On the surface electrocardiogram, an abnormally wide QRS|T angle reflects changes in the regional action potential duration profiles and in the direction of the repolarization sequence, which is thought to increase the risk of ventricular arrhythmia. We investigated the relation between an abnormal QRS|T angle and mortality in a nationally representative sample of subjects without clinically evident heart disease. We studied 7,052 participants ≥40 years old in the third National Health and Nutrition Examination Survey with 12-lead electrocardiograms. Those with self-reported or electrocardiographic evidence of a previous myocardial infarction, QRS duration of ≥120 ms, or history of heart failure were excluded. Borderline and abnormal spatial QRS|T angles were defined according to gender-specific 75th and 95th percentiles of frequency distributions. All-cause (1,093 women and 1,191 men) and cardiovascular (462 women and 455 men) mortality during the 14-year period was assessed through linkage with the National Death Index. On multivariate analyses, an abnormal spatial QRS|T angle was associated with an increased hazard ratio (HR) for cardiovascular mortality in women (HR 1.82, 95% confidence interval 1.05 to 3.14) and men (HR 2.21, 95% confidence interval 1.32 to 3.68). Also, the multivariate adjusted HR for all-cause mortality associated with an abnormal QRS|T angle was 1.30 (95% confidence interval 0.95 to 1.78) for women and 1.87 (95% confidence interval 1.29 to 2.7) for men. A borderline QRS|T angle was not associated with an increased risk of all-cause or cardiovascular mortality. In conclusion, an abnormal QRS|T angle, as measured on a 12-lead electrocardiogram, was associated with an increased risk of cardiovascular and all-cause mortality in this population-based sample without known heart disease.
Measures on the 12-lead electrocardiogram (ECG), such as the QT interval, left ventricular hypertrophy, and ST-segment depression, are known to provide prognostic information for cardiovascular morbidity and mortality. The spatial QRS|T angle quantifies the deviation in the direction of ventricular depolarization and repolarization. An abnormally wide QRS|T angle reflects changes in the regional action potential duration profiles and in the spatial direction of the repolarization sequence, which might be associated with increased dispersion of repolarization and malignant arrhythmia. An abnormal spatial QRS|T angle has been associated with all-cause mortality, cardiac mortality, and sudden cardiac death in several cohorts. One previous study evaluated the relation between the QRS|T angle and mortality in subjects without heart disease, and it remains unconfirmed whether the QRS|T angle is a useful clinical predictor of cardiac outcomes in the general population. We hypothesized that the spatial QRS|T angle, determined from a 12-lead ECG, is an independent predictor of cardiovascular and all-cause mortality in the general population without known cardiac disease, and we examined this question in the third National Health and Nutrition Examination Survey (NHANES III). A second aim of the present study was to determine the clinical correlates associated with an abnormal spatial QRS|T angle.
Methods
The NHANES III was a stratified, multistage probability survey designed to select a representative sample of the civilian noninstitutionalized United States population. Overall, 10,294 adults, ≥40 years old, completed the NHANES III interview and examination from 1988 to 1994. We excluded 1,809 participants who did not have a 12-lead ECG, 775 participants with a self-report or electrocardiographic evidence of previous myocardial infarction, 192 with a history of congestive heart failure, 452 with a QRS interval ≥120 ms, and 14 without valid electrocardiographic data for calculating the spatial QRS|T angle. After these exclusions, 7,052 NHANES III participants were included in the present analyses. Compared to those who were included in the present analysis, the 1,809 participants who were excluded because of missing ECGs were older (63.0 ± 0.7 years vs 55.9 ± 0.4 years, p <0.001) and more likely to be non-Hispanic black (15.0% vs 8.9%, p <0.001). The National Center for Health Statistics of the Center for Disease Control and Prevention institutional review board approved the protocol for NHANES III. All participants gave written informed consent.
NHANES III baseline data were collected during an in-home interview and a subsequent visit to a mobile examination center. The data collected during the in-home interview included demographics, physical activity, smoking, use of antihypertensive and cholesterol-lowering medication, and a history of stroke.
Using the height and weight measured during the visit to the mobile examination center, the body mass index was calculated as the weight in kilograms divided by the height in meters squared. The blood pressure was measured 3 times during the in-home interview and 3 additional times during the visit to the mobile examination center. All blood pressure measurements for each participant were averaged. Serum C-reactive protein was quantified using latex-enhanced nephelometry, a low sensitivity assay, and levels ≥3 mg/L were defined as elevated. Plasma glucose was measured using an enzymatic reaction. Diabetes mellitus was defined as a fasting plasma glucose of ≥126 mg/dL, a nonfasting plasma glucose of ≥200 mg/dL and/or a self-reported history of diabetes with concurrent use of antidiabetes medication. The total serum cholesterol and high-density lipoprotein cholesterol were measured enzymatically. Serum creatinine was measured using the Jaffe modified kinetic method. The estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation after aligning the serum creatinine concentrations with the assay used in the development of the equation. A reduced estimated glomerular filtration rate was defined as that <60 ml/min/1.73 m 2 . A spot urine sample was collected, and albuminuria was defined as a urinary albumin/creatinine concentration ratio of ≥30 mg/g.
