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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:368-374.)
© 1996 American Heart Association, Inc.

Articles

Visceral Fat Accumulation and Its Relation to Plasma Hemostatic Factors in Healthy Men

M. Cigolini; G. Targher; I.A. Bergamo Andreis; M. Tonoli; G. Agostino; G. De Sandre

From the Institute of Clinical Medicine (M.C., M.T., G.A., G. De S.), the Department of Metabolic Diseases (G.T.), and the Institute of Radiology (I.A.B.A.), University of Verona, Verona, Italy.

Correspondence to Massimo Cigolini, MD, Institute of Clinical Medicine, University of Verona, I-37134 Verona, Italy.

	Abstract

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Abstract The associations between abdominal visceral fat and the plasma hemostatic system were examined in 38-year-old healthy men (n=52) with a wide range of fatness and fat distribution. Plasma hemostatic factors and metabolic parameters, including glucose tolerance, were measured, and body fatness and adipose tissue distribution were assessed by using computed tomography. The men with more visceral fat (ie, higher than the median value [n=26]) had a less favorable metabolic profile than the men with less visceral fat (n=26). They also had significantly (P<.05) higher plasma fibrinogen, factor VIII clotting activity, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor–1 (PAI-1) activity (19.2±2.4 versus 8.5±1.6 AU/mL, P<.001) and lower basal tissue-type plasminogen activator activity. After adjustment for plasma insulin, the men with larger abdominal visceral fat area still had significantly higher plasma PAI-1 activity, but no difference was found in any of the other hemostatic factors. In multiple linear regression analysis, abdominal visceral fat area was a positive predictor of plasma PAI-1 activity, but it failed to show any significant association with other hemostatic factors after controlling for plasma insulin. These results suggest the presence of relationships between abdominal visceral fat and several plasma hemostatic factors that are largely mediated by concomitant alterations in plasma insulin concentration. In addition, our results suggest that abdominal accumulation of visceral fat is an independent predictor of plasma PAI-1 activity.

Key Words: visceral fat • insulin • plasminogen activator inhibitor–1 • fibrinogen • hemostatic factors

	Introduction

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Prospective studies have demonstrated that a predominant accumulation of AT in the abdominal region, commonly evaluated by anthropometric indicators of body fat distribution, confers an increased risk of mortality and morbidity for CHD (for review, see Reference 1). There is ample evidence to suggest that this increased cardiovascular risk is at least partly accounted for by the metabolic and hemodynamic abnormalities associated with abdominal fat distribution. Indeed, disturbances in lipoprotein metabolism and plasma insulin-glucose homeostasis and elevations of BP, which are risk factors for CHD, have been reported in subjects with an excessive deposition of AT in the abdomen.¹ Abnormalities of a number of plasma hemostatic factors may be also added as new candidate risk factors for CHD^{2 3 4 5 6 7} to the cluster of metabolic and hemodynamic disorders (including glucose intolerance, hyperinsulinemia, hypertension, and dyslipidemia) that are closely associated with abdominal fat distribution. In fact, we and others have reported that abdominal distribution of body fat is associated with increased plasma levels of fibrinogen, FVII and FVIII coagulant activities, and TPA antigen and its circulating inhibitor (PAI-1),^{8 9 10 11 12 13 14 15 16 17} thus suggesting that such a relation is dependent on the amount of abdominal visceral AT, which has been demonstrated to be the most critical correlate of the metabolic complications associated with abdominal obesity.¹ Furthermore, interventional studies have reported a beneficial effect of weight loss, which is known to primarily reduce intra-abdominal fat deposits,¹ on plasma PAI-1 activity and other hemostatic factors in overweight individuals.^{18 19} However, to the best of our knowledge, in all these reports, abdominal distribution of body fat has been measured as WHR or by using other anthropometric measurements, which provide only an indirect and crude estimation of the amount of abdominal visceral AT.²⁰ Thus, although plasma hemostatic factors have been reported to be associated with abdominal distribution of body fat, their direct relation to abdominal visceral fat has not yet been demonstrated.

In this context, the main aim of the present study was to examine whether the distribution of abdominal visceral fat as determined by CT, which is a more direct and accurate measure of regional fat distribution, correlates with various plasma hemostatic factors, and, if so, to what extent such a relation is mediated by the concomitant metabolic disorders that are closely associated with increased visceral fat accumulation, particularly plasma insulin concentration.

