Few studies have investigated the relationships between visceral adipose tissue (VAT) and coronary stenosis and noncalcified plaques at the subclinical stage. The aim of this study was to investigate relationship between VAT and coronary lesions assessed by coronary computed tomography (CT) in an apparently healthy population.
Retrospective cross-sectional study.
One thousand six hundred and fifty-eight subjects free of cardiovascular disease underwent coronary CT and abdominal fat CT as part of a routine medical examination.
VAT area was measured at the level of the umbilicus using CT. Coronary stenoses and plaques were evaluated using coronary CT.
The mean age of the study population was 55.9±8.0 years, and 1198 (72.3%) subjects were men. There were 201 subjects (12.1%) with coronary stenosis <50% and 144 (8.7%) had significant stenosis. Noncalcified plaques were observed in 108 (6.5%) subjects. Coronary stenosis <50% and noncalcified plaques increased steadily as the VAT area increased (P<0.001). The 4th quartile of VAT area was significantly associated with prevalence of coronary stenosis <50% and the presence of noncalcified plaques when compared with the first through third VAT quartiles in the cardiovascular risk factor-adjusted model (odds ratio (OR): 1.58, 95% confidence interval (CI): 1.09–2.30 and OR: 1.66; 95% CI: 1.02–2.68, respectively).
Excess VAT area was associated with coronary stenosis <50% and noncalcified plaques, independent of traditional cardiovascular risk factors, in an asymptomatic population without a history of coronary artery disease.
The prevalence of obesity has been rapidly increasing in developed and developing countries alike.1 Obesity is associated with an increased risk of cardiovascular disease (CVD) and type 2 diabetes, and thus the American Heart Association has categorized it as a major risk factor for coronary artery disease (CAD).2, 3, 4 Many studies have demonstrated that regional fat depots may be more important than overall adiposity.5, 6 The Framingham Heart Study has reported that abdominal visceral adipose tissue (VAT) has a strong association with metabolic syndrome,7 systemic markers of inflammation8 and the coronary artery calcium (CAC) score.9
Whereas the presence and severity of CAC are strongly associated with the overall atherosclerotic plaque burden, it is assumed that noncalcified coronary plaques are more prone to rupture with subsequent coronary events.10 Recent advances in coronary computed tomography (CT) have enabled the noninvasive detection of noncalcified plaques.11, 12 Many studies have shown an association between VAT and CAD and CT-detected plaques.10, 13, 14, 15 However, a correlation between VAT and noncalcified plaques has been identified only in populations with advanced CAD10, 13 and diabetes.14 It is not well known that VAT is associated with coronary stenosis and noncalcified plaques in asymptomatic and subclinically staged populations without advanced CAD. Recently, a follow-up study including subjects who were suspected of having CAD and underwent coronary CT revealed that the cumulative probability of 3-year major cardiac events in individuals with noncalcified plaques was 22.7%.16 VAT associated with noncalcified plaques in asymptomatic individuals could be a target of therapeutic lifestyle changes for primary prevention.
Thus, we investigated the association between CT-measured abdominal VAT area and coronary stenosis and coronary plaque lesions detected by coronary CT in a large, apparently healthy population.
Materials and methods
Study population and study design
The study population consisted of 1900 asymptomatic individuals aged 40 years or older who underwent a general health checkup, including abdominal fat CT and coronary CT with good or adequate image quality, between July 2006 and March 2010 in the Seoul National University Hospital Healthcare System Gangnam Center. Of the 1900 subjects, we excluded 242 subjects who had a history of heart attack, CAD including acute myocardial infarction, angina or congestive heart failure. Thus, 1658 participants who had a CT measurement of their abdominal fat and coronary CT results without a history of CAD were finally enrolled for analysis.
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the international review board of Seoul National University Hospital. Informed consent was waived because of retrospective nature of this study.
