Coronary Artery Calcification (CAC) and Post-Trial Cardiovascular Events and Mortality Within the Women's Health Initiative (WHI) Estrogen-Alone Trial.

BACKGROUND: Among women aged 50 to 59 years at baseline in the Women's Health Initiative (WHI) Estrogen-Alone (E-Alone) trial, randomization to conjugated equine estrogen-alone versus placebo was associated with lower risk of myocardial infarction and mortality, and, in an ancillary study, the WHI-CACS (WHI Coronary Artery Calcification Study) with lower CAC, measured by cardiac computed tomography ≈8.7 years after baseline randomization. We hypothesized that higher CAC would be related to post-trial coronary heart disease (CHD), cardiovascular disease (CVD), and total mortality, independent of baseline randomization or risk factors. METHODS AND RESULTS: WHI-CACS participants (n=1020) were followed ≈8 years from computed tomography scan in 2005 (mean age=64.4) through 2013 for incident CHD (myocardial infarction and fatal CHD, n=17), CVD (n=69), and total mortality (n=55). Incident CHD and CVD analyses excluded women with CVD before scan (n=89). Women with CAC=0 (n=54%) had very low age-adjusted rates/1000 person-years of CHD (0.91), CVD (5.56), and mortality (3.45). In comparison, rates were ≈2-fold higher for women with any CAC (>0). Associations were not modified by baseline randomization to conjugated equine estrogen-alone versus placebo. Adjusted for baseline randomization and risk factors, the hazard ratio (95% confidence interval) for CAC >100 (19%) was 4.06 (2.11, 7.80) for CVD and 2.70 (1.26, 5.79) for mortality. CONCLUSIONS: Among a subset of postmenopausal women aged 50 to 59 years at baseline in the WHI E-Alone Trial, CAC at mean age of 64 years was strongly related to incident CHD, CVD, and to total mortality over ≈8 years, independent of baseline randomization to conjugated equine estrogen-alone versus placebo or CVD risk factors. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000611.

Lipoprotein particles and incident type 2 diabetes in the multi-ethnic study of atherosclerosis.

OBJECTIVE: In the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated associations of baseline levels of a lipoprotein-based insulin resistance (IR) index (LP-IR), IR-related lipoprotein particles, mean particle sizes, and lipids, with incident type 2 diabetes, independent of confounders, glucose, insulin, and HOMA-IR. RESEARCH DESIGN AND METHODS: Among 5,314 adults aged 45-84 years without baseline diabetes or cardiovascular disease, 656 cases of diabetes were identified during a mean follow-up of 7.7 years. Lipoprotein particle concentrations, size, and LP-IR were determined by nuclear magnetic resonance spectroscopy of stored baseline plasma. Potential effect modification, by race/ethnicity, sex, baseline use of lipid-lowering medications or hormone therapy, or glucose strata (<90, 90-99, and ≥ 100 mg/dL), was also evaluated. RESULTS: Higher levels of LP-IR, large VLDL particles (VLDL-P), small LDL particles, triglycerides (TG), and TG-to-HDL cholesterol (HDL-C) ratio and lower levels of large HDL particles, smaller HDL and LDL size, and larger VLDL size were significantly associated with incident diabetes adjusted for confounders and glucose or insulin. These also were similar by race/ethnicity, sex, and treatment group. Associations were similar for LP-IR, large VLDL-P, mean VLDL size, TG, and TG-to-HDL-C ratio; they persisted for LP-IR, large VLDL-P, or mean VLDL size adjusted for HOMA-IR or TG-to-HDL-C ratio and glucose but not for the TG-to-HDL-C ratio adjusted for LP-IR or for HOMA-IR or insulin if adjusted for LP-IR and glucose. CONCLUSIONS: Among ethnically diverse men and women, LP-IR, large VLDL-P, large VLDL size, TG, and TG-to-HDL-C ratio were associated with incident diabetes independent of established risk factors, glucose, insulin, or HOMA-IR, as well as the use of lipid-lowering medications or hormone therapy.

Relationship between circulating serum osteoprotegerin and total receptor activator of nuclear κ-B ligand levels, triglycerides, and coronary calcification in postmenopausal women.

OBJECTIVE: This study evaluates the relationship of blood osteoprotegerin (OPG) and receptor activator of nuclear κ-B ligand (RANKL) levels with coronary artery calcium (CAC) and cardiovascular risk factors in two studies of postmenopausal women. OPG, a marker of bone turnover, and its ligand, RANKL, may contribute to cardiovascular disease risk. METHODS: We tested the hypothesis that serum OPG and RANKL levels were associated with CAC and cardiovascular disease risk factors among postmenopausal women in the Women On the Move through Activity and Nutrition Study (WOMAN Study; n = 86; mean [SD], age 58 [2.9] y) and replicated our findings in the Healthy Women Study (HWS; n = 205; mean [SD] age, 61 [2.3] y). Serum OPG, total RANKL, and CAC were measured at baseline and 48 months in the WOMAN Study and on the eighth postmenopausal visit in the HWS. RESULTS: In the WOMAN Study, higher OPG was associated with higher CAC, and higher total RANKL was associated with lower CAC and triglycerides. In the HWS, higher total RANKL was also associated with lower CAC and triglycerides. In logistic regression models adjusted for body mass index and triglycerides, the odds ratios (95% CIs) for CAC per unit increase in OPG were 1.78 (1.17-2.73) for the WOMAN Study and 1.02 (0.84-1.24) for the HWS, and the odds ratios (95% CIs) for CAC per unit increase in log total RANKL were 0.86 (0.64-1.17) for the WOMAN Study and 0.83 (0.72-0.96) for the HWS. CONCLUSIONS: The inverse association of total RANKL with CAC and triglycerides is a new finding and may have important implications given the increasing use of drugs that modify total RANKL and its receptor, receptor activator of nuclear κ-B.