Postmenopausal Women With Greater Paracardial Fat Have More Coronary Artery Calcification Than Premenopausal Women: The Study of Women's Health Across the Nation (SWAN) Cardiovascular Fat Ancillary Study
Background Volumes of paracardial adipose tissue (PAT) and epicardial adipose tissue (EAT) are greater after menopause. Interestingly, PAT but not EAT is associated with estradiol decline, suggesting a potential role of menopause in PAT accumulation. We assessed whether volumes of heart fat depot (EAT and PAT) were associated with coronary artery calcification (CAC) in women at midlife and whether these associations were modified by menopausal status and estradiol levels.
Methods and Results EAT and PAT volumes and CAC were measured using electron beam computed tomography scans. CAC was evaluated as (1) the presence of CAC (CAC Agatston score ≥10) and (2) the extent of any CAC (log CAC Agatston score >0). The study included 478 women aged 50.9 years (58% pre‐ or early perimenopausal, 10% late perimenopausal, and 32% postmenopausal). EAT was significantly associated with CAC measures, and these associations were not modified by menopausal status or estradiol. In contrast, associations between PAT and CAC measures were modified by menopausal status (interaction‐P≤0.01). Independent of study covariates including other adiposity measures, each 1‐SD unit increase in log PAT was associated with 102% higher risk of CAC presence (P=0.04) and an 80% increase in CAC extent (P=0.008) in postmenopausal women compared with pre‐ or early perimenopausal women. Additional adjustment for estradiol and hormone therapy attenuated these differences. Moreover, the association between PAT and CAC extent was stronger in women with lower estradiol levels (interaction P=0.004).
Conclusions The findings suggest that PAT is a potential menopause‐specific coronary artery disease risk marker, supporting the need to monitor and target this fat depot for intervention in women at midlife.
The incidence of coronary artery disease (CAD), which is the leading cause of death in women, increases after menopause.1, 2 As women transition though menopause, they are undergo adverse alterations in body fat composition,3, 4, 5, 6, 7 lipids, and lipoproteins8 and vascular remodeling9 that could increase their CAD risk. The menopausal transition, independent of aging, is believed to be associated with changes in body fat deposition rather than increases in weight.3, 4, 5, 6, 7, 10, 11 The fat surrounding the heart (heart fat) is hypothesized to be more detrimental for cardiovascular risk than other fat depots because of its close anatomic location.12 Increasing evidence supports a role of heart fat in the pathogenesis of CAD,13, 14 cardiovascular disease (CVD) events,15, 16, 17 and all‐cause mortality.18 Based on fat location in the pericardium, 2 distinct heart fat depots can be quantified: (1) epicardial adipose tissue (EAT), which is the fat that directly covers the heart and is located between the outer wall of the myocardium and the visceral layer of the pericardium, and (2) paracardial adipose tissue (PAT), which is located anterior to EAT, outside the parietal layer of the pericardium.19 Although EAT and PAT have different anatomic locations and endocrine features, the terms EAT and PAT have been used interchangeably in the literature because they were thought to be identical fat depots. We recently showed that postmenopausal women have greater volumes of EAT and PAT than premenopausal women, independent of age, race, obesity, and other potential risk factors.20 Interestingly, greater volumes of PAT, but not EAT, were significantly associated with lower levels and declines of estradiol (E2) in women at midlife,20 suggesting a potential role of menopause and menopause‐related alterations in sex hormones in PAT accumulation. In addition, these findings support the notions that EAT and PAT depots have distinct endocrine features and should not be evaluated as a single fat depot.
