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Association between non-subcutaneous adiposity and calcified coronary plaque: a substudy of the Multi-Ethnic Study of Atherosclerosis^1,2,3

¹ From the Sticht Center on Aging (JD and SBK), and Division of Public Health Science (F-CH and GLB), Wake Forest University School of Medicine, Winston-Salem, NC; Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD (TBH); Division of Cardiology, Los Angeles Biomedical Research Institute, Torrance, CA (RCD); Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (MS); Department of Family & Preventive Medicine, University of California, San Diego, CA (MHC and MA); Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland (PO); Department of Biostatistics, University of Washington, Seattle, WA (ERB); Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC (JJC)

² Supported by the National Heart, Lung, and Blood Institute (grant R01-HL-085323 to JD; contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169) and the Wake Forest University Claude D. Pepper Older Americans Independence Center (NIH P30-AG21332).

³ Address reprint requests to J Ding, Sticht Center on Aging, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: jding{at}wfubmc.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background:Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids.

Objective:We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a noninvasive measure of coronary artery disease burden.

Design:Participants in the Multi-Ethnic Study of Atherosclerosis underwent computed tomography (CT) assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men, 43% black), aged 47–86 y, from Forsyth County, NC, during 2002–2005, with the use of cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index with the standard scores of non-subcutaneous fat depots.

Results:A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors, and height, calcified coronary plaque was associated with a 1 SD increment in the non-subcutaneous fat index [odds ratio (OR): 1.41; 95% CI: 1.08, 1.84], pericardial fat (OR: 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR: 1.35; 95% CI: 1.03, 1.76) but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR: 1.40; 95% CI: 1.00, 1.94). The relation did not differ by sex and ethnicity.

Conclusions:The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis.

	INTRODUCTION

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Increased total body fat is a well-established risk factor for coronary heart disease (1). Accumulation of abdominal fat measured by waist-to-hip ratio may be associated with the development of coronary heart disease independent of the total amount of body fat (2). Computed tomography (CT) can further distinguish subcutaneous fat depot from various non-subcutaneous fat depots, such as pericardial fat (3), abdominal visceral fat (4), fat content in the liver (hepatic steatosis) (5), and intermuscular fat (6). Pathophysiologic studies show that, compared with subcutaneous fat, pericardial fat (7) and abdominal visceral fat (8) have a higher expression of inflammatory cytokines. Corroborating these findings, epidemiologic studies suggest that abdominal visceral fat predicts future events (9) of coronary heart disease and pericardial fat is associated with coronary artery disease (10), independent of body mass index. It is postulated that inability of subcutaneous fat deposition to buffer the energy excess results in accumulation of non-subcutaneous fat deposition (also termed ectopic fat deposition) around and within the heart, liver, and skeletal muscle, and excess non-subcutaneous fat deposition then impairs the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids (11, 12). However, heretofore studies have not addressed the association between the overall burden of non-subcutaneous fat depots and coronary artery disease.

Coronary arterial calcification is a stage in the progression of atherosclerosis documenting the presence of advanced atheroma (13, 14). Although the relation between calcified coronary plaque and plaque rupture is unclear, pathologic studies suggest that the amount of calcified coronary plaque may reflect the total coronary atherosclerotic disease burden (15). In fact, calcified coronary plaque predicts subsequent events of coronary heart disease independent of the Framingham Risk Score in asymptomatic adults (16).

We have investigated the cross-sectional relation of various CT-measured fat depots, including pericardial fat, abdominal visceral fat, fat content in the liver, and intermuscular fat, to calcified coronary plaque in a community-based sample of whites and blacks. In addition to examining each fat depot separately, we also created a non-subcutaneous fat index to reflect the overall burden of non-subcutaneous adiposity. These data are expected to further our understanding of the mechanisms underlying obesity-related coronary heart disease.

