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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Objective: Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) were associated with vascular function.

Design and Methods

TAT and VAT were quantified in Framingham Heart Study participants using multidetector-computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone, and arterial tonometry (n = 2,735; 48% women; mean age, 50 years; mean body mass index [BMI], 27.7 kg/m2). Using multiple linear regression, the relationships between TAT, VAT, and vascular measures was examined while adjusting for cardiovascular risk factors.

Results

Mean TAT and VAT volumes were 13.2 and 1763 cm3. TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (P < 0.02); TAT was negatively associated with hyperemic mean flow velocity (P = 0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all P > 0.06).

Conclusions

Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Abnormal vascular function may be a biologic intermediary between obesity, cardiovascular disease risk factors, and clinical vascular disease [1]. Prior studies have demonstrated an association between obesity and measures of vascular function [2], but mechanisms by which increasing adiposity might contribute to vascular dysfunction are incompletely understood. Adipose tissue inflammation is believed to be important to any link between obesity and vascular function [7]. One theory is that inflammation in perivascular fat, which surrounds blood vessels, may have a local toxic effect on the vasculature [10, 11]. Possible mechanisms include perivascular adipose tissue-mediated recruitment of inflammatory cells to the arterial wall, diffusion of adipokines/cytokines into the arterial wall, or release of adipokines/cytokines into the vasa vasorum [10]. These inflammatory adipokines and reactive oxygen species are known determinants of vascular function [11, 12, 14, 15]. Alternatively, central fat deposition may be more important than local perivascular fat in obesity-mediated vascular disease. Visceral adipose tissue (VAT), a large systemic fat depot, expresses inflammatory adipokines and has a volume nearly 100 times greater than thoracic periaortic adipose tissue (TAT). VAT has previously been shown to be associated with certain measures of vascular functions [16], cardiometabolic risk factors [17, 18], and clinical cardiovascular diseases [18].

Thoracic periaortic fat (TAT) is a type of perivascular fat that can be reproducibly measured using multidetector-computed tomography (MDCT) and may serve as a marker of perivascular fat throughout the vascular tree. In this study, we sought to determine whether TAT was associated with the measures of vascular function after adjustment for BMI (a measure of generalized adiposity) and whether TAT remained associated with vascular function measures after adjustment for VAT (a measure of central obesity). In addition, building upon prior work examining the association between VAT and brachial artery measures [16], we sought to determine whether VAT was associated with measures of microvascular function and arterial stiffness. We hypothesized that both fat depots would be associated with multiple measures of vascular function. We further hypothesized that given TAT's location adjacent to the aorta, associations with vascular function, particularly aortic stiffness, would persist after adjustment for VAT.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Study sample

Participants from this study were drawn from the Framingham Heart Study Offspring and Third-Generation cohorts who underwent MDCT assessment of adipose tissue depots as well as assessment of vascular function. The study designs have been previously described [5, 21]. Briefly, participants underwent MDCT of the thorax and abdomen using an eight-slice scanner. Fat volumes were measured by a semi-automatic technique requiring manual definition of tissue borders and identification of adipose tissue by its characteristic Hounsfield units. Vascular function measures included brachial artery flow-mediated dilation (FMD), brachial artery hyperemic mean flow velocity, peripheral arterial tone ratio, and arterial tonometry measures (carotid femoral pulse wave velocity, forward wave amplitude, and augmentation index). Full details of the MDCT assessment of adipose tissue volumes and the noninvasive vascular hemodynamic protocols and analyses have been previously published and are summarized in the Supporting Information material. As reported previously, reproducibility has been high with both adipose tissue and vascular function measures [5, 24].

Between June 2002 and April 2005, 3,529 participants (2,111 Third Generation, 1,418 Offspring) underwent MDCT assessment of adipose tissue depots. Brachial artery ultrasound studies were performed at the seventh examination (1998-2001) in the Offspring participants and the first examination (2002-2005) of the Third-Generation participants. Peripheral arterial tone and arterial tonometry measurements were performed at the eighth examination (2005-2008) in Offspring participants and the first examination (2002-2005) of Third-Generation participants.