To the best of our knowledge, no previous study has evaluated whether heart fat depots (EAT and PAT separately) are significantly associated with greater risk of subclinical CVD in women at different stages of the menopausal transition or assessed the effect modification of menopausal status and/or endogenous E2 levels on associations between heart fat depots and subclinical CVD. Previous studies were mainly limited to postmenopausal women.21, 22 Premenopausal women were not included for comparisons in any of these studies; therefore, determining whether PAT or EAT might be a menopause‐specific CAD risk marker could not be evaluated in any of the previous studies. The SWAN Cardiovascular Fat Ancillary Study, an ancillary study to the Study of Women’s Health Across the Nation (SWAN), was specifically designed (1) to assess the distinct associations between each heart fat depot and coronary artery calcification (CAC)—a robust subclinical measure of CAD23, 24—in midlife women and (2) to investigate whether the associations between heart fat depots and CAC are modified by menopausal status and/or endogenous levels of E2. Given our recent findings showing greater volumes of EAT and PAT in postmenopausal than in premenopausal women and that levels of endogenous E2 could be an important contributor to PAT but not to EAT volumes,20 we hypothesized that greater volumes of EAT and PAT would be significantly associated with CAC and that the association between PAT and CAC, but not between EAT and CAC, would be significantly modified by menopausal status and E2 levels in women at midlife.
Participants and Methods
SWAN is an ongoing longitudinal community‐based study of the menopausal transition.25 Briefly, 3302 participants aged 42 to 52 years were recruited during the period 1996–2009 from 7 study sites (Boston, MA; Detroit, MI; Oakland, CA; Los Angeles, CA; Pittsburgh, PA; Chicago, IL; and Newark, NJ). The eligibility criteria for the SWAN study were (1) an intact uterus and ≥1 ovary, (2) ≥1 menstrual period within the past 3 months, and (3) no hormone therapy (HT) use within the past 3 months. At the Pittsburgh and Chicago sites, subclinical measures of atherosclerosis were collected as part of the SWAN Heart ancillary study. The SWAN Cardiovascular Fat Ancillary Study was designed to measure cardiovascular fat volumes among SWAN Heart study participants. To be part of the SWAN Cardiovascular Fat Ancillary Study, participants had to have electron beam computed tomography scans performed at the SWAN Heart baseline visit. Of 608 SWAN Heart participants, 564 had electron beam computed tomography scans to measure heart fat depots. For the current analyses, women were excluded if they were surgically menopausal, had undetermined menopausal status due to HT use, or were missing information on menopausal status (n=42). Another 44 women were excluded either because of missing CAC data or inability to quantify heart fat depots because of technical issues, leaving 478 women in final analyses.
The institutional review board at each site approved the study protocol, and all participants signed informed consent prior to participation.
Coronary Artery Calcification
Calcification in the coronary arteries was quantified using the C‐150 Ultrafast CT Scanner (GE Imatron). An initial scout scan was performed to identify anatomic landmarks. To evaluate the coronary arteries, 30 to 40 contiguous 3‐mm‐thick transverse images were obtained from the level of the aortic root to the apex of the heart during maximal breath holding. All scan data were saved to an optical disk for central scoring, using a DICOM workstation and software by Accu‐Image, Inc. This software program implements the Agatston scoring method.26 CAC was defined as a hyperattenuating lesion >130 Hounsfield units, with an area of at least 3 pixels. The total calcification score was the sum of the individual scores for the 4 major epicardial coronary arteries. The scoring system had high reproducibility as measured in 40 consecutive participants from another study selected to have a wide range of calcium. The intraclass correlation for CAC scores was 0.99.27
Heart Fat Depots
Electron beam computed tomography scans (GE Imatron C‐150 Ultrafast CT Scanner) were used to quantify EAT, the adipose tissue within the pericardium, and PAT, the adipose tissue outside the pericardium. EAT and PAT were quantified at the Biomedical Research Institute, Harbor‐ UCLA Medical Center, as described previously.20 In brief, total heart fat volume (EAT plus PAT) was determined from 15 mm above to 30 mm below the superior extent of the left main coronary artery. This region of the heart was selected because it includes the epicardial fat surrounding the proximal coronary arteries. The anterior border of the heart fat volume was the chest wall, and the posterior borders were the aorta and the bronchus. Using the volume analysis software (GE Healthcare), fat was distinguished from other heart tissue by a threshold of −190 to −30 Hounsfield units. EAT was measured by manually tracing out the pericardium every 2 to 3 slices below the start point and then using the software to automatically trace out the segments in between these selected slices. PAT was measured by subtracting EAT volume from total heart fat volume. Reproducibility measurements of EAT and PAT were performed on 20 randomly selected scans from another study that used a similar protocol.21 Both Spearman and intraclass correlation coefficients between readers (intrareader) were 0.99 each for EAT and 0.86 and 0.96, respectively, for PAT. Similarly, both Spearman and intraclass correlation coefficients between repeated readings (interreader) were 0.98 each for EAT and 0.96 and 0.90, respectively, for PAT.21