	Methods

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Subjects
This study enrolled 52 healthy men from a random population sample of 38-year-old men who had participated in previous studies whose design and recruitment methods are available.^{11 12} In this study, we examined only those male volunteers who agreed to have an evaluation of their abdominal AT by CT scan. All individuals were clinically healthy as evaluated by medical history, physical examination, and routine laboratory analyses. In particular, no subjects had clinical evidence suggestive of any endocrine disorder, diabetes mellitus, or kidney or liver disease. None of them were taking any drugs. Written informed consent was obtained from all participants.

Anthropometry and CT Measurements
Anthropometric measurements were performed on all participants by one trained investigator. Details of these measurements, which included weight, height, waist circumference (measured midway between the lower rib margin and the iliac crest), and hip circumference (the widest circumference over the great trochanters), are available.¹¹ BMI was calculated by dividing weight in kilograms by height in meters squared. WHR was calculated as a measure of body fat distribution. CT was performed on a Siemens Somatom DR-2 CT scanner by using the procedures of Sjöström et al²¹ with the following scanning parameters: 125 kV, 350 mA, scanning time 4 seconds, and slice thickness 8 mm. Total abdominal AT, visceral abdominal AT, and subcutaneous abdominal AT areas were evaluated by a single scan made at the level of the L4 and L5 vertebrae. Subject centering was obtained by a longitudinal tomogram at the L4 level. Attenuation intervals were determined between -50 to -150 Hounsfield units. A cursor was used to define the total cross-sectional abdominal area and visceral fat. Data were elaborated by using a histogram-based statistical program.

BP and Behavioral Variables
With the patient seated after at least 10 minutes of rest, BP was measured with a standard mercury manometer by a trained staff member by using phase V (disappearance of Korotkoff's sound) as the criterion for diastolic BP. The measurements were repeated after 5 minutes, and the average of the two measurements was used in analysis. Information on smoking habits, physical activity, and daily alcohol consumption was obtained from all participants from a questionnaire.²² Subjects were categorized according to smoking habits (yes/no) and physical activity level at work and during leisure time (three categories for each: light, moderate, or intense). Alcohol intake was determined by a diet questionnaire that asked for information about the daily consumption of wine, liquor, and beer; the data were expressed as grams of alcohol consumed per day.

Blood Sampling and Analysis
Venous blood was sampled without stasis from fasting subjects between 8:00 and 8:30 AM after 10 minutes of supine rest and at least 8 hours of abstention from smoking and alcohol intake. Plasma TC, HDL-C, TG, and glucose concentrations were determined by using standard enzymatic methods.^{11 12} Insulin was tested by a radioimmunoassay kit (Insik-5, Sorin Biomedica) with intra-assay and interassay coefficients of variation of 6.7% and 7.5%, respectively. A standard 75-g oral glucose tolerance test was performed, and 2-hour plasma insulin and glucose concentrations were measured. All subjects had normal glucose tolerance as assessed by conventional criteria.²³ Blood for coagulation analysis was collected in citrated tubes and immediately centrifuged at 2500g for 15 minutes at 4°C. Several aliquots of each plasma sample were then quick-frozen and stored at -70°C in plastic vials until determinations were performed. All stored sera were assayed by an experienced laboratory technician. All determinations were performed in duplicate. We took care to avoid cold-promoting activation and contact-surface activation of FVII and FVIII during both the preanalytical and analytical phases. Plasma fibrinogen was assayed by using a nephelometric method (IL-Test-PT-Fibrinogen HS; Instrumentation Laboratory).¹² Comparison of data obtained by using this automatic assay and the most common clotting method (Clauss) are well correlated (r=.96).²⁴ The functional activities of both PAI-1 and TPA were determined by using chromogenic substrate assays (Spectrolyse/PL and Spectrolyse/fibrin, Biopool). TPA activity was measured under basal conditions (without stasis) and after 10 minutes of venous occlusion. FVIIc and FVIIIc were assayed in a one-stage chronometric assay (Coagulation Analyzer, Behring), FVIIc by using human brain thromboplastin and FVII-deficient plasma (Instrumentation Laboratory), and FVIIIc by performing a modified activated partial thromboplastin time with FVIII-deficient plasma (Instrumentation Laboratory). Plasma levels of antigens for PAI-1, TPA, and FVII were measured in a subgroup of 36 subjects by using specific and sensitive commercial enzyme-linked immunosorbent assay kits from Biopool (Tint-Elize and Imulyse-5) and Diagnostica Stago. All FVII and FVIII determinations were expressed as a percentage of an internal reference human plasma pool. Intra-assay and interassay coefficients of variation were 6.9% and 7.0%, 7.0% and 8.5%, 7.4% and 9.6%, 6.2% and 7.5%, 7.0% and 8.9%, 7.2% and 8.9%, 7.5% and 9.2%, and 7.1% and 8.9% for fibrinogen, PAI-1 activity, TPA activity, FVII activity, FVIII activity, PAI-1 antigen, TPA antigen, and FVII antigen, respectively.

