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1.  The association of pericardial fat with calcified coronary plaque 
Obesity (Silver Spring, Md.)  2008;16(8):1914-1919.
Pericardial fat has a higher secretion of inflammatory cytokines than subcutaneous fat. Cytokines released from pericardial fat around coronary arteries may act locally on the adjacent cells.
We examined the relationship between pericardial fat and calcified coronary plaque.
Participants in the community-based Multi-Ethnic Study of Atherosclerosis underwent a computed tomography scan for the assessment of calcified coronary plaque in 2001/02. We measured the volume of pericardial fat using these scans in 159 whites and blacks without symptomatic coronary heart disease from Forsyth County, NC, aged 55–74 years.
Calcified coronary plaque was observed in 91 participants (57%). After adjusting for height, a one standard deviation increment in pericardial fat was associated with an increased odds of calcified coronary plaque (odds ratio (95% confidence interval): 1.92 (1.27, 2.90)). With further adjustment of other cardiovascular factors, pericardial fat was still significantly associated with calcified coronary plaque. This relationship did not differ by gender and ethnicity. On the other hand, body mass index and height-adjusted waist circumference were not associated with calcified coronary plaque.
Pericardial fat is independently associated with calcified coronary plaque.
PMCID: PMC4098129  PMID: 18535554
coronary heart disease; body mass index; waist circumference
2.  Genome-Wide Association of Pericardial Fat Identifies a Unique Locus for Ectopic Fat 
PLoS Genetics  2012;8(5):e1002705.
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7×10-08). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
Author Summary
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. To test whether genetic loci are associated with pericardial fat independent of other body fat depots, we measured pericardial fat in 5,487 individuals of European ancestry. After performing an unbiased screen using genome-wide association, we identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7×10-08). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38). Our findings were robust among multi-ethnic participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
PMCID: PMC3349742  PMID: 22589742
3.  Association of Fat Density With Subclinical Atherosclerosis 
Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis.
Methods and Results
Participants were drawn from the Multi‐Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable‐adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age‐/sex‐specific cutoffs). Per 5‐unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC.
Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis.
PMCID: PMC4310364  PMID: 25169793
atherosclerosis; epidemiology; fat density; obesity
4.  Genome-Wide Association for Abdominal Subcutaneous and Visceral Adipose Reveals a Novel Locus for Visceral Fat in Women 
PLoS Genetics  2012;8(5):e1002695.
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.
Author Summary
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.
PMCID: PMC3349734  PMID: 22589738
5.  Regional Adipose Tissue Associations With Calcified Atherosclerotic Plaque: African American–Diabetes Heart Study 
Obesity (Silver Spring, Md.)  2010;18(10):2004-2009.
Coronary artery calcified atherosclerotic plaque (CP) is strongly associated with nonsubcutaneous adipose tissue, particularly pericardial adipose tissue (PAT), in community-based studies. We tested for relationships between regional adipose tissue depots and CP in African Americans with longstanding type 2 diabetes. Infrarenal aorta, coronary, and carotid artery CP and pericardial, visceral, intermuscular, and subcutaneous organ-specific adipose tissue volumes were measured using single and multidetector computed tomography (CT) in 422 African Americans with type 2 diabetes. Generalized estimating equations using exchangeable correlation and the sandwich estimator of the variance were used to test for associations between CP and adipose tissue depots. Mean (s.d.) age was 56.5 (7.6) years, diabetes duration 10.3 (7.6) years, PAT 85.3 (36.1) cm3/45 mm and visceral adipose tissue (VAT) 174.9 (70.1) cm3/15 mm. Adjusting for age, gender, BMI, blood pressure, medications, proteinuria, smoking, lipids, and 25-hydroxyvitamin D, PAT was positively associated with the presence (P = 0.009) and quantity of coronary artery CP in African Americans (P = 0.004), as well as the quantity of infrarenal aorta CP (P = 0.004). As in European Americans, PAT is associated with CP in African Americans with type 2 diabetes. Ethnic differences in the relationships between organ-specific adipose tissue depots and atherosclerosis require further study.
PMCID: PMC2920341  PMID: 20186134
6.  MMP-1 serum levels predict coronary atherosclerosis in humans 
Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease.
260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time) to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified.
