 350 ms (P ⫽ .23); none had QTcF ⬍330 ms or ⬍340 ms (Table 5).
Discussion Our study had two main objectives: (1) to study the prevalence of ER and its variants in healthy adults and (2) to study the association between ER and short QT interval, both of which have been associated with idiopathic VF.3,4,7,10,14 We found ER in 27.3% of ECGs from 1886 healthy subjects. ER pattern was seen in inferior and/or
Age and gender distribution of subjects with and without early repolarization With early repolarization
Without early repolarization
No. of subjects Age group (y)
All
18–29 30–39 40–49 50–59 ⬎60 Total
264 124 82 31 13 514
(55.3%) (36.4%) (19.1%) (10.3%) (3.8%) (27.3%)
No. of subjects Males
Females
Heart rate for all subjects (mean ⫾ SD)
263 124 81 28 9 505
1 0 1 3 4 9
60.0 61.8 62.0 61.7 59.9 60.9
(57.0%) (39.7%) (23.8%) (18.8%) (5.3%) (35.2%)
(6.3%) (0.0%) (1.1%) (2.0%) (2.4%) (1.9%)
*P ⬍.05 vs subjects without early repolarization.
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
9.6* 8.6* 10.2* 11.5* 10.1* 9.7*
All 213 217 347 269 326 1372
(44.7%) (63.6%) (80.9%) (89.7%) (96.2%) (72.7%)
Males
Females
Heart rate for all subjects (mean ⫾ SD)
198 188 259 121 162 928
15 29 88 148 164 444
69.3 68.1 68.9 70.8 72.6 70.1
(43.0%) (60.3%) (76.2%) (81.2%) (94.7%) (64.8%)
(93.8%) (100.0%) (98.9%) (98.0%) (97.6%) (98.1%)
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
16.7 12.4 13.5 15.2 13.8 14.4
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Figure 2 Morphological patterns of early repolarization in healthy individuals. Note the following: (1) Slurring of the terminal portion of the QRS complex was more commonly seen in anterior leads whereas notching was more common in inferior leads. (2) In 60% to 80% of ECGs with notched pattern, a non-ascending (horizontal/descending) ST segment was present, regardless of the lead in the pattern was seen. (3) An ascending pattern was seen in 75% of ECGs with early repolarization in the anterior leads vs 31% in inferior and/or lateral leads.
lateral leads in 9.3% of subjects and only in the anterior leads in 18%. The overall prevalence of 27.3% in our study appears higher than the 5.8% prevalence reported by Tikkanen et al6 in a retrospective cohort, 5% by Haïssaguerre et al5 in 412 healthy controls, and 13% by Rosso et al21 in healthy adults. However, these studies excluded subjects with ER pattern in anterior leads to avoid possible inclusion of individuals with right ventricular dysplasia or Brugada syndrome.5,6,21 The corresponding value was 9.3% in our study which is comparable with these previous studies. We observed a definite age-related trend in the prevalence of ER. The prevalence was highest (55.3%) in the 18to 29-year age group and declined progressively to 3.8% in the seventh decade. Tikkanen et al also found that ER was more prevalent in young athletes than in middle-aged healthy subjects.8 We also found that 98% of healthy subjects with ER were males. This male preponderance, also observed in previous studies,5,6,15,16 is attributed to the effect of androgens, which can modulate the function of potassium and sodium channels that play important roles in cardiac repolarization.22–26 Heart rate was slower in subjects with ER by a mean of 10 bpm, a phenomenon that also was reported in previous studies.1,12,27 Mehta and Jain15 observed that ER disappears with exercise and suggested that this may be due vagal influence on ventricular repolarization. Acetylcholine can Table 2
produce an ER pattern on the ECG in the canine arterially perfused ventricular wedge preparation.3 This could explain why ER is more common in athletes who have higher vagal tone and lower heart rates.8,9 Interestingly, the gender difference in ST-segment elevation persists even after autonomic blockade.28 Antzelevitch and Yan12 and Wellens11 suggest that the amplitude of the J wave seen at the end of the QRS complex in ER increases at lower heart rates and may disappear at higher heart rates. Because ER is common in the healthy population and the relative risk of idiopathic VF or death from cardiac arrhythmias in individuals with ER is low,29 some authors have looked for other morphological patterns associating ER with idiopathic VF or death from cardiac arrhythmias. Based on the leads showing the ER pattern, Antzelevitch and Yan12 classified ER into three types. In type 1, the ER pattern occurs in lateral precordial leads and is associated with a low risk of VF. This type was seen in 26.1% of our subjects with ER. In type 2, ER is seen in inferior/inferolateral leads and is associated with higher risk of VF. This type was seen in 8.0% of our subjects with ER. Type 3 pattern, which is associated with the highest level of risk for development of malignant arrhythmias, is characterized by the presence of ER globally (ie, inferior, lateral, and right precordial leads) and was seen in 1.9% of our subjects with ER. Merchant et al30 found that ER with notching had a closer association
ECG parameters in healthy subjects with and without early repolarization
ECG parameter
With early repolarization (n ⫽ 514)
Heart rate (bpm) QT interval (ms) Corrected QT–Bazett (QTcB ) (ms) Corrected QT–Fridericia (QTcF) (ms) QRS duration (ms) JT interval (ms) Corrected JT interval–Fridericia (JTcF) (ms)
60.9 394.7 394.6 394.3 92.9 301.8 301.5
Values are given as mean ⫾ SD.
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
9.7 28.0 20.3 18.2 8.5 27.8 19.0
Without early repolarization (n ⫽ 1372) 70.1 388.2 414.8 405.3 92.1 296.1 313.2
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
14.4 33.0 27.4 23.1 13.0 31.9 22.4
P value ⬍.001 ⬍.001 ⬍.001 ⬍.001 .942 ⬍.001 ⬍.001
Panicker et al Table 3
Early Repolarization and Short QT Interval in Healthy Subjects
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ECG parameters in healthy male subjects with and without early repolarization
ECG parameter
With early repolarization (n ⫽ 505)
Heart rate (bpm) QT interval (ms) Corrected QT–Bazett (QTcB) (ms) Corrected QT–Fridericia (QTcF) (ms) QRS duration (ms) JT interval (ms) Corrected JT interval–Fridericia (JTcF) (ms)
60.8 394.5 394.2 394.0 93.0 301.5 301.0
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
Without early repolarization (n ⫽ 928)
9.6 27.9 20.0 18.0 8.5 27.7 18.7
68.6 387.0 409.2 401.3 94.4 292.6 306.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
P value ⬍.001 ⬍.001 ⬍.001 ⬍.001 .942 ⬍.001 ⬍.001
13.9 32.7 27.3 23.0 12.9 30.9 20.5
Values are given as mean ⫾ SD.