Statistical Analysis
Nonparametric statistical tests yielded very similar results to parametric tests, so the latter are presented. Student's t test for unpaired data was used to compare groups with different values of visceral AT area. The subjects were divided according to the median value (ie, 91 cm²) of the distribution of the visceral fat area. The adjustment for confounding variables (ie, BMI and plasma insulin) was performed by using ANCOVA. Pearson's product-moment correlation and multiple linear regression analysis were used to investigate the association between hemostatic factors and other variables in pooled subjects. Mann-Whitney U tests, Spearman rank correlation coefficients, and ² test (for categorical variables) were also performed. To improve the skewness and kurtosis of the distributions, daily alcohol intake, plasma TG levels, 2-hour insulin after glucose load, TPA activity (measured after venous occlusion), TPA antigen, FVII antigen, PAI-1 antigen, and CT-derived visceral fat area were logarithmically transformed for statistical analyses and then back-transformed to their natural units for presentation in the Tables. Distributions of all other variables were normal. Probability values less than .05 were considered significant. Data are presented as mean±SE.

	Results

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Tables 1 and 2 show the clinical and metabolic characteristics as well as the hemostatic parameters of the subjects. The men with more visceral fat area had significantly higher CT-derived parameters (including total abdominal and visceral fat areas), higher BMI, waist girth, and WHR, increased levels of plasma TGs, 2-hour glucose and 2-hour insulin after glucose load, higher systolic BP, and lower HDL-C/TC than the men with less visceral fat. No significant differences were found in daily alcohol intake, physical activity, or cigarette smoking.

View this table: [in this window] [in a new window]   Table 1. Clinical, Biochemical, and Behavioral Variables in 38-Year-Old Healthy Men According to Their Median Value of Abdominal Visceral Fat Area

View this table: [in this window] [in a new window]   Table 2. Plasma Hemostatic Factors in 52 Healthy Men According to Their Median Value of Visceral Fat Area

The men with a larger abdominal visceral fat area also had a more thrombogenic risk profile (Table 2). In fact, they showed higher plasma levels of fibrinogen, FVIIIc, TPA antigen, and PAI-1 activity and lower levels of TPA activity (measured before venous occlusion) than the men with less visceral fat. The plasma concentrations of PAI-1 antigen, FVII (both activity and antigen), and TPA activity (measured after venous occlusion) did not significantly differ between the groups, but there was a trend toward higher plasma levels of both PAI-1 antigen and FVII and lower TPA activity in men with more abdominal visceral AT.

After matching for BMI, most of the observed differences in plasma hemostatic factors remained substantially unchanged; only the levels of TPA activity, measured before venous occlusion, were no longer significant (not shown). However, after matching for 2-hour plasma insulin concentration, the men with more visceral fat still had significantly higher plasma PAI-1 activity, but no significant difference was found in any of the other plasma hemostatic factors (Fig 1).

View larger version (41K): [in this window] [in a new window]   Figure 1. Plasma levels of PAI-1 activity, PAI-1 antigen, TPA (t-PA) activity (measured before and after venous occlusion), TPA antigen, fibrinogen, and FVIIIc in 38-year-old healthy men with more (n=26; hatched bars) and less (n=26; open bars) abdominal visceral fat after adjusting for BMI and 2-hour plasma insulin concentration. Data are mean±SE. Plasma levels of PAI-1 antigen and TPA antigen were measured in 19 and 17 subjects for each group, respectively.

When our subjects were divided according to the median value of their subcutaneous fat area, plasma FVII activity (112±6.5% versus 94±5%, P<.05) and FVII antigen (129±7.5% versus 106±5%, P=.02) were significantly higher in men with larger subcutaneous fat areas. All other plasma hemostatic factors as well as plasma TG and insulin concentrations tended to parallel those obtained by stratifying for visceral fat, but they did not achieve significance (not shown).