Menopausal status was determined based on frequency and regularity of menstrual bleeding as follows: (1) premenopause, no perceived change in bleeding; (2) early perimenopause, perceived change in cycle interval but at least 1 menstrual period within the past 3 months; (3) late perimenopause, 3 consecutive months of amenorrhea; (4) postmenopause, 12 consecutive months of amenorrhea. Because the sample size of premenopausal women was small (n=49) and their characteristics and E2 and CAC levels were similar to those of early perimenopausal women (data not shown), pre‐ and early perimenopausal women were combined in 1 group in the current study. In contrast, only 50 women were classified as late perimenopausal; however, we did not combine those women with postmenopausal women, as we have done previously,20 given that the 2 groups had different CAC levels. Late peri‐ and postmenopausal women were analyzed as separate groups in the current study.
Women provided fasting blood samples during the early follicular phase (days 2–5 of the menstrual cycle) at each visit. Fasting samples were obtained within 90 days of the recruitment anniversary date if a timed sample could not be obtained. Accordingly, cycle day of blood draw was reported either as days 2 to 5 or as being outside that period. Blood was prepared and serum shipped to the Clinical Ligand Assay Satellite Services Central Laboratory at the University of Michigan. E2 was measured using a modified, off‐line Automated Chemiluminescence System 180 (E2‐6). E2 assays were conducted in duplicate. The average for the duplicate measures was calculated and reported (coefficients of variation of 3–12%). The lower limit of detection was between 1 and 7 pg/mL. The inter‐ and intra‐assay coefficients of variation were 10.6% and 6.4%, respectively. E2 values between zero and the lower limit of detection were replaced with a random value between zero and the lower limit of detection.
Lipids, glucose, and insulin were assayed at the Medical Research Laboratories in Lexington, Kentucky, certified by the National Heart, Lung, and Blood Institute, Centers for Disease Control and Prevention Part III program. Total cholesterol and triglyceride levels were analyzed using enzymatic methods on a Hitachi 747 analyzer (Boehringer Mannheim Diagnostics),28 and high‐density lipoprotein was isolated using heparin–manganese.29 Low‐density lipoprotein was calculated using the Friedewald equation.30 Serum insulin was measured by a radioimmunoassay (Coat‐a‐Count; Diagnostic Products Corp) procedure and monitored as part of the monthly quality assurance program by the Diabetes Diagnostic Laboratory at the University of Missouri. Glucose was measured with a hexokinase‐coupled reaction (Boehringer Mannheim Diagnostics). The homeostasis model assessment index was calculated from fasting insulin and glucose as follows: (insulin [in uIU/ml]×glucose [in mmol/L])/22.5.31, 32
Weight and height were measured to calculate body mass index (BMI; kg/m2). Blood pressure was averaged from 2 sequential measures in the right arm with the participant seated after at least 5 minutes of rest. Race and ethnicity, age, smoking status, use of HT, and educational level were self‐reported. Physical activity was self‐reported and was assessed via a modified Baecke score of habitual physical activity,33 with higher scores indicating more physical activity. Morbidity was defined as yes if participant reported a history of hypertension, diabetes mellitus, angina, stroke, or heart attack. Medication use was defined as yes if the participant reported use of medications for hypertension, diabetes mellitus, or high cholesterol. Visceral adipose tissue (VAT) area was measured using 6‐mm‐thick transverse electron beam computed tomography scan (C‐150 Ultrafast CT Scanner; GE Imatron) between L4 and L5 obtained during suspended respiration. Computed tomography scans were read by a single individual at the University of Pittsburgh. A pixel range of −30 to −190 Hounsfield units was used to define fat in the scan circumference. VAT area was defined using image analysis (Accu‐Image software). A region‐of‐interest line was drawn at the interior of abdominal musculature along the fascial plane. Fat within this area was considered VAT area. Intraobserver reliability was 0.94 for the VAT area.