with malignant ventricular arrhythmias than did slurring. We found ER with notching in 43.1% of all subjects with ER. Tikkanen et al8 and Rosso et al9 found that horizontal/ descending ST-segment pattern was associated with increased risk of cardiac arrhythmias, whereas an ascending/ concave ST segment was more common in healthy subjects, including athletes. The ascending ST-segment pattern was seen in 31.6% of healthy subjects with ER pattern in inferior/lateral leads in our study. Noseworthy et al31 found the ascending pattern in 95% of competitive athletes with ER pattern in inferior/lateral leads. Tikkanen et al8 also found an ascending pattern in 96% of athletes with ER in inferior/ lateral leads, but the prevalence decreased to 32.8% in the general population, which closely matches our results. None of these studies, however, looked for the coexistence of these patterns. We found that notching was seen in 76% of ECGs with ER pattern in inferior/lateral leads but in only 29% of ECGs with ER pattern in anterior leads. Similarly, the “non-ascending” (horizontal/descending) ST segment was present in 68.4% of ECGS with ER in inferior/ lateral leads but in only 25% of ECGs with ER in anterior leads. Moreover, the non-ascending ST-segment pattern (horizontal/descending ST segment pattern of Tikkanen and Rosso) was seen in 71% of ECGs with notched ER pattern but in only 12.3% of ECGs with slurred ER pattern. Thus, in ECGs with ER, an ascending ST-segment pattern is more common in ECGs showing ER in anterior leads or in those with a slurred terminal portion of the QRS complex. Another objective of this study was to study the length of QT/QTc interval in ECGs with and those without ER. We Table 4
found that the mean QTcB interval was shorter by 20 ms and the mean QTcF by 11 ms in subjects with ER. However, QT interval did not differ between subgroups based on leads or morphologies of the terminal portion of the QRS complex and ST segment (Table 4). Because heart rate is slower in subjects with ER, the QT correction method may impact the results of studies of QT intervals in ER. We found that the Bazett formula overcorrected for the effect of heart rate and gave lower QTc values at lower heart rates, whereas the Fridericia formula corrected for the effect of heart rate more appropriately. Haïssaguerre et al5 found that QTcB was shorter by 9 ms in patients with ER, whereas Tikkanen et al6 found that QTcB was 4 ms shorter in subjects with ER. In both of these studies as well as our study, the prevalence of ER was disproportionately higher in males. Because the QT interval is normally shorter in men than in women,18,25,32 it is possible that the shorter QT interval in subjects with ER is due to gender differences in the two groups. To avoid this confounding effect of gender, we analyzed data from male subjects separately and found that the mean QTcB interval was still significantly shorter in male subjects with ER by 15 ms and QTcF by 7 ms. In 2004, Viskin et al10 described a cohort of 28 patients with idiopathic VF in whom the mean QTcB interval was 14 ms shorter than in healthy controls. The same group subsequently described a higher prevalence of ER in idiopathic VF21; however, QT interval in patients with ER in the latter study was not described. Haïssaguerre et al5 found that mean QTc is shorter in survivors of idiopathic VF with ER
ECG parameters in healthy subjects with and without early repolarization With ER Leads with ER pattern
ECG parameter
Without ER (n ⫽ 1372)
Heart rate (bpm) QT interval (ms) QTcB–Bazett (ms) QTcF–Fridericia (ms)
70.1 388.2 414.8 405.3
⫾ ⫾ ⫾ ⫾
14.4 33.0 27.4 23.1
Inferior (n ⫽ 41) 59.4 393.5 390.1 391.1
⫾ ⫾ ⫾ ⫾
Lateral (n ⫽ 134) 7.5* 22.8* 17.9* 15.9*
59.4 395.3 390.5 391.9
⫾ ⫾ ⫾ ⫾
9.3* 28.2* 18.8* 17.7*
Inferior and lateral (n ⫽ 34) 58.4 393.4 386.5 388.7
⫾ ⫾ ⫾ ⫾
7.5* 23.1* 14.9* 14*
Terminal QRS complex
ST-segment morphology
Notched (n ⫽ 222)
Ascending (n ⫽ 320)
60.1 395.7 393.3 393.8
⫾ ⫾ ⫾ ⫾
9.2* 27* 18.4* 16.6*
Slurred (n ⫽ 292) 61.4 393.9 395.6 394.7
⫾ ⫾ ⫾ ⫾
9.9* 28.7* 21.6* 19.3*
60.8 395.6 395.2 395.1
⫾ ⫾ ⫾ ⫾
9.9* 28.5* 21.3* 18.9*
Non-ascending (n ⫽ 194) 60.9 393.1 393.6 393.2
⫾ ⫾ ⫾ ⫾
9.2* 27.1* 18.6* 16.9*
Values are given as mean ⫾ SD. Subjects with ER were further subgrouped based on leads showing ER (inferior, lateral, inferolateral), terminal QRS complex morphology (notched or slurred), and ST-segment morphology (ascending or non-ascending). *P ⬍.05 vs subjects without early repolarization (ER).
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Figure 3 Effect of heart rate on QT, QTcF, and QTcB intervals in 1886 healthy subjects. There was a negative correlation between QT interval and heart rate (P ⫽ .001). A positive correlation between QTcB and heart rate (P ⫽ .001) and between QTcF and heart rate (P ⫽ .001) was seen. The slope of the regression line for QTcF was closest to zero, suggesting that this was a better correction method for the effect of heart rate than was QTcB.
in their 12-lead ECGs.5 The association between ER and short QT interval was evaluated further by Watanabe et al, who studied patients with familial short QT syndrome and found ER in 65% of these patients with ventricular arrhythmias compared to 35% of subjects with the short QT syndrome but no arrhythmias.14 Various cutoff values of ⬍330 ms,13 ⬍340 ms,17 and ⬍350 ms18 have been used to define short QT syndrome. In the present study, 5 subjects with ER had QTcB ⬍350 ms and 1 had QTcB ⬍340 ms, whereas only 1 subject without ER had QTcB value ⬍350 ms and none had QTcB ⬍340 ms. On the other hand, 4 subjects with ER and 4 subjects without ER had QTcF ⬍350 ms, and none had QTcF ⬍340 ms. Thus, only a handful of healthy subjects could be categorized as having a short QT interval; among these subjects, more were in the ER group when QTcB was studied, possibly because the Bazett formula gave shorter QTc values at lower heart rates. When the Fridericia formula was used, the number of subjects with QTcF ⬍350 ms in the 2 groups was comparable. Although the underlying mechanisms of ER are not yet completely understood, Boineau4 attributes it to deep invagination of Purkinje fibers into the subepicardial tissue, resulting in early transmural activation followed by ER. Gussak and Antzelevitch3 have proposed that, akin to that in the
Brugada syndrome, ER occurs because of a greater transmural gradient of repolarization. Furthermore, like ER, the Brugada syndrome has a male predominance3,27 and a shorter QT interval, particularly when associated with a loss-of-function mutation in the cardiac calcium channel.3,33
Conclusion Our study is a large cross-sectional study of healthy volunteers who were thoroughly screened to exclude heart disease and other comorbid conditions for whom high-quality digital ECGs were interpreted by trained readers in a central ECG laboratory. However, the study had one important limitation. Being a cross-sectional study, subjects in this study were not followed up to determine the association between ER and its various morphologies, and the QT interval with ventricular arrhythmias. Nevertheless, our observations show that ER is seen in 27.3% of healthy subjects, occurring in inferior and/or lateral leads in 9.3%. We also found that notching was more common in inferior/ lateral leads and slurring in anterior leads. The non-ascending ST-segment pattern was seen in 71% of ECGs with a notched ER pattern but in only 12.3% of ECGs with a slurred ER pattern.