Tables 3 and 4 show univariate correlations of plasma hemostatic factors with visceral fat as well as anthropometric and biochemical parameters and BP in pooled subjects. Generally, visceral fat area appeared to be more strongly correlated with plasma hemostatic parameters than did BMI and WHR. In line with the data reported in Table 2, when the subjects were pooled, abdominal visceral AT was inversely correlated with TPA activity (measured before venous occlusion) and positively with plasma levels of fibrinogen, FVIIIc, TPA antigen, PAI-1 antigen and, more significantly, with plasma PAI-1 activity. The scattergram of the univariate linear correlation between visceral fat and PAI-1 activity is shown in Fig 2. No significant association was found between visceral fat and plasma FVII activity and antigen. Among the other dependent variables, plasma TG and insulin (fasting and after the glucose load) concentrations were the most important associates of plasma hemostatic factors. Plasma TGs correlated positively with plasma levels of FVII activity and antigen, TPA antigen, PAI-1 antigen, and more significantly, with PAI-1 activity. Plasma insulin concentration (both fasting and after the glucose load) correlated positively with plasma FVIIIc, TPA antigen, PAI-1 antigen, and more significantly, with plasma fibrinogen and PAI-1 activity. TC and HDL-C concentrations and BP (except for a positive association with plasma PAI-1 activity) did not significantly correlate with any plasma hemostatic factor.

View this table: [in this window] [in a new window]   Table 3. Simple Correlation Coefficients of BMI, WHR, Visceral AT Area, and BP With Plasma Hemostatic Factors in 52 Healthy Men

View this table: [in this window] [in a new window]   Table 4. Simple Correlation Coefficients of Plasma Lipids and Plasma Insulin Concentrations (Fasting and After a Glucose Load) With Plasma Hemostatic Factors in 52 Healthy Men

View larger version (15K): [in this window] [in a new window]   Figure 2. Scattergram of the univariate linear relationship of abdominal visceral fat area as derived by CT scan and plasma PAI-1 activity in 52 adult healthy men. Abdominal visceral fat values are logarithmically transformed. Corresponding simple correlation coefficients are shown in Table 3.

As behavioral variables, daily alcohol intake and physical activity did not show any significant relationship with plasma hemostatic factors (not shown). On the contrary, when the subjects were divided according to their smoking habits, smokers (n=31) had significantly higher levels of plasma fibrinogen than men who never smoked (2.86±0.14 versus 2.26±0.10 g/L, P<.001); no significant differences were found in any other plasma hemostatic factors.

To more fully examine the relationships of plasma hemostatic factors to abdominal visceral fat after controlling for other potential confounders, multiple linear regression analyses were performed in pooled subjects. Independent variables in these analyses were visceral fat area and the variables that were significantly related to hemostatic factors in univariate correlation analysis that might have a potentially pathophysiological role in controlling the plasma levels of prothrombotic factors.

Table 5 shows the data from multiple linear regression analyses for plasma PAI-1 activity and fibrinogen levels. The levels of PAI-1 activity maintained a positive independent association with abdominal visceral AT area when allowance was made for BMI and plasma TG and 2-hour insulin levels. The only other variable that had a positive independent relationship with PAI-1 was plasma TG concentration. Furthermore, when BMI, abdominal visceral fat area, fasting plasma insulin concentration, and smoking were included as covariates in a multiple linear regression model to predict plasma fibrinogen, only cigarette smoking and plasma insulin concentration were independently associated with plasma fibrinogen. Neither BMI nor abdominal visceral fat made any significant contribution to the prediction of plasma fibrinogen after smoking and plasma insulin had been taken into account. These models accounted for 54% and 34% (R²=.538 and .341) of total variance in plasma levels of PAI-1 activity and fibrinogen, respectively. Multivariate linear regression analyses were also performed for the other plasma hemostatic factors. Abdominal visceral fat did not show any significant association with FVIIIc, PAI-1 antigen, or TPA activity and antigen after controlling for plasma insulin levels. Furthermore, in all these analyses neither plasma insulin nor plasma TG (except for a borderline significance with TPA antigen) concentrations were independent predictors of plasma FVIIIc, PAI-1 antigen, or TPA levels (data not shown).

View this table: [in this window] [in a new window]   Table 5. Standardized Regression Coefficients From Multiple Linear Regression Analysis of Plasma PAI-1 Activity and Fibrinogen Levels in Relation to Independent Variables in 52 Pooled Subjects

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
To our knowledge, this is the first time that abdominal visceral fat as determined by CT was found to be associated with several plasma hemostatic factors in healthy men. When our subjects, who had a wide range of fatness and fat distribution, were divided according to their visceral fat area, the men with a larger amount of abdominal visceral fat showed a more thrombogenic risk profile with higher plasma levels of fibrinogen, FVIIIc, TPA antigen, and PAI-1 activity and lower levels of TPA activity than the men with less visceral fat. The two groups were comparable for physical activity, alcohol consumption, and cigarette smoking. Plasma concentrations of PAI-1 antigen and FVII were nonsignificantly higher. The univariate correlation analyses in pooled subjects substantially confirmed these results. Generally, visceral fat area appeared to be more strongly correlated with plasma hemostatic factors than did BMI and WHR; it was negatively associated with TPA activity and positively with plasma TPA antigen, FVIIIc, fibrinogen, and PAI-1 antigen and activity. Moreover, this study suggests a predominant effect of visceral fat on plasma hemostatic factors compared with subcutaneous fat, which was marginally correlated with plasma FVII concentration and not at all with the other measured factors.

