Mean (SD) age at baseline for the 15,632 initially healthy women followed for this portion of the study was 53.5 (7.7) years and the mean (SD) body mass index (BMI) was 26.3 (5.3) kg/m2
. As previously reported (28
), total cholesterol, LDL-C, non-HDL-C, and apolipoprotein B100 were all highly correlated with one another (r values ranged from 0.76 to 0.93, all significant to P<0.0001). HDL-C and apolipoprotein A-I were highly correlated with one another (r=0.80) but only weakly correlated with the other lipid variables. By contrast, the correlation between hs-CRP and the lipid variables was weaker, ranging from r = −0.33 (P<0.0001) with HDL-C to 0.15 (P<0.0001) with LDL-C.
Over the follow-up period of 10 years, 468 subjects suffered a first cardiovascular event (132 ischemic stroke, 336 coronary heart disease). As expected, there were significant differences in mean age, mean BMI, history of hypertension, diabetes, and smoking status across the groups of women who did not suffer a cardiovascular event and those who reached either cardiovascular endpoint (). The median levels of the lipid values, their ratios, and hs-CRP in each of the three groups of women are also shown in . Women with incident CHD were more likely to have a parental history of myocardial infarction before the age of 60 than women with ischemic stroke, and had slightly lower HDL-C and apolipoprotein A-I levels. Perhaps because of these differences in HDL-C and apolipoprotein A-I, lipid ratios were slightly higher among women with incident CHD when compared to women with incident stroke.
Table 1 Baseline clinical characteristics of the study participants. P-values for women with incident ischemic stroke versus those without incident CHD or ischemic stroke were all ≤ 0.0002 except BMI (P=0.03), parental history of myocardial infarction (more ...)
The fully adjusted HRs for developing future ischemic stroke and coronary heart disease for each of the single lipid variables and hs-CRP are presented in . After adjustment for age (years), blood pressure (Framingham categories), diabetes, BMI (kg/m2), current smoking status and randomized treatment assignment, increasing tertiles of total cholesterol, non-HDL-C, HDL-C, and hs-CRP were all associated with future ischemic stroke (Ptrend = 0.02, 0.03, 0.02, and 0.003, respectively). Specifically, the HR of future stroke for those women in the highest as compared with the lowest tertile was 1.91 (95% CI, 1.13–3.21) for total cholesterol, 1.72 (95% CI, 1.03–2.86) for non-HDL-C, 0.57 (95% CI, 0.36–0.92) for HDL-C, and 2.76 (95% CI, 1.51–5.05) for hs-CRP. While the associations between increasing tertiles of LDL-C and apolipoproteins B100 and A-I were not statistically significant, the estimates of the HRs were in the expected direction (HR = 1.29, 95% CI, 0.83–2.02 for LDL-C; HR = 1.47, 95% CI, 0.88–2.44 for apolipoprotein B100, and HR = 0.72, 95% CI, 0.47–1.11 for apolipoprotein A-I), consistent with the direction of effect for other highly correlated lipid variables. Among the significant risk determinants for future ischemic stroke, the magnitude of association as measured by the likelihood ratio (LR) χ2 statistic was 213.7 for hs-CRP, 208.0 for total cholesterol, 207.3 for HDL-C, and 206.1 for non-HDL-C.
Adjusted* hazard ratios (HRs) of future coronary heart disease (CHD) and ischemic stroke in initially healthy women according to tertile of baseline lipid levels and high-sensitivity C-reactive protein (CRP).
The fully adjusted HRs for lipid ratios as determinants of ischemic stroke are summarized in . The ratios of total to HDL cholesterol, LDL-C to HDL-C and apolipoprotein B100 to HDL-C all associated with future ischemic stroke (Ptrend = 0.004, 0.01, and 0.03, respectively), while the ratio of apolipoprotein B100 to A-I was of borderline significance (Ptrend = 0.08). Specifically, the HRs of future ischemic stroke for those in the highest as compared with the lowest tertile were 1.95 (95% CI, 1.16–3.26) for total to HDL cholesterol ratio, 1.77 (95% CI, 1.08–2.90) for the LDL-C to HDL-C ratio, 1.42 (95% CI, 0.88–2.30) for the ratio of apolipoproteins B100 to A-I, and 1.62 (95% CI, 0.98–2.68) for the apolipoprotein B100 to HDL-C ratio. The ratio of total to HDL cholesterol had a LR χ2 statistic of 210.1, which was similar to that of many of the single lipid measures, but smaller than the statistic for hs-CRP (LR χ2 statistic=213.7).
Adjusted* hazard ratios (HRs) of future CHD and ischemic stroke in initially healthy women according to tertile of various lipid ratios at baseline.
As anticipated, all the measured lipid levels and hs-CRP were associated with future CHD (). After adjustment, the magnitude of association appeared to be greatest between HDL-C, with a HR of CHD for the highest as compared with the lowest tertile equal to 0.38 (95% CI, 0.27–0.52; LR χ2 statistic=435.2), although the highly correlated variables non-HDL-C (HR 2.93, 95% CI, 2.04–4.21, LR χ2 statistic=431.1) and apolipoprotein B100 (HR 3.25, 95% CI, 2.18–4.82; LR χ2 statistic=429.7) also showed close association with future CHD.
