The risk of incident hospitalized heart failure (HF) was evaluated for 23 electrocardiographic (ECG) variables in men and women free from cardiovascular disease. The hazard ratios with 95% confidence intervals were determined from Cox regression analysis for 13,428 participants 45 to 65 years old in the Atherosclerosis Risk in Communities (ARIC) study. New-onset HF during a 14-year follow-up period occurred in 695 men (11.9%) and 721 women (9.5%). Several ECG variables were significant predictors of incident HF when evaluated as single ECG variables. Predominant among them were spatial angles, reflecting deviations of the direction of the repolarization sequence from the normal reference direction. After controlling for collinearity among the ECG variables, the spatial angle between T peak and normal T reference vectors, Ө(T p |T ref ), was a significant independent predictor in men (HF risk increased 31%) and women (HF risk increased 46%). Other independent predictors in men included epicardial repolarization time (62% increased risk) and T wave peak to T wave end (T p T e ) interval, reflecting global dispersion of repolarization (27% increased risk). The independent predictors in women, in addition to Ө(T p |T ref ), were Ө(R|STT) the spatial angle between the mean QRS and STT vectors (54% increased risk) and QRS nondipolar voltage (46% increased risk). In conclusion, wide Ө(T p |T ref ), wide Ө(R|STT), and increased QRS nondipolar voltage in women and wide Ө(T p |T ref ), increased epicardial repolarization time, prolonged T p T e interval and T wave complexity in men were independent predictors of incident HF, and the presence of these abnormal findings could warrant additional diagnostic evaluation for possible preventive action for HF.
Evaluation of the risk of adverse cardiac effects for QT prolongation has been the focal point of many clinical trials, particularly in the evaluation of arrhythmic events such as torsades de pointes as adverse effects of cardioactive agents. Of particular concern has been that 70% of torsades de pointes events occur in women. However, QT is known to have notable limitations. Earlier investigations have found several other electrocardiographic (ECG) variables to be valuable supplements to QT in the prediction of new-onset heart failure (HF), including a wide spatial angle between the mean QRS and T vectors [Ө(R|STT)], QRS nondipolar voltage, ST depression in V 1 and increased T wave V 1 amplitude. The main objective of the present study was to evaluate the risk of incident hospitalized HF for a comprehensive set of repolarization-related ECG parameters derived by a recently developed repolarization model and to evaluate gender differences in the predictors of HF.
Methods
The Atherosclerosis Risk in Communities (ARIC) study was designed as a prospective investigation of the cause and natural history of atherosclerosis, its clinical manifestations, and the community burden of coronary heart disease. The risk factors were measured and the outcomes evaluated in this population-based probability sample of adults aged 45 to 65 years at the 1987 to 1989 baseline examination; follow-up of the cohort is ongoing. The study population and definition of prevalent diseases at baseline and the outcomes have been previously described.
The clinical outcomes were evaluated at the follow-up examinations through December 31, 2006. Deaths were classified as definite or possible coronary heart disease death, noncoronary heart disease death, and unclassified death. Coronary heart disease at baseline was classified as angina pectoris identified using the questionnaire from Rose et al. Myocardial infarction was defined by a self-reported episode requiring hospitalization for >1 week, myocardial infarct diagnosed by a physician, major Q waves at the baseline electrocardiogram (Minnesota Code 1.1), or previous coronary artery bypass grafting or coronary angioplasty. HF events were defined as a hospitalization discharge diagnosis code (“International Classification of Disease, Ninth Revision, Clinical Modification,” code 428). Prevalent (baseline) HF was determined on the basis of evidence of the use of HF-related medications and classified according to the Gothenburg criteria. Baseline cerebrovascular disease was defined as self-reported stroke or transient ischemic attack verified by a study physician’s review of the reported symptoms.
The study group of 13,428 men and women was derived from a source file of 14,126 ARIC participants, excluding those with bundle branch block or Wolf-Parkinson-White patterns (QRS duration ≥120 ms), participants with cardiovascular disease at entry classified as coronary heart disease, stroke, or HF according to the criteria listed, and 193 participants with missing clinical data or ECG parameters from various ECG programs and special algorithms derived for the study. The mean follow-up period was 14 years.
Standardized procedures were used to record the 12-lead electrocardiograms using a MAC personal computer (Marquette Electronics, Milwaukee, Wisconsin) at each clinical center. The electrocardiograms were processed in a central ECG laboratory, initially using the Dalhousie ECG program. All electrocardiograms in the initial digital ECG file of 15,571 records were inspected visually. In addition, the ECG quality was graded using a computer algorithm. A total of 116 electrocardiograms was rejected because of poor quality or lead reversals, and electrocardiograms with a QRS duration of ≥120 ms were excluded. Occasional outliers in interval measurements by computer were corrected using an interactive computer graphics display system. All electrocardiograms were reprocessed using the GE Marquette 12-SL program (GE Marquette), and the global time points from that program were used to compute the derived ECG parameters used in the present study. However, the time point of the T wave end from the Dalhousie program was found to match more closely the visually verified T wave end, and the QT interval from Dalhousie program was used in the present study.
