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1.  The association of pericardial fat with calcified coronary plaque 
Obesity (Silver Spring, Md.)  2008;16(8):1914-1919.
Background
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.
Objective
We examined the relationship between pericardial fat and calcified coronary plaque.
Design
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.
Results
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.
Conclusions
Pericardial fat is independently associated with calcified coronary plaque.
doi:10.1038/oby.2008.278
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.
doi:10.1371/journal.pgen.1002705
PMCID: PMC3349742  PMID: 22589742
3.  Association of Fat Density With Subclinical Atherosclerosis 
Background
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.
Conclusions
Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis.
doi:10.1161/JAHA.114.000788
PMCID: PMC4310364  PMID: 25169793
atherosclerosis; epidemiology; fat density; obesity
4.  Associations of Physical Activity and Sedentary Behavior with Regional Fat Deposition 
Introduction
Increased sedentary behavior predicts greater cardiovascular morbidity and mortality, and does so independently of physical activity (PA). This association is only partially explained by BMI and overall body fat, suggesting mechanisms besides general increased adiposity. The purpose of this study was to explore associations of self-reported leisure PA and sitting time with regional fat depositions and abdominal muscle among community-dwelling older adults.
Methods
Participants were 539 diverse adults (mean age 65) who completed a study visit in 2001-2002. Areas of pericardial, intra-thoracic, subcutaneous, visceral, and intermuscular fat, as well as abdominal muscle, were measured using computed tomography. Leisure PA and sitting hours were entered simultaneously into multivariate regression models to determine associations with muscle and fat areas.
Results
After adjusting for demographics, smoking, diabetes, hypertension, triglycerides, and cholesterol, greater PA was associated with less intra-thoracic, visceral, subcutaneous, and intermuscular fat (for all p < .05), while greater sedentary time was associated with greater pericardial and intra-thoracic fat (for both p < .05). After further adjusting for BMI, each hour of weekly PA was associated with 1.85 cm2 less visceral fat (p < .01), but was not associated with other fat depositions. Conversely, each hour of daily sitting was associated with 2.39cm2 more pericardial fat (p < .05), but was not associated with any other fat depositions. There were no associations with abdominal muscle area. Adjusting for common inflammatory markers had little effect. Associations between fat and PA were stronger for men.
Conclusions
Sitting and physical activity have distinct associations with regional fat deposition in older adults. The association between sitting and pericardial fat could partially explain the link between sitting and coronary heart disease.
doi:10.1249/MSS.0b013e3182a77220
PMCID: PMC3916942  PMID: 23924920
sitting; body composition; visceral fat; pericardial fat; cardiovascular disease
5.  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.
doi:10.1371/journal.pgen.1002695
PMCID: PMC3349734  PMID: 22589738
6.  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.
doi:10.1038/oby.2010.30
PMCID: PMC2920341  PMID: 20186134
7.  MMP-1 serum levels predict coronary atherosclerosis in humans 
Background
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.
Methods
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.
Results
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.
Conclusion
MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.
doi:10.1186/1475-2840-8-50
PMCID: PMC2754422  PMID: 19751510
8.  Prediction of mortality using a multi-bed vascular calcification score in the Diabetes Heart Study 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/s12933-014-0160-5
PMCID: PMC4266952  PMID: 25496604
Vascular calcified plaque; Mortality; Computed tomography; Type 2 diabetes
9.  Fat Distribution and Mortality: The AGES-Reykjavik Study 
Obesity (Silver Spring, Md.)  2015;23(4):893-897.
Objective
This study examined associations of regional fat depots with all-cause mortality over 11 years of follow-up.
Design and Methods
Data were from 2187 men and 2900 women, aged 66–96 years in AGES-Reykjavik Study. Abdominal visceral fat and subcutaneous fat, and thigh intermuscular fat and subcutaneous fat were measured by CT.
Results
In men, every standard deviation (SD) increment in thigh intermuscular fat was related to a significantly greater mortality risk (HR:1.17, 95%CI:1.08–1.26) after adjustment for age, education, smoking, physical activity, alcohol, BMI, type 2 diabetes and coronary heart disease. In women, visceral fat (per SD increment) significantly increased mortality risk (HR:1.13, 95%CI:1.03–1.25) while abdominal subcutaneous fat (per SD increment) was associated with a lower mortality risk (HR:0.70; 95%CI:0.61–0.80). Significant interactions with BMI were found in women indicating that visceral fat was a strong predictor of mortality in obese women while abdominal and thigh subcutaneous fat were associated with a lower mortality risk in normal and overweight women.