	SUBJECTS AND METHODS

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Study population
The Multi-Ethnic Study of Atherosclerosis (MESA) is a community-based cohort study designed primarily to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (17). A total of 6814 whites, blacks, Hispanics, and Asian Americans aged 45–84 y were recruited from Baltimore, MD, Chicago, IL, Forsyth County, NC, Los Angeles, CA, New York, NY, and St Paul, MN, in 2000–2002. Individuals with physician-diagnosed cardiovascular disease or any related procedures were not eligible. The study was approved by the Institutional Review Boards of the participating institutions, and the participants gave informed consent. All MESA participants underwent a cardiac CT scan for the assessment of calcified coronary plaque at either examination 2 or 3 (2002–2005), when information on anthropometry and other cardiovascular factors used in this report was collected. A random sample of 398 MESA white and black participants (47% men, 43% black), aged 47–86 y, in Forsyth County, NC, also received abdominal CT scans immediately after cardiac CT scans to measure abdominal aorta calcification. For the present study, we measured various fat depots in these 398 participants with existing cardiac and abdominal CT scans.

Calcified coronary plaque
Coronary calcification was determined with a LightSpeed Plus 4-detector row CT system (GE Medical Systems, Milwaukee, WI) at the Forsyth County site of MESA. Details of the method were previously published (18). The CT scan has a minimum gantry rotation period of 500 msec and an exposure time of 330 msec. The system was operated in the axial scan mode (cine) with 120 kVp, 320–400 mA, 4 x 2.5 mm collimation, standard reconstruction kernel, and a display field of view of 350 mm. The electrocardiography triggering was set at 50% of the R-R interval.

Trained technologists scanned the heart of each participant twice and transmitted the scans over the Internet to the CT Reading Center (Harbor-UCLA Research and Education Institute, Torrance, CA). All scans were read masked to information about the participants. The Agatston score (19), averaged from the 2 scans, was used to quantify the amount of calcified coronary plaque. The presence of calcified coronary plaque was defined as Agatston score > 0. The agreement for the presence of calcified coronary plaque between duplicate scans (: 0.92) (20) as well as the re-read agreement of the same scans ( for intraobserver and interobserver agreements: 0.93 and 0.90, respectively) (21) were found to be excellent.

Fat depots
Three experienced CT analysts, masked to the measurement of calcification, determined pericardial fat volume and liver attenuation (a measure of fat content in the liver) on the cardiac CT scans. For pericardial fat volume, slices within 15 mm above and 30 mm below the superior extent of the left main coronary artery were included. This region of the heart was selected because it includes the pericardial fat located around the proximal coronary arteries (left main coronary, left anterior descending, right coronary, and circumflex arteries). The anterior border of the volume was defined by the chest wall and the posterior border by the aorta and the bronchus. The Advantage Windows Workstation (GE Healthcare, Waukesha, WI) with the use of volume analysis software was used to discern fat from other tissues with a threshold of –190 to –30 Hounsfield units. The volume was the sum of all voxels containing fat. Our measure of pericardial fat volume was highly correlated with total volume of pericardial fat volume (3) in a random subset of 10 participants in the Diabetes Heart Study (correlation coefficient: 0.93; P < 0.0001). Liver attenuation was measured as the average density of 3 regions (1 cm² each). The 3 regions were consistently placed in the parenchyma of the right lobe of the liver 15 mm from the top. Liver attenuation was shown to be inversely correlated with fatty change assessed by liver biopsy (correlation coefficient: –0.90; P < 0.0001) (5).

Abdominal visceral, subcutaneous, and intermuscular fat volumes were measured on abdominal CT scans. Technical factors for abdominal CT scans were helical mode, 120 kVp, 250 mA, 4 x 2.5 mm collimation, standard reconstruction kernel, and a display field of view of 500 mm. For abdominal visceral, subcutaneous, and intermuscular fat volumes, slices within 15 mm centered at the L4–L5 level were selected. We manually traced the inner and outer aspects of the abdominal wall. Abdominal visceral fat was defined as the fat enclosed by the inner aspect of the abdominal wall. Abdominal subcutaneous fat was defined as the fat outside the outer aspects of the abdominal wall. We also measured intermuscular fat within the abdominal wall. Studies of human cadavers showed that the area measured by CT scanning was an accurate estimate of abdominal visceral fat (4), appendicular subcutaneous, and intermuscular fat (6) volumes.