Table 5 Frequency of subjects with and without early repolarization with QTc values within predefined cutoffs for long QTc and short QTc intervals With early repolarization
Variable QTcB
QTcF
Without early repolarization
Cutoff values (ms)
Male (n ⫽ 505)
Female (n ⫽ 9)
Total (n ⫽ 514)
Male (n ⫽ 928)
Female (n ⫽ 444)
Total (n ⫽ 1372)
P value*
ⱖ450 ⬍350 ⬍340 ⬍330 ⱖ450 ⬍350 ⬍340 ⬍330
3 5 1 0 3 4 0 0
1 0 0 0 1 0 0 0
4 5 1 0 4 4 0 0
59 1 0 0 27 4 0 0
72 0 0 0 19 0 0 0
131 1 0 0 46 4 0 0
⬍.0001 .0069 .2725 — .0018 .2249 — —
*By Fisher exact test or 2 test comparing total subjects with and without early repolarization.
Panicker et al
Early Repolarization and Short QT Interval in Healthy Subjects
We also found that healthy individuals with ER have a shorter QTc interval, and the extent of QTc shortening is similar to that reported in survivors of idiopathic VF.5 However, in absolute terms, only a few subjects in this study had a short QT interval (QTcF ⬍350 ms), but these subjects were equally distributed between the group with and that without ER. Thus, although ER may be common in familial short QT syndrome,14 the converse probably is not true. Because ER is common in individuals with a slower heart rate, our study shows that the Bazett formula, which gives spuriously low values of QTc at lower heart rates, should be avoided and the Fridericia formula used instead. Tikkanen et al6 found that 9.5% of individuals with ER died due to cardiac arrhythmia compared to 7.2% of those without ER. Haruta et al34 found that sudden cardiac death occurred in 1.9% of Japanese subjects with ER compared to 1% of those without ER. Thus, even in individuals with ER, only a small percent are at increased risk for cardiac arrhythmias. Attempts have been made to identify morphological features to differentiate between the benign and malignant types of ER. However, we found that even the “malignant” variants of ER are widely prevalent in healthy subjects. More studies are needed to determine whether the extent of QTc shortening can identify healthy subjects with ER in inferolateral leads who are at increased risk for developing ventricular arrhythmias, by itself or in combination with the morphological variants.
11. 12. 13. 14. 15. 16.
17. 18. 19.
20.
21.
22.
23.
Acknowledgments
24.
We thank Jim Chestnut, MS, MLS, Associate Director, Quintiles Library & Information Services, for assistance in literature review.
25.
References 1. Surawicz B, Knilans T. Normal electrocardiogram: origin and description. In: Surawicz B, Knilans T, editors. Chou’s Electrocardiography in Clinical Practice. Sixth Edition. Philadelphia: WB Saunders Elsevier, 2008:23. 2. Bjerregaard P, Nallapaneni H, Gussak I. Short QT interval in clinical practice. J Electrocardiol 2010;43:390 –395. 3. Gussak I, Antzelevitch C. Early repolarization syndrome: clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol 2000;33:299 –309. 4. Boineau JP. The early repolarization variant-normal or a marker of heart disease in certain subjects. J Electrocardiol 2007;40:e11– e16. 5. Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016 –2023. 6. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529 – 2537. 7. Rosso R, Adler A, Halkin A, Viskin S. Risk of sudden death among young individuals with J waves and early repolarization: putting the evidence into perspective. Heart Rhythm 2011;8:923–929. 8. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666 –2673. 9. Rosso R, Glikson E, Belhassen B, et al. Distinguishing “benign” from “malignant early repolarization”: the value of the ST-segment morphology. Heart Rhythm 2012;9:225–229. 10. Viskin S, Zeltser D, Ish-Shalom M, et al. Is idiopathic ventricular fibrillation
26. 27. 28.
29. 30.
31.
32.
33.
34.
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a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm 2004;1:587–591. Wellens HJ. Early repolarization revisited. N Engl J Med 2008;358:2063– 2065. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010;7:549 –558. Gross GJ. Early repolarization and ventricular fibrillation: vagally familiar? Heart Rhythm 2010;7:653– 654. Watanabe H, Makiyama T, Koyama T, et al. High prevalence of early repolarization in short QT syndrome. Heart Rhythm 2010;7:647– 652. Mehta MC, Jain AC. Early repolarization on scalar electrocardiogram. Am J Med Sci 1995;309:305–311. Klatsky AL, Oehm R, Cooper RA, Udaltsova N, Armstrong MA. The early repolarization normal variant electrocardiogram: correlates and consequences. Am J Med 2003;115:171–177. Bjerregaard P, Gussak I. Short QT syndrome: mechanisms, diagnosis and treatment. Nat Clin Pract Cardiovasc Med 2005;2:84 – 87. Viskin S. The QT interval: too long, too short or just right. Heart Rhythm 2009;6:711–715. Document E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential of Non-Antiarrhythmic Drugs. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration, October 2005. Crow RS, Hannan PJ, Folsom AR. Prognostic significance of corrected QT and corrected JT interval for incident coronary heart disease in a general population sample stratified by presence or absence of wide QRS complex: the ARIC Study with 13 years of follow-up. Circulation 2003;108:1985– 1989. Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects incidence and clinical significance. J Am Coll Cardiol 2008;52:1231–1238. 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;40:1870 –1876. Ezaki K, Nakagawa M, Taniguchi Y, et al. Gender differences in the ST segment: effect of androgen-deprivation therapy and possible role of testosterone. Circ J 2010;74:2448 –2454. Pham TV, Rosen MR. Sex, hormones, and repolarization. Cardiovasc Res 2002;53:740 –751. Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992;8:690 – 695. Fox K, Borer JS, Camm AJ, et al; Heart Rate Working Group. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823– 830. Antzelevitch C, Yan GX, Viskin S. Rationale for the use of the terms J-wave syndromes and early repolarization. J Am Coll Cardiol 2011;57:1587–1590. Endres S, Mayuga KA, de Cristofaro A, Taneja T, Goldberger JJ, Kadish AH. Age and gender difference in ST height at rest and after double autonomic blockade in normal adults. Ann Noninvasive Electrocardiol 2006; 11:253–258. Viskin S, Rosso R, Halkin A. Making sense of early repolarization. Heart Rhythm 2012;9:566 –569. Merchant FM, Noseworthy PA, Weiner RB, Singh SM, Ruskin JN, Reddy VY. Ability of terminal QRS notching to distinguish benign from malignant electrocardiographic forms of early repolarization. Am J Cardiol 2009;104: 1402–1406. Noseworthy PA, Weiner R, Kim J, et al. Early repolarization pattern in competitive athletes: clinical correlates and the effects of exercise training. Circ Arrhythm Electrophysiol 2011;4:432– 440. Anttonen O, Junttila MJ, Rissanen H, Reunanen A, Viitasalo M, Huikuri HV. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation 2007;116:714 –720. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007;115:442– 449. Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011;123:2931–2937.