Heart fat volumes, E2, triglycerides, and homeostasis model assessment index were log transformed to reduce skewed distributions. CAC was evaluated at 2 different levels: (1) by the presence of CAC (CAC Agatston score ≥10) and (2) by the extent of any CAC (log CAC Agatston score >0). Study variables were compared by the presence of CAC and by menopausal status (data not shown) using ANOVA, t tests, or chi‐square tests, as appropriate. Separate logistic regression (for presence of CAC) and linear regression (for extent of CAC) models were developed to evaluate the associations between each CAC measure as an outcome, with each log‐transformed heart fat depot volume as the main independent variable. Results from logistic and linear regression were presented per 1‐SD increase in each log heart fat depot volume. For ease of interpretation, beta coefficients from linear regression models of log heart fat depots as related to log CAC >0 (CAC extent) were presented as percentage changes and 95% CI in CAC extent. For multivariable analyses, age, race, study site, and menopausal status were a priori selected covariates and were forced into the base model regardless of statistical significance. All other variables that were found to be significantly associated with study outcomes (Table 1) and independent variables in the univariate analyses (data not shown) were considered as potential covariates to be adjusted for in model 2. To build the best parsimonious model 2, step‐up regression was used. Models with the best fit statistics (highest C or R2 statistics) were chosen. Because of the high correlations between adiposity measures (BMI, VAT) and heart fat depots (EAT, PAT), we could not adjust for both BMI and VAT in the same model. Models adjusted for BMI fit the data better than models adjusted for VAT; however, for some models, adjusting for BMI resulted in significant associations in the direction opposite what we expected, which is a sign of collinearity. Adjusting for obesity (BMI ≥30) instead did not severely affect model stability, and thus final models were adjusted for obesity instead of BMI. Model 3 was additionally adjusted for log E2, HT use, and cycle day of the blood draw (days 2–5 versus outside that period) to assess the impact of endogenous E2 and exogenous HT use on the tested associations. Effect modifications by menopausal status or by log E2 were tested, and stratified analyses were presented if interactions were significant. For significant interactions between continuous measures of log E2 and PAT volumes as related to CAC, interactions were retested using tertiles of both E2 and PAT for easier interpretation. Statistical tests were 2‐sided with a significance level of 0.05. SAS software (version 9.3; SAS Institute Inc) was used for the analysis.
Participants’ characteristics in the total sample and by presence of CAC are presented in Table 1. Participants were aged 50.9±2.9 years and were 38% black; 58% were pre‐ or early perimenopausal, 10% were late perimenopause, and 32% were postmenopausal. Participants with CAC ≥10 were more likely to be older, postmenopausal, and obese and to have higher systolic blood pressure, BMI, VAT, low‐density lipoprotein cholesterol, triglycerides, and homeostasis model assessment index and lower physical activity score and high‐density lipoprotein cholesterol, and E2 levels. In addition, those participants were more likely to report comorbid conditions and use of medications (all P<0.05).
Associations between heart fat depots and presence of CAC and extent of CAC are presented in Table 2. In base models (model 1) adjusted for age, race, study site, and menopausal status, both EAT and PAT were significantly associated with greater odds of CAC presence and greater extent of log (CAC >0). Further adjustments for obesity, systolic blood pressure, smoking status, log triglycerides, and medication use explained the associations with PAT but not with EAT. Additional adjustment for log E2, HT use, and cycle day of the blood draw did not affect the associations between EAT and CAC measures. In contrast, the magnitude of the associations between PAT and CAC increased and the reported P values decreased when models were additionally adjusted for log E2 and HT use.
