Associations of HDL metrics with coronary artery calcium score and density among women traversing menopause.

The cardioprotective association of high-density lipoprotein cholesterol (HDL-C) may vary by menopause stage or estradiol level. We tested whether associations of comprehensive HDL metrics (HDL subclasses, phospholipid and triglyceride content, and HDL cholesterol efflux capacity [HDL-CEC]) with coronary artery calcium (CAC) score and density vary by menopause stage or estradiol level in women transitioning through menopause. Participants (N = 294; mean age [SD]: 51.3 [2.9]) had data on HDL metrics and CAC measures at one or two time points during the menopause transition. Generalized estimating equations were used for analyses. Effect modifications by menopause stage or estradiol level were tested in multivariable models. In adjusted models, menopause stage modified the associations of specific HDL metrics with CAC measures. Higher small HDL particles (HDL-P) concentrations (p-interaction = 0.008) and smaller HDL size (p-interaction = 0.02) were associated with greater odds of CAC presence in late perimenopause than in pre/early perimenopause stage. Women in the highest estradiol tertile, but not the lower tertiles, showed a protective association of small HDL-P with CAC presence (p-interaction = 0.007). Lower large HDL-P concentrations (p-interaction = 0.03) and smaller HDL size (p-interaction = 0.03) were associated with lower CAC density in late perimenopause than in postmenopause stage. Associations of HDL phospholipid and triglyceride content and HDL-CEC with CAC measures did not vary by menopause stage or estradiol level. We concluded that HDL subclasses may impact the likelihood of CAC presence and the stability of coronary plaque differently over the menopause transition. Endogenous estradiol levels may contribute to this observation.

Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma.

BACKGROUND: We previously reported early on-treatment significant modulation in circulating regulatory T cell (Treg), myeloid derived suppressor cells (MDSC) and antigen-specific type I CD4+ and CD8+ T cells that correlated with clinical outcome in regionally advanced melanoma patients treated with neoadjuvant ipilimumab. Here, we investigated the long term immunologic impact of CTLA4 blockade. METHODS: Patients were treated with ipilimumab given at 10 mg/kg IV every 3 weeks for 2 doses bracketing surgery. Blood specimens were collected at baseline and during treatment for up to 9 months. We tested immune responses at 3, 6, and 9 months utilizing multicolor flow cytometry. We compared frequencies of circulating Treg and MDSC on-study to baseline levels, as well as frequencies of CD4+ and CD8+ T cells specific to shared tumor-associated antigens (Gp-100, MART-1, NY-ESO-1). RESULTS: Levels of Treg significantly increased when measured at 6 weeks following ipilimumab but returned to baseline by 3 months, with no significant difference in Treg levels between relapsed and relapse-free groups at 3, 6 or 9 months. However, lower baseline levels of circulating Treg (CD4+CD25hi+CD39+) were significantly associated with better relapse free survival (RFS) (p = 0.04). Levels of circulating monocytic HLA-DR+/loCD14+ MDSC were lower at baseline in the relapse-free group and further decreased at 6 weeks, though the differences did not reach statistical significance including measurements at 3, 6 or 9 months. We detected evidence of type I (interferon-γ producing), activated (CD69+) CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) as well as melanocytic lineage (MART-1, gp100) antigens in the absence of therapeutic vaccination. These responses were significantly boosted at 6 weeks and persisted at 3, 6 and 9 months following the initiation of ipilimumab. CONCLUSIONS: Lower Treg levels at baseline are significantly associated with RFS and increased Treg frequency after CTLA4 blockade was only transient. Lower MDSC was also associated with RFS and MDSC levels were further decreased after ipilimumab. Tumor specific effector immune responses are boosted with CTLA4 blockade and tend to be durable. Trial registration ClinicalTrials.gov Identifier: NCT00972933.

Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off?