In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85); p < 0.05) in a model adjusted for age, sex, BMI, classical cardiovascular risk factors, hsCRP, adiponectin, pericardial fat volume and medication. Specification of plaque morphology revealed significant association of MMP-1 serum levels with non-calcified plaques (OR: 1.16 (CI: 1.0-1.34); p = 0.05) and calcified plaques (OR: 1.22 (CI: 1,03-1.45); p < 0.05) while association with mixed plaques was lost in the fully adjusted model. No associations were found between MMP9 serum levels and total plaque burden or plaque morphology.
MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.
PMCID: PMC2754422  PMID: 19751510
7.  Prediction of mortality using a multi-bed vascular calcification score in the Diabetes Heart Study 
Cardiovascular Diabetology  2014;13(1):160.
Vascular calcified plaque, a measure of subclinical cardiovascular disease (CVD), is unlikely to be limited to a single vascular bed in patients with multiple risk factors. Consideration of vascular calcified plaque as a global phenomenon may allow for a more accurate assessment of the CVD burden. The aim of this study was to examine the utility of a combined vascular calcified plaque score in the prediction of mortality.
Vascular calcified plaque scores from the coronary, carotid, and abdominal aortic vascular beds and a derived multi-bed score were examined for associations with all-cause and CVD-mortality in 699 European-American type 2 diabetes (T2D) affected individuals from the Diabetes Heart Study. The ability of calcified plaque to improve prediction beyond Framingham risk factors was assessed.
Over 8.4 ± 2.3 years (mean ± standard deviation) of follow-up, 156 (22.3%) participants were deceased, 74 (10.6%) from CVD causes. All calcified plaque scores were significantly associated with all-cause (HR: 1.4-1.8; p < 1x10−5) and CVD-mortality (HR: 1.5-1.9; p < 1×10−4) following adjustment for Framingham risk factors. Associations were strongest for coronary calcified plaque. Improvement in prediction of outcome beyond Framingham risk factors was greatest using coronary calcified plaque for all-cause mortality (AUC: 0.720 to 0.757, p = 0.004) and the multi-bed score for CVD mortality (AUC: 0.731 to 0.767, p = 0.008).
Although coronary calcified plaque and the multi-bed score were the strongest predictors of all-cause mortality and CVD-mortality respectively in this T2D-affected sample, carotid and abdominal aortic calcified plaque scores also significantly improved prediction of outcome beyond traditional risk factors and should not be discounted as risk stratification tools.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0160-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4266952  PMID: 25496604
Vascular calcified plaque; Mortality; Computed tomography; Type 2 diabetes
8.  Prevalence, Distribution and Risk Factor Correlates of High Pericardial and Intra-thoracic Fat Depots in the Framingham Heart Study 
Pericardial and intra-thoracic fat depots may represent novel risk factors for obesity-related cardiovascular disease. We sought to determine the prevalence, distribution and risk factor correlates of high pericardial and intra-thoracic fat deposits.
Methods and Results
Participants from the Framingham Heart Study (n=3312; mean age 52 years, 48% women) underwent multi-detector CT imaging in 2002–2005; high pericardial and high intra-thoracic fat were defined based on the sex-specific 90th percentile for these fat depots in a healthy reference sample. For men and women, the prevalence of high pericardial fat was 29.3% and 26.3%, respectively, and high intra-thoracic fat was 31.4% and 35.3%, respectively. Overall, 22.1% of the sample was discordant for pericardial and intra-thoracic fat depots: 8.3% had high pericardial but normal intra-thoracic fat, and 13.8% had high intra-thoracic but normal pericardial fat. Higher body mass index, higher waist circumference (WC) and increased prevalence of metabolic syndrome were more likely in participants with high intra-thoracic fat depots than with high pericardial fat (p<0.05 for all comparisons). High abdominal visceral adipose tissue was more frequent in participants with high intra-thoracic adipose tissue compared to those with high pericardial fat (p<0.001). Intra-thoracic fat, but not WC, was more highly correlated with VAT (r=0.76 and 0.78 in men and women, respectively; p<0.0001) than with SAT (r=0.46 and 0.54 in men and women, respectively; p<0.0001).
Although prevalence of pericardial fat and intra-thoracic fat were comparable at 30%, intra-thoracic fat correlated more closely with metabolic risk and visceral fat. Intra-thoracic fat may be a potential marker of metabolic risk and visceral fat on thoracic imaging.
PMCID: PMC3063852  PMID: 20525769
pericardial fat; obesity; epidemiology
9.  Fatty Liver, Abdominal Adipose Tissue and Atherosclerotic Calcification in African Americans: the Jackson Heart Study 
Atherosclerosis  2012;224(2):521-525.