Significant interactions were found between PAT and menopausal status as related to presence (Table 3) and extent (Table 4) of CAC. Interestingly, the odds of CAC presence per 1‐SD unit increase in log PAT were 102% higher in postmenopausal women compared with pre‐ or early perimenopausal women, independent of study covariates (model 2) but not independent of endogenous E2 levels and HT use (model 3). Additional adjustment for these 2 covariates explained the difference in risk of CAC presence between the 2 groups (Table 3). Similarly, postmenopausal women showed an 80% increase in CAC extent compared with pre‐ or early perimenopausal women per 1‐SD unit increase in log PAT in model 2 (Table 4). These differences were attenuated after additional adjustment for endogenous E2 levels and HT use (model 3) (Table 4). Stratified analyses by menopausal status showed stronger associations and larger effect sizes in the relationships of PAT with presence of CAC (Table 5) and the extent of CAC (Table 6) in postmenopausal women than in pre‐ or early perimenopausal women. Adjusting for VAT instead of obesity in model 2 in Tables 3, 4, 5 through 6 provided similar findings (data not shown).
Association between PAT and CAC extent was dependent on E2 levels, adjusting for study site, age, race and ethnicity, menopausal status, obesity, systolic blood pressure, smoking, log triglycerides, medication use, cycle day of the blood draw, and HT use (interaction P=0.004). Similar results were seen if the model was adjusted for VAT instead of obesity (data not shown). Higher volumes of PAT were significantly associated with greater CAC extent only among women with E2 levels in the lowest tertile (E2 ≤18.65 pg/mL; trend P=0.038) (Figure 1.
Associations between EAT and CAC measures were not significantly modified by menopausal status. In addition, E2 levels did not significantly modify these associations, except for a weak interaction between E2 and EAT related to extent of calcification (P=0.04) that became nonsignificant once models were adjusted for VAT instead of obesity.
To the best of our knowledge, this study is the first to assess associations between volumes of heart fat depots and CAC in women at different stages of the menopausal transition and to evaluate the impact of menopausal status and endogenous E2 levels on these associations. We demonstrated that greater volumes of EAT are significantly associated with presence and extent of CAC, independent of age, race, menopausal status, and traditional CVD risk factors. In addition, we reported that the associations between PAT and CAC measures are significantly modified by women's menopausal status and E2 levels independent of age, race, obesity (or VAT; data not shown), and other CVD risk factors; similar effect modifications were not found for EAT as related to CAC measures.
Our findings of significant associations of CAC measures with EAT volumes in women at midlife are in agreement with previous studies in other populations, which suggests a significant role of EAT in the pathogenesis of CAD. Higher heart fat volumes are associated with CVD risk factors, CVD events, and CAC.13, 14, 15, 16, 17, 18 It is well recognized that heart fat is a metabolically active organ that releases various substances with known vascular actions that, in turn, could locally modulate the morphology and functions of the heart and thus contribute to increase CVD risk.12
We demonstrated that the associations between CAC measures and EAT do not depend on women's menopausal status or E2 levels, whereas the associations between CAC measures and PAT were menopause‐specific and may be modulated by women's endogenous levels of E2. In our previous work, although late peri‐ and postmenopausal women had greater volumes of EAT and PAT than pre‐ and early perimenopausal women,20 late peri‐ and postmenopausal women had greater volumes of PAT (20% higher) than EAT (10% higher) compared with pre‐ and early perimenopausal women. In addition, we reported that women with the greatest E2 decline over almost 5 years of follow‐up had 20% higher PAT volumes compared with women with the least decline in E2 over time.20 We hypothesized, based on these previous findings, that heart fat could play a role in the higher risk of CVD reported in women after menopause. In the current study, we showed that postmenopausal women had ≈80% greater CAC extent than pre‐ and early perimenopausal women per 1 SD greater log PAT. The current results, together with our noted previous findings,20 support our hypothesis that PAT is a potential menopause‐specific CAD risk marker in women at midlife. Further research is needed to confirm our hypothesis using a longitudinal study design.