Clinical and laboratory assessments
Each subject underwent a questionnaire assessment, an anthropometric assessment and laboratory examination on the same day. Systolic and diastolic blood pressures were measured twice on the same day, and the mean of the two values was used in the analysis. Height and body weight were measured using a digital scale. Body mass index (BMI) was calculated as follows: BMI=weight (kg)/height squared (m2). Waist circumference (WC) was measured at the midpoint between the lower costal margin and the iliac crest by a well-trained nurse. Current smokers were defined as those who had smoked at least one cigarette per day during the previous year.17 Alcohol use was classified as alcohol consumption ⩾140 g per week. We used the proposed definition of CVD risk factors of the National Cholesterol Education Program Adult Treatment Panel III.18 Systolic blood pressure ⩾140 mm Hg or diastolic blood pressure ⩾90 mm Hg and/or previous use of antihypertensive medication were used to define hypertension. Subjects with fasting plasma glucose levels ⩾126 mg dl−1 and/or treatment with a hypoglycemic agent or insulin were defined as having diabetes mellitus.19
Laboratory evaluations included total serum cholesterol, serum triglycerides, serum high-density lipoprotein cholesterol and fasting glucose. Low-density lipoprotein cholesterol levels were estimated indirectly using the Friedewald formula for subjects with triglyceride levels <400 mg dl−1. Venous blood samples were taken from all subjects before 1000 hours after a 12-h overnight fast. All biochemical determinations were performed in the same laboratory using standard laboratory methods.
Measurement of abdominal adipose tissue areas by CT
The technique used for adipose tissue area measurements in cross-sectional CT images has been previously standardized and validated,20, 21 and has only negligible interobserver variation.22, 23 We used a previously described method for VAT area measurement in cross-sectional CT images.19 Briefly, the subjects were examined with a 16-detector row CT scanner (Somatom Sensation 16; Siemens Medical Solutions, Forchheim, Germany) in a supine position. The cross-sectional surface area (in cm2) of different abdominal fat compartments at the level of the umbilicus was calculated at this slice using commercially available CT software (Rapidia 2.8; INFINITT, Seoul, Korea), which electronically determined the adipose tissue area by setting the attenuation values for a region of interest within a range of −250 to −50 Hounsfield units. VAT area was defined as intra-abdominal fat bound by parietal peritoneum or transversalis fascia, excluding the vertebral column and paraspinal muscles. Subcutaneous abdominal adipose tissue (SAT) area was defined as fat superficial to the abdominal and back muscles.24 VAT and SAT areas were stratified as quartiles. The total VAT quartiles for men were as follows: quartile 1, <112.2 cm2; quartile 2, 112.2–147.3 cm2; quartile 3, 147.4–183.3 cm2 and quartile 4, ⩾183.4 cm2. For women, the VAT quartiles were the following: quartile 1, <72.9 cm2; quartile 2, 72.9–102.3 cm2; quartile 3, 102.4–132.7 cm2 and quartile 4, >132.8 cm2. The SAT quartile ranges were as follows: <103.1 cm2, 103.1–131.6 cm2, 131.7–164.5 cm2 and >164.6 cm2 for men and <146.1 cm2, 146.2–187.0 cm2, 187.1–235.3 cm2 and >235.4 cm2 for women.
Measurement of coronary lesions by coronary CT
Coronary CT was performed using a 16-row multi-slice CT (Sensation 16, Siemens Medical Systems, Erlangen, Germany), as described previously.25, 26 Briefly, after obtaining a topogram of the chest, a calcium score scan and angiography were performed using the retrospective method with a tube voltage of 120 kV and a 400 effective mAs tube current with a 200-mm field of view and electrocardiographically gated dose modulation. Before CT scan, the heart rate was measured, and when it was over 60 beats per minute patients received 50–100 mg metoprolol.
All images were analyzed by a radiologist who was blinded to the clinical and laboratory results of the subjects. Each lesion was identified by using a multiplanar reconstruction technique, maximum intensity projection of the short-axis and two- and four-chamber views.
The degree of stenosis and the plaque characterization were measured from coronary CT image analysis with a dedicated three-dimensional computer station (Rapidia 2.8; INFINITT). Coronary artery stenosis was estimated when the contrast-enhanced portion of the coronary lumen was semiautomatically traced at the maximal stenotic site and compared with the mean value for the proximal and distal reference sites.27 Stenosis of ⩾50% was considered as clinically significant stenosis, and luminal narrowing, which is >0% and <50%, was categorized as stenosis <50%.