Both fatty liver and abdominal visceral fat (VAT) are associated with cardiometabolic risk factors. Whether fatty liver and VAT are jointly associated with coronary artery (CAC) or abdominal aortic (AAC) calcification is not clear.
Jackson Heart Study (JHS) participants (n=2884, mean age 60 years, 65% women) underwent non-contrast CT Exam for assessment of fatty liver, VAT, and CAC and AAC. Fatty liver was measured by liver attenuation (LA; low LA=high fatty liver). The Agatston score was used to quantify the amount of calcified artery plaque and the presence of calcified artery plaque was defined as Agatston score>0. Cross-sectional associations of LA and VAT with CAC and AAC were examined in logistic regression models.
LA (per 1-standard deviation [SD] decrement) was associated inversely with CAC in age-sex-adjusted (OR 0.84, 95%CI 0.7–0.9, p=0.0001) and multivariable adjusted models (OR 0.89, 95%CI 0.8–0.9, p=0.01). The association persisted for LA with CAC when additionally adjusted for body mass index (BMI) (OR 0.89, 95%CI 0.8–0.9, p=0.03) or VAT (OR 0.90, 95%CI 0.8–0.9, p=0.04). Abdominal VAT (per 1-SD increment) was positively associated with CAC in age-sex-adjusted models (OR 1.27, 95%CI 1.2–1.4, p=0.0001), but the association was diminished with multivariable adjustment (OR 1.10, 95%CI 0.9–1.2, p=0.09) and with additional adjustment for LA (p = 0.24) or BMI (p = 0.33). For AAC, the associations with LA and VAT were only present in age-sex-adjusted models. Finally, we did not observe interactions between LA and VAT for CAC (p=0.18) or AAC (p=0.24).
Fatty liver is associated with coronary atherosclerotic calcification independent of abdominal VAT or BMI in African Americans. Further investigations to uncover the clinical implications of fatty liver on coronary atherosclerosis in obesity are warranted.
PMCID: PMC3459068  PMID: 22902209
10.  Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques 
PLoS ONE  2009;4(3):e4733.
Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined.
Methodology/Principal Findings
We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = −0.21, p = 0.0004), mixed (r = −0.20, p = 0.0007) and non-calcified plaques (r = −0.18, p = 0.003). No correlation was seen with calcified plaques (r = −0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: −0.036, 95%CI: −0.052 to −0.020, p<0.0001), mixed (estimate: −0.087, 95%CI: −0.132 to −0.042, p = 0.0001) and non-calcified plaques (estimate: −0.076, 95%CI: −0.115 to −0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: −0.021, 95% CI: −0.043 to −0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden.
Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS.
PMCID: PMC2649379  PMID: 19266101
11.  Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study 
European Heart Journal  2009;30(7):850-856.
The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdominal adipose tissue (VAT) are associated with the prevalence of cardiovascular disease (CVD).
Methods and results
Participants from the Framingham Heart Study Offspring cohort underwent abdominal and chest multidetector computed tomography to quantify volumes of pericardial fat, intrathoracic fat, and VAT. Relations between each fat depot and CVD were assessed using logistic regression. The analysis of 1267 participants (mean age 60 years, 53.8% women, 9.7% with prevalent CVD) demonstrated that pericardial fat [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.11–1.57; P = 0.002] and VAT (OR 1.35, 95% CI 1.11–1.57; P = 0.003), but not intrathoracic fat (OR 1.14, 95% CI 0.93–1.39; P = 0.22), were significantly associated with prevalent CVD in age–sex-adjusted models and after adjustment for body mass index and waist circumference. After multivariable adjustment, associations were attenuated (P > 0.14). Only pericardial fat was associated with prevalent myocardial infarction after adjusting for conventional measures of adiposity (OR 1.37, 95% CI 1.03–1.82; P = 0.03).
Pericardial fat and VAT, but not intrathoracic fat, are associated with CVD independent of traditional measures of obesity but not after further adjustment for traditional risk factor. Taken together with our prior work, these findings may support the hypothesis that pericardial fat contributes to coronary atherosclerosis.
PMCID: PMC3693564  PMID: 19136488
Pericardial fat; Visceral abdominal fat; Cardiovascular disease; Framingham Heart Study; Epidemiology
12.  Associations of pericardial and intra-thoracic fat with coronary calcium presence and progression in a multi-ethnic study 
Obesity (Silver Spring, Md.)  2013;21(8):1704-1712.