OBJECTIVE: Youth type 2 diabetes mellitus (T2DM) occurs decades earlier than adult T2DM and is characterized by high therapeutic failure rates and decreased response to insulin sensitizers suggesting a more severe disease process than in adults. To explain these observations, we hypothesized that insulin resistance is worse in obese youth than adults with impaired glucose tolerance (IGT), a state of high-risk for T2DM. As proof-of-concept, we compared insulin sensitivity between BMI-, sex-, and race-matched obese youth vs adults with IGT. METHODS: This retrospective analysis of IGT youth and adults included 34 obese adolescents matched (2:1) for BMI, sex, and race to 17 adults. Hepatic and peripheral insulin sensitivity were measured by [6,6-2 H2 ]glucose and hyperinsulinemic-euglycemic clamp. Body composition (DEXA) and serum lipid profile were examined. RESULTS: Despite similar percent body fat, obese adolescents had 2-fold higher fasting insulin concentration, lower hepatic (~53%) and peripheral (~42%) insulin sensitivity and lower HDL compared with adults (all P < .01). Surrogate estimate of insulin sensitivity, 1/fasting insulin was lower and HOMA-IR was higher in adolescents vs adults. Adults had a more atherogenic lipid profile with higher total-, LDL-, and non-HDL cholesterol. CONCLUSIONS: Obese youth and adults with IGT differ in that youth are more insulin resistant than adults in spite of similar adiposity. This could potentially explain the earlier onset of T2DM in youth through an early and amplified burden on a ß-cell destined to decompensate, and explicate their lower therapeutic response to insulin sensitizers.

High-density lipoprotein metrics during midlife and future subclinical atherosclerosis in women: the SWAN HDL study.

OBJECTIVE: The clinical utility of high-density lipoprotein cholesterol (HDL-C) in risk classification is limited, especially in midlife women. Novel metrics of HDL may better reflect this risk. We clustered a comprehensive profile of HDL metrics into favorable and unfavorable clusters and assessed how these two clusters are related to future subclinical atherosclerosis (carotid intima media thickness [cIMT], interadventitial diameter [IAD], and carotid plaque presence) in midlife women. METHODS: Four hundred sixty-one women (baseline age: 50.4 [2.7] years; 272 White, 137 Black, 52 Chinese) from the Study of Women's Health Across the Nation HDL ancillary study who had baseline measures of HDL cholesterol efflux capacity (HDL-CEC), lipid contents (HDL-phospholipids [HDL-PL] and HDL triglycerides [HDL-Tg]), and HDL particle (HDL-P) distribution and size, followed by carotid ultrasound (average 12.9 [SD: 2.6] years later), were included. Using latent cluster analysis, women were clustered into a favorable (high HDL-CEC, HDL-PL, large and medium HDL-P, less HDL-Tg and small HDL-P, larger size) or an unfavorable HDL cluster (low HDL-CEC, HDL-PL, large and medium HDL-P, more HDL-Tg, and small HDL-P, smaller size) and then linked to future subclinical atherosclerosis using linear or logistic regression. RESULTS: The favorable HDL cluster was associated with lower cIMT, IAD, and odds of carotid plaque presence. These associations were attenuated by body mass index, except in Chinese women where the association with cIMT persisted (0.72 [0.63, 0.83]). CONCLUSIONS: The association between favorable HDL clusters and a better postmenopausal subclinical atherosclerosis profile is largely explained by body mass index; however, racial/ethnic differences may exist.

Cardiovascular Disease in Women: Does Menopause Matter?

It is known that the menopause transition (MT) is a complex period during a woman's life, but there has been ongoing debate on whether the increase in cardiovascular disease (CVD) during midlife is due to chronological aging or ovarian aging. The purpose of this review is to summarize the recent findings on the role of ovarian aging versus chronological aging on cardiovascular disease (CVD) outcomes and its risk factors in women. Recent data from longitudinal studies have shown that menopause-related factors, such as earlier age at menopause and surgical menopause are associated with higher CVD outcomes. The MT is also associated with detrimental changes in vascular health as well as cardiometabolic risk factors including body composition, visceral fat accumulation, lipids/lipoproteins, blood pressure and the metabolic syndrome. The robust evidence from recent research indicating increases in CVD risk over the MT beyond aging call for immediate efforts to rise awareness among women and their health care providers of CVD risk acceleration accompanying the MT. Efforts should also be directed toward developing and testing novel preventive approaches that target women during this time period to counteract the expected increase in CVD risk.

