(1)
Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
Synopsis
In many industrialized countries including the US cardiovascular disease (CVD) continues to be the leading cause of death. Women have been increasingly included in CVD intervention efforts but substantial gender differences still remain in CVD prevalence and mortality. Annual number of adults with diagnosed heart attack of fatal coronary heart disease (CHD) occurs 10 years later in women than in men. Differences in population demographics account for the fact that in terms of absolute numbers more women are living with and dying from CVD including stroke than men, and more women than men are discharged from hospitals with diagnosis heart failure and stroke. These facts emphasize the need for identification of improved ECG predictors for CVD death and HF.
In the WHI study in post-menopausal women the main independent predictors of CHD death were Ѳ(Tp|Tref), the spatial angle between the Tpeak (Tp) vector and the reference vector for normal repolarization (Rfef) and TaVR amplitude, with an over twofold increased risk for both. Ѳ(Tp|Tref) is the spatial angle between the T peak vector and the normal T reference vector. In the ARIC study in CVD-free middle-aged men and women, the spatial angle between the mean QRS and Tvectors, [Ѳ(Rm|Tm)] was the strongest independent predictor of CHD death with over twofold increased risk in women and 1.4-fold increased risk in men. Ѳ(Tp|Tref) was also an independent predictor of CHD death, with 1.7-fold increased risk. TV1amplitude was an additional independent predictor in women with a twofold increased risk and TaVR amplitude and the rate-adjusted QT interval were additional independent predictors in men, with an approximately 50 % increased risk.
Ѳ(Tp|Tref) angle was consistently a strong independent predictor for CHD death. This spatial angle is a measure of deviant direction of the spatial repolarization sequence from the direction of normal repolarization approximately in the direction of the axis of lead aVR. Widened Ѳ(Tp|Tref) angle commonly occurs with anterior-right rotation of the Tp vector. TaVR and also TV1 can thus be expected to be sensitive indicators of deviant direction of repolarization. TaVR is functionally dependent on Ѳ(Tp|Tref) angle and both can be considered as primary alternative choices as independent predictors of CHD death. The simplicity of aVR makes it a particularly attractive choice in practical clinical applications.
Abbreviations and Acronyms
AHA
American Heart Association
ARIC
Arteriosclerosis research in communities
CHD
Coronary heart disease
CV
Cornell voltage
CVD
Cardiovascular disease
MRFIT
Mutiple risk factor intervention trial
ToV/TpV
Ratio of T vectors at time points of the onset and peak of the T wave vector magnitude function
WHI
Women’s health initiative
Ѳ(Rm|STTm)
Spatial angle between the mean QRS and ST-T vectors
Ѳ(Rm|Tm)
Spatial angle between the mean QRS and T vectors
Ѳ(Tinit|Tterm)
Spatial angle between the initial and terminal T vectors from repolarization quintiles 1 to 3 and 4 to 5, respectively
Ѳ(Tp|Tref)
Spatial angle between Tpeak (Tp)vector and tne normal reference T vector (Tref)
4.1 Introduction
Early epidemiological studies on coronary heart disease (CHD) focused almost exclusively on men. CHD was considered a male disease and major epidemiological studies such as the Seven Countries’ Study [1] and major clinical trials such as the Multiple Risk Factor Intervention Trial (MRFIT) [2] involved men only. Women’s health issues had a low priority in medical research until after 1985 when Federal and American Heart Association (AHA) launched initiatives to reduce gender disparities in research and clinical care. Political pressure gradually changed the situation and as a result major research programs including women were introduced such as the large-scale Women’s Health Initiative (WHI) study in 1991 [3].
In spite of intervention efforts, cardiovascular disease (CVD) continues to be the leading killer in the US and substantial sex differences still remain in CVD prevalence and mortality. In terms of absolute numbers, more women are living with and dying from CVD including stroke than men and more women than men are discharged from hospitals with diagnosis heart failure and stroke [4]. This is due to differences in population demographics with a larger proportion of women than men in elderly population groups where CVD prevalence is highest. However, the prevalence of and the mortality from CHD in each stratum of age is higher in men than in women until after 75 years of age as shown in Fig. 4.1a from Mosca et al. [4]. As the authors comment, this may have contributed to the perception that heart disease is man’s disease. A closer examination of Fig. 4.1 of Mosca et al. shows that CHD events in men occur approximately at 10 years younger age than in women. This is apparent from Fig. 4.1b where the age strata in women are shifter by 10 years. Mosca et al. also comment on a statistically significant trend in CHD mortality rates among younger women 35–44 years of age which were found to have increased an average of 1.3 % annually between 1997 and 2002 [5].
Fig. 4.1
Annual number of adults having diagnosed heart attack or fatal coronary heart disease in men (M) and women (W) (a), and with age groups of women shifted by 10 years compared to men (b) (Modified from Mosca et al. [4], with permission)
4.2 QRS and ST-T Variables as Predictors of Coronary Heart Disease Death in Post-menopausal Women
Table 4.1 lists hazard ratios for QRS and ST-T variables which were significant predictors for CHD death from an early report from the WHI study with a 9.2 year follow-up [6]. Two of the significant CHD mortality predictors, Cornell voltage and rate-adjusted QT interval had a significant interaction with CVD status at baseline. Hazard ratios for these two variables are listed separately for CVD-Free and CVD groups, and hazard ratios for the rest of the significant ECG predictors are listed for the combined group. In this study, the cut-off point selected at 95th percentile of the normal reference group which for instance for the Cornell-voltage (CV) was 1,800 μV. This cut-off point is lower than the commonly used the upper normal limit for CV (2,000 μV). The table lists hazard ratios for multivariable-adjusted single variable models and for multivariable-adjusted multiple ECG variable models. The ECG variables chosen by the multivariable model were selected by a reverse selection procedure from a set of variables with low correlations. The variables remaining in these models can be considered as independent predictors of CHD mortality.