For the brachial artery vasodilatory analyses, out of the 3,529 participants who underwent MDCT, 269 did not have brachial measures available, 64 were missing covariates, 348 had missing information on adipose tissue measures, 28 had unusable brachial FMD data, and 293 had unusable or unavailable brachial flow velocity data, resulting in a sample size of 2,735 for FMD analyses and 2,470 for brachial flow velocity analyses. For the peripheral arterial tone and tonometry analyses, out of the 3,529 participants who underwent MDCT, 79 were missing covariate data, 367 had missing information on either adipose tissue measure, 1,336 did not have peripheral arterial tone performed, and 299 did not have tonometry performed, resulting in a sample size of 1,679 for peripheral arterial tone analyses and 2,716 for tonometry analyses.

The study protocol was approved by the Institutional Review Boards of Boston University Medical Center and Massachusetts General Hospital. All participants provided written informed consent.

Covariate assessment

For each analysis, covariates were used from the same examination at which the vascular function test was performed. BMI was defined as weight (in kilograms) divided by the square of the height (in meters). Current smoking was defined as smoking at least one cigarette per day in the past year. Alcohol use was dichotomized on the basis of consumption of >14 drinks per week (in men) or 7 drinks per week (in women). Serum triglycerides, total and high-density lipoprotein cholesterol, and fasting plasma glucose were measured on fasting morning samples. Fasting plasma glucose ≥126 mg/dL or treatment with a hypoglycemic agent or insulin was used to define diabetes mellitus. If periods had stopped for >1 year, women were considered postmenopausal. Hypertension was defined as a systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or treatment with an antihypertensive agent. Cardiovascular disease included coronary heart disease, stroke, intermittent claudication and heart failure [29]. Participants in the Offspring Study without contraindication underwent a 6-min walk test at the seventh examination.

Statistical analysis

The primary “exposures” of interest were TAT and VAT. The primary dependent variables of interest for TAT were FMD, hyperemic mean flow velocity, peripheral arterial tone ratio, carotid femoral pulse wave velocity (CFPWV), forward wave amplitude, and mean arterial pressure. As the peripheral arterial tone ratio had a heteroscedastic error structure, we used a natural logarithmic transformation. As CFPWV had a heteroscedastic error structure, it was transformed to 1,000/CFPWV. As the association between VAT and brachial artery measures in the Framingham Heart Study has been previously published [16], for the VAT analysis, the primary dependent variables of interest were peripheral arterial tone ratio, CFPWV, forward wave amplitude, and mean arterial pressure. We examined the association between both fat depots and baseline vascular function measures to allow appropriate interpretation of our main findings.

Partial Pearson correlations (adjusted for age, sex, and cohort) were examined to assess the relationships between clinical and MDCT adiposity measures and vascular function measures. Multivariable linear regression was performed to assess the significance of covariate-adjusted relationships between MDCT adiposity measures and vascular function measures. All adipose tissue measurements were standardized within sex to a mean of 0 and a standard deviation of 1; estimated regression coefficients are presented per one standard deviation increment.

The multivariable model included age, sex, cohort, smoking (never/former/current), moderate to heavy alcohol use (>14 drinks/week [men], >7 drinks/week [women]), mean arterial pressure (except when the dependent variable was mean arterial pressure), heart rate, walk test (no, before, or after brachial artery vasodilatory function measures to account for any influence of the walk test on brachial artery measures), total/high-density lipoprotein (HDL) cholesterol, log triglycerides, fasting glucose level, menopause status, use of hormone replacement therapy, diabetes, hypertension treatment, lipid treatment, and prevalent cardiovascular disease. In secondary analyses, we aimed to disentangle the relative associations of TAT versus VAT with vascular function, given the known correlation between the two fat depots. As both fat depots were associated with the measures of microvascular function and arterial stiffness after adjustment for BMI, we compared mean peripheral arterial tone ratio values and mean 1,000/CFPWV values within sex-specific VAT and TAT tertiles. In addition, we examined the association of both fat depots with augmentation index, a measure of wave reflection. We adjusted for c-reactive protein in any multivariable models that included BMI and demonstrated significant associations between either TAT or VAT and vascular function measures to assess whether adjustment for inflammation affected the association between fat depots and vascular function. We tested for interactions of sex by fat depots and age by fat depots in multivariable models. We performed a sensitivity analysis limited to the Third-Generation cohort in whom MDCT and vascular function measures were performed at the same study visit.