Body mass index (BMI) may not accurately or adequately reflect body composition or its role in the development of cardiovascular disease (CVD). Ectopic adipose depots may provide a more refined representation of the role of adiposity in CVD. Thus, we examined the association of pericardial and intra-thoracic fat with coronary artery calcium (CAC). Nearly 600 white men and women, as well as Filipina women and African-American women, all without known CVD, had abdominal and chest computed tomography (CT) scans at two time points about four years apart from which CAC presence, severity and progression, as well as pericardial and intra-thoracic fat volumes were obtained. Logistic and linear regression models with staged adjustment were used to assess associations of pericardial and intra-thoracic fat with CAC presence, severity and progression. After adjustment for age, BMI, sex/ethnic group, ever smoking, and lipids, each standard deviation higher increment of intra-thoracic fat, but not pericardial fat, was significantly associated with 3.84-fold higher odds of prevalent CAC (95% CI (1.54, 9.58), p=0.004) and a 38.4% higher CAC score (95% CI (3.5%, 90.0%), p=0.03). Neither pericardial nor intra-thoracic fat were associated with CAC progression. Contrary to previous reports, pericardial fat was not associated with the presence, severity or progression of CAC. We did, however, demonstrate a significant association between intra-thoracic fat and both the presence and severity of CAC. Studies measuring fat in the thoracic cavity may consider defining intra-thoracic fat as a separate entity from pericardial fat.
PMCID: PMC3748173  PMID: 23666866
13.  Hostility is associated with Visceral, but not Subcutaneous, Fat in Middle-Aged African-American and White women 
Psychosomatic medicine  2009;71(7):733-740.
The current study was designed to examine the cross-sectional association between hostility and measures of abdominal fat (visceral, subcutaneous) in middle-aged African-American and white women. Because fat-patterning characteristics are known to differ by race,we were particularly interested in examining whether these associations were similar for women of both racial/ethnic groups.
Participants were 418 (45% African-American, 55% white) middle-aged women from the Chicago site of the Study of Women’s Health Across the Nation (SWAN). Visceral and Subcutaneous fat were measured by Computed Tomographic Scans and hostility was assessed via questionnaire. Multivariate linear regression models were conducted to test associations among race/ethnicity, hostility and measures of abdominal fat.
In models adjusted for race/ethnicity and total percent fat, higher levels of hostility were associated with a greater amount of visceral fat (B=1.8, s.e.=.69, p=.01). This association remained significant after further adjustments for age, education, and multiple coronary heart disease (CHD) risk factors. Hostility was not associated with subcutaneous fat (p=.8). Although there were significant racial/ethnic differences in hostility (p<.001) and the amount of total body (p<.001), subcutaneous (p<.001) and visceral fat (p<.001), the associations between hostility and measures of abdominal fat did not differ for African-American compared to white women (race/ethnicity*hostility interaction p=.67 for visceral, p=.85 for subcutaneous).
Hostility may affect CHD risk in women via the accumulation of visceral fat. Despite significant black-white differences in fat patterning and overall CHD risk, the association between hostilty and visceral fat appears to be similar for both African-American and white women.
PMCID: PMC2880186  PMID: 19592520
Hostility; visceral fat; African-American; White; race; psychosocial risk factors; cardiovascular disease (CVD); women’s health
14.  Association of Aortic Valve Calcification to the Presence, Extent, and Composition of Coronary Artery Plaque Burden: ROMICAT Study 
American heart journal  2009;158(4):562-568.
Aortic valve calcification (AVC) is associated with cardiovascular risk factors and coronary artery calcification. We sought to determine whether AVC is associated with the presence and extent of overall plaque burden, as well as to plaque composition (calcified, mixed, and non-calcified).
We examined 357 subjects (mean age: 53 ± 12 years, 61% male) who underwent contrast-enhanced ECG-gated 64-slice multi-detector computed tomography from the ROMICAT trial for the assessment of presence and extent of coronary plaque burden according to the 17-coronary segment model and presence of AVC.
Patients with AVC (n=37, 10%) were more likely than those without AVC (n=320, 90%) to have coexisting presence of any coronary plaque (89% vs. 46%, p<0.001) and had a greater extent of coronary plaque burden (6.4 segments vs. 1.8 segments, p<0.001). Those with AVC had over 3-fold increase odds of having any plaque (adjusted odds ratio [OR] 3.6, p=0.047) and an increase of 2.5 segments of plaque (p<0.001) as compared to those without AVC. When stratified by plaque composition, AVC was associated most with calcified plaque (OR 5.2, p=0.004), then mixed plaque (OR 3.2, p=0.02), but not with non-calcified plaque (p=0.96).