To examine the reproducibility of the measures of fat depots, a random sample of 80 MESA participants was selected, and their CT scans were reanalyzed masked to the prior results. The intraclass correlation coefficients of intrareader and interreader reliability were 0.99 and 0.89, respectively, for pericardial fat, 0.89 and 0.74 for liver attenuation, and 0.99 and 0.99 for abdominal visceral, subcutaneous, and intermuscular fat.

We then created a non-subcutaneous fat index by subtracting the standard score (derived by subtracting the mean from an individual measure and then dividing the difference by the SD) of liver attenuation from the sum of the standard scores of pericardial fat, abdominal visceral fat, and intermuscular fat. Because low liver attenuation indicates high fat content in the liver, we subtracted, rather than added, the standard score of liver attenuation in the calculation.

Anthropometry
Weight was measured with a Detecto Platform Balance Scale (Detecto, Webb City, MO) to the nearest 0.5 kg. Height was measured with a stadiometer [Accu-Hite Measure Device (Seca, Hamburg, Germany) with level bubble] to the nearest 0.1 cm. Waist circumference (at the umbilicus) was measured to the nearest 0.1 cm with the use of a steel measuring tape with standard 4-ounce tension (Gulick II 150 cm anthropometric tape; Sammons Preston, Chicago, IL). Body mass index (in kg/m²) was calculated.

Other covariates
Standardized questionnaires were used to collect information on demographics, smoking status, alcohol use, medical history, and medication use. Cigarette smoking status was classified as never, former, and current. Blood pressure was measured in the right arm of the participant after 5 min in a sitting position with a Dinamap model Pro 100 automated oscillometric sphygmomanometer (Critikon, Tampa, FL). The second and third of 3 readings were averaged to obtain the blood pressure values. HDL cholesterol and triacylglycerols were measured in EDTA-treated plasma on a Roche COBAS FARA centrifugal analyzer (Roche Diagnostics, Indianapolis, IN). Glucose was measured by rate reflectance spectrophotometry with the use of thin film adaptation of the glucose oxidase method on the Vitros analyzer (Johnson & Johnson Clinical Diagnostics Inc, Rochester, NY). Diabetes was defined as fasting glucose > 6.99 mmol/L (126 mg/dL) or use of hypoglycemic medication, and impaired fasting glucose was defined as fasting glucose 5.55–6.94 mmol/L (100–125 mg/dL) (22).

Statistical analysis
Cardiovascular characteristics by the presence or absence of calcified coronary plaque were compared with the use of analysis of variance for continuous variables and the chi-square test for categorical variables. Spearman's correlation coefficients between fat measures were calculated. Logistic regression was used to assess the association of fat measures with the presence of calcified coronary plaque, after adjusting for other relevant factors. One SD was used as the unit increment for each fat measure. In addition, each quartile of non-subcutaneous fat index was compared with the lowest quartile of non-subcutaneous fat index for the odds of the presence of calcification. Interaction terms for sex and ethnicity with non-subcutaneous fat index were examined with the use of likelihood ratio tests. SAS version 9.00 (SAS Institute Inc, Cary, NC) was used for the analysis.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Among 398 participants, 219 (55%) had calcified coronary plaque. Participants with calcified coronary plaque were older and were more likely to be men and white than were participants without calcified coronary plaque (Table 1). In addition, they also had greater height, higher systolic blood pressure, and lower concentrations of HDL cholesterol and were more likely to be former smokers, be antihypertensive medication users, and have diabetes. No statistically significant differences were observed in alcohol drinking status, triacylglycerol concentrations, and lipid-lowering medication use between participants with and without calcified coronary plaque. Waist circumference; the average volumes of pericardial fat, abdominal visceral fat, and intermuscular fat; and the non-subcutaneous fat index were significantly greater in participants with a calcified coronary plaque, but the mean abdominal subcutaneous fat volume was lower. Body mass index and liver attenuation did not differ significantly between the groups defined by the presence of calcification.