Plaques were identified as structures larger than 1 mm2 within or adjacent to the vessel lumen, which should be clearly distinguished from the lumen and surrounding epicardial fat. Plaque type was classified as follows: (a) plaques that contained any calcified tissue (attenuation >130 Hounsfield units on native images) were classified as any calcified plaque; (b) plaques without any calcium component were classified as noncalcified plaques.27
We used χ2-tests for categorical variables, and Student’s t-test or the Mann–Whitney test and an analysis of variance or the Kruskal–Wallis test for continuous variables. Body fat measurements were stratified as quartiles and analyzed by quartiles or by 1st–3rd quartile versus 4th quartile. A multivariate logistic regression analysis was used to assess the significance of covariate-adjusted cross-sectional relationships between coronary lesions by coronary CT and VAT areas. The covariates in the multivariate model, which were chosen for clinical importance and statistical significance, included age, sex, hypertension, diabetes mellitus, smoking, alcohol consumption (dichotomized as >15 drinks per week versus ⩽14 drinks per week), total cholesterol, dyslipidemia treatment and SAT area (quartiles). BMI and WC were not included as covariates because of their multicollinearity to VAT area. A two-tailed P-value of <0.05 was considered statistically significant. Statistical analyses were conducted using SPSS version 19.0 (SPSS Inc., Chicago, IL, USA).
Overall, 460 women and 1198 men were available for analysis. The mean ages of men and women were 55.4 and 57.4 years, respectively, (Table 1). Approximately, 29.7% (n=355) of men and 32.6% (n=150) of women were hypertensive and 12.3% (n=147) of men and 8.3% (n=38) of women had diabetes. The mean SAT area of women was larger than that of men (191.7±67.0 cm2 versus 137.5±48.5 cm2, P<0.001). The mean VAT area in women, however, was 104.6±45.5 cm2, whereas 149.1±54.8 cm2 in men (P<0.001). Coronary stenosis (<50%) and significant stenosis (⩾50%) were present in 201 subjects (12.1%) and 144 subjects (8.7%), respectively. Any calcified plaques were found in 543 subjects (32.8%) and noncalcified plaques were observed in 108 (6.5%). Subjects with increased VAT area had higher prevalence of coronary stenosis <50% (P=0.002 for men, P=0.003 for women).
The VAT areas were stratified into quartiles and analyzed as categorical variables. Figure 1 illustrates the relationship between coronary stenosis and plaques and VAT. The proportion of subjects with coronary stenosis of any degree progressively increased from 16.4% in subjects in the 1st VAT quartile to 29.4% in the 4th VAT quartile (P<0.001). Dose-dependent increases in the proportion of significant stenosis, any calcified plaque and noncalcified plaque were also observed as the VAT area increased (P=0.013, P<0.001 and P=0.003, respectively).
A formal analysis of the relationship between coronary stenotic lesions and VAT area is shown in Table 2. In the age- and sex-adjusted analysis, the 4th VAT quartile was associated with a 97% increase in the risk of coronary stenosis <50%. This effect of VAT was attenuated in the multivariate analyses when other well-established risk factors of CAD were considered. Increase of VAT was positively associated with increase of prevalence of coronary stenosis <50% (P for trend=0.015; Table 2). Moreover, the 4th quartile of VAT, when compared with the first to third quartile of VAT, was significantly associated with coronary stenosis <50% (odds ratio (OR): 1.58; 95% confidence interval (CI): 1.09–2.30, P-value=0.017, Supplementary Table 2). However, the increase of VAT area was not significantly associated with significant stenosis, which might be because of the small number of subjects with significant stenosis in apparently healthy subjects.