The ECGs were recorded on a Marquette MAC 12 system (Marquette Medical Systems, Milwaukee, Wisconsin) by trained technicians during the participant’s visit to the mobile examination center. Computerized analysis of the electrocardiographic data was performed using the Minnesota and Novacode algorithms. Coding included rhythm analysis, detection of electrocardiographic abnormalities, and selective averaging to obtain the representative durations and amplitudes of electrocardiographic components.
The spatial QRS|T angle was approximated by a simple algorithm derived from the electrocardiographic data file of the Atherosclerosis Research in Communities (ARIC) study, which uses a combination of 3 QRS and 3 T-wave peak-to-peak amplitudes available in the NHANES III public release electrocardiographic data file. The reported correlation between the QRS|T angle from the simple algorithm and that from matrix transformation of the 12-lead ECGs was 0.87, and the sensitivity and specificity of this simple method for detecting an abnormal QRS|T angle was 0.88 and 0.91, respectively.
We classified the spatial QRS|T angle 2 ways. First, we categorized the QRS|T angle values according to the gender-specific frequency distribution as abnormal (≥95th percentile), borderline (≥75th and <95th percentile), and normal (<75th percentile), as previously described. The 75th and 95th percentile was 90° and 121° for women and 107° and 136° for men, respectively. Second, based on a previous study of an elderly sample, we categorized the spatial QRS|T angle as abnormal (135° to 180°), borderline (105° to 135°), and normal (0° to 105°).
In addition, we calculated the frontal plane QRS|T angle as the absolute difference between the frontal plane QRS axis and T axis. We defined the normal, borderline, and abnormal frontal plane QRS|T angle according to the gender-specific 75th (39° and 81° for women and men, respectively) and 95th (43° and 95° for women and men, respectively) percentiles of its distribution.
The NHANES III participants have been followed up for mortality through December 31, 2006. The method of probabilistic matching was used to link the NHANES III participants with the National Death Index to identify vital status and, for those who died, the cause of death. Matching was based on 12 identifiers for each participant, including Social Security number, gender, and date of birth. The follow-up period for each study participant was calculated as the interval between their NHANES III examination and the date of death or December 31, 2006, whichever occurred first. The cause of death was determined using the underlying cause listed on the death certificates. The “International Classification of Disease” (ICD), 9th revision, was used for deaths occurring from 1988 to 1998 and ICD-10 for deaths occurring from 1999 to 2006. Cardiovascular mortality was defined by any of the ICD-9 codes 390 to 434 and 436 to 459 and ICD-10 codes I00 to I99.
Because the distribution of the QRS|T angle could differ for men and women, a priori, we chose to conduct all analyses stratified by gender. The baseline characteristics of the study population, mean or percentage, were calculated for each level of spatial QRS|T angle (normal, borderline, or abnormal). Using logistic regression models, the factors associated with an abnormal spatial QRS|T angle were calculated. The factors investigated included age, race/ethnicity, heart rate, physical inactivity, current smoking, body mass index, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, cholesterol-lowering medication use, elevated C-reactive protein, diabetes, reduced estimated glomerular filtration rate, albuminuria, and a history of stroke, simultaneously. The initial models included age and race/ethnicity, with the subsequent models including all variables simultaneously.
Cox proportional hazards regression was used to calculate the age- and race/ethnicity- and multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals for all-cause and cardiovascular-related mortality associated with a borderline and an abnormal versus a normal spatial QRS|T angle. The multivariate-adjusted HRs for all-cause and cardiovascular-related mortality were also calculated for the spatial QRS|T angle modeled as a continuous variable using restricted quadratic splines with knots at the 75th and 95th percentiles of the spatial QRS|T distribution. Two sensitivity analyses were conducted. First, the age- and race/ethnicity- and multivariate-adjusted HRs for all-cause and cardiovascular mortality were calculated using cutpoints of <135°, 105° to 135°, and ≥135° to define the normal, borderline, and abnormal spatial QRS|T angles, respectively. Second, HRs were calculated for the borderline and abnormal versus normal frontal plane QRS|T angle.
The data were analyzed using SUDAAN, version 9.0 (Research Triangle Institute, Research Triangle Park, North Carolina), to account for the complex NHANES sampling design, including data clustering and unequal probabilities of selection, oversampling, and nonresponse. NHANES III sampling weights were applied in all analyses.