Table 2

Table 3

Figure 1

View larger version (5K): [in this window] [in a new window]   FIGURE 1.. Odds ratio (error bars indicate 95% CI) of calcified coronary plaque according to quartiles of the non-subcutaneous fat index, adjusting for age, sex, ethnicity, smoking status, alcohol drinking status, and height, in a logistic regression analysis in 398 participants of the Multi-Ethnic Study of Atherosclerosis, 2002–2005.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

To our knowledge, our study is the first to support the presence of an association between the overall burden of non-subcutaneous adiposity and coronary atherosclerosis. Frayn (23) postulated a few years ago that adipose tissue, especially subcutaneous adipose tissue, serves as a buffer for the flux of circulating fatty acids during the postprandial period. If this buffering ability were impaired, an excessive flux of lipid fuels could lead to fat accumulation in the liver, skeletal muscle, and the pancreatic beta cells, resulting in insulin resistance. It was recently hypothesized that excessive fat storage around and within non-subcutaneous tissues, such as the heart, blood vessels, and kidney, induces cardiovascular disease through the release of inflammatory cytokines and free fatty acids (11, 24). Our data lend support to the notion that excessive non-subcutaneous fat deposition is associated with coronary atherosclerosis.

Pericardial fat may also be associated with coronary atherosclerosis, although in our study the association was found to be only marginally significant after adjusting for cardiovascular risk factors, possibly because of the overadjustment for factors on the causal pathway. Two epidemiologic studies have reported an association of pericardial fat with angiography-detected coronary artery disease (10, 25), but another study did not find such an association (26). The results from those previous studies could, however, be biased because they only included clinic patients referred for diagnostic coronary angiography. However, the present analysis, with the use of a community-based random sample, furthers our knowledge of the possible role of pericardial fat in the development of coronary heart disease. Local inflammation may be an important mechanism underlying the link between pericardial fat and coronary atherosclerosis. A large amount of pericardial fat is distributed around coronary arteries. Compared with subcutaneous fat, pericardial fat expresses higher concentrations of inflammatory cytokines, such as monocyte chemotactic protein 1, interleukin-6, and tumor necrosis factor (7). It was shown that fat tissue around coronary arteries, in addition to the layers of the artery (ie, intima, media, and adventitia), is also involved in inflammatory reactions (27, 28). Moreover, both human and animal studies indicated that atherosclerotic lesions are absent in the segments of coronary arteries lacking pericardial fat (29, 30).

Abdominal visceral fat was not associated with coronary calcification after adjustment for cardiovascular risk factors in the present study. This negative finding may again be due to the overadjustment for cardiovascular risk factors. In fact, abdominal visceral fat may be a risk factor for clinical coronary heart disease (9, 31). Abdominal visceral fat has a higher secretion rate of inflammatory cytokines, such as interleukin-6, than abdominal subcutaneous fat (8). It was suggested that abdominal visceral fat may be an important site for the secretion of interleukin-6 and therefore promotes systemic inflammation (32). Systemic inflammation plays a crucial role in the development of coronary heart disease (33).

In summary, the overall burden of non-subcutaneous adiposity, but not abdominal subcutaneous fat, may be associated with coronary atherosclerosis. The results from the present study should be interpreted with caution because of its cross-sectional study design. Future studies to evaluate the association of non-subcutaneous fat and coronary atherosclerosis should have a longitudinal design, which would allow the proper evaluation of its temporal sequence.

	ACKNOWLEDGMENTS

 
We thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions and especially the CT Reading Center personnel at both Harbor UCLA and Wake Forest University School of Medicine for their hard work on this project. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.

The author's responsibilities were as follows—JD, JJC, and SBK: were responsible for the conception, design, and conduct of the study and for the data interpretation; F-CH, TBH, GLB, RCD, MS, MHC, MA, PO, and ERB: were responsible for the conduct of the study and the data interpretation. None of the authors had a personal or financial conflict of interest.

	REFERENCES

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