The schematic in Figure 1 illustrates the key variables of the repolarization model, defined in more explicit terms in Table 1 . Because of the special importance of the QT peak interval (QT p ) and QT end interval (QT e ) for the parameters used in the repolarization model, special algorithms were used to detect the outlier measurements of QT p and QT e . Gender-specific predicted values were first computed for QT e as a linear function of the RR interval derived in cardiovascular disease-free men and women. QT e values above the 99th or below the 1st percentile limit of the distribution of the difference of each interval from the predicted value were replaced by the predicted value. The rate-adjusted QT e was computed using the formula also listed in Table 1 . The rate-adjusted QT p was then derived as the difference of the rate-adjusted QT e -T wave peak (T p )–T wave end interval. In 2% of the T p –T wave end measurements, the values were >128 ms and were <50 ms in another 2%. Outlier measurements >128 ms were constrained to 128 ms and those <50 ms to 50 ms. Similarly, the rate-adjusted QT onset was computed using the rate-adjusted QT p (QT pa ) and T wave onset to T p as the difference between the 2 ( Table 1 ).
| Acronym | Description | Excel Algorithm |
|---|---|---|
| Pred. QT e | Predicted QT end interval (ms) | Pred. QT e = 183 × RR + 224 in men Pred. QT e = 188 × RR + 228 in women |
| QT ea ∗ | Rate-adjusted QT e interval (ms) | QT ea = QT e + 183 × (1 − RR) for men QT ea = QT e + 186 × (1 − RR) for women |
| QT pa | Rate-adjusted QT peak interval (ms) | QT pa = QT ea − T p T e , where T p T e is the interval from T wave peak to T wave end |
| QT oa | Rate-adjusted QT onset interval (ms) | QT oa = QT pa − T o T p , where T o T p is the interval from T wave onset to T wave peak |
| Ө(T p |T ref ) | T p vector deviation angle from normal reference direction (°) | Ө(T p |T ref ) = 57.3 × archcosine (T ref x × T p x + T ref y × T p y + T ref z × T p z)/(T ref V × T p V) † |
| T p T xd | Left ventricular cross-mural repolarization time gradient (ms) | T p T xd = interval from T p to T xd , where Txd is the inflection point at global T wave downstroke |
| RT epi | Epicardial repolarization time (ms) | RT epi = QT pa − (CosӨ(T p |T ref ) − 1) × T p T xd /2 |
| RT xd | Left ventricular repolarization time at time point Txd (ms) | RT xd = QT pa + (CosӨ(T init |T ref ) + 1) × T p T xd /2 |
∗ R-square 0.81 for men, 0.77 for women in regression of QT e on RR interval.
† In Ө(T p |T ref ) algorithm, T ref x, T ref y, T ref z, T p x, T p y, and T p z are the x, y, and z components of T ref and T p vectors; T ref V is the vector magnitude of T ref vector (=1); and T p V is the vector magnitude of T p vector; T ref is the normal T reference vector in men and women free of cardiovascular disease with unit vector xyz components (0.66, 0.48, −0.67). Spatial direction of repolarization is diametrically opposite to T ref vector.
Repolarization measurements were made using temporal reference points derived from the “global” T wave, the spatial T vector magnitude curve obtained from a transformation matrix used to derive the XYZ leads from the 8 linearly independent component leads of the 12-lead ECG signals. The QRS nondipolar voltage, QRS duration, and a set of 21 repolarization-related ECG variables from the repolarization model were chosen for evaluation because of their role in the generation of abnormal repolarization waveforms or because of previous data of their value as risk predictors. The QRS duration was included as the second depolarization-related parameter with the QRS nondipolar voltage, because even moderate QRS prolongation has been known to induce secondary repolarization abnormalities.
