The aim of this study was to investigate the prognostic utility of isolated T-wave inversion (TWI), QRS duration, and QRS/T angle on electrocardiogram at rest as predictors for sudden cardiac death (SCD) and death from all causes. The assessment of electrocardiographic findings was based on a population-based cohort of 1,951 men (age 42 to 61 years) with a follow-up period of 20 years. Isolated TWI in the absence of ST depression, bundle branch block or major arrhythmias, prolonged QRS duration from 110 to 119 ms, and a wide QRS/T angle of >67° were identified from the 12-lead electrocardiograms. SCD was observed in 171 men (8.3%) during the follow-up. As a single electrocardiographic parameter, TWI (prevalence 2.4%) was associated with an increased risk of SCD (hazard ratio [HR] 3.30, 95% confidence interval [CI] 1.91 to 5.71, p <0.001) after adjustment for age and clinical factors. Similarly, prolonged QRS duration and wide QRS/T angle were significantly related to the risk of SCD, with HR 1.50 (95% CI 1.08 to 2.19, p = 0.017) for QRS duration and HR 3.03 (95% CI 2.23 to 4.14, p <0.001) for QRS/T angle. The integrated discrimination improvement was significant when TWI (0.014, p = 0.036) or QRS/T angle (0.015, p = 0.002) was added to the model with age and clinical factors. In conclusion, TWI, QRS duration, and QRS/T angle are significantly associated with the risk of SCD and death from all causes beyond conventional cardiovascular risk predictors in the general population.
Sudden cardiac death (SCD) occurs in most cases outside hospital with few or no early warning signs. As electrocardiography at rest is one of the most commonly used diagnostic techniques, readily available in hospitals and out-of-hospital settings, it serves as a useful tool to screen for electrophysiological changes. Some previous studies have shown that common electrocardiographic findings at rest, including the changes in ventricular depolarization and repolarization phases, are associated with an increased risk of coronary heart disease (CHD) death in the general population. Other investigations have suggested that T wave and QRS/T angle are related to an increased risk of CHD and all-cause mortality. In addition, the duration of QRS complex, representing ventricular depolarization phase, has also been shown to be a valuable risk predictor of SCD. However, the prognostic value of isolated T-wave inversion (TWI) as a predictor of SCD in the general population has not been thoroughly studied. The objective of the present prospective study was to evaluate the risk of SCD for TWI, QRS duration, and QRS/T angle in a general population-based male cohort.
Methods
The study population is a representative sample of men living in the city of Kuopio and its surrounding rural communities in Eastern Finland, the participants in a longitudinal population-based study designed to investigate risk factors for cardiovascular outcomes. The men were aged 42 to 61 years at baseline examinations performed from March 1984 to December 1989. Of 3,235 potentially eligible men, 2,682 (83%) volunteered to participate in this study, whereas 186 did not respond to the invitation and 367 declined to give informed consent.
Our study is based on 1,951 participants with complete clinical and electrocardiographic (at rest) data for further evaluation. The assessment of electrocardiograms (ECGs) and demographic or clinical variables was available from the baseline only. All subjects with ST-segment depression by the Minnesota Code (MC 4-1 and 4-2), complete right or left bundle branch block (MC 7-1 and 7-2), and atrial fibrillation or supraventricular or sinus tachycardia were excluded. The study was approved by the Research Ethics Committee of the University of Eastern Finland, and each participant gave written informed consent.
The following criteria were used for defining TWI. MC 5-1: negative T waves, ≥5.0 mm in either of the leads I, II, V 2 to V 6 , in lead aVL when R-wave amplitude is ≥5.0 mm, or in lead aVF when QRS is upright; MC 5-2: T amplitude negative or biphasic (positive-negative or negative-positive type) with negative phase at least 1.0 mm but not as deep as 5.0 mm in lead I, II, V 2 to V 6 , in lead aVL when R amplitude is ≥5.0 mm, or in lead aVF when QRS is mainly upright; or MC 5-3: T-wave amplitude flat, negative, or biphasic (negative-positive type only) with <1.0-mm negative phase in lead I, II, V 3 to V 6 , or lead aVL when R-wave amplitude is ≥5.0 mm.