Results
The baseline characteristics of the women and men included in the present analysis, stratified by spatial QRS|T angle status (normal, borderline and abnormal), are presented in Table 1 . The men and women with an abnormal QRS|T angle were older and more likely to be non-Hispanic black. In the age- and race-adjusted, gender-specific, analyses, body mass index, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and albuminuria were associated with an abnormal QRS|T angle. After multivariate adjustment, smoking, systolic blood pressure, and albuminuria were associated with an abnormal QRS|T angle in women ( Table 2 ). In men, only cholesterol-lowering medication use and diabetes mellitus were associated with an abnormal QRS|T angle.
| Variable | QRS|T Angle | ||
|---|---|---|---|
| Normal | Borderline | Abnormal | |
| Range of QRS|T angle values for women | <90° | 90°–120° | ≥121° |
| Women (n) | 2,796 | 751 | 243 |
| Age (years) | 56.1 ± 0.4 | 57.1 ± 0.9 | 60.5 ± 1.1 |
| Race/ethnicity | |||
| Non-Hispanic white | 86.5% | 88.4% | 83.3% |
| Non-Hispanic black | 9.7% | 8.9% | 14.0% |
| Mexican-American | 3.8% | 2.7% | 2.7% |
| Physically inactive | 28.9% | 32.5% | 36.0% |
| Current smoking | 19.2% | 20.3% | 27.9% |
| Body mass index (kg/m 2 ) | 27.1 ± 0.2 | 27.3 ± 0.4 | 28.5 ± 0.7 |
| Systolic blood pressure (mm Hg) | 125.6 ± 0.5 | 130.5 ± 1.1 | 136.3 ± 1.7 |
| Antihypertensive medication use | 19.0% | 23.4% | 38.8% |
| Heart rate (beats/min) | 68.6 ± 0.3 | 70.9 ± 0.6 | 70.7 ± 1.7 |
| Total cholesterol (mg/dl) | 219.1 ± 1.1 | 227.0 ± 2.2 | 228.4 ± 3.6 |
| High-density lipoprotein cholesterol (mg/dl) | 56.2 ± 0.6 | 55.9 ± 0.9 | 53.4 ± 1.4 |
| Cholesterol-lowering medication use | 4.6% | 4.6% | 8.0% |
| C-reactive protein ≥3 mg/L | 38.2% | 40.1% | 49.3% |
| Diabetes mellitus | 5.9% | 11.8% | 18.6% |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 | 8.4% | 10.5% | 13.5% |
| Albuminuria ≥30 mg/g | 7.5% | 13.6% | 23.5% |
| History of stroke | 1.8% | 1.3% | 5.4% |
| Range of QRS|T angle values for men | <107° | 107°–135° | ≥136° |
| Men (n) | 2,348 | 711 | 203 |
| Age (years) | 54.7 ± 0.4 | 55.4 ± 0.8 | 58.8 ± 1.4 |
| Race/ethnicity | |||
| Non-Hispanic white | 87.4% | 84.7% | 80.7% |
| Non-Hispanic black | 8.4% | 11.5% | 15.4% |
| Mexican-American | 4.3% | 3.9% | 3.9% |
| Physically inactive | 16.1% | 17.5% | 22.5% |
| Current smoking | 24.6% | 29.9% | 31.1% |
| Body mass index (kg/m 2 ) | 27.3 ± 0.2 | 27.0 ± 0.2 | 28.2 ± 0.5 |
| Systolic blood pressure (mm Hg) | 127.7 ± 0.6 | 131.9 ± 1.1 | 136.7 ± 2.3 |
| Antihypertensive medication use | 14.6% | 14.9% | 27.3% |
| Heart rate (beats/min) | 66.4 ± 0.4 | 67.3 ± 0.6 | 69.8 ± 1.4 |
| Total cholesterol (mg/dl) | 212.5 ± 1.4 | 214.1 ± 2.1 | 211.7 ± 5.9 |
| High-density lipoprotein cholesterol (mg/dl) | 45.3 ± 0.5 | 45.8 ± 0.9 | 46.0 ± 2.1 |
| Cholesterol-lowering medication use | 3.8% | 3.1% | 9.3% |
| C-reactive protein ≥3 mg/L | 27.2% | 31.0% | 44.1% |
| Diabetes mellitus | 8.1% | 12.1% | 21.5% |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 | 5.0% | 5.8% | 7.6% |
| Albuminuria ≥30 mg/g | 7.6% | 13.5% | 23.6% |
| History of stroke | 2.1% | 2.3% | 2.9% |
| Variable | Women | Men |
|---|---|---|
| Age- and race-adjusted odds ratio | ||
| Age, 10 years | 1.30 (1.15–1.48) | 1.32 (1.11–1.57) |
| Race/ethnicity | ||
| Non-Hispanic white | 1 (referent) | 1 (referent) |
| Non-Hispanic black | 1.73 (1.21–2.49) | 2.08 (1.31–3.31) |
| Mexican-American | 0.95 (0.64–1.42) | 1.21 (0.64–2.32) |
