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Delayed QRS transition in the precordial leads of an electrocardiogram as a predictor of sudden cardiac death in the general population
Delayed QRS transition in the precordial leads of an electrocardiogram as a predictor of sudden cardiac death in the general population Aapo L. Aro, MD,* Antti Eranti, MD,† Olli Anttonen, MD,† Tuomas Kerola, MD,† Harri A. Rissanen, MSc,‡ Paul Knekt, PhD,‡ Kimmo Porthan, MD,* Jani T. Tikkanen, MD,§ M. Juhani Junttila, MD,§ Heikki V. Huikuri, MD§ From the *Division of Cardiology, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland, †Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti, Finland, ‡National Institute for Health and Welfare, Helsinki, Finland, and §Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. BACKGROUND QRS transition zone is related to the electrical axis of the heart in the horizontal plane and is easily determined from the precordial leads of a standard 12-lead ECG. However, whether delayed QRS transition, or clockwise rotation of the heart, carries prognostic implications and predicts sudden cardiac death (SCD) is unclear. OBJECTIVE The purpose of this study was to study whether delayed transition is associated with mortality and SCD. METHODS We evaluated 12-lead ECGs of 10,815 Finnish middleaged subjects from the general population (52% men, mean age 44 ⫾ 8.5 years) and followed them for 30 ⫾ 11 years. Main end-points were mortality and SCD. RESULTS Delayed QRS transition at lead V4 or later occurred in 1770 subjects (16.4%) and markedly delayed transition at lead V5 or later in 146 subjects (1.3%). Delayed transition zone was associated with older age, male gender, higher body mass index, hypertension, baseline cardiovascular disease, leftward shift of the frontal QRS axis, wider QRS-T angle, and ECG left ventricular hypertrophy. After adjusting for several clinical and ECG variables, delayed transition was associated with overall mortality (hazard
Introduction Sudden cardiac death (SCD) is a major medical and public health concern responsible for up to 50% of cardiovascular deaths and 15% to 20% of overall mortality, with coronary heart disease being the underlying cause of most of these deaths.1 The majority of sudden deaths occur among subjects with no previously diagnosed cardiac disease or in subjects Dr. Aro was supported by grants from the Paavo Nurmi Foundation and the Finnish Foundation for Cardiovascular Research. Dr. Porthan was supported by grants from the Aarne Koskelo Foundation, the Finnish Foundation for Cardiovascular Research, and the Finnish Medical Foundation. Address reprint requests and correspondence: Dr. Aapo Aro, Division of Cardiology, Heart and Lung Center, Helsinki University Central Hospital, Haartmaninkatu 4, PL340, 00029 HUS, Helsinki, Finland. E-mail address: aapo.aro@helsinki.fi.
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
ratio [HR] 1.15, 95% confidence interval [CI] 1.07–1.22, P o .001) and SCD (HR 1.23, 95% CI 1.03–1.47, P ¼ .029). Markedly delayed transition at V5 or later predicted significantly SCD (HR 1.89, 95% CI 1.18–3.03, P ¼ .008) and all-cause mortality (HR 1.30, 95% CI 1.07–1.58, P ¼ .01). However, further adjustments for repolarization abnormalities attenuated this effect. CONCLUSION Delayed QRS transition in the precordial leads of an ECG seems to be a novel ECG risk marker for SCD. In particular, markedly delayed transition was associated with significantly increased risk of SCD, independent of confounding factors. KEYWORDS Sudden cardiac death; Electrocardiography; QRS transition; Population; Clockwise rotation ABBREVIATIONS BMI ¼ body mass index; BP ¼ blood pressure; CI ¼ confidence interval; ECG ¼ electrocardiography; ER ¼ early repolarization; HR ¼ hazard ratio; LVH ¼ left ventricular hypertrophy; SCD ¼ sudden cardiac death (Heart Rhythm 2014;0:1–7) rights reserved.
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2014 Heart Rhythm Society. All
consider to be at low risk; thus, there has been growing interest in identifying these individuals before the devastating SCD event. Common risk factors for atherosclerosis predict nonspecifically SCD,2 and large epidemiologic surveys have recently pursued ECG risk markers for SCD.3 The QRS transition zone is an ECG phenomenon related to the electrical axis of the heart in the horizontal plane. However, unlike the frontal QRS axis, information on the horizontal axis has been largely neglected in clinical practice. The transition zone can be readily established from the standard 12-lead ECG by determining the precordial lead in which the R wave of the QRS complex exceeds the S wave in amplitude. Although the transition zone does not precisely correlate with the position of the heart in the chest, delayed transition leftward from lead V4 has been traditionally called http://dx.doi.org/10.1016/j.hrthm.2014.08.014
2 clockwise rotation and early transition before V3 counterclockwise rotation of the heart.4 Few studies have investigated the prognostic significance associated with delayed QRS transition, and, to our knowledge, no previous studies exist on its value in predicting SCD. Based on a 30-year follow-up of nearly 11,000 middleaged Finnish individuals, we previously described several ECG depolarization and repolarization patterns that have been associated with SCD.5–8 The aim of the present study was to determine, from the same general population cohort, whether delayed QRS transition zone predicts SCD in the general population and whether it yields additional prognostic information on top of clinical risk factors and ECG patterns associated with SCD.
Methods Study population The original study population consisted of 10,899 men and women between the ages of 30 and 59 years (52% male, mean age 44.0 ⫾ 8.5 years) for whom an ECG was recorded as part of the Finnish Social Insurance Institution’s CHD Study, which comprised 12 population groups from 4 different geographical areas in Finland with variable mortality and morbidity rates representative of the middle-aged Finnish population. Baseline examinations were performed from 1966 to 1972, and 89.6% of the invited subjects participated in the study. Eighty-four ECGs were excluded because of left or right bundle branch block, second- or third-degree AV block, paced rhythm, or ventricular preexcitation; thus, our final study group included 10,815 subjects from the original cohort.
Baseline examination and ECG measurements A detailed account of the study rationale, procedures performed at baseline examinations, and ECG measurements has been described previously.9 In brief, during the initial visit, in addition to standard 12-lead ECG recording, the participants were measured and weighed, their blood pressure (BP) was determined, and they underwent routine laboratory assessment of traditional cardiovascular risk factors. Before the examination, subjects completed a questionnaire about their previous illnesses, smoking habits, and medications, which was then checked by a specially trained nurse. Any cardiovascular symptoms were documented during the examination. Hypertension was defined as systolic BP Z160 mm Hg, diastolic BP Z100 mm Hg or antihypertensive medication, and obesity as body mass index (BMI) Z30 kg/m2. Thirty minutes after arrival at the Mobile Clinic, a standard 12-lead ECG was recorded with the subject at rest in the supine position. Paper speed was 50 mm/s, calibration was 1 mV/10 mm, and each ECG sheet contained on average 7 to 8 QRS complexes. Eight trained technicians supervised by a doctor obtained the initial measurements, and the quality of the recordings and positioning of the electrodes were systematically monitored. QRS duration and QT interval were measured, and the presence or absence of ECG left ventricular hypertrophy (LVH) according to the
Heart Rhythm, Vol 0, No 0, Month 2014 Sokolow-Lyon criteria (SV1 þ RV5 or RV6 Z35 mm) and Romhilt-Estes criteria (Z5 points) was assessed. Frontal QRS axis and T-wave axis were determined from the limb leads at 101 intervals, and the QRS-T angle was calculated as the absolute value of the difference between QRS and T-wave axes. Later, ECGs were reanalyzed for the presence of early repolarization (ER) pattern and T-wave inversions, as previously described.5,7 The transition zone was determined manually from the precordial leads by determining where the QRS pattern changed from an rS to an Rs configuration, or in which lead an isoelectric RS pattern was present. If the transition occurred before V3, it was considered early; if it occurred at V4 or leftward from V4, transition was considered delayed; and if it occurred at V5 or beyond, transition was considered markedly delayed. The transition zone was considered normal when transition occurred at V3 or between V3 and V4. To minimize errors in the process and to assess the reliability of the ECG measurements, all readers were continuously evaluated using a separate standard ECG material that was not part of the study. When compared with the reference values, intraclass correlation coefficient of r = 0.91 was demonstrated between all readers and the test material for measuring the transition zone. Of note, intraclass correlation coefficient of 0.50 indicates moderate, 0.75 excellent, and 1.0 perfect correlation.