Table 4.1
Hazard ratios (95 % confidence intervals) for ECG predictors of CHD death in WHI women by CVD status at baseline
aMultivariable-adjusted single ECG variable models | aMultivariable-adjusted multiple ECG variable models | |||
|---|---|---|---|---|
ECG variable (95 % cutpoint from reference group) | CVD-free group | CVD group | CVD-free group | CVD group |
‡QTrr | ||||
Reference (<437 ms) | 1 | 1 | 1 | 1 |
Prolonged (≥437 ms) | 2.17 (1.24–3.73)** | 0.47 (0.14–1.54) | 1.90 (1.09–3.33)* | 0.45 (0.14–1.50) |
§Cornell voltage | ||||
Reference (<1,800 μV) | 1 | 1 | 1 | 1 |
High (≥1,800 μV) | 1.91 (1.09–1.36) | 0.48 (0.17–1.37) | 1.25 (0.69–2.26) | 0.36 (0.12–1.05) |
CVD-free and CVD groups combined | CVD-free and CVD groups combined | |||
||Ѳ(Rm|Tm) | ||||
Reference (<56°) | 1 | 1 | ||
Borderline (57–96°) | 1.32 (0.85–2.04) | 1.23 (0.79–1.93) | ||
Wide (≥97°) | 2.70 (1.65–4.39)*** | 2.12 (1.23–3.62)** | ||
#ECG MI/ischemic injury | ||||
No | 1 | 1 | ||
Yes | 2.41 (1.52–3.81)*** | 1.87 (1.15–3.03)* | ||
††QRS non-dipolar voltage | ||||
Reference (<65 μV) | 1 | 1 | ||
Increased (≥65 μV) | 2.18 (1.33–3.57)** | 1.85 (1.11–3.08)* | ||
TV5 mean amplitude | ||||
Normal (73–235 μV) | 1 | Removed in backward selection | ||
Low (<73 μV); (Tpeak <117 μV) | 1.80 (1.16–2.81)** | |||
STV5 mean amplitude | ||||
Reference (>0 μV) | 1 | Removed in backward selection | ||
Depressed (≤0 μV) | 1.63 (1.07–2.47)* | |||
The strongest predictors of CHD mortality in multivariable-adjusted single ECG variable models in women with CVD and CVD-free groups combined were the spatial angle between the mean QRS and T vectors (Ѳ(Rm|Tm)) and old myocardial infarct by ECG (ECG-MI), with 2.70-fold increased risk for Ѳ(Rm|Tm) and 2.14-fold increased risk for ECG-MI. The risk for high QRS nondipolar voltage was also increased over twofold. CHD mortality risk for rate adjusted QT was increased significantly, 2.17-fold, only in CVD-free women (P < 0.01). Rate adjustment for QT in that 2006 report was done as a linear function of the RR interval whereby in women QTrr = QT-0.185*(RR-1), with QT and RR in seconds [7].
Among the ECG variables identified as independent predictors, wide Ѳ(Rm|Tm) was associated with a 2.12-fold increased risk of CHD death, and the risk increase for old myocardial infarction (MI) by ECG (ECG-MI) was1.87-fold, 1.85-fold for QRS nondipolar voltage and 1.90-fold for rate -adjusted QT (for the latter variable in CVD-free group only).
4.3 Repolarization-Related Variables as Predictors of Coronary Heart Disease Death in Post-menopausal Women
4.3.1 ECG Predictors Evaluated as Single Variables in Women
A recent WHI report evaluated the risk for CHD death for ECG variables from the repolarization model in 52,994 women from a longer follow-up period (average 16.9 years) during which 941 CHD deaths occurred [8]. The study group was stratified by CVD status at baseline. Selection criteria for participants considered to have CVD (N = 12,569) included history of angina pectoris, coronary bypass operation, and congestive heart failure. In addition, from the group of women initially classified as CVD-free, those with silent ECG-MI, AF or ECG-LVH (Cornell voltage >1,200 μV combined with Minnesota Code 4.1–4.3) or ischemic ST depression (isolated Minnesota Code 4.1–4.2) were transferred to the CVD group, leaving 52,092 women into the CVD-free group.
A large number of ECG variables were significant predictors of CHD death when evaluated as single ECG variables even after multivariable-adjustment for demographic/clinical factors (Table 4.2). The strongest predictors of CHD death in CVD-free women were heart rate, Ѳ(Rm|Tm), Ѳ(Tp|Tref), Tampl.V6 and ToV/TpV, with an over 1.5-fold increase in risk for each. The risk was nearly twofold for ToV/TpV (the ratio of T onset and T peak vector magnitudes (ToV and TpV, respectively)) of the ST-T spatial magnitude curve at time points To and Tp. A high ToV/TpV ratio reflects reduced convexity or triangularization of the action potentials of the left lateral wall myocytes. As in CVD-free women, a large number of ECG variables including ToV/TpV in women with CVD were strong predictors of CHD death when evaluated as single ECG variables. The risk for CHD death was increased over-1.5-fold for 12 ECG variables and over twofold increase for two of them, Ѳ(Tp|Tref) and STJV6.
Table 4.2
Single ECG variable multivariable-adjusted hazard ratios with 95 % confidence intervals for CHD death in women by CVD status at baseline
CVD-free group | CVD group | |||||||
|---|---|---|---|---|---|---|---|---|
Test quintile | Limita
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