Conclusions
Fat distribution is associated with mortality over 11 years of follow-up independent of overall fatness. The divergent mortality risks for visceral fat and subcutaneous fat in women suggest complex relationships between overall fatness and mortality.
doi:10.1002/oby.21028
PMCID: PMC4758353  PMID: 25755182
Body Fat Distribution; Body Composition; Mortality; Obesity; Aged
10.  Association of Television Viewing Time with Body Composition and Calcified Subclinical Atherosclerosis in Singapore Chinese 
PLoS ONE  2015;10(7):e0132161.
Objective
Sedentary behavior such as television viewing may be an independent risk factor for coronary heart disease. However, few studies have assessed the impact of television viewing time on coronary artery calcification and it remains unclear how body fat contributes to this relationship. The aim of this study is to evaluate the association between television viewing time and subclinical atherosclerosis and whether effects on visceral or subcutaneous fat may mediate any associations observed.
Methods
This was a cross-sectional study of 398 Chinese participants (192 men and 206 women) from Singapore prospective study. Participants were free from known cardiovascular diseases and underwent interview, health screening, computed tomography scans of coronary arteries and abdomen. Spearman’s correlation was used to test the correlation between television viewing time, physical activity, body composition and abdominal fat distribution. The association between television viewing time and subclinical atherosclerosis was assessed by multiple logistic regression analysis.
Results
In men, television viewing time was significantly correlated with higher body fat mass index, percent body fat, subcutaneous and visceral fat. These associations were in the same direction, but weaker and not statistically significant in women. Television viewing time (hours/day) was associated with subclinical atherosclerosis in men (odds ratio: 1.41, 95% CI: 1.03-1.93) but no significant association was observed in women (odds ratio: 0.88, 95% CI: 0.59-1.31) after adjusting for potential socio-demographic and lifestyle confounders. Further adjustments for biological factors did not affect these associations.
Conclusions
Television viewing time was associated with greater adiposity and higher subcutaneous and visceral fat in men. TV viewing time was also associated with subclinical atherosclerosis in men and the potential mechanisms underlying this association require further investigation.
doi:10.1371/journal.pone.0132161
PMCID: PMC4488493  PMID: 26132754
11.  Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques 
PLoS ONE  2009;4(3):e4733.
Background
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.
Conclusions/Significance
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.
doi:10.1371/journal.pone.0004733
PMCID: PMC2649379  PMID: 19266101
12.  Anatomic Fat Depots and Coronary Plaque Among Human Immunodeficiency Virus-Infected and Uninfected Men in the Multicenter AIDS Cohort Study 
Open Forum Infectious Diseases  2016;3(2):ofw098.
Methods. In a cross-sectional substudy of the Multicenter AIDS Cohort Study, noncontrast cardiac computed tomography (CT) scanning for coronary artery calcium (CAC) scoring was performed on all men, and, for men with normal renal function, coronary CT angiography (CTA) was performed. Associations between fat depots (visceral adipose tissue [VAT], abdominal subcutaneous adipose tissue [aSAT], and thigh subcutaneous adipose tissue [tSAT]) with coronary plaque presence and extent were assessed with logistic and linear regression adjusted for age, race, cardiovascular disease (CVD) risk factors, body mass index (BMI), and human immunodeficiency virus (HIV) parameters.
Results. Among HIV-infected men (n = 597) but not HIV-uninfected men (n = 343), having greater VAT was positively associated with noncalcified plaque presence (odds ratio [OR] = 1.04, P < .05), with a significant interaction (P < .05) by HIV serostatus. Human immunodeficiency virus-infected men had lower median aSAT and tSAT and greater median VAT among men with BMI <25 and 25–29.9 kg/m2. Among HIV-infected men, VAT was positively associated with presence of coronary plaque on CTA after adjustment for CVD risk factors (OR = 1.04, P < .05), but not after additional adjustment for BMI. There was an inverse association between aSAT and extent of total plaque among HIV-infected men, but not among HIV-uninfected men. Lower tSAT was associated with greater CAC and total plaque score extent regardless of HIV serostatus.
