The study participants were middle-aged women at baseline (), with mean (SD) concentrations of 1.40 (0.39) mmol/L (54  mg/dL) for HDL-C and 151 (26
) mg/dL for apolipoprotein A-1. As expected, baseline prevalence of cardiovascular risk factors was inversely associated with HDL-C. Similar results were found when these baseline risk factors were examined across quintiles of apolioprotein A-1 (data not shown).
Baseline Characteristics of 26,861 Participants in the Women’s Health Study
HDL-C, apolipoprotein A-1, and incident events
During a mean (SD) follow-up of 11.1 (1.3) years, there were 929 incident total CVD events, of which 602 were coronary (myocardial infarction, coronary revascularization, or coronary death) and 319 were stroke. The incident CVD and coronary event rates increased linearly with lower concentrations of HDL-C or apolipoprotein A-1 (P for linear trend, <0.001; ), while only the lowest quintile of HDL-C had increased risk of stroke. After adjusting for known cardiovascular risk factors (models 1 and 2), HDL-C remained inversely associated with CVD and coronary events. Adjusted coronary event hazard ratios (HRs) for decreasing quintiles of HDL-C were 1.00 (reference), 1.23 (95% CI, 0.85–1.78), 1.42 (CI, 0.98–2.06), 1.90 (CI, 1.33–2.71), and 2.19 (CI, 1.51–3.19), P for linear trend<0.001. Broadly similar but generally weaker associations were noted for apolipoprotein A-1, with adjusted coronary event HRs for decreasing quintiles of apolipoprotein A-1 of 1.00 (reference), 0.98 (CI, 0.71–1.35), 1.02 (CI, 0.72–1.44), 1.37 (CI, 0.98–1.90), and 1.58 (CI, 1.14–2.20), P for linear trend=0.005.
Association of High-Density Lipoprotein Cholesterol and Apolipoprotein A-I with Cardiovascular Outcomes
Inverse associations were also noted for HDL-C and apolipoprotein A-1 with CVD and coronary events within subgroups of women stratified according to age, race, hypertension, smoking status, diabetes, hormone use, and body mass index (data not shown).
In multivariable analyses, no associations were noted for either HDL-C or apolipoprotein A-1 in relation to stroke.
Associations across strata of LDL-C
Since the associations of HDL-C and apolipoprotein A-1 with CVD were driven by coronary events and not stroke, we then performed stratified analyses to examine coronary events across concentrations for LDL-C. As shown in , the lowest event rates (0.62/1000 person-years) were seen among women with values in the top quintile of HDL-C (>1.60 mmol/L, 61.6 mg/dL) and concomitantly low LDL-C (<2.80 mmol/L, 108 mg/dL). After adjusting for other risk factors, the inverse association of HDL-C remained statistically significant for coronary events across a range of concentrations for LDL-C, even among women with low LDL-C (model 2 adjusted coronary HRs for decreasing quintiles of HDL-C were 1.00 [reference], 1.78 [CI, 0.77–4.08], 0.98 [CI, 0.33–2.84], 2.30 [CI, 0.99–5.34], and 2.71 [CI, 1.14–6.46], P for linear trend=0.031).
Association of High-Density Lipoprotein Cholesterol with Coronary Heart Disease Events According to Tertiles of Low-Density Lipoprotein Cholesterol
Weaker inverse associations were found for apolipoprotein A-1 with coronary events (), particularly among women with LDL-C below 3.50 mmol/L (135 mg/dL). Further, there were no associations for HLD-C or apolipoprotein A-1 with stroke across strata of LDL-C after multivariable adjustment (data not shown).
Association of Apolipoprotein A-1 with Coronary Heart Disease Events According to Tertiles of Low-Density Lipoprotein Cholesterol or Apolipoprotein B100
Associations across strata of apolipoprotein B100
Associations were noted for HDL-C or apolipoprotein A-1 only among women with apolipoprotein B100 ≥ 90 mg/dL ( and ), i.e. in the presence of atherogenic particles that include LDL and the triglyceride-rich lipoprotein particles. The P value for interaction of apolipoprotein B100 by HDL-C was 0.28, and for apolipoprotein B100 by apolipoprotein A-1 0.21. In multivariable analysis, there were no associations for HDL-C or apolipoprotein A-1 with stroke across strata of apolipoprotein B100.
Association of High-Density Lipoprotein Cholesterol with Coronary Heart Disease Events According to Tertiles of Apolipoprotein B100
We performed sensitivity analyses to assess the extent to which an unmeasured covariate might explain the results (16
). An unobserved dichotomous covariate that is near-perfectly correlated with coronary events would have to increase the odds of having a low (below median) HDL-C by a factor of 1.90, or apolipoprotein A-1 by a factor of 1.35, in order to account for the results (at a 5% significance level), regardless of the assumed prevalence of the unobserved covariate.
In other sensitivity analyses that used clinically relevant cutpoints for LDL-C instead of LDL-C thirds, similar results were obtained.
Extreme Elevation of HDL-C and Incident Events
Finally, among non-hormone users (to examine naturally-occurring elevations), we stratified participants according to deciles of HDL-C or apolipoprotein A-1. There were inverse associations with coronary events that appeared to plateau above an HDL-C concentration of approximately 1.48 mmol/L (57 mg/dL, ). Compared with women in the bottom decile, women in the top decile of HDL-C (≥1.80 mmol/L, 69.6 mg/dL) or apolipoprotein A-1 (≥170.9 mg/dL) had age-adjusted HRs for coronary events of 0.21 (CI, 0.13–0.35) and 0.28 (CI, 0.18–0.45), respectively. These were only modestly attenuated after fully adjusting for LDL-C and the model 2 covariates (HRs 0.32, CI, 0.16–0.63, and 0.45, CI, 0.24–0.85).
Coronary event age-adjusted hazard ratios (95% CIs) for deciles of HDL cholesterol and apolipoprotein A-1. The bottom decile is the reference group.
Women in the top decile of HDL-C experienced first events at older ages compared with women in the bottom decile (mean [SD] age of onset of first coronary event 70.3 [9.4] versus 63.8 [7.7] years, respectively; and age of onset of first CVD event 72.2 [8.8] versus 64.2 [8.3] years, respectively). Women who were in the top decile of HDL-C yet developed CVD were not only older but were more likely to have hypertension (48.7% vs 17.0%), diabetes (8.1% vs 1.1%), and higher concentrations of LDL-C (median 3.81 mmol/L [147 mg/dL] vs 3.06 mmol/L [118 mg/dL]) and triglycerides (median 0.97 mmol/L [86 mg/dL] vs 0.84 mmol/L [74 mg/dL]).
Lastly, the inverse association with coronary disease persisted among women with HDL-C ≥ 2.07 mmol/L (80 mg/dL; approximately the top 3% of women), with an age-adjusted HR of 0.20 (CI, 0.09–0.43) compared with women in the bottom decile. Similarly for women with the top 3% of apolipoprotein A-1 (≥185 mg/dL), the age-adjusted HR was 0.35 (CI, 0.18–0.66).