The conceptual model used to derive the repolarization parameters for the present study has been previously reported. The algorithms used to derive the epicardial repolarization time (RT epi ) and other the key parameters of the repolarization model are described explicitly in Table 1 . The RT epi was obtained from the QT pa , modified by the cosine of the T wave peak deviation angle [Ө(T p |T ref )] from the normal reference direction of repolarization (T ref ) in men and women free from cardiovascular disease. Thus, RT epi was assigned the value equal to QT pa when the T p vector deviation angle was 0 (reverse repolarization sequence) and the value equal to QT pa plus left ventricular cross-mural RT gradient if the T p vector deviation angle was 180° (concordant repolarization sequence). The left ventricular cross-mural RT gradient will be equal to the T p T xd interval, where T xd is the time point of the minimum slope (inflexion point) at the T wave downstroke. Ө(T p |T ref ) is a measure of the deviation of the repolarization sequence from the normal direction of repolarization. In addition to Ө(T p |T ref ) and Ө(R|STT), several other spatial angles between the T vectors from various repolarization subintervals and other interval and amplitude variables were used in various phases of the study. Their definitions are listed in the footnotes of the corresponding tabular data. Left ventricular hypertrophy was defined by the Cornell voltage.
Descriptive statistics were used to determine the mean values, SDs, and upper and lower 20th percentiles (quintiles) for continuous variables and numbers and percentages for categorical variables. Cox proportional hazards regression analysis was used to compute hazard ratios (HR) and 95% confidence intervals (CIs) for the risk of HF. The ECG predictors were first evaluated as continuous variables and then stratified into quintiles. Quintiles 2 to 4 were first used as the reference group to evaluate the risk for the lowest and highest quintile to observe breakpoints at the high or low end of the distributions. The HRs were evaluated for increased values of the ECG parameters (quintile 5) as the test group, with quintiles 1 to 4 as the reference group. Finally, quintile 1, corresponding to decreased values, was used as the test group for T wave in lead aVL and T p in lead V, with the remaining 4 quintiles as the reference group.
Gender interactions with HF risk for each ECG variable was evaluated, and the HRs for variables with a significant gender interaction (p <0.05) were listed separately for men and women; otherwise, both gender groups were combined. The HF risk data were summarized first by listing the unadjusted HRs and 95% CIs and then for multivariate-adjusted models with an adjustment for demographic (age, race, gender, education) and clinical (smoking status, diabetes, hypertension, family history of coronary heart disease or stroke, body mass index, systolic blood pressure, total cholesterol to high-density lipoprotein cholesterol ratio, glucose, creatinine, uric acid) factors. In addition to the single ECG variable models, the independent ECG predictors for incident HF were identified. When evaluating the collinearity among the ECG variables, it was observed that rate-adjusted QT e and rate-adjusted QT onset correlated highly with QT pa , which is functionally closely related to RT epi . From these 4 variables, it was decided to retain RT epi because of its central role in the repolarization model. The remaining set of ECG variables with low correlations (r <0.5) was chosen to evaluate the independent ECG predictors of incident HF. These variables were entered simultaneously into Cox regression model, first without additional adjustment and then after adjustment for demographic and clinical factors. Statistical analyses were performed using Statistical Analysis Systems, version 9.1.3 (SAS Institute, Cary, North Carolina) and Microsoft Excel 2007 version 5.0 (Microsoft, Redmond, Washington).
Results
The age range of the study population was 45 to 65 years (mean age 54; Table 2 ). The study population was predominantly white (73%). Some notable gender differences of clinical interest were present in the ECG parameters. The rate-adjusted QT e was 10 ms shorter and the rate-adjusted QT p 18 ms shorter in the men than in the women. The Ө(R|STT) was 10° wider in the men than in the women. Notable among the other gender differences were the lower T onset vector magnitude and T p vector magnitude in women than in men and greater T wave onset/T p vector magnitude ratio in the men than in the women.