Conclusions. The presence of greater amounts of VAT and lower SAT may contribute to increased risk for coronary artery disease among HIV-infected persons.
doi:10.1093/ofid/ofw098
PMCID: PMC4943560  PMID: 27419170
adiposity; coronary plaque
13.  Fatty Liver, Abdominal Adipose Tissue and Atherosclerotic Calcification in African Americans: the Jackson Heart Study 
Atherosclerosis  2012;224(2):521-525.
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.atherosclerosis.2012.07.042
PMCID: PMC3459068  PMID: 22902209
14.  Prevalence, Distribution and Risk Factor Correlates of High Pericardial and Intra-thoracic Fat Depots in the Framingham Heart Study 
Background
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).
Conclusions
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.
doi:10.1161/CIRCIMAGING.110.956706
PMCID: PMC3063852  PMID: 20525769
pericardial fat; obesity; epidemiology
15.  Epicardial Fat is Associated with Duration of Antiretroviral Therapy and Coronary Atherosclerosis: The Multicenter AIDS Cohort Study 
AIDS (London, England)  2014;28(11):1635-1644.
Objective
Cytokines released by epicardial fat are implicated in the pathogenesis of atherosclerosis. HIV infection and anti-retroviral therapy have been associated with changes in body fat distribution and coronary artery disease. We sought to determine if HIV infection is associated with greater epicardial fat and if epicardial fat is associated with subclinical coronary atherosclerosis.
Design
We studied 579 HIV-infected and 353 HIV-uninfected men age 40 to 70 years with non-contrast computed tomography (CT) to measure epicardial adipose tissue volume (EAT) and coronary artery calcium (CAC). Total plaque score (TPS), and plaque subtypes (non-calcified, calcified and mixed) were measured by coronary CT angiography in 706 men.
Methods
We evaluated the association between EAT and HIV serostatus, and the association of EAT with subclinical atherosclerosis, adjusting for age, race and serostatus and with additional cardiovascular (CV) risk factors and tested for modifying effects of HIV serostatus.
Results
HIV-infected men had greater EAT than HIV-uninfected men (p=0.001). EAT was positively associated with duration of antiretroviral therapy (p=0.02), specifically AZT (p<0.05). EAT was associated with presence of any coronary artery plaque (p=0.006) and non-calcified plaque (p=0.001), adjusting for age, race, serostatus and CV risk factors. Among men with CAC, EAT was associated with CAC extent (p=0.006). HIV serostatus did not modify associations between EAT and either CAC extent or presence of plaque.
Conclusions
Greater epicardial fat volume in HIV-infected men and its association with coronary plaque and antiretroviral therapy duration suggest potential mechanisms that might lead to increased risk for cardiovascular disease in HIV.
doi:10.1097/QAD.0000000000000116
PMCID: PMC4169787  PMID: 24809732
Imaging; plaque; risk factors; HIV; ART
16.  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.
Aims
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).
Conclusion
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.
doi:10.1093/eurheartj/ehn573
PMCID: PMC3693564  PMID: 19136488
Pericardial fat; Visceral abdominal fat; Cardiovascular disease; Framingham Heart Study; Epidemiology
17.  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.
doi:10.1002/oby.20111
PMCID: PMC3748173  PMID: 23666866
18.  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.
Background
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).
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.ahj.2009.07.027
PMCID: PMC2764241  PMID: 19781415
Aortic valve calcification; coronary artery disease; multi-detector computed tomography; calcified plaque; non-calcified plaque; mixed plaque
19.  Hostility is associated with Visceral, but not Subcutaneous, Fat in Middle-Aged African-American and White women 
Psychosomatic medicine  2009;71(7):733-740.
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/PSY.0b013e3181ad13a7
PMCID: PMC2880186  PMID: 19592520
Hostility; visceral fat; African-American; White; race; psychosocial risk factors; cardiovascular disease (CVD); women’s health
20.  Development and Reproducibility of a Computed Tomography–Based Measurement for Upper Body Subcutaneous Neck Fat 
Background
Upper body subcutaneous neck fat (UBSF) is a unique fat depot anatomically separate from visceral abdominal fat that appears to be associated with cardiometabolic risk above and beyond generalized adiposity. We sought to develop a protocol to quantify UBSF using multidetector computed tomography measurements.