common in inferior/lateral leads, and slurring was common in anterior leads. A non-ascending ST segment was seen in 71% of ECGs with a notched pattern but in only 12.3% of ECGs with a slurred pattern. The ER group had slower heart rates (9.3 ⫾ 13.3 bpm [mean difference ⫾ SD], P ⬍.001) and shorter QTc intervals (QTcB ⫽ 20.2 ⫾ 25.6 ms, QTcF ⫽ 11.0 ⫾ 21.9 ms; P ⬍.001). Four subjects in each group had a short QT interval (QTcF ⬍350 ms). CONCLUSION ER and all of its variants are common in healthy young males with slower heart rates and slightly shorter QTc intervals. A short QT interval (QTcF ⬍350 ms) is rare.
RESULTS ER, defined as J-point elevation ⱖ0.1 mV in ⱖ2 contiguous leads, was present in 514 subjects (27.3%), of whom 505 (98.2%) were males. The prevalence of ER declined progressively with increasing age. ER pattern was seen in lateral leads (I, aVL, V4–V6) in 26.1%, in inferior (II, III, aVF) or inferolateral leads in 8%, and was global in 1.9%. The terminal portion of the QRS complex was notched in 43.1% and slurred in 56.9%. Notching was
KEYWORDS Arrhythmia; Cardiac repolarization; Early repolarization; Electrocardiography; Short QT interval; Sudden cardiac death
Introduction
probably results from transmural repolarization heterogeneity from endocardium to epicardium resulting from a longer duration of action potentials in subendocardial cells than in subepicardial cells,3,4 which in turn could predispose to cardiac arrhythmias. More recently, subtypes of the ER pattern have been described based on leads showing ER, morphology of the terminal part of QRS complex (notching or slurring), and shape of the ST segment (horizontal/ downsloping and ascending/concave) in an attempt to differentiate between malignant and benign variants of ER.8,9 Interestingly, the studies by Tikkanen et al6 and Haïssaguerre et al5 found that the QTc interval was shorter in patients with ER. In 2004, Viskin et al10 reported that the QTc interval is shorter in survivors of idiopathic VF than in healthy controls. However, the extent of QT shortening in these studies was small, and whether shorter QT interval itself contributes to the development of ventricular arrhythmias in individuals with ER is being debated.2,11–13 Watanabe et al14 studied patients with short QT syndrome and found ER in 65% of patients with ventricular arrhythmias compared to 10% of healthy controls. However, Gross13 suggested that the shorter mean QTc interval found in some of the ER cohort studies5,6 may have resulted from the inclusion of a few unrecognized patients with familial short QT syndrome.10 Although several studies have reported on the prevalence of ER in the healthy population, most of
Early repolarization (ER) is a widely recognized ECG pattern characterized by J-point elevation in the ST segment, usually in the inferior or lateral leads of a 12-lead ECG.1 Until recently, it was generally regarded as a normal variant2 of limited clinical significance that could be mistaken for conditions such as acute myocardial infarction, pericarditis, or intraventricular conduction defects.3 Recent studies have now identified a possible link between ER and the risk of malignant ventricular arrhythmias.4 –7 Haïssaguerre et al5 found ER in 31% of survivors of idiopathic ventricular fibrillation (VF) compared to 5% of healthy controls. Tikkanen et al6 prospectively studied a cohort of middle-aged Finnish individuals and observed higher mortality from cardiac causes in subjects with ER at baseline. The ER pattern
G.K. Panicker, D. Manohar, V. Salvi, and S. Kothari are employees of Quintiles Cardiac Safety Services, Mumbai. Y. Lokhandwala is a consultant to Quintiles Cardiac Safety Services. D. Karnad is a consultant to Quintiles Cardiac Safety Services, Abbott Nutrition (India), and Bharat Serum and Vaccines Limited. A portion of the results from this study was published as a research abstract in the abstract supplement issue (ESC Congress, Paris, France, August 2011) of the European Heart Journal. Address reprint requests and correspondence: Dr. Gopi Krishna Panicker, Quintiles Cardiac Safety Services, 502 A, Leela Business Park, M.V. Road, Andheri (East), Mumbai 400 059, India. E-mail address: gopi. [email protected].
ABBREVIATIONS ER ⫽ early repolarization; VF ⫽ ventricular fibrillation (Heart Rhythm 2012;9:1265–1271) © 2012 Heart Rhythm Society. All rights reserved.
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2012.03.046
1266 those studies preceded the reports that drew attention to this association. Because the prevalence of ER and its various morphological patterns and their association with the length of the QTc interval in healthy subjects are not clear, we studied ECGs from volunteers participating in Phase I clinical trials who had been screened to exclude comorbid conditions.
Methods Subjects We retrospectively studied ECGs from 1886 healthy subjects (1433 males and 453 females, age 18 –92 years) participating in 41 Phase I clinical trials for which Quintiles Cardiac Safety Services was the central ECG laboratory. For each subject, a single drug-free ECG that served as a baseline for the trial was included in the present study. All ECGs were recorded using digital ECGs (ELI 250, Mortara Inc, Milwaukee, WI) with 1000-Hz sampling rate, 25 mm/s speed, and 10 mm/mV amplitude. All subjects were screened by history, physical examination, and laboratory tests for abnormalities. Tests included hemoglobin; total, differential leukocyte, and platelet counts; and urine examination. Blood chemistry included serum bilirubin, transaminases, alkaline phosphatase, sodium, potassium, chloride, calcium, bicarbonate, blood urea nitrogen, creatinine, albumin, and glucose. Appropriate tests for viral hepatitis (hepatitis A, B, and C) and HIV were performed. Subjects with a history of clinically significant cardiac disease were excluded from the study. Only normotensive subjects with resting blood pressure ⱖ90 mm Hg and ⱕ140 mm Hg systolic and ⱖ60 mm Hg and ⱕ90 mm Hg diastolic and normal resting heart rate (ⱖ50 bpm and ⱕ100 bpm) on screening were included. ECGs with bundle branch block or intraventricular conduction defects were excluded because of the difficulty in reliably identifying J-point elevation in these ECGs. Female subjects were included only if they were not pregnant or lactating. Individuals with body mass index ⬍18 or ⬎30 kg/m2, clinically significant abnormality at the screen-
Heart Rhythm, Vol 9, No 8, August 2012 ing medical assessment, history of drug/alcohol abuse, or use of tobacco/nicotine products in the 6-month period preceding the screening visit were excluded. All studies were approved by the respective institutional review boards, and all subjects consented to participate in the studies.