The positive correlation between TPA antigen and abdominal visceral fat could seem surprising at first glance. However, it should be noted that such a relation accords with the results of prospective studies that identify TPA antigen as a marker of increased cardiovascular risk.^{25 26} It is noteworthy that because of the role of PAI-1, a rapid inhibitor of TPA, TPA antigen level does not necessarily reflect TPA activity. Thus, our finding of inverse relationships between plasma TPA activity, visceral fat distribution, and other CHD risk factors is consistent with reports of decreased plasma TPA activity in patients at risk of developing myocardial infarction.^{27 28 29}

The men with larger visceral fat area significantly differed from their leaner counterparts on BMI and plasma insulin and TG concentrations, thus suggesting that the relation between visceral fat and prothrombotic factors could be at least partly dependent on one or more of these potentially confounding variables. In fact, while the differences in plasma hemostatic factors were substantially unchanged after adjustment for BMI, they totally disappeared when further allowance was made for 2-hour insulin concentration, with the exception of plasma PAI-1 activity, which retained a significant difference.

Overall, therefore, these data indicate that increased abdominal visceral fat is specifically associated with elevated levels of several plasma hemostatic factors and suggest that such a relation is largely mediated by concomitant alterations in plasma insulin concentration. This conclusion accords with studies that clearly support the possibility of an involvement of the plasma hemostatic system in the insulin resistance syndrome.^{8 9 12 13 14 30 31 32} In this context, it should be noted that the results obtained by multivariate regression analyses showed an independent association of plasma insulin (along with smoking) with plasma fibrinogen as well as a lack of any significant association of abdominal visceral fat with fibrinogen, FVIIIc, and TPA levels after controlling for plasma insulin. All these findings, therefore, highlight the role of plasma insulin in the relation between visceral fat and the plasma hemostatic system.

Importantly, in our study plasma PAI-1 activity retained a significant difference even after controlling for BMI and plasma insulin concentration. These results were confirmed by multivariate regression analysis, in which PAI-1 activity maintained a strong positive association with abdominal visceral fat even when allowance was made for all potential confounders. Lifestyle characteristics, such as smoking, physical activity, and alcohol intake, did not seem to confound these results, since no relationships were found between these factors and PAI-1 levels. Plasma TG level was the only other variable that had a positive independent relationship with PAI-1. This latter finding is supported by several epidemiological^{2 9 11 17 30 33 34} and in vitro^{35 36} studies that demonstrate that plasma TGs are an important and strong predictor of PAI-1. The lack of an independent association between plasma insulin and PAI-1 levels observed in this study is in partial disagreement with some studies^{9 30} but consistent with others.^{29 34} It should be noted that CT measurements of the amount of visceral fat were not performed in any of the previous studies and that the lack of an independent relationship does not exclude a priori a role of plasma insulin in controlling PAI-1 levels. Insulin may act either directly or indirectly via lipoprotein changes in the cells that synthesize PAI-1.^{2 9 30} Taken together, therefore, these data suggest that the relation between abdominal visceral AT and plasma PAI-1 activity is only partly explained by plasma insulin and TG concentrations and that abdominal visceral fat per se (or some unmeasured factors closely related to visceral fat, ie, nonesterified fatty acids, glucocorticoids, or sex hormones) plays an important role.

In conclusion, these results indicate that men with a larger visceral fat area have increased plasma hemostatic factors and suggest the possibility that such a relation is, in large part, mediated by one or more of the metabolic disorders closely related to visceral obesity, particularly plasma insulin concentration. In addition, our results highlight the role of the abdominal accumulation of visceral fat as an independent predictor of plasma PAI-1 activity.

	Selected Abbreviations and Acronyms

 

AT = adipose tissue BMI = body mass index BP = blood pressure CHD = coronary heart disease CT = computed tomography FVII = factor VII FVIII = factor VIII FVIIc = factor VII clotting activity FVIIIc = factor VIII clotting activity HDL-C = HDL cholesterol PAI-1 = plasminogen activator inhibitor–1 TC = total cholesterol TG = triglyceride TPA = tissue-type plasminogen activator WHR = waist-to-hip ratio

Received September 21, 1995; accepted November 20, 1995.

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