AVC is associated with the presence and greater extent of coronary artery plaque burden and may be part of the later stages of the atherosclerosis process, as its relation is strongest with calcified plaque, less with mixed plaque, and nonsignificant with non-calcified plaque. If AVC is present, consideration for aggressive medical therapy may be warranted.
PMCID: PMC2764241  PMID: 19781415
Aortic valve calcification; coronary artery disease; multi-detector computed tomography; calcified plaque; non-calcified plaque; mixed plaque
15.  Aortic Distensibility and its Relationship to Coronary and Thoracic Atherosclerosis Plaque and Morphology by MDCT: Insights from the ROMICAT Trial 
International journal of cardiology  2012;167(4):1616-1621.
Multi-detector cardiac computed tomography (CT) allows for simultaneous assessment of aortic distensibility (AD), coronary atherosclerosis, and thoracic aortic atherosclerosis.
We sought to determine the relationship of AD to the presence and morphological features in coronary and thoracic atherosclerosis.
In 293 patients (53±12 years, 63% male), retrospectively-gated MDCT were performed. We measured intraluminal aortic areas across 10 phases of the cardiac cycle (multiphase reformation 10% increments) at pre-defined locations to calculate the ascending, descending, and local AD (at locations of thoracic plaque). AD was calculated as maximum change in area/(minimum area × pulse pressure). Coronary and thoracic plaques were categorized as calcified, mixed, or non-calcified.
Ascending and descending AD were lower in patients with any coronary plaque, calcified or mixed plaque than those without (all p<0.0001) but not with non-calcified coronary plaque (p≥0.46). Per 1 mmHg−110−3 increase in ascending and descending AD, there was an 18–29% adjusted risk reduction for having any coronary, calcified plaque, or mixed coronary plaque (ascending AD only) (all p≤0.04). AD was not associated with non-calcified coronary plaque or when age was added to the models (all p>0.39). Local AD was lower at locations of calcified and mixed thoracic plaque when compared to non-calcified thoracic atherosclerosis (p<0.04).
A stiffer, less distensible aorta is associated with coronary and thoracic atherosclerosis, particularly in the presence of calcified and mixed plaques, suggesting that the mechanism of atherosclerosis in small and large vessels is similar and influenced by advancing age.
PMCID: PMC3419779  PMID: 22578738
aortic distensibility; coronary atherosclerosis; thoracic atherosclerosis; peripheral vascular disease; computed tomography; cardiovascular aging
16.  Susceptibility Variants for Waist Size in Relation to Abdominal, Visceral and Hepatic Adiposity in Postmenopausal Women 
Genome-wide association studies (GWAS) have identified common genetic variants that may contribute specifically to the risk of abdominal adiposity, as measured by waist circumference or waist-to-hip ratio. However, it is unknown whether these genetic risk factors affect relative body fat distribution in the abdominal visceral and subcutaneous compartments. The association between imaging-based abdominal fat mass and waist size risk variants in the FTO, LEPR, LYPLAL1, MSRA, NRXN3, and TFAP2B genes was investigated. A cross-sectional sample of 60 women were selected among study participants of Multiethnic Cohort, who were of ages 60–65 years, of European or Japanese descent, and with body mass index (BMI) between 18.5 and 40 kg/m2. Dual energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) scans were used to measure adiposity. After adjustments for age, ethnicity and total fat mass, the FTO variants showed an association with less abdominal subcutaneous fat and a higher visceral-to-subcutaneous abdominal fat ratio, with the variant rs9941349 showing significant associations most consistently (p=0.003 and 0.03, respectively). Similarly, the LEPR rs1137101 variant was associated with less subcutaneous fat (p=0.01) and a greater visceral-to-subcutaneous fat ratio (p=0.03) and percent liver fat (p=0.007). MSRA rs545854 variant carriers had a lower percent leg fat. Our findings provide initial evidence that some of the genetic risk factors identified for larger waist size may also contribute to disproportionately greater intra-abdominal and liver fat distribution in postmenopausal women. If replicated, these genetic variants may be incorporated with other biomarkers to predict high-risk body fat distribution.
PMCID: PMC3419359  PMID: 22889634
body composition; central obesity; fatty liver; single nucleotide polymorphisms; liver fat; race/ethnicity; subcutaneous adipose tissue; visceral adipose tissue
17.  Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults 
Obesity (Silver Spring, Md.)  2013;21(9):E439-E447.
Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n=942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n=1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index. In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p<0.001 for each). VAT also associated with prevalent diabetes, metabolic syndrome, hepatic steatosis, and aortic plaque (p<0.001 for each). VAT independently associated with C-reactive protein but not with any other inflammatory biomarkers tested. In contrast, SAT associated with leptin and inflammatory biomarkers, but not with dyslipidemia or atherosclerosis. Associations between SAT and HOMA-IR were significant in univariable analyses but attenuated after multivariable adjustment. In conclusion, VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk.
PMCID: PMC3751977  PMID: 23687099
Obesity; Lipoproteins; Inflammation; Atherosclerosis; Diabetes
18.  Visceral Adiposity and Subclinical Coronary Artery Disease in Older Adults: Rancho Bernardo Study 
Obesity (Silver Spring, Md.)  2008;16(4):853-858.
Despite growing attention to central obesity as a predictor of clinical coronary heart disease (CHD), there are few reports about the association between directly measured visceral obesity and subclinical coronary atherosclerosis in older adults. We examined this association in older community-dwelling adults without clinically recognized CHD.
Research Methods and Procedures
Older adults (190 men, BMI 27.2 ± 3.6 kg/m2; 220 women, BMI 25.8 ± 4.6) aged 55 to 88 years (median 69 years) with no history of CHD or coronary revascularization had an electron-beam computed tomography (EBCT) to measure coronary-artery calcification score (CACS), an estimate of coronary-plaque burden. Visceral and subcutaneous adiposity were assessed by a triple-slice EBCT scan at the lumbar 4–5 disc level and height, weight, and waist and hip circumferences were measured.
In sex-specific ordinal logistic regression analyses, no measure of obesity or body fat distribution, including body mass index, waist-hip ratio, waist girth, visceral and subcutaneous fat by EBCT, was significantly associated with CACS before or after adjusting for multiple covariates of CACS (age, smoking, alcohol intake, exercise, pulse pressure, LDL/HDL-cholesterol ratio, and fasting plasma glucose).
In older adults without clinically recognized CHD, body weight and fat distribution do not predict coronary artery plaque burden. These results raise questions about the value of weight reduction diets for preventing heart disease in elderly survivors without clinical heart disease.
PMCID: PMC2673099  PMID: 18356852
Atherosclerosis; coronary disease; aging; population
19.  Increased adipose tissue lipolysis after a two-week high-fat diet in sedentary overweight/obese men 
Metabolism: clinical and experimental  2010;60(7):10.1016/j.metabol.2010.09.007.
The purpose of this study was to determine if a high fat diet would result in a higher lipolytic rate in subcutaneous adipose tissue than a lower fat diet in sedentary non-lean men.
Six participants (healthy males: 18-40 yrs old: body mass index 25-37 kg/m2) underwent two weeks on a high-fat or well-balanced diet of similar caloric content (approx. 1600 kcal) in randomized order with a ten-day washout period between diets. Subcutaneous abdominal adipose tissue lipolysis was determined over the course of a day using microdialysis after both two-week diet sessions.
Average interstitial glycerol concentrations (index of lipolysis) as determined using microdialysis were higher following the high-fat diet (210.8 ±27.9 μM) than following a well-balanced diet (175.6 ± 23.3 μM; P = 0.026). There was no difference in adipose tissue microvascular blood flow as determined using the microdialysis ethanol technique.
These results demonstrate that healthy non-lean men who diet on the high-fat plan have a higher lipolytic rate in subcutaneous abdominal adipose tissue than when they diet on a well-balanced diet plan. This higher rate of lipolysis may result in a higher rate of fat mass loss on the high-fat diet; however, it remains to be determined if this higher lipolytic rate in men on the high-fat diet results in a more rapid net loss of triglyceride from the abdominal adipose depots, or if the higher lipolytic rate is counteracted by an increased rate of lipid storage.
PMCID: PMC3868457  PMID: 21040937
blood flow; glucose; fatty acids; glycerol; insulin; ketones; microdialysis
20.  Abdominal Adiposity in Rheumatoid Arthritis: Association with Cardiometabolic Risk Factors and Disease Characteristics 
Arthritis and rheumatism  2010;62(11):3173-3182.
Abdominal adiposity, especially visceral adiposity, is an emerging cardiometabolic risk factor. How abdominal fat is distributed in rheumatoid arthritis (RA) and its RA-related determinants have not been explored.
Men and women with RA were compared to non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric measures and quantification of visceral and subcutaneous fat areas (VFA, SFA) using abdominal computed tomography.