ECG analysis All ECGs were analyzed manually by trained readers in a central ECG laboratory using onscreen analysis software (CalECG version 2.7, AMPS_LLC, New York, NY). ER was defined as J-point elevation ⱖ0.1 mV, visually determined onscreen using mouse-driven digital calipers, present in at least 2 contiguous leads.5,15,16 ECGs with ER were further classified based on leads showing ER pattern: inferior (II, III, aVF), lateral (I, aVL, V4–V6), and anterior (V1–V3) leads, or global (anterior, lateral, and inferior leads).12 ER was further classified as notched if there was a definite notch followed by a small rounded positive deflection at the junction of the QRS complex and the ST segment, or slurred if the transition occurred gradually without a notch5 (Figure 1). ER pattern was also classified based on the shape of the ST segment as concave/rapidly ascending (defined as ⬎0.1 mV elevation of the ST segment within 100 ms after the J point or persistent elevation ⬎0.1 mV throughout) or horizontal/descending (defined as ⱕ0.1 mV elevation of the ST segment within 100 ms after the J point).8,9 QT interval was measured between QRS onset and the point where the T wave met the isoelectric baseline in 5 consecutive complexes in lead II. If the amplitude of the T wave in lead II was ⬍1 mV, then QT interval was measured in lead V5. R-R intervals were measured between the complex in which QT was measured and the preceding complex. QT interval was corrected for the effect of heart rate using the Bazett formula (QTcB ⫽ QT/公RR) and the Fridericia formula (QTcF ⫽ QT/3公RR). In the absence of a universal definition for a short QTc interval, 3 cutoff values (330,14 340,17 and 35018 ms) from previous studies were used. Long QTc interval was defined as QTc ⬎450 ms.19
Figure 1 Single lead from ECGs from different healthy individuals showing notched (A) and slurred (B) patterns of the terminal portion of the QRS complex (arrows). The shape of the ST segment is ascending (defined as ⬎0.1 mV elevation of ST segment within 100 ms after the J point) in A and is non-ascending (defined as ⱕ0.1 mV elevation of the ST segment within 100 ms after the J point) in B.
Panicker et al
Early Repolarization and Short QT Interval in Healthy Subjects
JT interval was calculated as the difference between the QT interval and QRS duration. The heart rate-corrected JT interval (JTcF) was obtained as the difference between QTcF and QRS duration.20
Statistical analysis SAS version 9 (SAS Institute, Cary, NC) was used for statistical analysis. Differences between groups were compared using the unpaired t test or 2 test, as appropriate. A two-sided ␣ of 0.05 was considered the cutoff for statistical significance. The uncorrected QT interval, QTcB, and QTcF from each ECG was plotted versus heart rate, and simple linear regression was used to determine the correction method that performed better (ie, gave a slope that was most horizontal).
Results Of the 1886 subjects included in the study, ER was present in 514 subjects (27.3%), of whom 505 (98%) were males; thus, 35.2% of 1433 males and 1.9% of 453 females had ER. The prevalence of ER was highest (57.0%) among subjects in the 18- to 29-year age group (Table 1) and declined progressively thereafter in males. A similar trend was seen in females (Table 1). The age-related trend persisted even after excluding subjects with ER pattern in anterior leads: 18.9% in the age group 18 –29 years, 11.1% in the fourth decade, 4.2% in the fifth decade, and 1.3% after the fifth decade. Subjects with ER had a significantly lower heart rate than did subjects without ER (mean difference 9.3 ⫾ 13.3 bpm; P ⬍.001; Table 1); 49.6% of subjects with ER and 23.4% of subjects without ER had heart rates ⬍60 bpm. This difference in heart rate was present in all age groups (Table 1). Of the 514 subjects with ER pattern, the pattern was seen in anterior leads in 362, inferior leads in 41, and lateral leads in 134; 34 subjects had ER in inferior and lateral leads, and 10 had ER in all leads. Slurring of the terminal portion of the QRS complex was more common in anterior leads, whereas notching was more common in inferior leads (Figure 2). In 60% to 80% of ECGs with notched pattern, a non-ascending (horizontal/descending) ST segment was present, regardless of the lead in which it was seen. An ascending (concave/ascending) ST segment was more common in ECGs with slurring of the terminal portion of the QRS complex. An ascending pattern was seen in 75% of Table 1
1267
ECGs with ER in the anterior leads vs 31% in inferior and/or lateral leads. Subjects with ER also had shorter mean QTc (QTcB difference 20.2 ⫾ 25.6 ms, QTcF difference 11.0 ⫾ 21.9 ms) and JTcF (11.8 ⫾ 21.5 ms) values, but QRS duration was similar in the two groups (Table 2). Because the proportion of female subjects was grossly different in the two groups (9 females with ER, 444 without ER), we repeated the analysis including only male subjects. In the male subgroup, heart rate also was significantly lower in those with ER (mean ⫾ SD 60.8 ⫾ 9.6 bpm) than in those without ER (68.6 ⫾ 13.9 bpm). Mean QTcB was shorter by 15.0 ⫾ 25.0 ms and QTcF by 7.3 ⫾ 21.4 ms, respectively (Table 3). Compared to subjects without ER, QTcB and QTcF values were lower in all subgroups of ER based on leads showing ER pattern, notching or slurring of the terminal portion of the QRS complex, and morphology of the ST segment (Table 4). There were no differences between the subgroups of individuals with ER (Table 4). Simple linear regression analysis showed that QTcF was better than QTcB in correcting for the effect of heart rate on QT interval in the present study (Figure 3). QTc prolongation, defined as interval ⬎450 ms, was more common in subjects without ER [131 subjects (9.5%) vs 4 subjects (0.8%) with ER; P ⬍.001] for QTcB. The proportion of subjects with QTcF interval ⬎450 ms in the two groups was similar. In contrast, QTcB interval ⬍350 ms was observed in only 6 of 1439 males, of whom 5 subjects had ER [1.0% vs 1 subject (0.1%) without ER; P ⬍.0069]. Only 1 subject (in the ER group) had QTcB interval ⬍340 ms, and none had QTcB ⬍330 ms. Four subjects with ER and 4 without ER had a short QTcF interval using a cutoff value of 350 ms (P ⫽ .23); none had QTcF ⬍330 ms or ⬍340 ms (Table 5).
Discussion Our study had two main objectives: (1) to study the prevalence of ER and its variants in healthy adults and (2) to study the association between ER and short QT interval, both of which have been associated with idiopathic VF.3,4,7,10,14 We found ER in 27.3% of ECGs from 1886 healthy subjects. ER pattern was seen in inferior and/or
Age and gender distribution of subjects with and without early repolarization With early repolarization
Without early repolarization
No. of subjects Age group (y)
All
18–29 30–39 40–49 50–59 ⬎60 Total
264 124 82 31 13 514
(55.3%) (36.4%) (19.1%) (10.3%) (3.8%) (27.3%)
No. of subjects Males
Females
Heart rate for all subjects (mean ⫾ SD)
263 124 81 28 9 505
1 0 1 3 4 9
60.0 61.8 62.0 61.7 59.9 60.9
(57.0%) (39.7%) (23.8%) (18.8%) (5.3%) (35.2%)
(6.3%) (0.0%) (1.1%) (2.0%) (2.4%) (1.9%)
*P ⬍.05 vs subjects without early repolarization.