Associations of Abdominal and Cardiovascular Adipose Tissue Depots With HDL Metrics in Midlife Women: the SWAN Study.

CONTEXT: The menopause transition is accompanied by declines in the atheroprotective features of high-density lipoprotein (HDL), which are linked to deleterious cardiovascular (CV) outcomes. OBJECTIVE: This work aimed to assess the relationship between abdominal and CV visceral adipose tissues (VAT) with future HDL metrics in midlife women, and the role of insulin resistance (IR) on these associations. METHODS: Temporal associations compared abdominal and CV fat with later measures of HDL metrics. This community-based cohort comprised 299 women, baseline mean age 51.1 years (SD: 2.8 years), 67% White, 33% Black, from the Study of Women's Health Across the Nation (SWAN) HDL ancillary study. Exposures included volumes of abdominal VAT, epicardial AT (EAT), paracardial AT (PAT), or perivascular AT (PVAT). Main outcomes included HDL cholesterol efflux capacity (HDL-CEC); HDL phospholipids (HDL-PL), triglycerides (HDL-Tgs), and cholesterol (HDL-C); apolipoprotein A-I (ApoA-I), and HDL particles (HDL-P) and size. RESULTS: In multivariable models, higher abdominal VAT was associated with lower HDL-CEC, HDL-PL, HDL-C, and large HDL-P and smaller HDL size. Higher PAT was associated with lower HDL-PL, HDL-C, and large HDL-P and smaller HDL size. Higher EAT was associated with higher small HDL-P. Higher PVAT volume was associated with lower HDL-CEC. The Homeostatic Model Assessment of Insulin Resistance partially mediated the associations between abdominal AT depots with HDL-CEC, HDL-C, large HDL-P, and HDL size; between PVAT with HDL-CEC; and PAT with HDL-C, large HDL-P, and HDL size. CONCLUSION: In midlife women, higher VAT volumes predict HDL metrics 2 years later in life, possibly linking them to future CV disease. Managing IR may preclude the unfavorable effect of visceral fat on HDL metrics.

Associations of Endogenous Hormones With HDL Novel Metrics Across the Menopause Transition: The SWAN HDL Study.

CONTEXT: Novel metrics of high-density lipoprotein (HDL) (subclasses, lipid content, and function) may improve characterization of the anti-atherogenic features of HDL. In midlife women, changes in these metrics vary by time relative to the final menstrual period (FMP), supporting a contribution of estradiol (E2) and follicle-stimulating hormone (FSH). OBJECTIVE: We tested associations of endogenous E2 and FSH with novel HDL metrics and assessed whether these associations varied by time relative to FMP. METHODS: This study was a longitudinal analysis from the Study of Women's Health Across the Nation (SWAN) HDL study, using a community-based cohort of 463 women, baseline mean age 50.2 (2.7) years. The main outcome measures were HDL cholesterol efflux capacity (HDL-CEC), HDL phospholipids (HDL-PL), HDL triglycerides (HDL-Tg), HDL particles (HDL-P), HDL size, and HDL cholesterol (HDL-C). RESULTS: In multivariable analyses, E2 was positively associated with HDL size, large HDL-P, HDL-CEC, and HDL-Tg, but negatively with medium HDL-P (P values < 0.05). The positive association between E2 and HDL-Tg was stronger 2 years post-FMP than before, (interaction P = 0.031). FSH was positively related to total and medium HDL-P, but negatively to HDL size, large HDL-P, and HDL-CEC per particle (P values < 0.05). Associations of higher FSH with greater total HDL-P and smaller HDL size were only evident at/after menopause (interaction P values < 0.05). CONCLUSION: Some of the associations linking E2 and FSH with novel HDL metrics were vulnerable to time relative to menopause onset. Whether a late initiation of hormone therapy relative to menopause could have a detrimental effect on lipid content of HDL particles should be tested in the future.