Our findings of significant impact of E2 levels on associations of CAC with PAT but not with EAT add to the lines of evidence that EAT and PAT are distinct heart fat depots with different endocrine properties and thus should be evaluated separately.12 EAT and PAT have different embryological origins; EAT originates from the splanchnopleuric mesoderm, whereas PAT originates from the primitive thoracic mesenchyme. Moreover, the coronary circulation supplies blood to EAT but not to PAT. Finally, EAT is the energy source for the heart, with high free fatty acid release and uptake and low glucose requirements; in contrast, to date, there are no known cardioprotective functions of PAT.34
It is not clear why E2 levels modulated the associations of CAC with PAT but not EAT. We previously reported significant associations between lower levels and greater declines of E2 with PAT but not EAT.20 These findings support that volumes of PAT but not EAT may be modulated by E2. Estrogen receptor Er‐α,35 expressed in human subcutaneous and visceral adipose tissues,36 plays a significant role in regulating adipocyte metabolism and sexual dimorphism of adipose tissue depots. E2 can directly increase the antilipolytic α2A‐adrenergic receptors37 and lipolytic β‐adrenergic expression38 to control the accumulation of fat in a certain adipose tissue depot. Consequently, it is possible that Er‐α estrogen receptors are more expressed in PAT than in EAT and could, in turn, make any changes in E2 levels affect PAT more than EAT. It would be of great interest to assess the potential role of HT use on heart fat volumes and their associations with subclinical atherosclerotic measures such as CAC in future studies.
In the current study, greater PAT volume was associated with higher odds of CAC presence and greater CAC extent in postmenopausal women compared with pre‐ and early perimenopausal women. These findings were independent of study covariates but not of endogenous E2 levels and HT use. Given the current uncertainty about the cardioprotective impacts of HT use39 and the lack of any publication on the impact of HT use on heart fat volumes, identifying other possible prevention strategies to decrease heart fat in general and PAT in particular in women at midlife may reduce CVD risk associated with excess heart fat. Interestingly, a recent systematic review and meta‐analysis of studies assessing whether heart fat volumes could be modified and whether different strategies could be utilized concluded that it is possible to reduce heart fat and that significant reductions occurred with dieting and bariatric surgery but not with exercise.40 Heart fat can be decreased by 17% in abdominally obese postmenopausal women on weight‐loss interventions of equal energy deficit with or without aerobic exercise.41
Our findings should be viewed in the context of some limitations, including the cross‐sectional design, which prevented us from testing whether the accumulation of heart fat is associated with CAC progression and whether the dynamic changes in E2 as women transition through menopause could modify this association. Our findings may not be generalizable to women of other ages or other racial and ethnic groups. Because of small sample sizes for the pre‐ and late perimenopausal categories, we may not have enough power to assess study aims in each category separately. In addition, our findings of the extent of CAC and PAT should be interpreted with caution, given the wide reported confidence intervals, which could be due to small sample size. This study has several strengths, which include using a well‐characterized cohort (SWAN) and being the first to evaluate whether volumes of heart fat are associated with CAC in women at midlife and whether women's menopausal status and their E2 levels modify this association. Future studies should evaluate the role of HT use on heart fat volume accumulation and the impact of HT use on the associations between heart fat volumes and subclinical measures of atherosclerosis.
In conclusion, although greater volumes of EAT were significantly associated with CAC, only the association of CAC with volumes of PAT was dependent on menopausal status and E2 levels. Our findings suggest PAT as a potential menopause‐specific CAD risk marker and maintain that EAT and PAT are distinct fat depots that should be evaluated separately. The current study supports the need to monitor and target heart fat depots for intervention in women at midlife.
Sources of Funding
The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), Department of Health and Human Services, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (Grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). SWAN Heart was supported by the National Heart, Lung, and Blood Institute (Grants HL065581, HL065591). The SWAN Cardiovascular Fat Ancillary Study was supported by an award from the American Heart Association Great River Affiliation Clinical Research Program: 12CRP11900031. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH.