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
9.6* 8.6* 10.2* 11.5* 10.1* 9.7*
All 213 217 347 269 326 1372
(44.7%) (63.6%) (80.9%) (89.7%) (96.2%) (72.7%)
Males
Females
Heart rate for all subjects (mean ⫾ SD)
198 188 259 121 162 928
15 29 88 148 164 444
69.3 68.1 68.9 70.8 72.6 70.1
(43.0%) (60.3%) (76.2%) (81.2%) (94.7%) (64.8%)
(93.8%) (100.0%) (98.9%) (98.0%) (97.6%) (98.1%)
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
16.7 12.4 13.5 15.2 13.8 14.4
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Heart Rhythm, Vol 9, No 8, August 2012
Figure 2 Morphological patterns of early repolarization in healthy individuals. Note the following: (1) Slurring of the terminal portion of the QRS complex was more commonly seen in anterior leads whereas notching was more common in inferior leads. (2) In 60% to 80% of ECGs with notched pattern, a non-ascending (horizontal/descending) ST segment was present, regardless of the lead in the pattern was seen. (3) An ascending pattern was seen in 75% of ECGs with early repolarization in the anterior leads vs 31% in inferior and/or lateral leads.
lateral leads in 9.3% of subjects and only in the anterior leads in 18%. The overall prevalence of 27.3% in our study appears higher than the 5.8% prevalence reported by Tikkanen et al6 in a retrospective cohort, 5% by Haïssaguerre et al5 in 412 healthy controls, and 13% by Rosso et al21 in healthy adults. However, these studies excluded subjects with ER pattern in anterior leads to avoid possible inclusion of individuals with right ventricular dysplasia or Brugada syndrome.5,6,21 The corresponding value was 9.3% in our study which is comparable with these previous studies. We observed a definite age-related trend in the prevalence of ER. The prevalence was highest (55.3%) in the 18to 29-year age group and declined progressively to 3.8% in the seventh decade. Tikkanen et al also found that ER was more prevalent in young athletes than in middle-aged healthy subjects.8 We also found that 98% of healthy subjects with ER were males. This male preponderance, also observed in previous studies,5,6,15,16 is attributed to the effect of androgens, which can modulate the function of potassium and sodium channels that play important roles in cardiac repolarization.22–26 Heart rate was slower in subjects with ER by a mean of 10 bpm, a phenomenon that also was reported in previous studies.1,12,27 Mehta and Jain15 observed that ER disappears with exercise and suggested that this may be due vagal influence on ventricular repolarization. Acetylcholine can Table 2
produce an ER pattern on the ECG in the canine arterially perfused ventricular wedge preparation.3 This could explain why ER is more common in athletes who have higher vagal tone and lower heart rates.8,9 Interestingly, the gender difference in ST-segment elevation persists even after autonomic blockade.28 Antzelevitch and Yan12 and Wellens11 suggest that the amplitude of the J wave seen at the end of the QRS complex in ER increases at lower heart rates and may disappear at higher heart rates. Because ER is common in the healthy population and the relative risk of idiopathic VF or death from cardiac arrhythmias in individuals with ER is low,29 some authors have looked for other morphological patterns associating ER with idiopathic VF or death from cardiac arrhythmias. Based on the leads showing the ER pattern, Antzelevitch and Yan12 classified ER into three types. In type 1, the ER pattern occurs in lateral precordial leads and is associated with a low risk of VF. This type was seen in 26.1% of our subjects with ER. In type 2, ER is seen in inferior/inferolateral leads and is associated with higher risk of VF. This type was seen in 8.0% of our subjects with ER. Type 3 pattern, which is associated with the highest level of risk for development of malignant arrhythmias, is characterized by the presence of ER globally (ie, inferior, lateral, and right precordial leads) and was seen in 1.9% of our subjects with ER. Merchant et al30 found that ER with notching had a closer association
ECG parameters in healthy subjects with and without early repolarization
ECG parameter
With early repolarization (n ⫽ 514)
Heart rate (bpm) QT interval (ms) Corrected QT–Bazett (QTcB ) (ms) Corrected QT–Fridericia (QTcF) (ms) QRS duration (ms) JT interval (ms) Corrected JT interval–Fridericia (JTcF) (ms)
60.9 394.7 394.6 394.3 92.9 301.8 301.5
Values are given as mean ⫾ SD.
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
9.7 28.0 20.3 18.2 8.5 27.8 19.0
Without early repolarization (n ⫽ 1372) 70.1 388.2 414.8 405.3 92.1 296.1 313.2
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
14.4 33.0 27.4 23.1 13.0 31.9 22.4
P value ⬍.001 ⬍.001 ⬍.001 ⬍.001 .942 ⬍.001 ⬍.001
Panicker et al Table 3
Early Repolarization and Short QT Interval in Healthy Subjects
1269
ECG parameters in healthy male subjects with and without early repolarization
ECG parameter
With early repolarization (n ⫽ 505)
Heart rate (bpm) QT interval (ms) Corrected QT–Bazett (QTcB) (ms) Corrected QT–Fridericia (QTcF) (ms) QRS duration (ms) JT interval (ms) Corrected JT interval–Fridericia (JTcF) (ms)
60.8 394.5 394.2 394.0 93.0 301.5 301.0
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
Without early repolarization (n ⫽ 928)
9.6 27.9 20.0 18.0 8.5 27.7 18.7
68.6 387.0 409.2 401.3 94.4 292.6 306.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
P value ⬍.001 ⬍.001 ⬍.001 ⬍.001 .942 ⬍.001 ⬍.001
13.9 32.7 27.3 23.0 12.9 30.9 20.5
Values are given as mean ⫾ SD.
