Abstract P118: Cardioprotective Association Between High Density Lipoprotein Cholesterol and Endothelial Function Attenuated at Lower Levels of Estradiol in Women at Midlife. The SWAN Heart Study
Authors: El Khoudary Samar R , Chen Xirun , Brooks Maria , Janssen Imke , Hollenberg Steve , Thurston Rebecca , Matthews Karen 
Published: July 2021

Objective:
Growing evidence suggests that the cardioprotective effects of high density lipoproteins (HDL) may be diminished over the menopause transition. Estradiol (E2), the leading ovarian estrogen that declines substantially during the menopause transition, is considered a potent antioxidant with potential impact on lipid peroxidation and formation of reactive oxygen species that could affect HDL cardioprotective capacities. Whether the cardioprotective effects of HDL on atherosclerotic subclinical measures are apparent only in the presence of high levels of E2 in women at midlife is not clear. We hypothesized that the expected positive association between levels of high density lipoprotein cholesterol (HDL-C) and endothelial function as indexed by flow-mediated dilation (FMD) is weaker at lower levels of E2.

Methods:
Participants were fromthe baseline visit of the Study of Women’s Health Across the Nation (SWAN) Heart study. Women with hysterectomy and/or bilateral oophorectomy and those on hormone therapy were excluded. B-mode ultrasound images of the right brachial artery before and after deflation were obtained to estimate % change in FMD. Linear regression analyses were utilized to model the difference between log-baseline arterial diameter and log-post-deflation arterial diameter as a function of the interaction between log-E2 and HDL-C levels. To illustrate, the interaction between E2 tertiles and HDL-C was presented as well. The final model adjusted for log-baseline arterial diameter, race, study site, cycle day of blood draw, menopause status, body mass index, and diastolic blood pressure. Results were presented as % change in FMD (95% CI).

Results:
The study included 322 women (60% White and 40% Black) aged 50.7±2.8 years who were either in pre-/early perimenopause (63%) or late peri-/postmenopause (37%). In the final model, a significant interaction between HDL-C and log-E2 levels on %FMD was found, P value for interaction=0.01; such that a positive association between HDL-C and %FMD was only evident among women in the high E2 tertile (E2 ≥51.1 pg/ml) [%FMD (95%CI) per 1 SD increase in HDL-C: 0.93%(0.21%, 1.64%)] and that %FMD per 1 SD increase in HDL-C was significantly lower in women in the low E2 tertile (E2 <21.5 pg/ml) compared to women in the high E2 tertile [%FMD difference (95%CI): low E2 tertile vs. high E2 tertile: -0.98 (-1.88, -0.07), P-value=0.03].

Conclusions:
The cardioprotective association of HDL-C on endothelial function depends on levels of E2 in women at midlife, such that HDL-C may not be protective to the vascular endothelium in the setting of low endogenous E2. Our analyses should be replicated in longitudinal settings. Future studies should investigate potential mechanistic pathways by which dynamic changes in E2 levels may impact HDL composition and functionality over the menopausal transition.