Follow-up Participants were followed from the baseline visit that occurred between 1966 and 1972 through the end of 2007, with mean follow-up of 30 ⫾ 11 years. Fewer than 2% of the subjects were lost to as a result of moving abroad, but the survival status of most of these subjects could still be determined. All episodes of hospitalization due to atrial fibrillation, heart failure, and coronary heart disease were obtained from the Finnish Hospital Discharge Register, which includes nationwide data on all inpatient episodes in Finland at an individual level. Mortality data were obtained from the Causes of Death Register maintained by Statistics Finland, which records every death in the country. The quality and reliability of these extensive registers have been previously validated.10 Death certificates were obtained for each deceased individual. Death from coronary heart disease was determined according to the appropriate International Classification of Diseases (ICD) codes (representing I20- to I25- codes in the ICD-10). To identify cases of definite or probable arrhythmic deaths, all deaths from cardiac causes were reviewed using death certificates, hospital records, and autopsy reports (if available) using the definitions of SCD presented in the Cardiac Arrhythmia Pilot Study,11 as we described previously.5
Statistical analysis All continuous data are presented as mean ⫾ SD. A general linear model was used to compare age- and sex-adjusted mean values for continuous variables and prevalence of categorical variables between groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) for death and hospitalization were
Aro et al
QRS Transition Zone and Risk of SCD
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calculated using the Cox proportional hazards models. Main end-points were all-cause mortality, coronary mortality, and SCD. The primary adjustments in these models were for age and gender, with further adjustment for covariates that differed between the group with delayed transition and rest of the cohort. Age, heart rate, systolic BP, BMI, QRS axis, and QRS duration were added as continuous variables. Gender, baseline cardiovascular disease, and the presence or absence of an ECG LVH according to either Romhilt-Estes or Sokolow-Lyon criteria were added as categorical variables in the multivariate model A. Diastolic BP was omitted because of marked colinearity with systolic BP. In addition to these variables, in the multivariate model B, inferolateral ER and T-wave inversions were added as categorical variables, and QTc and QRS-T angle as continuous variables. To further assess the differences in SCD between groups, Kaplan–Meier survival curves were plotted and the significance of the difference between them tested with the logrank test. Statistical analyses were performed using SPSS Statistics software (version 21.0, IBM Corp, Armonk NY). Two-sided statistical tests were used, and P o .05 was considered significant.
Results Baseline characteristics A total of 10,815 subjects had a transition zone determined from ECG. Early QRS transition before lead V3 (counterclockwise rotation) occurred in 2861 subjects (26.4%), very early transition before V2 (distinct counterclockwise rotation) in 334 (3.1%), normal transition at V3 or before V4 in 6184 (57.2%), and delayed transition at lead V4 or beyond (clockwise rotation) in 1770 (16.4%). In 146 subjects (1.3%), transition was markedly delayed and shifted leftward to lead V5 or V6 (distinct clockwise rotation). An example of a markedly delayed transition is shown in Figure 1. Of the subjects with delayed transition, 959 were men (17.0% of all men) and 811 were women (15.7% of all women). Prevalence of delayed transition increased significantly with age, being 13.1% among subjects aged 30–39 years, 15.4% among subjects aged 40–49 years, and 21.5% among subjects aged 50–59 years (P o .001 for difference between groups). BMI was also strongly associated with the proportion of subjects presenting with delayed transition. In the lowest quintile (BMI o22.7 kg/m2), 12.2% of the subjects had delayed transition compared to 25.4% in the highest quintile (BMI 428.7 kg/m2). Baseline characteristics of the participants are given in Table 1. Subjects with delayed transition were older, more likely were male, had higher BMI and higher blood pressure, and were more likely to have suspected cardiovascular disease than were subjects with normal transition. They also had slightly longer QRS and QTc durations, had more inverted T waves, and presented with a more leftward frontal axis and wider QRS-T angle than the rest of the subjects. According to the Sokolow-Lyon voltage criteria, LVH was less common among subjects with delayed QRS transition. However, according to the point score of Romhilt and Estes,
Figure 1 Twelve-lead ECG of a 49-year-old woman with body mass index of 32 kg/m2 who presented with markedly delayed QRS transition zone at lead V5, a slight leftward shift of the frontal QRS axis, and QRS duration of 100 ms. She experienced sudden cardiac death during follow-up. Paper speed is 50 mm/s.
which incorporates, in addition to voltage criteria, abnormal QRS axis and QRS duration, QRS onset to peak time, and P-wave and ST-T morphology,12 LVH was more frequent in the group with delayed transition.
4 Table 1
Heart Rhythm, Vol 0, No 0, Month 2014 Age- and gender-adjusted baseline characteristics of subjects according to transition zone
Males (%)* Age (years)† Current smoker (%) Cholesterol (mmol/L)‡ BMI (kg/m2) Heart rate (bpm) Systolic BP (mm Hg) Diastolic BP (mm Hg) Hypertension (%) Obesity (%) Chronotropic medication (%) Cardiovascular disease (%) History of myocardial infarction (%) LVH Sokolow-Lyon (%) LVH Romhilt-Estes (%) QTc duration (ms) QRS duration (ms) QRS axis (degrees) QRS axis o–301 (%) Inferolateral ER Z0.1 mV (%) T-wave inversions (%) QRS-T angle (1)
Normal transition (transition oV4)
Early transition (transition oV3)
Delayed transition (transition ZV4)
Very delayed transition (transition ZV5)
P value
(N ¼ 9045)
(N ¼ 2861)
(N ¼ 1770)
(N ¼ 146)
oV3 vs ZV3
oV4 vs ZV4
oV4 vs ZV5
51.8 43.7 ⫾ 8.4 34.0 6.51 ⫾ 1.32 25.7 ⫾ 3.7 76 ⫾ 15 138 ⫾ 21 82 ⫾ 12 18.8 12.2 3.7 7.6 1.1 34.1 6.4 408 ⫾ 27 87 ⫾ 8 38 ⫾ 30 1.3 6.0 1.1 27 ⫾ 23
52.0 43.6 ⫾ 8.4 32.6 6.52 ⫾ 1.30 25.7 ⫾ 3.6 76 ⫾ 15 137 ⫾ 20 81 ⫾ 12 16.7 12.0 3.4 7.0 0.8 35.4 6.9 408 ⫾ 27 86 ⫾ 8 37 ⫾ 27 1.0 6.6 1.1 24 ⫾ 30
54.6 45.7 ⫾ 8.4 34.1 6.48 ⫾ 1.32 27.0 ⫾ 4.5 76 ⫾ 16 141 ⫾ 24 85 ⫾ 14 27.5 22.5 7.1 10.4 1.3 18.2 8.6 410 ⫾ 29 87 ⫾ 8 31 ⫾ 42 6.5 5.1 1.8 37 ⫾ 31
50.3 48.5 ⫾ 8.1 31.5 6.53 ⫾ 1.37 28.5 ⫾ 5.3 81 ⫾ 19 144 ⫾ 28 87 ⫾ 17 34.9 41.1 8.5 15.8 1.1 10.8 10.9 414 ⫾ 31 88 ⫾ 8 15 ⫾ 56 22.5 5.3 1.2 52 ⫾ 39
0.76 .004 .043 0.57 .009 0.67 o.001 o.001 o.001 o.001 .004 .009 .07 o.001 0.27 0.23 .01 0.57 o.001 .046 0.63 o.001
.04 o.001 0.92 0.32 o.001 .09 o.001 o.001 o.001 o.001 o.001 o.001 0.31 o.001 .001 .009 o.001 o.001 o.001 0.15 .009 o.001
0.47 o.001 0.47 0.72 o.001 o.001 .005 o.001 o.001 o.001 .06 .002 0.90 o.001 .03 .02 .02 o.001 o.001 0.74 0.88 o.001
Values are given as mean ⫾ SD unless otherwise indicated. BMI ¼ body mass index; BP ¼ blood pressure; ER ¼ early repolarization; LVH ¼ left ventricular hypertrophy; QTc ¼ QT corrected for heart rate according to the Bazett formula. * Adjusted for age. † Adjusted for gender. ‡ To convert the values of cholesterol to mg/dL, divide by 0.02586.