QRS duration and other electrocardiographic intervals and amplitudes were measured automatically from standard 12-lead electrocardiographic recording. QRS duration was measured from the earliest onset to the latest end of the QRS complex. Spatial QRS/T angle was determined by a simplified method using net QRS and net T and T prime measurements from 3 electrocardiographic leads. QT interval was rate-adjusted by Fridericia’s formula. Left ventricular hypertrophy was defined by Sokolow-Lyon voltage criteria (MC 3-3).
The collection of blood specimens and measurement of fasting levels of serum lipids, serum electrolytes, and assessment of smoking, alcohol consumption, heart rate, and the definition of previous myocardial infarction and type 2 diabetes are described elsewhere. Blood pressure at rest was measured by an experienced nurse using a random-zero sphygmomanometer (Hawksley, United Kingdom) after 5 and 10 minutes of rest in a seated position in a quiet room from 8 to 10 a.m. The lifelong exposure to smoking (cigarette pack-years) was estimated as the product of the number of smoking years multiplied by the number of tobacco products smoked daily. Body mass index (BMI) was computed as weight in kilograms divided by the square of height in meters. Baseline diseases, family histories, and the use of medications including the use of β blockers were assessed by self-administered questionnaires that were checked during the medical examination by a physician. Previous CHD was defined as a previous myocardial infarction, typical angina pectoris symptoms, or the use of nitroglycerin for chest pain once a week or more frequently. Information about chronic diseases was checked during a medical examination. Cardiorespiratory fitness was defined as the highest value for, or the plateau of, oxygen uptake during standardized exercise testing.
All deaths that occurred by the end of 2010 were checked against the hospital documents, health centers, and death certificates. There were no losses to follow-up. A death was classified as SCD when it occurred within 24 hours of the onset of, or an abrupt change in, symptoms when clinical findings did not reveal a noncardiac cause of sudden death. SCDs that occurred in out-of-hospital conditions were also defined as places in which the events occurred had been reported accurately in hospital documents. The deaths due to aortic aneurysm rupture, cardiac rupture or tamponade, and pulmonary embolism were not included as SCD. The sources of information were interviews, hospital documents, death certificates, autopsy reports, and medicolegal reports. The diagnostic classification of events was based on symptoms, electrocardiographic findings, cardiac enzyme elevations, autopsy findings (80% of all cardiac deaths), and history of CHD together with the clinical and electrocardiographic findings of the paramedic staff. All the documents related to the death were cross-checked in detail by 2 physicians. The documents related to the deaths were cross-checked in detail by two physicians. The independent events committee, blind to clinical data, performed the classification of deaths.
Descriptive data are presented as means ± SD and percentages. Cox proportional hazards models were used to evaluate the risk of SCD first for TWI, QRS duration (110 to 119 ms, highest fifth), and QRS/T angle (>67°, highest fifth) as age-adjusted variables and subsequently with multivariable adjustment for age and clinical factors (age, alcohol consumption, cigarette smoking, serum low- and high-density lipoprotein cholesterol, systolic blood pressure, type 2 diabetes, BMI, high-sensitivity C-reactive protein, previous myocardial infarction, and cardiorespiratory fitness). To evaluate the importance of TWI, QRS duration, and QRS/T angle as independent predictors of SCD, they were entered simultaneously into the supplementary Cox model, and each electrocardiographic variable was adjusted for another 2 electrocardiographic variables showing the multivariable-adjusted association of TWI, QRS duration, and QRS/T angle with the risk of SCD. Cox proportional hazards models also stratified according to age, BMI, and other clinically relevant subgroups.
The risk factor–adjusted hazard ratios (HRs) were estimated as antilogarithms of coefficients from multivariable models. The fit of the proportional hazards models was examined by plotting the hazard functions in different categories of risk factors over time. The proportional hazards assumption was verified for all variables by inspection of the plots of Schoenfeld residual for covariates. The linearity assumption was satisfied for all continuous variables and was assessed with martingale residuals for each continuous variable against survival time. The cumulative survival from SCD according to the presence of TWI was calculated using the Kaplan-Meier method. A p value of <0.05 was considered statistically significant. The incremental value of a specific electrocardiographic finding in addition to previously documented risk factors and diseases was evaluated. To assess the discrimination improvement ability of electrocardiography, we calculated the integrated discrimination index (IDI) for the multivariable model (age and clinical factors) with and without the electrocardiographic finding, defined as the average increase in predicted SCD risk.