with malignant ventricular arrhythmias than did slurring. We found ER with notching in 43.1% of all subjects with ER. Tikkanen et al8 and Rosso et al9 found that horizontal/ descending ST-segment pattern was associated with increased risk of cardiac arrhythmias, whereas an ascending/ concave ST segment was more common in healthy subjects, including athletes. The ascending ST-segment pattern was seen in 31.6% of healthy subjects with ER pattern in inferior/lateral leads in our study. Noseworthy et al31 found the ascending pattern in 95% of competitive athletes with ER pattern in inferior/lateral leads. Tikkanen et al8 also found an ascending pattern in 96% of athletes with ER in inferior/ lateral leads, but the prevalence decreased to 32.8% in the general population, which closely matches our results. None of these studies, however, looked for the coexistence of these patterns. We found that notching was seen in 76% of ECGs with ER pattern in inferior/lateral leads but in only 29% of ECGs with ER pattern in anterior leads. Similarly, the “non-ascending” (horizontal/descending) ST segment was present in 68.4% of ECGS with ER in inferior/ lateral leads but in only 25% of ECGs with ER in anterior leads. Moreover, the non-ascending ST-segment pattern (horizontal/descending ST segment pattern of Tikkanen and Rosso) was seen in 71% of ECGs with notched ER pattern but in only 12.3% of ECGs with slurred ER pattern. Thus, in ECGs with ER, an ascending ST-segment pattern is more common in ECGs showing ER in anterior leads or in those with a slurred terminal portion of the QRS complex. Another objective of this study was to study the length of QT/QTc interval in ECGs with and those without ER. We Table 4
found that the mean QTcB interval was shorter by 20 ms and the mean QTcF by 11 ms in subjects with ER. However, QT interval did not differ between subgroups based on leads or morphologies of the terminal portion of the QRS complex and ST segment (Table 4). Because heart rate is slower in subjects with ER, the QT correction method may impact the results of studies of QT intervals in ER. We found that the Bazett formula overcorrected for the effect of heart rate and gave lower QTc values at lower heart rates, whereas the Fridericia formula corrected for the effect of heart rate more appropriately. Haïssaguerre et al5 found that QTcB was shorter by 9 ms in patients with ER, whereas Tikkanen et al6 found that QTcB was 4 ms shorter in subjects with ER. In both of these studies as well as our study, the prevalence of ER was disproportionately higher in males. Because the QT interval is normally shorter in men than in women,18,25,32 it is possible that the shorter QT interval in subjects with ER is due to gender differences in the two groups. To avoid this confounding effect of gender, we analyzed data from male subjects separately and found that the mean QTcB interval was still significantly shorter in male subjects with ER by 15 ms and QTcF by 7 ms. In 2004, Viskin et al10 described a cohort of 28 patients with idiopathic VF in whom the mean QTcB interval was 14 ms shorter than in healthy controls. The same group subsequently described a higher prevalence of ER in idiopathic VF21; however, QT interval in patients with ER in the latter study was not described. Haïssaguerre et al5 found that mean QTc is shorter in survivors of idiopathic VF with ER
ECG parameters in healthy subjects with and without early repolarization With ER Leads with ER pattern
ECG parameter
Without ER (n ⫽ 1372)
Heart rate (bpm) QT interval (ms) QTcB–Bazett (ms) QTcF–Fridericia (ms)
70.1 388.2 414.8 405.3
⫾ ⫾ ⫾ ⫾
14.4 33.0 27.4 23.1
Inferior (n ⫽ 41) 59.4 393.5 390.1 391.1
⫾ ⫾ ⫾ ⫾
Lateral (n ⫽ 134) 7.5* 22.8* 17.9* 15.9*
59.4 395.3 390.5 391.9
⫾ ⫾ ⫾ ⫾
9.3* 28.2* 18.8* 17.7*
Inferior and lateral (n ⫽ 34) 58.4 393.4 386.5 388.7
⫾ ⫾ ⫾ ⫾
7.5* 23.1* 14.9* 14*
Terminal QRS complex
ST-segment morphology
Notched (n ⫽ 222)
Ascending (n ⫽ 320)
60.1 395.7 393.3 393.8
⫾ ⫾ ⫾ ⫾
9.2* 27* 18.4* 16.6*
Slurred (n ⫽ 292) 61.4 393.9 395.6 394.7
⫾ ⫾ ⫾ ⫾
9.9* 28.7* 21.6* 19.3*
60.8 395.6 395.2 395.1
⫾ ⫾ ⫾ ⫾
9.9* 28.5* 21.3* 18.9*
Non-ascending (n ⫽ 194) 60.9 393.1 393.6 393.2
⫾ ⫾ ⫾ ⫾
9.2* 27.1* 18.6* 16.9*
Values are given as mean ⫾ SD. Subjects with ER were further subgrouped based on leads showing ER (inferior, lateral, inferolateral), terminal QRS complex morphology (notched or slurred), and ST-segment morphology (ascending or non-ascending). *P ⬍.05 vs subjects without early repolarization (ER).
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Heart Rhythm, Vol 9, No 8, August 2012
Figure 3 Effect of heart rate on QT, QTcF, and QTcB intervals in 1886 healthy subjects. There was a negative correlation between QT interval and heart rate (P ⫽ .001). A positive correlation between QTcB and heart rate (P ⫽ .001) and between QTcF and heart rate (P ⫽ .001) was seen. The slope of the regression line for QTcF was closest to zero, suggesting that this was a better correction method for the effect of heart rate than was QTcB.
in their 12-lead ECGs.5 The association between ER and short QT interval was evaluated further by Watanabe et al, who studied patients with familial short QT syndrome and found ER in 65% of these patients with ventricular arrhythmias compared to 35% of subjects with the short QT syndrome but no arrhythmias.14 Various cutoff values of ⬍330 ms,13 ⬍340 ms,17 and ⬍350 ms18 have been used to define short QT syndrome. In the present study, 5 subjects with ER had QTcB ⬍350 ms and 1 had QTcB ⬍340 ms, whereas only 1 subject without ER had QTcB value ⬍350 ms and none had QTcB ⬍340 ms. On the other hand, 4 subjects with ER and 4 subjects without ER had QTcF ⬍350 ms, and none had QTcF ⬍340 ms. Thus, only a handful of healthy subjects could be categorized as having a short QT interval; among these subjects, more were in the ER group when QTcB was studied, possibly because the Bazett formula gave shorter QTc values at lower heart rates. When the Fridericia formula was used, the number of subjects with QTcF ⬍350 ms in the 2 groups was comparable. Although the underlying mechanisms of ER are not yet completely understood, Boineau4 attributes it to deep invagination of Purkinje fibers into the subepicardial tissue, resulting in early transmural activation followed by ER. Gussak and Antzelevitch3 have proposed that, akin to that in the
Brugada syndrome, ER occurs because of a greater transmural gradient of repolarization. Furthermore, like ER, the Brugada syndrome has a male predominance3,27 and a shorter QT interval, particularly when associated with a loss-of-function mutation in the cardiac calcium channel.3,33
Conclusion Our study is a large cross-sectional study of healthy volunteers who were thoroughly screened to exclude heart disease and other comorbid conditions for whom high-quality digital ECGs were interpreted by trained readers in a central ECG laboratory. However, the study had one important limitation. Being a cross-sectional study, subjects in this study were not followed up to determine the association between ER and its various morphologies, and the QT interval with ventricular arrhythmias. Nevertheless, our observations show that ER is seen in 27.3% of healthy subjects, occurring in inferior and/or lateral leads in 9.3%. We also found that notching was more common in inferior/ lateral leads and slurring in anterior leads. The non-ascending ST-segment pattern was seen in 71% of ECGs with a notched ER pattern but in only 12.3% of ECGs with a slurred ER pattern.