Delayed QRS transition and outcome events During mean follow-up of 30 ⫾ 11 years, 6100 of the 10,815 participants (56.4%) died. Of these deaths, 1953 (32.0% of all-cause mortality) were due to coronary heart disease, and 791 (13.0% of all-cause mortality) were classified as SCD. Unadjusted and adjusted HRs for fatal outcomes according to the transition zone are given in Table 2. Delayed transition predicted all-cause mortality and SCD after several adjustments (model A). When parameters representing repolarization abnormalities were added to the model (model B), only all-cause mortality remained statistically significant. The outcomes remained similar in further analysis in which subjects with suspected cardiovascular disease were excluded. In this group of 9940 persons, delayed transition was moderately associated with all-cause mortality (HR 1.11, 95% CI 1.03–1.19, P ¼ .004) and SCD (HR 1.22, 95% CI 1.00–1.49, P ¼ .045) in model A. When subjects with QRS axis o–301 were excluded from the analysis (remaining N ¼ 10,421), risk for SCD did not change markedly (HR 1.22, 95% CI 1.01–1.47, P ¼ .041). The risk of fatal events appeared even higher when QRS transition was more markedly delayed, occurring at lead V5 or leftward (Table 2). When this group was analyzed
separately, adjusted HR for SCD was 1.64 and HR for allcause mortality was 1.27 (model B). Kaplan–Meier survival curves for SCD in subjects with markedly delayed transition are shown in Figure 2. Delayed transition was not associated with an increase in hospitalizations due to coronary heart disease, atrial fibrillation, or heart failure.
Early QRS transition: Characteristics and outcome People with early transition occurring before V3 were slightly younger, were less likely to smoke, had a slightly lower BMI and blood pressure, and were less likely to have cardiovascular disease or be taking medication than the rest of the subjects (Table 1). When subjects with early transition were compared with rest of the population, after adjusting for age and gender, a slightly increased overall survival was observed (HR for allcause mortality 0.94, 95% CI 0.89–1.00, P ¼ .03), but this finding lost statistical significance after further adjustments. Fewer atrial fibrillation hospitalizations were observed even after multivariate adjustments in this group (HR 0.85, 95% CI 0.76–0.95, P ¼ .006), but no significant differences in coronary mortality, SCD, or hospitalization due to coronary heart disease or heart failure were detected.
Aro et al Table 2
QRS Transition Zone and Risk of SCD
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Risk of death in subjects with delayed QRS transition
All-cause mortality No. of deaths Unadjusted HR Age- and sex-adjusted HR Multivariate adjusted HR, model Multivariate adjusted HR, model Coronary mortality No. of deaths Unadjusted HR Age- and sex-adjusted HR Multivariate adjusted HR, model Multivariate adjusted HR, model Sudden cardiac death No. of deaths Unadjusted HR Age- and sex-adjusted HR Multivariate adjusted HR, model Multivariate adjusted HR, model
Transition oV4
Transition ZV4
Transition ZV5
P value
(N ¼ 9045)
(N ¼ 1770)
(N ¼ 146)
oV4 vs ZV4
oV4 vs ZV5
A* B†
4946 1 1 1 1
1154 1.38 (1.29–1.47) 1.18 (1.10–1.26) 1.15 (1.07–1.22) 1.13 (1.05–1.21)
109 1.92 (1.59–2.32) 1.44 (1.19–1.75) 1.30 (1.07–1.58) 1.27 (1.04–1.56)
o.001 o.001 o.001 .001
o.001 o.001 .010 .020
A* B†
1571 1 1 1 1
382 1.42 (1.27–1.59) 1.21 (1.08–1.36) 1.12 (1.00–1.26) 1.08 (0.96–1.21)
37 2.01 (1.45–2.79) 1.56 (1.13–2.17) 1.32 (0.94–1.85) 1.19 (0.84–1.68)
o.001 .001 .050 0.23
o.001 .008 0.11 0.34
A* B†
631 1 1 1 1
160 1.46 (1.23–1.74) 1.28 (1.08–1.53) 1.23 (1.03–1.47) 1.15 (0.96–1.38)
19 2.49 (1.58–3.94) 2.11 (1.34–3.33) 1.89 (1.18–3.03) 1.64 (1.00–2.69)
o.001 .005 .029 0.14
o.001 .001 .008 .048
Hazard ratio (HR) values are given as HR (95% confidence interval). * Adjusted for age, gender, body mass index, systolic blood pressure, ECG left ventricular hypertrophy, baseline cardiovascular disease, QRS duration, QRS axis, and heart rate. † Adjusted for age, gender, body mass index, systolic blood pressure, ECG left ventricular hypertrophy, baseline cardiovascular disease, QRS duration, QRS axis, heart rate, QTc, early repolarization, T-wave inversion, and QRS-T angle.
Discussion The results of the present study demonstrate that even a moderately delayed QRS transition zone, a phenomenon sometimes called clockwise rotation of the heart, is associated with increased mortality and risk of SCD in the general
Figure 2 Kaplan–Meier survival plots for sudden cardiac death in subjects with markedly delayed QRS transition zone at lead V5 or beyond. They are compared by log-rank analysis with subjects having QRS transition occurring before lead V5.
population. When QRS transition is markedly delayed, that is, it occurs at lead V5 or later, the risk of SCD is 460% higher than in the group with a normal transition zone after adjustments for several clinical and ECG parameters. It is well established that numerous abnormalities in the ECG are associated with reduced survival among patients with structural heart disease.13 However, especially during the last decade, several ECG variables have been identified that predict SCD in subjects without overt cardiac disease. For example, prolonged QRS duration, LVH, ST-T abnormalities, wide QRS-T angle, prolonged QT-interval, and inferior ER pattern have been linked to increased risk of SCD in studies conducted among the general population.5–7,14,15 QRS transition zone is another parameter easily estimated from the precordial leads of a 12-lead ECG, and, based on the present study, delayed QRS transition can be added to the growing list of ECG variables that may prove helpful in SCD risk stratification in the general population. In the present study, delayed transition at V4 or later was a relatively common phenomenon, occurring in 16% of the study population. This is significantly higher than the 8% reported in Japanese population,16 a difference that likely is due to the different demographics between the peoples. However, markedly delayed transition at V5 or later was a much rarer finding, occurring in only 1.3% of the Finnish subjects. Despite the simplicity of transition zone determination, only a few studies have addressed its prognostic significance. In a Finnish study from the 1980s, stroke mortality was higher in elderly patients with clockwise rotation of the heart, that is, with delayed transition zone.17 In a recent study from
6 Japan using the NIPPON DATA80 database, Nakamura et al16 examined the relationship between Minnesota-coded clockwise and counterclockwise rotation and outcome. During the 24-year follow-up of 9067 participants, a 15% increase in mortality was observed in the group with clockwise rotation. Those results are in line with the present study, as in the Finnish population (surprisingly corresponding to the Japanese study), delayed transition was associated with a 13% increase and markedly delayed transition with a 27% increase in all-cause mortality. The Japanese study also hinted that counterclockwise rotation was inversely associated with cardiovascular mortality.16 Correspondingly, in the present study, a rightward shift of the transition zone seemed to be associated with somewhat lower mortality, although this finding mainly lost statistical significance after adjustments for baseline characteristics. QRS transition zone is only partly explained by the true cardiac position. When studied by cardiac computed tomography, only about two thirds of the early or delayed transition was explained by real counterclockwise or clockwise anatomic rotation of the heart.18 Several clinical conditions, such as acute massive pulmonary embolism19 and increased heart volume and hypertrophy as seen in severe aortic insufficiency,20 have been demonstrated to result in delayed transition. In heart failure patients, shift of the horizontal QRS axis from the left to a more posterior direction has also been associated with an adverse prognosis.21 However, these unusual conditions do not explain the increased risk of SCD observed in our study population. The reasons behind increased risk of SCD associated with a shift in the transition zone deserve attention. An increase in some traditional cardiovascular risk markers, such as age, BMI, blood pressure, and heart rate, was observed with a delayed transition zone, and cardiovascular disease was more prevalent among these subjects. Thus, it is possible that delayed transition serves as an ECG indicator of these risk factors despite the efforts to exclude their influence with multivariate adjustments to the analyses. Incorporating parameters representing altered repolarization known to be associated with SCD attenuated the risk associated with delayed transition. These findings hint that delayed transition could serve as a marker of underlying subclinical cardiac disease, which could, by altering cardiac chamber and wall geometry, cause changes in the transition zone. Indeed, ventricular dilation can be responsible for a posterior shift of the depolarization vector, which can present as delayed QRS transition in the precordial leads.22 Poor R-wave progression may sometimes accompany the leftward shift of the QRS transition zone. This phenomenon usually is a variant of normal ECG with diminished anterior depolarization forces, but small R waves in the precordial leads can sometimes also result from a clinical condition such as remote anterior myocardial infarction, or right or left ventricular hypertrophy, which could predispose an individual to SCD.23 However, in the present study, the impact of delayed transition on coronary mortality or hospitalizations was minimal. Moreover, when subjects with suspected
Heart Rhythm, Vol 0, No 0, Month 2014 cardiovascular disease were excluded from the analyses, mortality risk did not change markedly; hence, prior myocardial infarction is an unlikely explanation for the increased SCD risk in this study. BMI and obesity were strongly associated with delayed transition in the present study. Obesity has been reported to cause leftward shift of the frontal QRS axis, a phenomenon that can be at least partly reversed with weight loss.24 QRS axis change in obese patients can be related to a leftward and more horizontal orientation of the heart attributed to increased diaphragmatic pressure, but it also can reflect the presence of LVH, which often is linked with obesity.25 Obesity can result in abnormal repolarization phase and pathologic myocardial changes, such as myocyte hypertrophy, fibrosis, and fat infiltration, which may also account for increased SCD risk.26 Increased thickness of the left ventricular free wall may cause leftward and posterior horizontal shift of the electrical axis of the heart. In the present study, delayed transition zone was associated with significantly higher blood pressures and leftward shift in the frontal axis often seen with LVH. Higher prevalence of obesity with delayed transition renders traditional ECG LVH criteria less useful in this population. Although adjustments were made for LVH in the analysis, because no echocardiographic data were available to more reliably identify hypertrophy, LVH can be 1 possible explanation for the SCD risk associated with delayed transition, as it is well known that a hypertrophied ventricular myocardium can serve as a substrate for ventricular arrhythmias.27
Study limitations Some limitations of the present study deserve attention. The results are based only on single recorded ECG, so perpetuity of the shifted transition zones cannot be estimated. Although electrode placement was rigorously controlled during the study, it is possible that in some cases shift of the transition zone is due to inaccurate positioning of the precordial leads. However, this more likely would result in conservative bias and attenuate the estimated SCD risk. Echocardiography was not available at the time of baseline examination, so we could not assess the relationship between delayed QRS transition and structural cardiac pathology such as ventricular hypertrophy or dilation.