A total of 131 RA patients were compared with 121 controls. Despite similar body mass index and waist circumference between the RA and control groups, the adjusted mean VFA was 45cm2 higher (+51%) for RA vs. control men (p=0.005) but not significantly different by RA status in women. The adjusted mean SFA was 119cm2 higher (+68%) for RA vs. control women (p<0.001) but not significantly different by RA status in men. Elevated VFA (>75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose, hypertension, or the composite definition of the metabolic syndrome for the RA group compared with controls. Within the RA group, rheumatoid factor seropositivity and higher cumulative prednisone exposure were significantly associated with a higher mean adjusted VFA. Higher C-reactive protein levels and lower Sharp scores were significantly associated with both VFA and SFA.
The distribution of abdominal fat differs significantly by RA status. Higher VFA in men with RA, and the more potent association of VFA with cardiometabolic risk factors in men and women with RA, may contribute to cardiovascular risk in RA populations.
PMCID: PMC2962724  PMID: 20589684
21.  Associations between HIV Infection and Subclinical Coronary Atherosclerosis: The Multicenter AIDS Cohort Study (MACS) 
Annals of internal medicine  2014;160(7):458-467.
Coronary artery disease (CAD) has been associated with HIV infection; however data are not consistent.
We performed cardiac CT to determine whether HIV-infected men have more coronary atherosclerosis than uninfected men.
Cross-sectional study within the Multicenter AIDS Cohort Study(MACS).
HIV-infected (n=618) and –uninfected (n=383) men who have sex with men (MSM) had non-contrast and contrast enhanced cardiac CT if they were between 40–70 years, weighed <300 pounds, and had no history of coronary revascularization.
Presence and extent, for those with plaque, of coronary artery calcium (CAC) on non-contrast CT, and of any plaque, non-calcified, mixed or calcified plaque and stenosis on CT angiography.
1001 men underwent non-contrast CT of whom 759 had coronary CT angiography. After adjusting for age, race, center, and cohort, HIV-infected men had a greater prevalence of CAC [Prevalence ratio(PR)=1.21, 95% confidence interval (CI) 1.08–1.35, p=0.001], and any plaque [PR=1.14(1.05–1.24),p=0.001], including non-calcified plaque [PR=1.28(1.13–1.45),p<0.001) and mixed plaque [PR=1.35(1.10–1.65),p=0.004] than HIV-uninfected men. Associations between HIV-infection and any plaque and non-calcified plaque remained significant (p<0.005) after CAD risk factor adjustment. HIV-infected men also had a greater extent of non-calcified plaque after CAD risk factor adjustment (p=0.026). HIV-infected men had a greater prevalence of coronary artery stenosis>50% than HIV-uninfected men [PR=1.48(1.06–2.07),p=0.020), but not after CAD risk factor adjustment. Longer duration of highly active antiretroviral therapy [PR=1.09(1.02–1.17), p=0.007,per year] and lower nadir CD4+ T-cell count [PR=0.80(0.69–0.94),p=0.005, per 100 cells] were associated with coronary stenosis>50%.
Coronary artery plaque, especially non-calcified plaque, is more prevalent and extensive in HIV-infected men, independent of CAD risk factors.
Cross-sectional observational study design and inclusion of only men.
Primary Funding Source
PMCID: PMC4143766  PMID: 24687069
22.  Body Composition Measures from CT and Inflammation 
Obesity (Silver Spring, Md.)  2009;17(5):1062-1069.
A growing body of evidence has consistently shown a correlation between obesity and chronic sub-clinical inflammation. Several studies have suggested that measures of body fat distribution, rather than overall adiposity, may be more closely associated with inflammation level.
To investigate the relationship between levels of inflammatory markers and specific measures of abdominal visceral and subcutaneous fat and thigh intermuscular and subcutaneous fat of older white and black adults.
Data of 2,651 black and white men and women aged 70-79 participating in the Health, Aging and Body Composition (Health ABC) study were used. Levels of the inflammatory markers, IL-6, CRP, and TNF-α were obtained from blood samples. The areas of abdominal visceral and subcutaneous fat and thigh intermuscular and subcutaneous fat were quantified on CT images. Linear regression analysis was used to evaluate the cross-sectional relationship between each body composition measure and serum levels of inflammatory markers in the four race/gender groups.
Abdominal visceral adiposity was most consistently associated with significantly higher IL-6 and CRP levels in all race/gender groups (p<0.05). Thigh intermuscular fat had an inconsistent but significant association with inflammation, and there was a trend toward lower inflammation level with increasing thigh subcutaneous fat in white and black women.