Methods and Results
Protocol development was performed in participants from the Framingham Heart Study who had participated in the multidetector computed tomography scanning substudy, consisting of chest scans. Volumetric assessment of UBSF was defined by 40 contiguous 0.625‐mm slices superior to the body of the sternum. The reader manually traced the chest to identify total neck fat. Breast tissue exterior to the chest wall was excluded. Subcutaneous and visceral fat volumes were obtained using standard protocols. Age‐ and sex‐adjusted Pearson correlation coefficients were used to assess the association among UBSF, traditional adiposity measures, and cardiometabolic risk factors. Inter‐ and intrareader reproducibility was assessed using intraclass correlation coefficients. Volumetric assessments were obtained in 92 participants because 8 scans were not readable (51% women; mean age: 59 years [women], 58 years [men]). The mean volume of UBSF was 310 cm3 for women and 345 cm3 for men. Intra‐ and interreader class correlation coefficients were 0.99 and 0.99, respectively. UBSF was correlated with waist circumference (r=0.90), neck circumference (r=0.75), body mass index (r=0.89), subcutaneous adipose tissue (r=0.87), and visceral adipose tissue (r=0.86).
Conclusions
UBSF can be quantified reproducibly using computed tomography in a community‐dwelling sample from the Framingham Heart Study.
doi:10.1161/JAHA.114.000979
PMCID: PMC4338686  PMID: 25523152
fat distribution; multidetector computed tomography; upper body subcutaneous neck fat
21.  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.
Background
Multi-detector cardiac computed tomography (CT) allows for simultaneous assessment of aortic distensibility (AD), coronary atherosclerosis, and thoracic aortic atherosclerosis.
Objectives
We sought to determine the relationship of AD to the presence and morphological features in coronary and thoracic atherosclerosis.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.ijcard.2012.04.107
PMCID: PMC3419779  PMID: 22578738
aortic distensibility; coronary atherosclerosis; thoracic atherosclerosis; peripheral vascular disease; computed tomography; cardiovascular aging
22.  Visceral Adiposity and the Risk of Metabolic Syndrome Across Body Mass Index 
JACC. Cardiovascular imaging  2014;7(12):1221-1235.
OBJECTIVES
This study sought to evaluate differential effects of visceral fat (VF) and subcutaneous fat and their effects on metabolic syndrome (MetS) risk across body mass index (BMI) categories.
BACKGROUND
The regional distribution of adipose tissue is an emerging risk factor for cardiometabolic disease, although serial changes in fat distribution have not been extensively investigated. VF and its alterations over time may be a better marker for risk than BMI in normal weight and overweight or obese individuals.
METHODS
We studied 1,511 individuals in the MESA (Multi-Ethnic Study of Atherosclerosis) with adiposity assessment by computed tomography (CT). A total of 253 participants without MetS at initial scan underwent repeat CT (median interval 3.3 years). We used discrete Cox regression with net reclassification to investigate whether baseline and changes in VF area are associated with MetS.
RESULTS
Higher VF was associated with cardiometabolic risk and coronary artery calcification, regardless of BMI. After adjustment, VF was more strongly associated with incident MetS than subcutaneous fat regardless of weight, with a 28% greater MetS hazard per 100 cm2/m VF area and significant net reclassification (net reclassification index: 0.44, 95% confidence interval [CI]: 0.29 to 0.60) over clinical risk. In individuals with serial imaging, initial VF (hazard ratio: 1.24 per 100 cm2/m, 95% CI: 1.08 to 1.44 per 100 cm2/m, p = 0.003) and change in VF (hazard ratio: 1.05 per 5% change, 95% CI: 1.01 to 1.08 per 5% change, p = 0.02) were associated with MetS after adjustment. Changes in subcutaneous fat were not associated with incident MetS after adjustment for clinical risk and VF area.