Early Midlife Cardiovascular Health Influences Future HDL Metrics in Women: The SWAN HDL Study.

Background Utility of high-density lipoprotein cholesterol (HDL-C) in assessing the antiatherogenic properties of HDL may be limited in midlife women. Novel metrics of HDL function, lipid contents, and subclasses may better reflect the atheroprotective capacities of HDL, supporting the need to evaluate how cardiovascular health affects these metrics in women. We assessed the relationship of early midlife Life's Simple 7 (LS7) score and its health behavior components with future HDL function (HDL-cholesterol efflux capacity), HDL-phospholipid, HDL-triglyceride, HDL particles (HDL-P) and size, and the relationship between LS7 score and changes in HDL metrics over time. Methods and Results We analyzed 529 women (baseline age: 46.4 [2.6] years, 57% White) from the SWAN HDL (Study of Women's Health Across the Nation HDL) study who had baseline LS7 followed by future repeated HDL metrics. Multivariable linear mixed models were used. Higher LS7 score was associated with favorable future HDL profile (higher HDL-phospholipid, total HDL-P and large HDL-P, lower HDL-triglyceride, and larger overall HDL size). Ideal body mass index was associated with higher HDL-cholesterol efflux capacity, HDL-phospholipid, and large HDL-P, lower HDL-triglyceride and small HDL-P, and larger overall HDL size. Ideal physical activity was associated with higher HDL-phospholipid, and total, large, and medium HDL-P. Ideal smoking was associated with less HDL-triglycerides. Diet was not related to HDL metrics. Higher LS7 score and ideal body mass index were associated with slower progression of HDL size over time. Conclusions Novel HDL metrics may better reflect the clinical utility of HDL. Improving lifestyle at midlife, particularly maintaining ideal body mass index, is associated with better future HDL phenotype.

Vasomotor symptoms and lipids/lipoprotein subclass metrics in midlife women: Does level of endogenous estradiol matter? The SWAN HDL Ancillary Study.

BACKGROUND: A greater frequency of vasomotor symptoms (VMSs) has been associated with higher low-density lipoprotein cholesterol (LDL-C), but the association with high-density lipoprotein cholesterol (HDL-C) remains unclear. Endogenous estradiol (E2) levels are associated with both VMS and lipid levels and thus may confound such associations. OBJECTIVES: To assess the relationship of VMS frequency with HDL-C, LDL-C, and lipoprotein concentrations (HDL and LDL particles [HDL-P; LDL-P]) and lipoprotein sizes in midlife women and to evaluate whether these associations are explained by E2. METHODS: Participants were from the Study of Women's Health Across the Nation (SWAN) HDL ancillary study who had both nuclear magnetic resonance (NMR) spectroscopy lipoprotein subclass metrics and self-reported frequency of VMS measured 2-5 times over the menopause transition. VMS frequency was categorized into none, 1-5 days (infrequent), or ≥6 days (frequent) within the past 2 weeks. RESULTS: We evaluated 522 women [at baseline: mean age 50.3 (SD: 2.8) years; infrequent VMS: 29.8%, frequent VMS: 16.5%]. Adjusting for potential confounders except E2, frequent VMS was associated with smaller HDL size [ß(SE): -0.06 (0.03); P = .04] and higher concentrations of LDL-C [ß(SE): 3.58 (1.77); P = .04] and intermediate LDL-P [ß(SE): 0.09 (0.05); P = .04] than no VMS. These associations were largely explained by E2, all P's > .05. CONCLUSIONS: Frequent VMSs were associated with smaller HDL size and higher concentrations of LDL-C and intermediate LDL-P. These associations were explained by endogenous E2. Whether treating frequent VMS with exogenous E2 could simultaneously improve lipids/lipoproteins profile should be assessed in future studies.

Daily luteal serum and urinary hormone profiles in the menopause transition: Study of Women's Health Across the Nation.