Table 5 Frequency of subjects with and without early repolarization with QTc values within predefined cutoffs for long QTc and short QTc intervals With early repolarization
Variable QTcB
QTcF
Without early repolarization
Cutoff values (ms)
Male (n ⫽ 505)
Female (n ⫽ 9)
Total (n ⫽ 514)
Male (n ⫽ 928)
Female (n ⫽ 444)
Total (n ⫽ 1372)
P value*
ⱖ450 ⬍350 ⬍340 ⬍330 ⱖ450 ⬍350 ⬍340 ⬍330
3 5 1 0 3 4 0 0
1 0 0 0 1 0 0 0
4 5 1 0 4 4 0 0
59 1 0 0 27 4 0 0
72 0 0 0 19 0 0 0
131 1 0 0 46 4 0 0
⬍.0001 .0069 .2725 — .0018 .2249 — —
*By Fisher exact test or 2 test comparing total subjects with and without early repolarization.
Panicker et al
Early Repolarization and Short QT Interval in Healthy Subjects
We also found that healthy individuals with ER have a shorter QTc interval, and the extent of QTc shortening is similar to that reported in survivors of idiopathic VF.5 However, in absolute terms, only a few subjects in this study had a short QT interval (QTcF ⬍350 ms), but these subjects were equally distributed between the group with and that without ER. Thus, although ER may be common in familial short QT syndrome,14 the converse probably is not true. Because ER is common in individuals with a slower heart rate, our study shows that the Bazett formula, which gives spuriously low values of QTc at lower heart rates, should be avoided and the Fridericia formula used instead. Tikkanen et al6 found that 9.5% of individuals with ER died due to cardiac arrhythmia compared to 7.2% of those without ER. Haruta et al34 found that sudden cardiac death occurred in 1.9% of Japanese subjects with ER compared to 1% of those without ER. Thus, even in individuals with ER, only a small percent are at increased risk for cardiac arrhythmias. Attempts have been made to identify morphological features to differentiate between the benign and malignant types of ER. However, we found that even the “malignant” variants of ER are widely prevalent in healthy subjects. More studies are needed to determine whether the extent of QTc shortening can identify healthy subjects with ER in inferolateral leads who are at increased risk for developing ventricular arrhythmias, by itself or in combination with the morphological variants.
11. 12. 13. 14. 15. 16.
17. 18. 19.
20.
21.
22.
23.
Acknowledgments
24.
We thank Jim Chestnut, MS, MLS, Associate Director, Quintiles Library & Information Services, for assistance in literature review.
25.
References 1. Surawicz B, Knilans T. Normal electrocardiogram: origin and description. In: Surawicz B, Knilans T, editors. Chou’s Electrocardiography in Clinical Practice. Sixth Edition. Philadelphia: WB Saunders Elsevier, 2008:23. 2. Bjerregaard P, Nallapaneni H, Gussak I. Short QT interval in clinical practice. J Electrocardiol 2010;43:390 –395. 3. Gussak I, Antzelevitch C. Early repolarization syndrome: clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol 2000;33:299 –309. 4. Boineau JP. The early repolarization variant-normal or a marker of heart disease in certain subjects. J Electrocardiol 2007;40:e11– e16. 5. Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016 –2023. 6. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529 – 2537. 7. Rosso R, Adler A, Halkin A, Viskin S. Risk of sudden death among young individuals with J waves and early repolarization: putting the evidence into perspective. Heart Rhythm 2011;8:923–929. 8. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666 –2673. 9. Rosso R, Glikson E, Belhassen B, et al. Distinguishing “benign” from “malignant early repolarization”: the value of the ST-segment morphology. Heart Rhythm 2012;9:225–229. 10. Viskin S, Zeltser D, Ish-Shalom M, et al. Is idiopathic ventricular fibrillation
26. 27. 28.
29. 30.
31.
32.
33.
34.
1271
a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm 2004;1:587–591. Wellens HJ. Early repolarization revisited. N Engl J Med 2008;358:2063– 2065. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010;7:549 –558. Gross GJ. Early repolarization and ventricular fibrillation: vagally familiar? Heart Rhythm 2010;7:653– 654. Watanabe H, Makiyama T, Koyama T, et al. High prevalence of early repolarization in short QT syndrome. Heart Rhythm 2010;7:647– 652. Mehta MC, Jain AC. Early repolarization on scalar electrocardiogram. Am J Med Sci 1995;309:305–311. Klatsky AL, Oehm R, Cooper RA, Udaltsova N, Armstrong MA. The early repolarization normal variant electrocardiogram: correlates and consequences. Am J Med 2003;115:171–177. Bjerregaard P, Gussak I. Short QT syndrome: mechanisms, diagnosis and treatment. Nat Clin Pract Cardiovasc Med 2005;2:84 – 87. Viskin S. The QT interval: too long, too short or just right. Heart Rhythm 2009;6:711–715. Document E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential of Non-Antiarrhythmic Drugs. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration, October 2005. Crow RS, Hannan PJ, Folsom AR. Prognostic significance of corrected QT and corrected JT interval for incident coronary heart disease in a general population sample stratified by presence or absence of wide QRS complex: the ARIC Study with 13 years of follow-up. Circulation 2003;108:1985– 1989. Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects incidence and clinical significance. J Am Coll Cardiol 2008;52:1231–1238. 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;40:1870 –1876. Ezaki K, Nakagawa M, Taniguchi Y, et al. Gender differences in the ST segment: effect of androgen-deprivation therapy and possible role of testosterone. Circ J 2010;74:2448 –2454. Pham TV, Rosen MR. Sex, hormones, and repolarization. Cardiovasc Res 2002;53:740 –751. Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992;8:690 – 695. Fox K, Borer JS, Camm AJ, et al; Heart Rate Working Group. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823– 830. Antzelevitch C, Yan GX, Viskin S. Rationale for the use of the terms J-wave syndromes and early repolarization. J Am Coll Cardiol 2011;57:1587–1590. Endres S, Mayuga KA, de Cristofaro A, Taneja T, Goldberger JJ, Kadish AH. Age and gender difference in ST height at rest and after double autonomic blockade in normal adults. Ann Noninvasive Electrocardiol 2006; 11:253–258. Viskin S, Rosso R, Halkin A. Making sense of early repolarization. Heart Rhythm 2012;9:566 –569. Merchant FM, Noseworthy PA, Weiner RB, Singh SM, Ruskin JN, Reddy VY. Ability of terminal QRS notching to distinguish benign from malignant electrocardiographic forms of early repolarization. Am J Cardiol 2009;104: 1402–1406. Noseworthy PA, Weiner R, Kim J, et al. Early repolarization pattern in competitive athletes: clinical correlates and the effects of exercise training. Circ Arrhythm Electrophysiol 2011;4:432– 440. Anttonen O, Junttila MJ, Rissanen H, Reunanen A, Viitasalo M, Huikuri HV. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation 2007;116:714 –720. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007;115:442– 449. Haruta D, Matsuo K, Tsuneto A, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011;123:2931–2937.