Results
The mean age of the subjects was 53 years (range 42 to 61). Characteristics of the study population are listed in Table 1 . There were 46 men (2.4%) with isolated TWI on the ECG at rest. Common electrocardiographic findings according to the presence of TWI are presented in Table 2 . Men with TWI had a greater prevalence of Q waves (8%), first- or second-degree atrioventricular conduction delays (12%), and ectopic ventricular and supraventricular complexes (17%). There were no subjects with third-degree atrioventricular block, although 3 patients had a left anterior or posterior fascicular block on the ECG at rest. The main electrocardiographic variables including TWI, QRS duration, and QRS/T angle were weakly correlated (R 2 <0.1).
| Characteristic | Inverted | Not Inverted | p Value |
|---|---|---|---|
| Mean ± SD or Percentage | |||
| Demographic/laboratory | |||
| Age (yrs) | 55.6 ± 5.4 | 52.3 ± 5.0 | 0.200 |
| BMI (kg/m 2 ) | 27.8 ± 3.9 | 26.9 ± 3.6 | 0.226 |
| Smokers | 52.7 | 30.9 | 0.013 |
| Cigarette smoking (pack-years) | 12.7 ± 17.1 | 8.7 ± 15.6 | 0.189 |
| Alcohol consumption (grams/week) | 81.0 ± 94.2 | 76.8 ± 1,401 | 0.547 |
| Serum total cholesterol (mg/dl) | 226.9 ± 41.8 | 228.9 ± 41.7 | 0.756 |
| Serum LDL cholesterol (mg/dl) | 158.2 ± 33.3 | 157.0 ± 39.4 | 0.845 |
| Serum HDL cholesterol (mg/dl) | 42.2 ± 8.7 | 49.9 ± 11.2 | <0.001 |
| Systolic blood pressure (mm Hg) | 134.0 ± 19.5 | 134.2 ± 16.7 | 0.951 |
| Fasting blood glucose (mmol/L) | 4.81 ± 1.26 | 4.79 ± 1.24 | 0.742 |
| Cardiorespiratory fitness (ml/kg/minute) ∗ | 25.0 ± 8.1 | 30.7 ± 8.0 | <0.001 |
| High-sensitivity C-reactive protein (mmol/L) | 2.91 ± 3.9 | 2.28 ± 3.5 | 0.836 |
| Previously diagnosed diseases and family histories | |||
| CHD † | 52.1 | 22.8 | <0.001 |
| Previous myocardial infarction | 32.1 | 6.1 | <0.001 |
| Family history of CHD | 78.8 | 47.1 | <0.001 |
| History of hypertension | 35.0 | 30.5 | 0.513 |
| Heart failure ‡ | 31.8 | 6.5 | <0.001 |
| Cerebrovascular disease | 2.6 | 0.5 | 0.083 |
| Pulmonary disease § | 6.7 | 9.7 | 0.778 |
| Type 2 diabetes mellitus | 5.0 | 5.8 | 0.972 |
| Regular use of medications | |||
| Antihypertensive medication | 32.1 | 19.3 | <0.001 |
| Medication for dyslipidemia | 6.9 | 5.9 | 0.731 |
| β Blocker | 28.2 | 15.8 | <0.001 |
| Acetylsalicylic acid | 6.1 | 6.8 | 0.867 |
∗ Cardiorespiratory fitness was defined as the highest value for or the plateau of oxygen uptake during standardized exercise testing.
† Previous CHD was defined as a previous myocardial infarction, typical angina pectoris symptoms, or the use of nitroglycerin for chest pain once a week or more frequently.
‡ Defined as a diagnosis of heart failure based on clinical findings and symptoms.