OBJECTIVE: To further characterize the endocrinology of the menopause transition, we sought to determine: whether relationships between urine and serum hormones are maintained as women enter their sixth decade; whether a single luteal phase serum progesterone (P) is reflective of integrated-luteal urinary pregnanediol glucuronide (uPdg); and whether serum P, like luteal uPdg, declines as women approach their final menses (FMP). METHODS: The Study of Women's Health Across the Nation (SWAN) Daily Hormone Study's (DHS) is a community-based observational study. A subset of participants underwent a timed, luteal blood draw planned for cycle days 16 to 24 during the same month of DHS collection. Serum-luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and P, and urine LH, FSH, estrone conjugates (E1c), and daily and integrated luteal uPdg were measured in 268 samples from 170 women. Serum/urine hormone associations were determined using Pearson's correlation and linear regression, adjusted for concurrent age, body mass index, smoking status, and race/ethnicity. RESULTS: Pearson's r ranged from 0.573 (for LH) to 0.843 (for FSH) for serum/urine correlations. Integrated luteal uPdg weakly correlated with serum P (Pearson's r = 0.26, P = 0.004) and explained 7% of the variability in serum P in adjusted linear regression (total R 0.09, P = 0.002). Serum P demonstrated a marginally significant decline with approaching FMP in adjusted analysis (P = 0.04). CONCLUSIONS: Urine and serum hormones maintain a close relationship in women into their sixth decade of life. Serum luteal P was weakly reflective of luteal Pdg excretion.

Greater Periaortic Fat Volume at Midlife Is Associated with Slower Gait Speed Later in Life in Women: The SWAN Cardiovascular Fat Ancillary Study.

BACKGROUND: Higher perivascular adipose tissue (PVAT) contributes to adverse physiologic alterations in the vascular wall, and thus could potentially limit normal physical function later in life. We hypothesize that higher PVAT volume at midlife is prospectively associated with slower gait speed later in life, independent of overall adiposity and other risk factors. METHODS: Participants from the Study of Women's Health Across the Nation (SWAN) cardiovascular fat ancillary study were included. PVAT volume around the descending aorta was quantified using existing computed tomography scans at midlife, while gait speed was measured after an average of 10.4 ± 0.7 years. RESULTS: Two hundred and seventy-six women (aged 51.3 ± 2.8 years at PVAT assessment) were included. Mean gait speed was 0.96 ± 0.21 m/s. Adjusting for study site, race, education level, menopausal status, and length of descending aorta at PVAT assessment, and age, body mass index, difficulty paying for basics, overall health and smoking status at gait speed assessment, a higher midlife PVAT volume was associated with a slower gait speed later in life (p = .03). With further adjustment for presence of any comorbid conditions by the time of gait speed assessment, the association persisted; every 1SD increase in log-PVAT was associated with 3.3% slower gait speed (95% confidence interval: 0.3-6.3%; p = .03). CONCLUSION: Greater PVAT in midlife women may contribute to poorer physical function in older age supporting a potential role of midlife PVAT in multiple domains of healthy aging. Additional research is needed to fully elucidate the physiologic changes associated with PVAT that may underlie the observed associations.

Increased Lipolysis, Diminished Adipose Tissue Insulin Sensitivity, and Impaired ß-Cell Function Relative to Adipose Tissue Insulin Sensitivity in Obese Youth With Impaired Glucose Tolerance.

Despite evidence of insulin resistance and ß-cell dysfunction in glucose metabolism in youth with prediabetes, the relationship between adipose tissue insulin sensitivity (ATIS) and ß-cell function remains unknown. We investigated whole-body lipolysis, ATIS, and ß-cell function relative to ATIS (adipose disposition index [DI]) in obese youth with impaired glucose tolerance (IGT) versus normal glucose tolerance (NGT). Whole-body lipolysis (glycerol appearance rate [GlyRa], [2H5]glycerol at baseline and during a hyperinsulinemic-euglycemic clamp), lipid oxidation (indirect calorimetry), insulin secretion (2-h hyperglycemic clamp), and body composition (dual-energy X-ray absorptiometry) were examined. Adipose DI was calculated as ATIS: (1/GlyRa × fasting insulin) × first-phase insulin secretion. Despite similar percent body fat, youth with IGT versus NGT had higher GlyRa, lower ATIS at baseline and during hyperinsulinemia, and higher lipid oxidation. Adipose DI was ∼43% lower in youth with IGT and correlated positively with glucose DI. The lower ATIS and diminished adipose DI in IGT versus NGT is in line with the compromised glucose metabolism reflected in impaired ß-cell function relative to peripheral insulin resistance. We conclude that youth with IGT manifest a global decline in insulin sensitivity, including impaired insulin action in suppressing lipolysis and lipid oxidation, accompanied by ß-cell dysfunction in fat and glucose metabolism, enhancing their risk of type 2 diabetes.