We also evaluated the association between VAT and coronary plaques. VAT was not significantly associated with any calcified plaques. However, noncalcified plaques were significantly associated with VAT in the age- and sex-adjusted analysis (OR: 1.93; 95% CI: 1.10–3.39). In the multivariate analysis, this association was attenuated and marginally significant (OR: 1.81; 95% CI: 0.91–3.58), but the trend between VAT and noncalcified plaques was statistically significant (P for trend=0.050).
Various body fat measures were stratified as quartiles and analyzed as categorical variables by quartiles 1–3 versus quartile 4. The 4th quartiles of BMI and WC were in excess of 26.5 kg m2 and 93.3 cm in men and 25.4 kg m−2 and 89.4 cm in women, respectively. The highest quartiles of BMI, WC and VAT area were all significantly associated with the presence of noncalcified plaques in the age- and sex-adjusted model and multivariate analysis, as shown in Table 3. In multivariable model including height, the ORs (95% CI) of the noncalcified plaques for the 4th quartiles of BMI, WC and VAT area were 2.23 (1.31–3.80), 2.11 (1.19–3.73) and 1.66 (1.02–2.68) with P<0.05 for all, respectively.
In this study, we investigated the relationship between visceral adiposity and coronary stenosis and noncalcified plaques in an apparently healthy population. VAT area measured by CT was independently associated with coronary stenosis <50% and the presence of noncalcified plaques in a model adjusted for known cardiovascular risk factors.
Although many studies have shown that visceral adiposity is one of the risk factors for CVD, there is a paucity of study on the association between visceral adiposity and early atherosclerosis defined by coronary stenosis <50% and presence of noncalcified coronary plaque. Khashper et al.14 reported increase VAT area was associated with multi-vessel coronary artery plaque in asymptomatic patients with type 2 diabetes mellitus. Increased VAT area was also associated with presence of vulnerable noncalcified plaque and progression of noncalcified plaque in subjects with CVD.10,13 However, these previous studies that have suggested an independent association between increase VAT area and coronary plaque did not involve asymptomatic population. In this study, we showed that highest quartile of VAT area was associated with coronary stenosis <50% and presence of noncalcified plaque measured by coronary CT angiography in apparently healthy subjects. Therefore, we suggest that VAT might be an independent risk factor for subclinical coronary atherosclerosis.
A number of recent studies have specifically reported on the effect of excess visceral adiposity on coronary artery calcification.19, 28 Whereas the presence and extent of CAC are associated with the overall atherosclerotic burden, noncalcified plaques are more vulnerable to rupture with subsequent coronary events.29 Our results suggest that VAT area positively associated with coronary noncalcified plaques are in agreement with the results of previous studies. Ohashi et al.10 found a significant association between VAT area and noncalcified plaque burden in 427 Japanese patients with proven or suspected CAD. In a prospective cohort study comprising 553 patients with CAD assessed by CT angiography, patients in the higher quartiles were at an increased risk of the progression of noncalcified plaques (OR 4.7; 95% CI 2.3–9.4), independent of cardiovascular risk factors.13 However, the participants in the previous two studies had CAD. To our knowledge, this is the first study that has examined the association between VAT with noncalcified plaques in apparently healthy subjects.
We demonstrated that VAT area was associated with stenosis <50% and noncalcified plaques in a model adjusted for age and sex, but this association was attenuated after adjusting for cardiovascular risk factors. In an previous report from the Framingham Heart Multi-Detector CT Study, Mahabadi et al.30 found an association between VAT volume and CVD in models adjusted for age and sex. After adjusting for traditional CVD risk factors, the associations were no longer significant. This finding suggests that the association between VAT and coronary atherosclerosis is mediated by shared risk factors in the pathogenesis of fat depots and atherosclerosis progression in populations with more risk factors. We, however, showed that VAT area was significantly associated with coronary stenosis <50% and noncalcified plaques after adjusting for traditional cardiovascular risk factors. This finding indicates that VAT area could be an independent risk factor for coronary atherosclerosis and, thus, could be a target of lifestyle modification for primary prevention.