Despite the previously established differences in abdominal fat distribution across gender and race, visceral fat remained a significant predictor of inflammatory marker level across all four subgroups examined.
PMCID: PMC3268118  PMID: 19165157
23.  Pericardial Fat Volume Correlates with Inflammatory Markers: The Framingham Heart Study 
Obesity (Silver Spring, Md.)  2009;18(5):1039-1045.
The objective of this study was to determine whether systemic inflammatory and oxidative stress marker concentrations correlate with pericardial and intrathoracic fat volumes. Participants of the Framingham Offspring Study (n=1175; 53% women; mean age 59±9 years) had pericardial and intrathoracic fat volumes assessed by multidetector computed tomography (MDCT) scans, and provided fasting blood and urine samples to measure concentrations of fourteen inflammatory markers: C-reactive protein (CRP); interleukin-6; monocyte chemoattractant protein-1 (MCP-1); CD40 ligand; fibrinogen; intracellular adhesion molecule-1; lipoprotein-associated phospholipase A2 activity and mass; myeloperoxidase; osteoprotegerin; P-selectin; tumor necrosis factor-alpha; tumor necrosis factor receptor 2; and urinary isoprostanes. Multivariable linear regression models were used to determine the association of log-transformed inflammatory marker concentrations with fat volumes, using fat volume as the dependent variable. Due to smaller sample sizes, models were rerun after adding urinary isoprostanes (n=961) and tumor necrosis factor-alpha (n=813) to the marker panel. Upon backward elimination, four of the biomarkers correlated positively with each fat depot: CRP (P<0.0001 for each fat depot); interleukin-6 (P<0.05 for each fat depot); MCP-1 (P<0.01 for each fat depot); and urinary isoprostanes (P<0.01 for pericardial fat; P<0.001 for intrathoracic fat). Even after adjusting for body mass index, waist circumference, and abdominal visceral fat, CRP (P=0.0001) and urinary isoprostanes (P=0.02) demonstrated significant positive associations with intrathoracic fat, but not with pericardial fat. Multiple markers of inflammation and oxidative stress correlated with pericardial and intrathoracic fat volumes, extending the known association between regional adiposity and inflammation and oxidative stress.
PMCID: PMC3014610  PMID: 19875999
Black South African women are less insulin sensitive than their white counterparts, despite less central and greater peripheral fat deposition. We hypothesized that this paradox may be explained, in part, by differences in the adipogenic capacity of subcutaneous adipose tissue (SAT).
To measure adipogenic and lipogenic gene expression in abdominal and gluteal SAT depots, and determine their relationships with insulin sensitivity (SI) in South African women.
14 normal-weight (BMI <25 kg/m2) black, 13 normal-weight white, 14 obese (BMI >30 kg/m2) black and 13 obese white premenopausal South African women.
Main outcomes
SI (frequently sampled intravenous glucose tolerance test) in relation to expression of adipogenic and lipogenic genes in abdominal and gluteal SAT depots.
With increasing BMI, black women had less visceral fat (P=0.03) and more abdominal (P=0.017) and gynoid (P=0.041) SAT but had lower SI (P<0.01) than white women. The expression of adipogenic and lipogenic genes was proportionately lower with obesity in black, but not white women in the gluteal and deep SAT depots (P<0.05 for ethnicity x BMI effect). In black women only, the expression of these genes correlated positively with SI (all P<0.05), independently of age and fat mass.
Obese black women have reduced SAT expression of adipogenic and lipogenic genes compared to white women, which associates with reduced SI. These findings suggest that obesity in black women impairs SAT adipogenesis and storage, potentially leading to insulin resistance and increased risk of type 2 diabetes.
PMCID: PMC3977037  PMID: 21956425
insulin sensitivity; ethnicity; adipogenesis; lipogenesis; adipose tissue distribution; hypertrophic obesity
25.  Body Fat Distribution, Incident Cardiovascular Disease, Cancer, and All-cause Mortality 
To determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer and all-cause mortality.
The morbidity associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited.
Participants from the Framingham Heart Study (n=3086, 49% women, mean age 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography, and were followed longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 standard deviation increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index.
Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (HR 1.44, 95% CI 1.08–1.92, p=0.01) and cancer (HR 1.43, 95% CI 1.12–1.84, p=0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality.
Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.
PMCID: PMC4142485  PMID: 23850922
obesity; visceral fat; body fat distribution; cardiovascular disease; cancer

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