§ Bronchial asthma and/or chronic obstructive pulmonary disease.
| Variable | Inverted | Not Inverted | p Value |
|---|---|---|---|
| Mean ± SD or Percentage | |||
| Heart rate at rest (beats/min) | 62 ± 13 | 62 ± 10 | 0.853 |
| QRS duration (ms) | 104 ± 10 | 103 ± 10 | 0.411 |
| QT interval (ms) | 407 ± 43 | 411 ± 31 | 0.351 |
| PR interval (ms) | 167 ± 46 | 160 ± 27 | 0.010 |
| Major Q waves ∗ | 8 | 1 | <0.001 |
| Atrioventricular conduction delay † | 12 | 2 | <0.001 |
| Ectopic complexes ‡ | 17 | 4 | 0.010 |
∗ Major Q waves by Minnesota Code (MC) 1.1 or 1.2.
† First- or second-degree atrioventricular block (Mobitz type I and/or II).
‡ Supraventricular, ventricular, and aberrant complexes (MC 8.1.1 to 8.1.3).
There were 171 SCDs (8.3% of men) during an average follow-up period of 20.4 years (median 22.8, interquartile range 18.0 to 24.5). A total of 128 SCDs (75% of all SCD events) occurred in out-of-hospital settings. The number of all-cause deaths was 767. The incident rates of SCDs were 22.7 cases/1,000 person-years for men with TWI and 3.7 cases/1,000 person-years in men without TWI. During follow-up, an implanted pacemaker device was placed in 32 men (25 because of bradycardia and 7 because of ventricular arrhythmias with implanted cardioverter defibrillator).
The age-adjusted HR was 5.76-fold higher for SCD and 6.40-fold higher for out-of-hospital SCD in men with TWI versus those without TWI, as listed in Table 3 . TWI on the ECG at rest was associated with a 3.30-fold risk of SCD and a 3.51-fold risk of out-of-hospital SCD, after adjustment for age and clinical factors (alcohol consumption, cigarette smoking, serum low- and high-density lipoprotein cholesterol, systolic blood pressure, type 2 diabetes, BMI, high-sensitivity C-reactive protein, previous myocardial infarction, and cardiorespiratory fitness; Table 3 ). After additional adjustment for QT interval or a history of CHD, TWI was associated with more than a threefold risk of SCD and out-of-hospital SCD. Progressive adjustment for electrocardiographic left ventricular hypertrophy (MC 3-3), heart rate at rest, and the use of β blockers did not attenuate the risk of either SCD or out-of-hospital SCD for TWI.
| Predictive Variable, Prevalence (%) | SCD ∗ | Deaths from All Causes (789 Deaths) | ||||
|---|---|---|---|---|---|---|
| All Sudden Deaths (171 Deaths) | Out-of-Hospital Sudden Deaths (128 Deaths) | |||||
| HR (95% CI) | p Value | HR (95% CI) | p Value | HR (95% CI) | p Value | |
| TWI (2.4) | ||||||
| Age adjusted | 5.76 (3.47–9.56) | <0.001 | 6.40 (3.65–11.23) | <0.001 | 2.25 (1.57–3.22) | <0.001 |
| Multivariable adjusted † | 3.30 (1.91–5.71) | <0.001 | 3.51 (1.91–6.44) | <0.001 | 1.78 (1.22–2.59) | 0.003 |
| QRS duration 110–119 ms (18.4) ‡ | ||||||
| Age adjusted | 1.68 (1.20–2.36) | 0.003 | 1.58 (1.06–2.35) | 0.023 | 1.11 (0.93–1.33) | 0.213 |
| Multivariable adjusted † | 1.50 (1.08–2.19) | 0.017 | 1.41 (0.97–2.17) | 0.081 | 1.09 (0.91–1.30) | 0.351 |
| QRS/T angle >67° (19.0) ‡ | ||||||
| Age adjusted | 3.03 (2.23–4.14) | <0.001 | 3.07 (2.15–4.28) | <0.001 | 1.77 (1.51–2.07) | <0.001 |
| Multivariable adjusted † | 2.02 (1.46–2.80) | <0.001 | 1.96 (1.35–2.84) | <0.001 | 1.41 (1.20–1.67) | <0.001 |
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