Conclusion Our study findings indicate that in the middle-aged general population, delayed QRS transition, especially to V5 and beyond, is associated with increased risk of SCD, independent of clinical confounding factors and ECG changes. As an easily estimated ECG pattern, transition zone may have practical utility for SCD risk stratification and for identifying patients who may benefit most from a more meticulous approach to cardiovascular risk factor modification and closer follow-up. Further research is needed to study the mechanisms behind this phenomenon.
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References 1. Deo R, Albert CM. Epidemiology and genetics of sudden cardiac death. Circulation 2012;125:620–637. 2. Estes NA 3rd. Predicting and preventing sudden cardiac death. Circulation 2011;124:651–656. 3. Aro AL, Huikuri HV. Electrocardiographic predictors of sudden cardiac death from a large Finnish general population cohort. J.Electrocardiol 2013;46: 434–438. 4. Mirvis DM, Goldberger AL. Electrocardiography. In: Libby P, Bonow RO, Mann DL, Zipes DP, eds. Braunwald’s Heart Disease. A Textbook of Cardiovascular Medicine, 8th Edition. Philadelphia: Saunders Elsevier; 2008:149–193. 5. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529–2537. 6. Aro AL, Huikuri HV, Tikkanen JT, Junttila MJ, Rissanen HA, Reunanen A, Anttonen O. QRS-T angle as a predictor of sudden cardiac death in a middle-aged general population. Europace 2012;14:872–876. 7. Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Prevalence and prognostic significance of T-wave inversions in right precordial leads of a 12-lead electrocardiogram in the middleaged subjects. Circulation 2012;125:2572–2577. 8. Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Intraventricular conduction delay in a standard 12-lead electrocardiogram as a predictor of mortality in the general population. Circ Arrhythm Electrophysiol 2011;4:704–710. 9. Reunanen A, Aromaa A, Pyorala K, Punsar S, Maatela J, Knekt P. The Social Insurance Institution's coronary heart disease study: baseline data and 5-year mortality experience. Acta Med Scand Suppl 1983;673:1–120. 10. Rapola JM, Virtamo J, Korhonen P, Haapakoski J, Hartman AM, Edwards BK, Heinonen OP. Validity of diagnoses of major coronary events in national registers of hospital diagnoses and deaths in Finland. Eur J Epidemiol 1997;13:133–138. 11. Greene HL, Richardson DW, Barker AH, Roden DM, Capone RJ, Echt DS, Friedman LM, Gillespie MJ, Hallstrom AP, Verter J. Classification of deaths after myocardial infarction as arrhythmic or nonarrhythmic (the Cardiac Arrhythmia Pilot Study). Am J Cardiol 1989;63:1–6. 12. Romhilt DW, Estes EH Jr. A point-score system for the ECG diagnosis of left ventricular hypertrophy. Am Heart J 1968;75:752–758. 13. Zimetbaum PJ, Buxton AE, Batsford W, Fisher JD, Hafley GE, Lee KL, O'Toole MF, Page RL, Reynolds M, Josephson ME. Electrocardiographic predictors of arrhythmic death and total mortality in the multicenter unsustained tachycardia trial. Circulation 2004;110:766–769. 14. Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, Deckers JW, Kingma JH, Sturkenboom MC, Stricker BH, Witteman JC.
15.
16.
17. 18.
19.
20.
21. 22.
23. 24.
25. 26.
27.
Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 2006;47:362–367. Kannel WB, Abbott RD. A prognostic comparison of asymptomatic left ventricular hypertrophy and unrecognized myocardial infarction. the Framingham Study. Am Heart J 1986;111:391–397. Nakamura Y, Okamura T, Higashiyama A, Watanabe M, Kadota A, Ohkubo T, Miura K, Kasagi F, Kodama K. Okayama A, Ueshima H, NIPPON DATA80 Research Group. Prognostic values of clockwise and counterclockwise rotation for cardiovascular mortality in Japanese subjects: a 24-year follow-up of the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980-2004 (NIPPON DATA80). Circulation 2012;125:1226–1233. Rajala S, Haavisto M, Kaltiala K, Mattila K. Electrocardiographic findings and 5year cardiovascular mortality in very old people. Ann Clin Res 1987;19:324–327. Tahara Y, Mizuno H, Ono A, Ishikawa K. Evaluation of the electrocardiographic transitional zone by cardiac computed tomography. J Electrocardiol 1991;24: 239–245. Yoshinaga T, Ikeda S, Shikuwa M, Miyahara Y, Kohno S. Relationship between ECG findings and pulmonary artery pressure in patients with acute massive pulmonary thromboembolism. Circ J 2003;67:229–232. Sobrino JA, Mate I, Codina J, Rico J, Sobrino N. Vectorcardiograms in severe aortic insufficiency: clockwise rotation of QRS loop in the horizontal plane. Chest 1975;67:568–572. Xiao HB, McCan S, Kaufman B. The prognostic significance of horizontal plane QRS axis in elderly heart failure. Int J Cardiol 2006;106:196–200. Bayes de, Luna A. Ventricular enlargement. In: Anonymous. Clinical Electrocardiography: A Textbook. In: 4th Edition. Oxford, UK: Wiley-Blackwell; 2012: 123–157. Zema MJ, Kligfield P. ECG poor R-wave progression. review and synthesis. Arch Intern Med 1982;142:1145–1148. Alpert MA, Terry BE, Hamm CR, Fan TM, Cohen MV, Massey CV, Painter JA. Effect of weight loss on the ECG of normotensive morbidly obese patients. Chest 2001;119:507–510. Fraley MA, Birchem JA, Senkottaiyan N, Alpert MA. Obesity and the electrocardiogram. Obes Rev 2005;6:275–281. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH, American Heart Association, Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2006;113:898–918. Wolk R. Arrhythmogenic mechanisms in left ventricular hypertrophy. Europace 2000;2:216–223.