Dr El Khoudary reports grants from the American Heart Association, during the conduct of the study; Dr Shields has nothing to disclose; Dr Janssen reports grants from the National Institutes of Health (NIH) during the conduct of the study; Dr Budoff reports grants from NIH, during the conduct of the study; grants from GE, outside the submitted work; Dr Everson‐Rose reports grants from National Institutes of Health and the University of Minnesota, outside the submitted work; Dr Powell and Dr Matthews report grants from National Institutes of Health during the conduct of the study.
Clinical Centers: University of Michigan, Ann Arbor—Siobán Harlow, PI 2011–present, MaryFran Sowers, PI 1994–2011; Massachusetts General Hospital, Boston, MA—Joel Finkelstein, PI 1999–present; Robert Neer, PI 1994–1999; Rush University, Rush University Medical Center, Chicago, IL—Howard Kravitz, PI 2009–present; Lynda H. Powell, PI 1994–2009; University of California, Davis/Kaiser—Ellen Gold, PI; University of California, Los Angeles—Gail Greendale, PI; Albert Einstein College of Medicine, Bronx, NY—Carol Derby, PI 2011–present, Rachel Wildman, PI 2010–2011; Nanette Santoro, PI 2004–2010; University of Medicine and Dentistry—New Jersey Medical School, Newark—Gerson Weiss, PI 1994–2004; and the University of Pittsburgh, Pittsburgh, PA—Karen Matthews, PI. NIH Program Office: National Institute on Aging, Bethesda, MD—Chhanda Dutta 2016–present; Winifred Rossi 2012–2016; Sherry Sherman 1994–2012; Marcia Ory 1994–2001; National Institute of Nursing Research, Bethesda, MD—Program Officers. Central Laboratory: University of Michigan, Ann Arbor—Daniel McConnell (Central Ligand Assay Satellite Services). Coordinating Center: University of Pittsburgh, Pittsburgh, PA—Maria Mori Brooks, PI 2012–present; Kim Sutton‐Tyrrell, PI 2001–2012; New England Research Institutes, Watertown, MA—Sonja McKinlay, PI 1995–2001. Steering Committee: Susan Johnson, Current Chair. Chris Gallagher, Former Chair. We thank the study staff at each site and all the women who participated in SWAN.
- ↵Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER III., Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee . Executive summary: heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:447–454.
- ↵Enzi G, Gasparo M, Biondetti PR. Subcutaneous and visceral fat distribution according to sex, age, and overweight, evaluated by computed tomography. Am J Clin Nutr. 1986;44:739–746.
- ↵van der Leeuw J, Wassink AM, van der Graaf Y, Westerveld HE, Visseren FL; Second Manifestations of ARTerial Disease (SMART) Study Group . Age‐related differences in abdominal fat distribution in premenopausal and postmenopausal women with cardiovascular disease. Menopause. 2013;20:409–417.
- ↵Matthews KA, Crawford SL, Chae CU, Everson‐Rose SA, Sowers MF, Sternfeld B, Sutton‐Tyrrell K. Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition? J Am Coll Cardiol. 2009;54:2366–2373.
- ↵Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS, O'Donnell CJ, Fox CS. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community‐based sample: the Framingham Heart Study. Circulation. 2008;117:605–613.
- ↵Mahabadi AA, Lehmann N, Kälsch H, Robens T, Bauer M, Dykun I, Budde T, Moebus S, Jöckel KH, Erbel R, Möhlenkamp S. Association of epicardial adipose tissue with progression of coronary artery calcification is more pronounced in the early phase of atherosclerosis: results from the Heinz Nixdorf Recall Study. JACC Cardiovasc Imaging. 2014;7:909–916.
- ↵Ding J, Hsu FC, Harris TB, Liu Y, Kritchevsky SB, Szklo M, Ouyang P, Espeland MA, Lohman KK, Criqui MH, Allison M, Bluemke DA, Carr JJ. The association of pericardial fat with incident coronary heart disease: the Multi‐Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr. 2009;90:499–504.
