High-Density Lipoprotein (HDL) Metrics in Midlife Women: Associations with Adiposity, Subclinical Atherosclerosis and Cardiovascular Health

Background: The clinical utility of high-density lipoprotein cholesterol (HDL-C) in evaluating the anti-atherogenic abilities of HDL is debated. With ovarian aging, HDL may become dysfunctional; this dysfunctionality may not be captured by HDL-C. Novel metrics of HDL function, lipid content, and subclasses may provide further information on role of HDL in cardiovascular risk. Objectives: The objectives of this dissertation are to (1) determine whether higher abdominal and cardiovascular visceral adipose tissue (AT) volumes are associated with worse HDL metrics [lower HDL-cholesterol efflux capacity (HDL-CEC), HDL-phospholipids, and large HDL particles, smaller overall HDL size, and higher HDL-triglycerides and small HDL particles]; (2) identify whether clusters of HDL metrics during midlife are associated with future subclinical atherosclerosis; and (3) evaluate whether early midlife cardiovascular health (CVH) impacts future HDL metrics. Methods: Participants from the Study of Women’s Health Across the Nation (SWAN)- HDL ancillary study [n=558] were evaluated. For Aim 1, associations between visceral AT volumes with each future HDL metric were assessed by multivariable linear regression. For Aim 2, women were clustered by latent class analysis based on their baseline HDL metrics, and the relation between clusters with future subclinical atherosclerosis was evaluated by multivariable linear/logistic regression. For Aim 3, the relationships between early midlife CVH and health behaviors with future HDL metrics were tested by multivariable mixed models. Results: Higher visceral AT volumes were associated with a worse HDL metrics profile. Based on their HDL profile, women were classified into favorable (higher HDL-CEC, and phospholipid contents, and larger HDL subclasses) and unfavorable (lower HDL-CEC, and phospholipid contents, and smaller HDL subclasses) clusters; association between favorable HDL clusters at midlife and better future subclinical atherosclerosis was explained by body mass index. Better CVH, particularly lower BMI, early in midlife was associated with a better HDL metrics profile later in life. Conclusions: A comprehensive HDL metric profile, particularly HDL subclasses and HDL phospholipids, may help decipher the increased risk of cardiovascular disease in midlife women. Obesity and fat distribution strongly impact these metrics. HDL metrics may be appropriate targets for novel therapeutic interventions to reduce cardiovascular disease burden in women