CLINICAL PERSPECTIVES QRS transition zone can be easily determined from the standard 12-lead ECG by observing in which precordial lead the R wave of the QRS complex exceeds the S wave in amplitude. In the present study conducted among a middle-aged general population, we addressed for the first time the risk of SCD associated with the transition zone. Delayed QRS transition zone correlated strongly with traditional cardiovascular risk factors, but even after adjusting for several clinical and ECG parameters, delayed transition at V4 or beyond was associated with mildly increased mortality. Markedly delayed transition at V5 or beyond was a much rarer finding, being present in only 1.3% of the population, but it was associated with a 27% increase in mortality and a 64% increase in the risk of SCD. As an easily estimated ECG pattern, the QRS transition zone may help clinicians to identify asymptomatic individuals with an unfavorable cardiovascular risk profile and who may have an elevated risk of SCD in the future. Thus, subjects who are found to have a markedly delayed QRS transition zone on routine ECG may benefit from a more rigorous approach to traditional cardiovascular risk factor modification and closer follow-up.
Introduction Sudden cardiac death (SCD) is a major medical and public health concern responsible for up to 50% of cardiovascular deaths and 15% to 20% of overall mortality, with coronary heart disease being the underlying cause of most of these deaths.1 The majority of sudden deaths occur among subjects with no previously diagnosed cardiac disease or in subjects Dr. Aro was supported by grants from the Paavo Nurmi Foundation and the Finnish Foundation for Cardiovascular Research. Dr. Porthan was supported by grants from the Aarne Koskelo Foundation, the Finnish Foundation for Cardiovascular Research, and the Finnish Medical Foundation. Address reprint requests and correspondence: Dr. Aapo Aro, Division of Cardiology, Heart and Lung Center, Helsinki University Central Hospital, Haartmaninkatu 4, PL340, 00029 HUS, Helsinki, Finland. E-mail address: aapo.aro@helsinki.fi.
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
ratio [HR] 1.15, 95% confidence interval [CI] 1.07–1.22, P o .001) and SCD (HR 1.23, 95% CI 1.03–1.47, P ¼ .029). Markedly delayed transition at V5 or later predicted significantly SCD (HR 1.89, 95% CI 1.18–3.03, P ¼ .008) and all-cause mortality (HR 1.30, 95% CI 1.07–1.58, P ¼ .01). However, further adjustments for repolarization abnormalities attenuated this effect. CONCLUSION Delayed QRS transition in the precordial leads of an ECG seems to be a novel ECG risk marker for SCD. In particular, markedly delayed transition was associated with significantly increased risk of SCD, independent of confounding factors. KEYWORDS Sudden cardiac death; Electrocardiography; QRS transition; Population; Clockwise rotation ABBREVIATIONS BMI ¼ body mass index; BP ¼ blood pressure; CI ¼ confidence interval; ECG ¼ electrocardiography; ER ¼ early repolarization; HR ¼ hazard ratio; LVH ¼ left ventricular hypertrophy; SCD ¼ sudden cardiac death (Heart Rhythm 2014;0:1–7) rights reserved.
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2014 Heart Rhythm Society. All
consider to be at low risk; thus, there has been growing interest in identifying these individuals before the devastating SCD event. Common risk factors for atherosclerosis predict nonspecifically SCD,2 and large epidemiologic surveys have recently pursued ECG risk markers for SCD.3 The QRS transition zone is an ECG phenomenon related to the electrical axis of the heart in the horizontal plane. However, unlike the frontal QRS axis, information on the horizontal axis has been largely neglected in clinical practice. The transition zone can be readily established from the standard 12-lead ECG by determining the precordial lead in which the R wave of the QRS complex exceeds the S wave in amplitude. Although the transition zone does not precisely correlate with the position of the heart in the chest, delayed transition leftward from lead V4 has been traditionally called http://dx.doi.org/10.1016/j.hrthm.2014.08.014
2 clockwise rotation and early transition before V3 counterclockwise rotation of the heart.4 Few studies have investigated the prognostic significance associated with delayed QRS transition, and, to our knowledge, no previous studies exist on its value in predicting SCD. Based on a 30-year follow-up of nearly 11,000 middleaged Finnish individuals, we previously described several ECG depolarization and repolarization patterns that have been associated with SCD.5–8 The aim of the present study was to determine, from the same general population cohort, whether delayed QRS transition zone predicts SCD in the general population and whether it yields additional prognostic information on top of clinical risk factors and ECG patterns associated with SCD.
Methods Study population The original study population consisted of 10,899 men and women between the ages of 30 and 59 years (52% male, mean age 44.0 ⫾ 8.5 years) for whom an ECG was recorded as part of the Finnish Social Insurance Institution’s CHD Study, which comprised 12 population groups from 4 different geographical areas in Finland with variable mortality and morbidity rates representative of the middle-aged Finnish population. Baseline examinations were performed from 1966 to 1972, and 89.6% of the invited subjects participated in the study. Eighty-four ECGs were excluded because of left or right bundle branch block, second- or third-degree AV block, paced rhythm, or ventricular preexcitation; thus, our final study group included 10,815 subjects from the original cohort.
Baseline examination and ECG measurements A detailed account of the study rationale, procedures performed at baseline examinations, and ECG measurements has been described previously.9 In brief, during the initial visit, in addition to standard 12-lead ECG recording, the participants were measured and weighed, their blood pressure (BP) was determined, and they underwent routine laboratory assessment of traditional cardiovascular risk factors. Before the examination, subjects completed a questionnaire about their previous illnesses, smoking habits, and medications, which was then checked by a specially trained nurse. Any cardiovascular symptoms were documented during the examination. Hypertension was defined as systolic BP Z160 mm Hg, diastolic BP Z100 mm Hg or antihypertensive medication, and obesity as body mass index (BMI) Z30 kg/m2. Thirty minutes after arrival at the Mobile Clinic, a standard 12-lead ECG was recorded with the subject at rest in the supine position. Paper speed was 50 mm/s, calibration was 1 mV/10 mm, and each ECG sheet contained on average 7 to 8 QRS complexes. Eight trained technicians supervised by a doctor obtained the initial measurements, and the quality of the recordings and positioning of the electrodes were systematically monitored. QRS duration and QT interval were measured, and the presence or absence of ECG left ventricular hypertrophy (LVH) according to the
Heart Rhythm, Vol 0, No 0, Month 2014 Sokolow-Lyon criteria (SV1 þ RV5 or RV6 Z35 mm) and Romhilt-Estes criteria (Z5 points) was assessed. Frontal QRS axis and T-wave axis were determined from the limb leads at 101 intervals, and the QRS-T angle was calculated as the absolute value of the difference between QRS and T-wave axes. Later, ECGs were reanalyzed for the presence of early repolarization (ER) pattern and T-wave inversions, as previously described.5,7 The transition zone was determined manually from the precordial leads by determining where the QRS pattern changed from an rS to an Rs configuration, or in which lead an isoelectric RS pattern was present. If the transition occurred before V3, it was considered early; if it occurred at V4 or leftward from V4, transition was considered delayed; and if it occurred at V5 or beyond, transition was considered markedly delayed. The transition zone was considered normal when transition occurred at V3 or between V3 and V4. To minimize errors in the process and to assess the reliability of the ECG measurements, all readers were continuously evaluated using a separate standard ECG material that was not part of the study. When compared with the reference values, intraclass correlation coefficient of r = 0.91 was demonstrated between all readers and the test material for measuring the transition zone. Of note, intraclass correlation coefficient of 0.50 indicates moderate, 0.75 excellent, and 1.0 perfect correlation.