Adipocytokine secretion from visceral fat may explain the relationship between excess VAT and noncalcified plaques. The specific composition and metabolic activity of visceral fat tissues differ from subcutaneous fat. Visceral fat tissues have a high rate of fatty-acid incorporation and fast insulin-induced fatty-acid breakdown and secrete several proinflammatory cytokines, such as adiponectin, interleukin-6, plasminogen activator-1 and tumor necrosis factor-α.31, 32 The inflammatory cytokines released from VAT may directly influence the vessel wall atherogenic environment by regulating gene expression, and the function of endothelial and arterial smooth muscle and macrophages, and sustain an active atherosclerotic process as proven by the presence of noncalcified plaques.33
It is also possible that insulin resistance can explain the relationship between excess VAT and noncalcified plaques. VAT has circulatory communication with the liver via the portal circulation, and may thus be highly associated with insulin resistance of the liver and hepatic production of inflammatory factors, such as free fatty acids. Increased levels of free fatty acids and a disturbance in the secretion of several adipokines, such as leptin or adiponectin, have been reported to be related to insulin resistance.34 VAT is also associated with metabolic risk factors,35, 36 traditional cardiovascular risk factors7 and systemic inflammatory markers.8 These associations further emphasize the importance of VAT as a mediator of systemic cardiovascular risk factors.
Our results demonstrated that VAT was not statistically associated with calcified plaques. VAT was reported to be associated with the CAC score in previous reports.19, 37 A report from the Framingham Study Multi-Detector CT study, however, showed that VAT was significantly associated with the CAC score but not with calcified plaques detected on coronary CT.37 These different associations might come from the fact that the CAC score reflected the severity of vascular calcification, whereas the mere presence of calcified plaques did not include the degree of calcification. Clinically, the presence of the extensive type of coronary calcium is more common in patients with stable angina pectoris, while being significantly less frequent in those with acute myocardial infarction.38, 39 Moreover, noncalcified plaques are a more precise indicator of future major cardiac events, such as cardiac death, new acute myocardial infarction and coronary revascularization, than calcified plaques.16 Thus, considering the significant association with noncalcified plaques, excess VAT area indicates an increased risk of coronary atherosclerosis in apparently healthy populations and can be a target of lifestyle modification for primary prevention.
The strengths of our study are the use of coronary CT results, the CT-measured VAT area, the high degree of validity and reproducibility, the high-quality data collected by trained personnel with a systematic protocol and the large number of included subjects. In addition, the subjects in our study were an apparently healthy population and can represent the general population.
Some limitations of our study merit comment. First, this study had a cross-sectional design, which makes it difficult to determine causal or temporal relationships between VAT and the development of noncalcified plaques. Second, in this study we used 16-detector row CT to detect coronary lesions. In some recent studies evaluating coronary plaques, 64-slice scanners were used.10, 13, 14 However, a meta-analysis comparing the diagnostic performance of 64-detector CT, 16-detector CT and 4-detector CT reported that the difference in the diagnostic performances between 64-detector and 16-detector CT was not statistically significant.40 Third, there could be a concern about using coronary CT for asymptomatic subjects. All patients in this study, coronary CT angiographies were performed for screening purpose on patients’ demand after explanations and advices from primary physicians. Also, radiation dose for cornary CT was minimized to the level of background radiation (<3 mSv) after exclusion of subjects with arrythmia and whose heart rates were not controlled under 60 per minute after metoprolol medication. In addition, because semiautomatic program used in the interpretation of images in this study were already validated,27 we did not measure interobserver and intraobserver reproducibility. So, there is possibility of intra- or interobserver variabilities. As we only used scans with good or adequate image quality for this study, our approach may have minimized this limitation. Finally, we did not have data on fasting insulin or adipocytokine levels, which could explain the contribution of VAT to atherosclerosis progression.
In conclusion, visceral adiposity was related to coronary stenosis <50% and the presence of noncalcified plaques in an asymptomatic population. Visceral obesity should signal the existence of increased cardiovascular risk independent of traditional risk factors for CVD and could be a target for therapeutic lifestyle changes for the primary prevention of CVD.
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The authors declare no conflict of interest.
Supplementary Information accompanies this paper on International Journal of Obesity website
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