- ↵Mahabadi AA, Berg MH, Lehmann N, Kälsch H, Bauer M, Kara K, Dragano N, Moebus S, Jöckel KH, Erbel R, Möhlenkamp S. Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf Recall Study. J Am Coll Cardiol. 2013;61:1388–1395.
- ↵Larsen BA, Laughlin GA, Saad SD, Barrett‐Connor E, Allison MA, Wassel CL. Pericardial fat is associated with all‐cause mortality but not incident CVD: the Rancho Bernardo Study. Atherosclerosis. 2015;239:470–475.
- ↵Kaushik M, Reddy YM. Distinction of “fat around the heart”. J Am Coll Cardiol. 2011;58:1640; author reply 1640‐1.
- ↵Huang G, Wang D, Zeb I, Budoff MJ, Harman SM, Miller V, Brinton EA, El Khoudary SR, Manson JE, Sowers MR, Hodis HN, Merriam GR, Cedars MI, Taylor HS, Naftolin F, Lobo RA, Santoro N, Wildman RP. Intra‐thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS). Atherosclerosis. 2012;221:198–205.
- ↵de Vos AM, Prokop M, Roos CJ, Meijs MF, van der Schouw YT, Rutten A, Gorter PM, Cramer MJ, Doevendans PA, Rensing BJ, Bartelink ML, Velthuis BK, Mosterd A, Bots ML. Peri‐coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in post‐menopausal women. Eur Heart J. 2008;29:777–783.
- ↵McEvoy JW, Blaha MJ, DeFilippis AP, Budoff MJ, Nasir K, Blumenthal RS, Jones SR. Coronary artery calcium progression: an important clinical measurement? A review of published reports. J Am Coll Cardiol. 2010;56:1613–1622.
- ↵Budoff MJ, Young R, Lopez VA, Kronmal RA, Nasir K, Blumenthal RS, Detrano RC, Bild DE, Guerci AD, Liu K, Shea S, Szklo M, Post W, Lima J, Bertoni A, Wong ND. Progression of coronary calcium and incident coronary heart disease events: MESA (Multi‐Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2013;61:1231–1239.
- Lobo RA
- Kelsey J
- Marcus R
- ↵Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr., Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–832.
- ↵Stein EA, Steiner PM, Gartside PS, Glueck CJ. Development and evaluation of a method for quantification of plasma high‐density‐lipoprotein cholesterol. Clin Chem. 1978;24:1112–1115.
- ↵Warnick GR, Albers JJ. A comprehensive evaluation of heparinmanganese precipitation procedure for estimating high‐density lipoprotein cholesterol. J Lipid Res. 1978;19:65–76.
- ↵Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low‐density lipoprotein cholesterol in plasma, without the use of preparative ultracentrifuge. Clin Chem. 1972;18:499–502.
- ↵Katsuki A, Sumida Y, Gabazza EC, Murashima S, Furuta M, Araki‐Sasaki R, Hori Y, Yano Y, Adachi Y. Homeostasis model assessment is a reliable indicator of insulin resistance during follow‐up of patients with type 2 diabetes. Diabetes Care. 2001;24:362–365.
- ↵Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor‐α knockout mice. Proc Natl Acad Sci USA. 2000;97:12729–12734.
- ↵Pedersen SB, Kristensen K, Hermann PA, Katzenellenbogen JA, Richelsen B. Estrogen controls lipolysis by up‐regulating alpha2A‐adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution. J Clin Endocrinol Metab. 2004;89:1869–1878.
- ↵Monjo M, Pujol E, Roca P. alpha2‐ to beta3‐Adrenoceptor switch in 3T3‐L1 preadipocytes and adipocytes: modulation by testosterone, 17beta‐estradiol, and progesterone. Am J Physiol Endocrinol Metab. 2005;289:e145–e150.
- ↵Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321–333.
- ↵Rabkin SW, Campbell H. Comparison of reducing epicardial fat by exercise, diet or bariatric surgery weight loss strategies: a systematic review and meta‐analysis. Obes Rev. 2015;16:406–415.