CONCLUSIONS
VF is modestly associated with BMI. However, across BMI, a single measure of and longitudinal change in VF predict MetS, even accounting for weight changes. Visceral adiposity is essential to assessing cardiometabolic risk, regardless of age, race, or BMI, and may serve as a marker and target of therapy in cardiometabolic disease.
doi:10.1016/j.jcmg.2014.07.017
PMCID: PMC4268163  PMID: 25440591
cardiometabolic risk; metabolic syndrome; obesity
23.  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.
doi:10.1016/j.jand.2012.03.034
PMCID: PMC3419359  PMID: 22889634
body composition; central obesity; fatty liver; single nucleotide polymorphisms; liver fat; race/ethnicity; subcutaneous adipose tissue; visceral adipose tissue
24.  Body Fat Patterning, Hepatic Fat and Pancreatic Volume of Non-Obese Asian Indians with Type 2 Diabetes in North India: A Case-Control Study 
PLoS ONE  2015;10(10):e0140447.
Objective
To evaluate body fat patterning and phenotype including hepatic fat and pancreatic volume of non-obese (BMI: < 25 kg/m2) Asian Indians with type 2 diabetes residing in North India.
Methods
Non-obese patients with type 2 diabetes (n = 93) and non-obese, normo-glycemic subjects (n = 40) were recruited. BMI, waist & hip circumferences, skinfold thickness at 8 sites, body fat, lean mass and detailed abdominal fat evaluation [total abdominal fat, total subcutaneous fat (superficial, deep, anterior, and posterior), total intra-abdominal fat (intra-peritoneal, retroperitoneal)], liver span, grades of fatty liver and pancreatic volume were compared.
Results
Waist circumference, subscapular skinfolds and total truncal fat (on DEXA) were higher whereas calf, total peripheral skinfolds and total leg fat (on DEXA) lower in patients. Specifically, the following volumes were higher in cases as compared to controls; total abdominal fat (19.4%), total intra-abdominal fat (49.7%), intra-peritoneal fat (47.7%), retroperitoneal fat (70.7%), pancreatic volume (26.6%), pancreatic volume index (21.3%) and liver span (10.8%). In cases, significant positive correlations were observed for pancreatic volume with BMI, waist and hip circumferences, W-HR, subscapular, abdominal and total truncal skinfolds, truncal, total subcutaneous, total intra-abdominal, intra-peritoneal, retroperitoneal fat depots, liver span and fatty liver.
Conclusions
In non-obese Asian Indians with type 2 diabetes, subcutaneous and intra-abdominal obesity, including fatty liver, and pancreatic volume were higher and peripheral subcutaneous adiposity was lower than BMI matched non-diabetic subjects. Importantly, increased pancreatic volume in patients was highly correlated with multiple measures of abdominal obesity and liver fat.
doi:10.1371/journal.pone.0140447
PMCID: PMC4608569  PMID: 26474415
25.  Abdominal fat depots associated with insulin resistance and metabolic syndrome risk factors in black African young adults 
BMC Public Health  2015;15:1013.
Background
Individuals of black African ethnicity tend to have less visceral adipose tissue (VAT) but more subcutaneous-abdominal adipose tissue (SCAT) than white Caucasians. However, it is unclear whether such distribution of abdominal fat is beneficial for metabolic disease risk in black individuals. Here we compared the associations between these specific abdominal fat depots, insulin sensitivity and metabolic syndrome risk.
Methods
A cross-sectional analysis of 76 black South African young adults (36 men; 40 women) aged 18–19 years participating in the Birth to Twenty Cohort Study had VAT and SCAT measured by MRI. The metabolic syndrome traits (blood pressure, lipid profile, fasting glucose and insulin) were measured and the values were combined into a metabolic syndrome risk score. Fasting glucose and insulin were used to derive the HOMA-index of insulin resistance (HOMA-IR).
Results
Compared to men, women had greater VAT (mean: 16.6 vs. 12.5 cm2) and SCAT (median 164.0 vs. 59.9 cm2). In men, SCAT (r = 0.50) was more strongly correlated to the metabolic syndrome score (MetS) than was VAT (r = 0.23), and was associated with both MetS (P = 0.001) and HOMA-IR (P = 0.001) after adjustment for VAT and total fat mass. In women, both abdominal fat compartments showed comparable positive correlations with MetS (r = 0.26 to 0.31), although these trends were weaker than in men.
Conclusions
In young black South African adults, SCAT appears to be more relevant than VAT to metabolic syndrome traits.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-2147-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-015-2147-x
PMCID: PMC4595061  PMID: 26437649

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