All of the lipid ratios strongly associated with future coronary heart disease (). In contrast to the single lipid measurements, where non-HDL-C and apolipoprotein B100 were more closely associated with CHD than total cholesterol, the lipid ratio with the strongest association was the total cholesterol to HDL-C ratio (HR for highest vs. lowest tertile, 4.20; 95% CI, 2.79–6.32; LR χ2 statistic=457.4). Similarly, the hazard ratio for future CHD for the top versus the bottom tertile for the ratio of apolipoprotein B100 to HDL-C was 3.98 (95% CI, 2.65–5.96; LR χ2 statistic=452.6).
and present the adjusted HRs for each lipid variable, hs-CRP and the lipid ratios for those in the highest compared with the lowest tertile. The association between each of the lipid variables and ischemic stroke is similar in direction of effect to its association with coronary heart disease. Visually, the HRs for future CHD for all of the lipid variables appear to be slightly stronger than the HR of future ischemic stroke for the same lipid, although we performed no formal statistical comparison. In contrast, the HR for future ischemic stroke for those in the highest tertile of hs-CRP appears to be somewhat larger than the HR of future CHD, although the 95% confidence intervals overlap (HR 2.76; 95% CI, 1.51–5.05 for ischemic stroke vs. HR 1.66;95% CI, 1.17–2.34 for CHD) and no formal statistical comparison was made.
Figure 1 Adjusted hazard ratios and 95% confidence intervals for future ischemic stroke (○) and coronary heart disease (●) among those in extreme tertiles of each lipid variable and high-sensitivity CRP. Hazard ratios are adjusted for age (years), (more ...)
Figure 2 Adjusted hazard ratios and 95% confidence intervals for future ischemic stroke (○) and coronary heart disease (●) among those in extreme tertiles of each lipid ratio. Hazard ratios are adjusted for age (years), blood pressure (Framingham (more ...)
In order to clarify whether this apparent difference in the strength of association between lipid levels and ischemic stroke as compared with CHD was due to a high proportion of cardioembolic strokes caused by atrial fibrillation, we repeated our analysis after excluding all patients who reported either prevalent atrial fibrillation at the time of enrollment in the WHS or subsequently developed the dysrrhythmia during the 10 years of follow-up. Of the 132 women who suffered an ischemic stroke as their first cardiovascular event, 5 had reported atrial fibrillation upon admission to the study and 18 developed atrial fibrillation during the course of follow-up, for a total of 109 women with ischemic stroke who had no history of atrial fibrillation. The point estimates for the HRs of future stroke for the third versus the first tertile of each of the lipid values, their ratios, and hs-CRP did not change substantially. Specifically, after multi-variable adjustment, the HRs of future ischemic stroke for those in the highest as compared with the lowest tertile were 1.87 (95% CI, 1.08–3.24; Ptrend = 0.03) for total cholesterol, 1.30 (95% CI, 0.80–2.10; Ptrend = 0.16) for LDL-C, 0.53 (95% CI, 0.32–0.89; Ptrend = 0.01) for HDL-C, 1.64 (95% CI, 0.95–2.82, Ptrend = 0.05) for non-HDL-C, 0.70 (95% CI, 0.44–1.12; Ptrend = 0.12) for apolipoprotein A-I, 1.42 (95% CI, 0.82–2.46; Ptrend = 0.17) for apolipoprotein B100 and 2.65 (95% CI, 1.39–5.08; Ptrend 0.007) for hs-CRP. Similarly, those estimates did not change for the lipid ratios, with the HRs of future ischemic stroke for the top versus the bottom tertile equal to 2.24 (95% CI, 1.26–4.00; Ptrend = 0.002) for the total cholesterol to HDL-C ratio, 1.81 (95% CI, 1.06–3.10; Ptrend = 0.02) for the LDL-C to HDL-C ratio, 1.46 (95% CI, 0.87–2.47; Ptrend = 0.07) for the ratio of apolipoproteins B100 to A-I, and 1.68 (95% CI, 0.97–2.91, Ptrend = 0.03) for the ratio of apolipoprotein B100 to HDL-C. Aside from the point estimate of the HR for the top versus the bottom tertile of the total cholesterol to HDL-C ratio, which changed from 1.95 (95% CI, 1.16–3.26) to 2.24 (95% CI, 1.26–4.00), or approximately 15%, no estimate for any of the HRs for extreme tertiles changed by more than 7% after we excluded women with incident or prevalent atrial fibrillation from the analysis.
During follow-up only 31 hemorrhagic strokes occurred, and we found no significant linear relationship between hemorrhagic stroke and any of the lipid variables or hs-CRP, using both minimally-adjusted (for age and randomized treatment assignment) and fully-adjusted proportional hazards models.
Finally, because there is evidence in the literature that exercise (29
) and alcohol consumption (30
) may be related to stroke risk, and both are known to be related to cholesterol (and in particular HDL-C) levels (31
), we constructed a Cox model which included exercise (exercise <1 time per week, 1–3 times per week, and at least 4 times per week) and alcohol consumption (less than 3 drinks per month, 1–6 drinks per week, and at least 1 drink per day) in addition to the other variables included in our fully adjusted model. None of the HRs for extreme tertiles of any of the lipid values or hs-CRP changed by more than 5% with the addition of alcohol and exercise to the previously constructed model.