| Variable | Men (n = 5,842) | Women (n = 7,596) |
|---|---|---|
| Demographic/clinical | ||
| Age (yrs) | 54.2 ± 5.8 | 53.6 ± 5.7 ∗ |
| Body mass index (kg/m 2 ) | 27 ± 4.1 | 28 ± 6.0 † |
| White | 4,563 (77%) | 5,450 (71%) ∗ |
| Current smokers | 1,623 (27%) | 1,877 (25%) ∗ |
| Systolic blood pressure (mm Hg) | 122 ± 17.5 | 120 ± 19.2 ∗ |
| Hypertension | 1,837 (31%) | 2,442 (32%) |
| Diabetes mellitus | 621 (11%) | 785 (10%) |
| Q wave myocardial infarction by Minnesota Code criteria | 179 (3.0%) | 107 (1.4%) ∗ |
| LVH by Cornell Voltage | 91 (1.5%) | 297 (3.9%) ∗ |
| LVH and strain | 9 (0.2%) | 34 (0.4%) |
| ECG parameters | ||
| Heart rate | 65 ± 10.2 | 67 ± 10.0 ∗ |
| PR interval (ms) | 166 ± 25.5 | 161 ± 25.4 ∗ |
| QRS duration (ms) | 95 ± 9.1 | 87 ± 8.3 ∗ |
| RNDPV (μV) | 54 ± 22.6 | 43 ± 17.4 ∗ |
| QT ea (ms) | 408 ± 12.9 | 415 ± 14.1 ∗ |
| QT pa (ms) | 316 ± 18.7 | 334 ± 18.2 ∗ |
| QT oa (ms) | 226 ± 18.9 | 244 ± 19.3 ∗ |
| RT epi (ms) | 318 ± 19.3 | 336 ± 18.7 ∗ |
| RT endo (ms) | 351 ± 18.6 | 367 ± 18.2 ∗ |
| T p T xd (ms) | 37 ± 10.2 | 35 ± 11.4 ∗ |
| T p T e (ms) | 91 ± 14.9 | 81 ± 14.98 ∗ |
| Ө(R|STT) (°) | 58 ± 26.8 | 48 ± 24.5 ∗ |
| Ө(R p |T p ) (°) | 51 ± 30.5 | 39 ± 19.4 ∗ |
| Ө(T p |T ref ) (°) | 21 ± 16.3 | 26 ± 18.4 ∗ |
| Ө(T init |T term ) (°) | 18 ± 11.5 | 16 ± 11.0 ∗ |
| T wave complexity | 0.34 ± 0.16 | 0.36 ± 0.18 ∗ |
| TaVR (μV) | −219 ± 96.9 | −201 ± 86.9 ∗ |
| TaVL (μV) | 94 ± 95.5 | 75 ± 80.3 ∗ |
| TV 1 (μV) | −133 ± 145.6 | −12 ± 119.8 ∗ |
| ST o V (μV) | 54 ± 27.9 | 36 ± 19.8 ∗ |
| T o V (μV) | 148 ± 56.7 | 104 ± 41.1 ∗ |
| T p V (μV) | 390 ± 141.3 | 315 ± 122.5 ∗ |
| VT o /VT p (μV) | 0.39 ± 0.09 | 0.36 ± 0.11 ∗ |
† p <0.05, z-test for proportions and t test for gender differences.
New-onset HF occurred in 695 men (11.9%) and 721 women (9.5%). Summary results for the ECG predictors of incident HF are presented in Table 3 for multivariate-adjusted single ECG variable models such that the risk of incident HF was evaluated separately for each of the 23 ECG variables. A significant gender interaction with incident HF was found for 13 ECG variables, which have been listed separately for men and women in Table 3 . For most of these 13 variables, the HRs were slightly stronger for the men than the women, and for 4 of the variables, the HR was significant for men only. The highest increased risk of incident HF in men, 1.76-fold, was observed for the spatial angle Ө(T init |T term ) and 1.71-fold increased risk for T-wave aVR amplitude. Of the remaining 10 ECG variables with no significant gender interaction, the HRs were significant for 5, with the highest level of increased risk of incident HF for 2 of the spatial angles, 1.63-fold for Ө(R|STT) and 1.59-fold for Ө(T p |T ref ).
| ECG Variable | Multivariate-Adjusted Single ECG Variable Model ∗ | ||
|---|---|---|---|
| Men | Women | p Value (Gender Interaction) | |
| RNDPV (μV) | 1.34 (1.09–1.64) | 1.50 (1.26–1.78) | <0.001 |
| QT oa (ms) | 1.57 (1.33–1.86) | 1.32 (1.16–1.51) | 0.018 |
| QT pa (ms) | 1.55 (1.31–1.83) | 1.35 (1.19–1.54) | 0.0027 |
| T p T e (ms) | 1.40 (1.17–1.67) | 1.09 (0.95–1.25) | 0.037 |
| RT epi (ms) | 1.65 (1.39–1.94) | 1.38 (1.21–1.57) | 0.006 |
| RT endo (ms) | 1.30 (1.09–1.55) | 1.39 (1.22–1.57) | 0.016 |
| Ө(T p |T ref ) (°) | 1.65 (1.40–1.95) | 1.07 (0.90–1.28) | <0.001 |
| Ө(T init |T term ) (°) | 1.76 (1.49–2.07) | 1.32 (1.12–1.57) | 0.024 † |
| T wave complexity | 1.57 (1.33–1.86) | 1.31 (1.16–1.48) | <0.001 |
| ST o Amp. aVR (μV) | 1.45 (1.23–1.71) | 1.27 (1.12–1.44) | 0.024 |
| T Amp. aVR (μV) | 1.71 (1.45–2.01) | 1.51 (1.34–1.70) | 0.037 |
| T o V (μV) | 1.31 (1.10–1.55) | 1.05 (0.92–1.20) | <0.001 |
| T p V (μV) | 1.31 (1.10–1.55) | 1.21 (0.07–1.37) | 0.040 |
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