Anti-Müllerian Hormone in Obese Adolescent Girls With Polycystic Ovary Syndrome.

PURPOSE: Anti-Müllerian hormone (AMH) is proposed as a biomarker of polycystic ovary syndrome (PCOS). This study investigated: (1) AMH concentrations in obese adolescents with PCOS versus without PCOS; (2) the relationship of AMH to sex steroid hormones, adiposity, and insulin resistance; and (3) the optimal AMH value and the multivariable prediction model to determine PCOS in obese adolescents. METHODS: AMH levels were measured in 46 obese PCOS girls and 43 obese non-PCOS girls. Sex steroid hormones, clamp-measured insulin sensitivity and secretion, body composition, and abdominal adiposity were evaluated. Logistic regression and receiver-operating characteristic curve analyses were used, and multivariate prediction models were developed to test the utility of AMH for the diagnosis of PCOS. RESULTS: AMH levels were higher in obese PCOS versus non-PCOS girls (8.3 ± .6 vs. 4.3 ± .4 ng/mL, p < .0001), of comparable age and puberty. AMH concentrations correlated positively with age in both groups, total and free testosterone in PCOS girls only, abdominal adipose tissue in non-PCOS girls, with no correlation to in vivo insulin sensitivity and secretion in either groups. A multivariate model including AMH (cutoff 6.26 ng/mL, area under the curve .788) together with sex hormone-binding globulin and total testosterone exhibited 93.4% predictive power for diagnosing PCOS. CONCLUSIONS: AMH may be a useful biomarker for the diagnosis of PCOS in obese adolescent girls.

The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test Heralds Biomarkers of Type 2 Diabetes Risk in Obese Youth.

OBJECTIVE: The shape of the glucose response curve during an oral glucose tolerance test (OGTT), monophasic versus biphasic, identifies physiologically distinct groups of individuals with differences in insulin secretion and sensitivity. We aimed to verify the value of the OGTT-glucose response curve against more sensitive clamp-measured biomarkers of type 2 diabetes risk, and to examine incretin/pancreatic hormones and free fatty acid associations in these curve phenotypes in obese adolescents without diabetes. RESEARCH DESIGN AND METHODS: A total of 277 obese adolescents without diabetes completed a 2-h OGTT and were categorized to either a monophasic or a biphasic group. Body composition, abdominal adipose tissue, OGTT-based metabolic parameters, and incretin/pancreatic hormone levels were examined. A subset of 106 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and ß-cell function relative to insulin sensitivity. RESULTS: Despite similar fasting and 2-h glucose and insulin concentrations, the monophasic group had significantly higher glucose, insulin, C-peptide, and free fatty acid OGTT areas under the curve compared with the biphasic group, with no differences in levels of glucagon, total glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and pancreatic polypeptide. Furthermore, the monophasic group had significantly lower in vivo hepatic and peripheral insulin sensitivity, lack of compensatory first and second phase insulin secretion, and impaired ß-cell function relative to insulin sensitivity. CONCLUSIONS: In obese youth without diabetes, the risk imparted by the monophasic glucose curve compared with biphasic glucose curve, independent of fasting and 2-h glucose and insulin concentrations, is reflected in lower insulin sensitivity and poorer ß-cell function, which are two major pathophysiological biomarkers of type 2 diabetes in youth.