Follow-up Participants were followed from the baseline visit that occurred between 1966 and 1972 through the end of 2007, with mean follow-up of 30 ⫾ 11 years. Fewer than 2% of the subjects were lost to as a result of moving abroad, but the survival status of most of these subjects could still be determined. All episodes of hospitalization due to atrial fibrillation, heart failure, and coronary heart disease were obtained from the Finnish Hospital Discharge Register, which includes nationwide data on all inpatient episodes in Finland at an individual level. Mortality data were obtained from the Causes of Death Register maintained by Statistics Finland, which records every death in the country. The quality and reliability of these extensive registers have been previously validated.10 Death certificates were obtained for each deceased individual. Death from coronary heart disease was determined according to the appropriate International Classification of Diseases (ICD) codes (representing I20- to I25- codes in the ICD-10). To identify cases of definite or probable arrhythmic deaths, all deaths from cardiac causes were reviewed using death certificates, hospital records, and autopsy reports (if available) using the definitions of SCD presented in the Cardiac Arrhythmia Pilot Study,11 as we described previously.5
Statistical analysis All continuous data are presented as mean ⫾ SD. A general linear model was used to compare age- and sex-adjusted mean values for continuous variables and prevalence of categorical variables between groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) for death and hospitalization were
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QRS Transition Zone and Risk of SCD
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calculated using the Cox proportional hazards models. Main end-points were all-cause mortality, coronary mortality, and SCD. The primary adjustments in these models were for age and gender, with further adjustment for covariates that differed between the group with delayed transition and rest of the cohort. Age, heart rate, systolic BP, BMI, QRS axis, and QRS duration were added as continuous variables. Gender, baseline cardiovascular disease, and the presence or absence of an ECG LVH according to either Romhilt-Estes or Sokolow-Lyon criteria were added as categorical variables in the multivariate model A. Diastolic BP was omitted because of marked colinearity with systolic BP. In addition to these variables, in the multivariate model B, inferolateral ER and T-wave inversions were added as categorical variables, and QTc and QRS-T angle as continuous variables. To further assess the differences in SCD between groups, Kaplan–Meier survival curves were plotted and the significance of the difference between them tested with the logrank test. Statistical analyses were performed using SPSS Statistics software (version 21.0, IBM Corp, Armonk NY). Two-sided statistical tests were used, and P o .05 was considered significant.
Results Baseline characteristics A total of 10,815 subjects had a transition zone determined from ECG. Early QRS transition before lead V3 (counterclockwise rotation) occurred in 2861 subjects (26.4%), very early transition before V2 (distinct counterclockwise rotation) in 334 (3.1%), normal transition at V3 or before V4 in 6184 (57.2%), and delayed transition at lead V4 or beyond (clockwise rotation) in 1770 (16.4%). In 146 subjects (1.3%), transition was markedly delayed and shifted leftward to lead V5 or V6 (distinct clockwise rotation). An example of a markedly delayed transition is shown in Figure 1. Of the subjects with delayed transition, 959 were men (17.0% of all men) and 811 were women (15.7% of all women). Prevalence of delayed transition increased significantly with age, being 13.1% among subjects aged 30–39 years, 15.4% among subjects aged 40–49 years, and 21.5% among subjects aged 50–59 years (P o .001 for difference between groups). BMI was also strongly associated with the proportion of subjects presenting with delayed transition. In the lowest quintile (BMI o22.7 kg/m2), 12.2% of the subjects had delayed transition compared to 25.4% in the highest quintile (BMI 428.7 kg/m2). Baseline characteristics of the participants are given in Table 1. Subjects with delayed transition were older, more likely were male, had higher BMI and higher blood pressure, and were more likely to have suspected cardiovascular disease than were subjects with normal transition. They also had slightly longer QRS and QTc durations, had more inverted T waves, and presented with a more leftward frontal axis and wider QRS-T angle than the rest of the subjects. According to the Sokolow-Lyon voltage criteria, LVH was less common among subjects with delayed QRS transition. However, according to the point score of Romhilt and Estes,
Figure 1 Twelve-lead ECG of a 49-year-old woman with body mass index of 32 kg/m2 who presented with markedly delayed QRS transition zone at lead V5, a slight leftward shift of the frontal QRS axis, and QRS duration of 100 ms. She experienced sudden cardiac death during follow-up. Paper speed is 50 mm/s.
which incorporates, in addition to voltage criteria, abnormal QRS axis and QRS duration, QRS onset to peak time, and P-wave and ST-T morphology,12 LVH was more frequent in the group with delayed transition.
4 Table 1
Heart Rhythm, Vol 0, No 0, Month 2014 Age- and gender-adjusted baseline characteristics of subjects according to transition zone
Males (%)* Age (years)† Current smoker (%) Cholesterol (mmol/L)‡ BMI (kg/m2) Heart rate (bpm) Systolic BP (mm Hg) Diastolic BP (mm Hg) Hypertension (%) Obesity (%) Chronotropic medication (%) Cardiovascular disease (%) History of myocardial infarction (%) LVH Sokolow-Lyon (%) LVH Romhilt-Estes (%) QTc duration (ms) QRS duration (ms) QRS axis (degrees) QRS axis o–301 (%) Inferolateral ER Z0.1 mV (%) T-wave inversions (%) QRS-T angle (1)
Normal transition (transition oV4)
Early transition (transition oV3)
Delayed transition (transition ZV4)
Very delayed transition (transition ZV5)
P value
(N ¼ 9045)
(N ¼ 2861)
(N ¼ 1770)
(N ¼ 146)
oV3 vs ZV3
oV4 vs ZV4
oV4 vs ZV5
51.8 43.7 ⫾ 8.4 34.0 6.51 ⫾ 1.32 25.7 ⫾ 3.7 76 ⫾ 15 138 ⫾ 21 82 ⫾ 12 18.8 12.2 3.7 7.6 1.1 34.1 6.4 408 ⫾ 27 87 ⫾ 8 38 ⫾ 30 1.3 6.0 1.1 27 ⫾ 23
52.0 43.6 ⫾ 8.4 32.6 6.52 ⫾ 1.30 25.7 ⫾ 3.6 76 ⫾ 15 137 ⫾ 20 81 ⫾ 12 16.7 12.0 3.4 7.0 0.8 35.4 6.9 408 ⫾ 27 86 ⫾ 8 37 ⫾ 27 1.0 6.6 1.1 24 ⫾ 30
54.6 45.7 ⫾ 8.4 34.1 6.48 ⫾ 1.32 27.0 ⫾ 4.5 76 ⫾ 16 141 ⫾ 24 85 ⫾ 14 27.5 22.5 7.1 10.4 1.3 18.2 8.6 410 ⫾ 29 87 ⫾ 8 31 ⫾ 42 6.5 5.1 1.8 37 ⫾ 31
50.3 48.5 ⫾ 8.1 31.5 6.53 ⫾ 1.37 28.5 ⫾ 5.3 81 ⫾ 19 144 ⫾ 28 87 ⫾ 17 34.9 41.1 8.5 15.8 1.1 10.8 10.9 414 ⫾ 31 88 ⫾ 8 15 ⫾ 56 22.5 5.3 1.2 52 ⫾ 39
0.76 .004 .043 0.57 .009 0.67 o.001 o.001 o.001 o.001 .004 .009 .07 o.001 0.27 0.23 .01 0.57 o.001 .046 0.63 o.001
.04 o.001 0.92 0.32 o.001 .09 o.001 o.001 o.001 o.001 o.001 o.001 0.31 o.001 .001 .009 o.001 o.001 o.001 0.15 .009 o.001
0.47 o.001 0.47 0.72 o.001 o.001 .005 o.001 o.001 o.001 .06 .002 0.90 o.001 .03 .02 .02 o.001 o.001 0.74 0.88 o.001
Values are given as mean ⫾ SD unless otherwise indicated. BMI ¼ body mass index; BP ¼ blood pressure; ER ¼ early repolarization; LVH ¼ left ventricular hypertrophy; QTc ¼ QT corrected for heart rate according to the Bazett formula. * Adjusted for age. † Adjusted for gender. ‡ To convert the values of cholesterol to mg/dL, divide by 0.02586.
Delayed QRS transition and outcome events During mean follow-up of 30 ⫾ 11 years, 6100 of the 10,815 participants (56.4%) died. Of these deaths, 1953 (32.0% of all-cause mortality) were due to coronary heart disease, and 791 (13.0% of all-cause mortality) were classified as SCD. Unadjusted and adjusted HRs for fatal outcomes according to the transition zone are given in Table 2. Delayed transition predicted all-cause mortality and SCD after several adjustments (model A). When parameters representing repolarization abnormalities were added to the model (model B), only all-cause mortality remained statistically significant. The outcomes remained similar in further analysis in which subjects with suspected cardiovascular disease were excluded. In this group of 9940 persons, delayed transition was moderately associated with all-cause mortality (HR 1.11, 95% CI 1.03–1.19, P ¼ .004) and SCD (HR 1.22, 95% CI 1.00–1.49, P ¼ .045) in model A. When subjects with QRS axis o–301 were excluded from the analysis (remaining N ¼ 10,421), risk for SCD did not change markedly (HR 1.22, 95% CI 1.01–1.47, P ¼ .041). The risk of fatal events appeared even higher when QRS transition was more markedly delayed, occurring at lead V5 or leftward (Table 2). When this group was analyzed
separately, adjusted HR for SCD was 1.64 and HR for allcause mortality was 1.27 (model B). Kaplan–Meier survival curves for SCD in subjects with markedly delayed transition are shown in Figure 2. Delayed transition was not associated with an increase in hospitalizations due to coronary heart disease, atrial fibrillation, or heart failure.