| Physically inactive | 1.18 (0.72–1.93) | 1.30 (0.80–2.12) |
| Current smoking | 1.82 (1.16–2.85) | 1.46 (0.89–2.40) |
| Body mass index, 5 kg/m 2 | 1.31 (1.03–1.65) | 1.19 (1.02–1.38) |
| Systolic blood pressure, 20 mm Hg | 1.47 (1.20–1.80) | 1.51 (1.10–2.07) |
| Antihypertensive medication use | 2.12 (1.48–3.03) | 1.82 (1.18–2.81) |
| Heart rate, 10 beats/min | 1.13 (0.90–1.41) | 1.23 (1.02–1.49) |
| Total cholesterol, 40 mg/dl | 1.09 (0.94–1.26) | 0.98 (0.73–1.31) |
| High-density lipoprotein cholesterol, 10 mg/dl | 0.88 (0.78–1.00) | 1.00 (0.79–1.25) |
| Cholesterol-lowering medication use | 1.63 (0.77–3.48) | 2.53 (1.12–5.71) |
| C-reactive protein ≥3 mg/L | 1.48 (0.98–2.24) | 1.77 (1.00–3.11) |
| Diabetes mellitus | 2.65 (1.71–4.12) | 2.46 (1.52–3.97) |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 | 1.15 (0.66–2.02) | 1.03 (0.53–2.02) |
| Albuminuria ≥30 mg/g | 2.69 (1.83–3.96) | 2.67 (1.54–4.64) |
| History of stroke | 2.46 (0.97–6.25) | 0.94 (0.39–2.27) |
| Multivariate-adjusted odds ratio | ||
| Age, 10 years | 1.12 (0.93–1.34) | 1.16 (0.90–1.50) |
| Race/ethnicity | ||
| Non-Hispanic white | 1 (referent) | 1 (referent) |
| Non-Hispanic black | 1.30 (0.83–2.01) | 1.34 (0.74–2.42) |
| Mexican-American | 0.74 (0.48–1.15) | 0.98 (0.50–1.90) |
| Physically inactive | 0.93 (0.59–1.44) | 1.27 (0.80–2.02) |
| Current smoking | 1.98 (1.16–3.38) | 1.55 (0.87–2.78) |
| Body mass index, 5 kg/m 2 | 1.06 (0.90–1.25) | 1.16 (0.90–1.49) |
| Systolic blood pressure, 20 mm Hg | 1.28 (1.03–1.59) | 1.28 (0.90–1.83) |
| Antihypertensive medication use | 1.43 (0.92–2.24) | 1.30 (0.83–2.04) |
| Heart rate, 10 beats/min | 0.99 (0.78–1.27) | 1.15 (0.90–1.47) |
| Total cholesterol, 40 mg/dl | 0.98 (0.87–1.10) | 0.91 (0.67–1.25) |
| High-density lipoprotein cholesterol, 10 mg/dl | 0.95 (0.85–1.07) | 1.10 (0.89–1.34) |
| Cholesterol-lowering medication use | 1.46 (0.67–3.19) | 2.44 (1.00–5.99) |
| C-reactive protein ≥3 mg/L | 1.04 (0.65–1.68) | 1.42 (0.74–2.73) |
| Diabetes mellitus | 1.80 (0.93–3.48) | 1.83 (1.02–3.31) |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 | 0.97 (0.53–1.80) | 0.76 (0.36–1.60) |
| Albuminuria ≥30 mg/g | 1.96 (1.27–3.04) | 1.68 (0.91–3.10) |
| History of stroke | 1.82 (0.61–5.40) | 0.78 (0.32–1.88) |
During a median follow-up of 14 years, mortality in both women and men was greatest among those with an abnormal QRS|T angle, followed by those with a borderline QRS|T angle ( Table 3 ). After adjustment for age and race/ethnicity, among both men and women, an abnormal QRS|T angle was associated with an increased HR for all-cause and cardiovascular mortality. After multivariate adjustment, an abnormal QRS|T angle was associated with a nonsignificant elevated risk of all-cause mortality in women and a significantly increased risk in men. An abnormal QRS|T angle was significantly associated with an increased risk of cardiovascular mortality in both women and men. The associations with all-cause and cardiovascular mortality were similar when using prespecified levels for defining the borderline and abnormal QRS|T angle ( Table 4 ). In both women and men, an abnormal QRS|T angle according to prespecified levels was significantly associated with both all-cause and cardiovascular mortality on multivariate analyses. When analyzed as a continuous variable, the risk of all-cause and cardiovascular mortality increased substantially for QRS|T angles of approximately >90°. However, for men, the mortality risk increased at QRS|T angles of approximately >120° ( Figure 1 ) .