Early QRS transition: Characteristics and outcome People with early transition occurring before V3 were slightly younger, were less likely to smoke, had a slightly lower BMI and blood pressure, and were less likely to have cardiovascular disease or be taking medication than the rest of the subjects (Table 1). When subjects with early transition were compared with rest of the population, after adjusting for age and gender, a slightly increased overall survival was observed (HR for allcause mortality 0.94, 95% CI 0.89–1.00, P ¼ .03), but this finding lost statistical significance after further adjustments. Fewer atrial fibrillation hospitalizations were observed even after multivariate adjustments in this group (HR 0.85, 95% CI 0.76–0.95, P ¼ .006), but no significant differences in coronary mortality, SCD, or hospitalization due to coronary heart disease or heart failure were detected.
Aro et al Table 2
QRS Transition Zone and Risk of SCD
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Risk of death in subjects with delayed QRS transition
All-cause mortality No. of deaths Unadjusted HR Age- and sex-adjusted HR Multivariate adjusted HR, model Multivariate adjusted HR, model Coronary mortality No. of deaths Unadjusted HR Age- and sex-adjusted HR Multivariate adjusted HR, model Multivariate adjusted HR, model Sudden cardiac death No. of deaths Unadjusted HR Age- and sex-adjusted HR Multivariate adjusted HR, model Multivariate adjusted HR, model
Transition oV4
Transition ZV4
Transition ZV5
P value
(N ¼ 9045)
(N ¼ 1770)
(N ¼ 146)
oV4 vs ZV4
oV4 vs ZV5
A* B†
4946 1 1 1 1
1154 1.38 (1.29–1.47) 1.18 (1.10–1.26) 1.15 (1.07–1.22) 1.13 (1.05–1.21)
109 1.92 (1.59–2.32) 1.44 (1.19–1.75) 1.30 (1.07–1.58) 1.27 (1.04–1.56)
o.001 o.001 o.001 .001
o.001 o.001 .010 .020
A* B†
1571 1 1 1 1
382 1.42 (1.27–1.59) 1.21 (1.08–1.36) 1.12 (1.00–1.26) 1.08 (0.96–1.21)
37 2.01 (1.45–2.79) 1.56 (1.13–2.17) 1.32 (0.94–1.85) 1.19 (0.84–1.68)
o.001 .001 .050 0.23
o.001 .008 0.11 0.34
A* B†
631 1 1 1 1
160 1.46 (1.23–1.74) 1.28 (1.08–1.53) 1.23 (1.03–1.47) 1.15 (0.96–1.38)
19 2.49 (1.58–3.94) 2.11 (1.34–3.33) 1.89 (1.18–3.03) 1.64 (1.00–2.69)
o.001 .005 .029 0.14
o.001 .001 .008 .048
Hazard ratio (HR) values are given as HR (95% confidence interval). * Adjusted for age, gender, body mass index, systolic blood pressure, ECG left ventricular hypertrophy, baseline cardiovascular disease, QRS duration, QRS axis, and heart rate. † Adjusted for age, gender, body mass index, systolic blood pressure, ECG left ventricular hypertrophy, baseline cardiovascular disease, QRS duration, QRS axis, heart rate, QTc, early repolarization, T-wave inversion, and QRS-T angle.
Discussion The results of the present study demonstrate that even a moderately delayed QRS transition zone, a phenomenon sometimes called clockwise rotation of the heart, is associated with increased mortality and risk of SCD in the general
Figure 2 Kaplan–Meier survival plots for sudden cardiac death in subjects with markedly delayed QRS transition zone at lead V5 or beyond. They are compared by log-rank analysis with subjects having QRS transition occurring before lead V5.
population. When QRS transition is markedly delayed, that is, it occurs at lead V5 or later, the risk of SCD is 460% higher than in the group with a normal transition zone after adjustments for several clinical and ECG parameters. It is well established that numerous abnormalities in the ECG are associated with reduced survival among patients with structural heart disease.13 However, especially during the last decade, several ECG variables have been identified that predict SCD in subjects without overt cardiac disease. For example, prolonged QRS duration, LVH, ST-T abnormalities, wide QRS-T angle, prolonged QT-interval, and inferior ER pattern have been linked to increased risk of SCD in studies conducted among the general population.5–7,14,15 QRS transition zone is another parameter easily estimated from the precordial leads of a 12-lead ECG, and, based on the present study, delayed QRS transition can be added to the growing list of ECG variables that may prove helpful in SCD risk stratification in the general population. In the present study, delayed transition at V4 or later was a relatively common phenomenon, occurring in 16% of the study population. This is significantly higher than the 8% reported in Japanese population,16 a difference that likely is due to the different demographics between the peoples. However, markedly delayed transition at V5 or later was a much rarer finding, occurring in only 1.3% of the Finnish subjects. Despite the simplicity of transition zone determination, only a few studies have addressed its prognostic significance. In a Finnish study from the 1980s, stroke mortality was higher in elderly patients with clockwise rotation of the heart, that is, with delayed transition zone.17 In a recent study from
6 Japan using the NIPPON DATA80 database, Nakamura et al16 examined the relationship between Minnesota-coded clockwise and counterclockwise rotation and outcome. During the 24-year follow-up of 9067 participants, a 15% increase in mortality was observed in the group with clockwise rotation. Those results are in line with the present study, as in the Finnish population (surprisingly corresponding to the Japanese study), delayed transition was associated with a 13% increase and markedly delayed transition with a 27% increase in all-cause mortality. The Japanese study also hinted that counterclockwise rotation was inversely associated with cardiovascular mortality.16 Correspondingly, in the present study, a rightward shift of the transition zone seemed to be associated with somewhat lower mortality, although this finding mainly lost statistical significance after adjustments for baseline characteristics. QRS transition zone is only partly explained by the true cardiac position. When studied by cardiac computed tomography, only about two thirds of the early or delayed transition was explained by real counterclockwise or clockwise anatomic rotation of the heart.18 Several clinical conditions, such as acute massive pulmonary embolism19 and increased heart volume and hypertrophy as seen in severe aortic insufficiency,20 have been demonstrated to result in delayed transition. In heart failure patients, shift of the horizontal QRS axis from the left to a more posterior direction has also been associated with an adverse prognosis.21 However, these unusual conditions do not explain the increased risk of SCD observed in our study population. The reasons behind increased risk of SCD associated with a shift in the transition zone deserve attention. An increase in some traditional cardiovascular risk markers, such as age, BMI, blood pressure, and heart rate, was observed with a delayed transition zone, and cardiovascular disease was more prevalent among these subjects. Thus, it is possible that delayed transition serves as an ECG indicator of these risk factors despite the efforts to exclude their influence with multivariate adjustments to the analyses. Incorporating parameters representing altered repolarization known to be associated with SCD attenuated the risk associated with delayed transition. These findings hint that delayed transition could serve as a marker of underlying subclinical cardiac disease, which could, by altering cardiac chamber and wall geometry, cause changes in the transition zone. Indeed, ventricular dilation can be responsible for a posterior shift of the depolarization vector, which can present as delayed QRS transition in the precordial leads.22 Poor R-wave progression may sometimes accompany the leftward shift of the QRS transition zone. This phenomenon usually is a variant of normal ECG with diminished anterior depolarization forces, but small R waves in the precordial leads can sometimes also result from a clinical condition such as remote anterior myocardial infarction, or right or left ventricular hypertrophy, which could predispose an individual to SCD.23 However, in the present study, the impact of delayed transition on coronary mortality or hospitalizations was minimal. Moreover, when subjects with suspected
Heart Rhythm, Vol 0, No 0, Month 2014 cardiovascular disease were excluded from the analyses, mortality risk did not change markedly; hence, prior myocardial infarction is an unlikely explanation for the increased SCD risk in this study. BMI and obesity were strongly associated with delayed transition in the present study. Obesity has been reported to cause leftward shift of the frontal QRS axis, a phenomenon that can be at least partly reversed with weight loss.24 QRS axis change in obese patients can be related to a leftward and more horizontal orientation of the heart attributed to increased diaphragmatic pressure, but it also can reflect the presence of LVH, which often is linked with obesity.25 Obesity can result in abnormal repolarization phase and pathologic myocardial changes, such as myocyte hypertrophy, fibrosis, and fat infiltration, which may also account for increased SCD risk.26 Increased thickness of the left ventricular free wall may cause leftward and posterior horizontal shift of the electrical axis of the heart. In the present study, delayed transition zone was associated with significantly higher blood pressures and leftward shift in the frontal axis often seen with LVH. Higher prevalence of obesity with delayed transition renders traditional ECG LVH criteria less useful in this population. Although adjustments were made for LVH in the analysis, because no echocardiographic data were available to more reliably identify hypertrophy, LVH can be 1 possible explanation for the SCD risk associated with delayed transition, as it is well known that a hypertrophied ventricular myocardium can serve as a substrate for ventricular arrhythmias.27
Study limitations Some limitations of the present study deserve attention. The results are based only on single recorded ECG, so perpetuity of the shifted transition zones cannot be estimated. Although electrode placement was rigorously controlled during the study, it is possible that in some cases shift of the transition zone is due to inaccurate positioning of the precordial leads. However, this more likely would result in conservative bias and attenuate the estimated SCD risk. Echocardiography was not available at the time of baseline examination, so we could not assess the relationship between delayed QRS transition and structural cardiac pathology such as ventricular hypertrophy or dilation.
Conclusion Our study findings indicate that in the middle-aged general population, delayed QRS transition, especially to V5 and beyond, is associated with increased risk of SCD, independent of clinical confounding factors and ECG changes. As an easily estimated ECG pattern, transition zone may have practical utility for SCD risk stratification and for identifying patients who may benefit most from a more meticulous approach to cardiovascular risk factor modification and closer follow-up. Further research is needed to study the mechanisms behind this phenomenon.
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QRS Transition Zone and Risk of SCD
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References 1. Deo R, Albert CM. Epidemiology and genetics of sudden cardiac death. Circulation 2012;125:620–637. 2. Estes NA 3rd. Predicting and preventing sudden cardiac death. Circulation 2011;124:651–656. 3. Aro AL, Huikuri HV. Electrocardiographic predictors of sudden cardiac death from a large Finnish general population cohort. J.Electrocardiol 2013;46: 434–438. 4. Mirvis DM, Goldberger AL. Electrocardiography. In: Libby P, Bonow RO, Mann DL, Zipes DP, eds. Braunwald’s Heart Disease. A Textbook of Cardiovascular Medicine, 8th Edition. Philadelphia: Saunders Elsevier; 2008:149–193. 5. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529–2537. 6. Aro AL, Huikuri HV, Tikkanen JT, Junttila MJ, Rissanen HA, Reunanen A, Anttonen O. QRS-T angle as a predictor of sudden cardiac death in a middle-aged general population. Europace 2012;14:872–876. 7. Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Prevalence and prognostic significance of T-wave inversions in right precordial leads of a 12-lead electrocardiogram in the middleaged subjects. Circulation 2012;125:2572–2577. 8. Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Intraventricular conduction delay in a standard 12-lead electrocardiogram as a predictor of mortality in the general population. Circ Arrhythm Electrophysiol 2011;4:704–710. 9. Reunanen A, Aromaa A, Pyorala K, Punsar S, Maatela J, Knekt P. The Social Insurance Institution's coronary heart disease study: baseline data and 5-year mortality experience. Acta Med Scand Suppl 1983;673:1–120. 10. Rapola JM, Virtamo J, Korhonen P, Haapakoski J, Hartman AM, Edwards BK, Heinonen OP. Validity of diagnoses of major coronary events in national registers of hospital diagnoses and deaths in Finland. Eur J Epidemiol 1997;13:133–138. 11. Greene HL, Richardson DW, Barker AH, Roden DM, Capone RJ, Echt DS, Friedman LM, Gillespie MJ, Hallstrom AP, Verter J. Classification of deaths after myocardial infarction as arrhythmic or nonarrhythmic (the Cardiac Arrhythmia Pilot Study). Am J Cardiol 1989;63:1–6. 12. Romhilt DW, Estes EH Jr. A point-score system for the ECG diagnosis of left ventricular hypertrophy. Am Heart J 1968;75:752–758. 13. Zimetbaum PJ, Buxton AE, Batsford W, Fisher JD, Hafley GE, Lee KL, O'Toole MF, Page RL, Reynolds M, Josephson ME. Electrocardiographic predictors of arrhythmic death and total mortality in the multicenter unsustained tachycardia trial. Circulation 2004;110:766–769. 14. Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, Deckers JW, Kingma JH, Sturkenboom MC, Stricker BH, Witteman JC.
15.
16.
17. 18.
19.
20.
21. 22.
23. 24.
25. 26.
27.
Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 2006;47:362–367. Kannel WB, Abbott RD. A prognostic comparison of asymptomatic left ventricular hypertrophy and unrecognized myocardial infarction. the Framingham Study. Am Heart J 1986;111:391–397. Nakamura Y, Okamura T, Higashiyama A, Watanabe M, Kadota A, Ohkubo T, Miura K, Kasagi F, Kodama K. Okayama A, Ueshima H, NIPPON DATA80 Research Group. Prognostic values of clockwise and counterclockwise rotation for cardiovascular mortality in Japanese subjects: a 24-year follow-up of the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980-2004 (NIPPON DATA80). Circulation 2012;125:1226–1233. Rajala S, Haavisto M, Kaltiala K, Mattila K. Electrocardiographic findings and 5year cardiovascular mortality in very old people. Ann Clin Res 1987;19:324–327. Tahara Y, Mizuno H, Ono A, Ishikawa K. Evaluation of the electrocardiographic transitional zone by cardiac computed tomography. J Electrocardiol 1991;24: 239–245. Yoshinaga T, Ikeda S, Shikuwa M, Miyahara Y, Kohno S. Relationship between ECG findings and pulmonary artery pressure in patients with acute massive pulmonary thromboembolism. Circ J 2003;67:229–232. Sobrino JA, Mate I, Codina J, Rico J, Sobrino N. Vectorcardiograms in severe aortic insufficiency: clockwise rotation of QRS loop in the horizontal plane. Chest 1975;67:568–572. Xiao HB, McCan S, Kaufman B. The prognostic significance of horizontal plane QRS axis in elderly heart failure. Int J Cardiol 2006;106:196–200. Bayes de, Luna A. Ventricular enlargement. In: Anonymous. Clinical Electrocardiography: A Textbook. In: 4th Edition. Oxford, UK: Wiley-Blackwell; 2012: 123–157. Zema MJ, Kligfield P. ECG poor R-wave progression. review and synthesis. Arch Intern Med 1982;142:1145–1148. Alpert MA, Terry BE, Hamm CR, Fan TM, Cohen MV, Massey CV, Painter JA. Effect of weight loss on the ECG of normotensive morbidly obese patients. Chest 2001;119:507–510. Fraley MA, Birchem JA, Senkottaiyan N, Alpert MA. Obesity and the electrocardiogram. Obes Rev 2005;6:275–281. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH, American Heart Association, Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2006;113:898–918. Wolk R. Arrhythmogenic mechanisms in left ventricular hypertrophy. Europace 2000;2:216–223.
CLINICAL PERSPECTIVES QRS transition zone can be easily determined from the standard 12-lead ECG by observing in which precordial lead the R wave of the QRS complex exceeds the S wave in amplitude. In the present study conducted among a middle-aged general population, we addressed for the first time the risk of SCD associated with the transition zone. Delayed QRS transition zone correlated strongly with traditional cardiovascular risk factors, but even after adjusting for several clinical and ECG parameters, delayed transition at V4 or beyond was associated with mildly increased mortality. Markedly delayed transition at V5 or beyond was a much rarer finding, being present in only 1.3% of the population, but it was associated with a 27% increase in mortality and a 64% increase in the risk of SCD. As an easily estimated ECG pattern, the QRS transition zone may help clinicians to identify asymptomatic individuals with an unfavorable cardiovascular risk profile and who may have an elevated risk of SCD in the future. Thus, subjects who are found to have a markedly delayed QRS transition zone on routine ECG may benefit from a more rigorous approach to traditional cardiovascular risk factor modification and closer follow-up.