All analyses were performed with SAS version 9.2 for Windows. P-values of <0.05 were considered statistically significant for the main analysis. A P-value of <0.001 (0.05/36 tests for interaction) was considered statistically significant in the analyses of potential interactions. The authors had full access to and take full responsibility for the integrity of the data.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Participant characteristics

Participant characteristics and mean values for vascular function measures are summarized in Table 1. Age-, sex-, and cohort-adjusted volumes of VAT and TAT were correlated (r = 0.75, P < 0.0001). Both fat depots were correlated with BMI (r = 0.56, P < 0.0001 and r = 0.72, P < 0.0001, respectively). All vascular function measures were significantly correlated with all adiposity measures, except for the correlation of hyperemic mean flow velocity with waist circumference and BMI (Table 2).

Table 1. Participant characteristics–data are means ± SD or %a
Clinical characteristics 
  1. a

    Clinical characteristics were assessed for the Offspring participants at exam 7. Adiposity measures were assessed for the Offspring participants between exams 7 and 8. Peripheral arterial tone and arterial tonometry variables were assessed for the Offspring participants at exam 8. Third-Generation participants had clinical characteristics and all vascular function measurements assessed at exam 1.

  2. b

    Defined as >14 drinks weekly for men and >7 drinks weekly for women.

  3. c

    Peripheral arterial tone measures are natural logarithm transformed.

N2,763
Age (years)50 ± 10
Women, N (%)1,337 (48)
Offspring, N (%)988 (36)
Smoking, N (%) 
Never1,364 (49)
Former1,041 (38)
Current358 (13)
Moderate/heavy alcohol useb, N (%)422 (15)
Heart rate (beats/min)63 ± 10
Total/HDL cholesterol4.0 ± 1.4
Triglycerides (mg/dl)127 ± 90
Fasting glucose (mmol/l) (mg/dl)5.5 ± 1.2 (99 ± 21)
Postmenopausal, N (%)644 (48)
Hormone replacement therapy, N (%)285 (21)
Diabetes, N (%)168 (6)
Hypertension treatment, N (%)481 (17)
Lipid treatment, N (%)358 (13)
Prevalent cardiovascular disease, N (%)117 (4)
Adiposity measures 
BMI (kg/m2)27.7 ± 5.2
Waist circumference (cm)97 ± 14
Subcutaneous adipose tissue (SAT) (cm3)2,868 ± 1,387
VAT (cm3)1,763 ± 1,004
TAT (cm3)13.2 ± 7.7
Vascular measures 
Baseline brachial artery diameter (mm)4.2 ± 0.8
Baseline mean flow velocity (cm/s)7.6 ± 4.4
Baseline pulse amplitude5.7 ± 0.9
Augmentation index (%)11.8 ± 12.3
Flow mediated dilation (%)4.4 ± 3.5
Hyperemic mean flow velocity (cm/s)57.7 ± 19.7
Peripheral arterial tone ratioc (unitless)0.71 ± 0.41
Carotid-femoral pulse wave velocity (m/s)8.4 ± 2.7
1,000/Carotid-femoral pulse wave velocity (ms/mm)127 ± 30
Forward-wave amplitude (mmHg)49.0 ± 14.2
Mean arterial pressure (mmHg)94 ± 11
Table 2. Partial Pearson correlation coefficients between adiposity measures and vascular function measures adjusted for cohort, sex, and age
  Thoracic periaortic fat Visceral adipose tissue BMI Waist circumference 
 NrP-valuerP-valuerP-valuerP-value
  1. a

    The correlation between VAT and FMD and hyperemic mean flow velocity in the Framingham Heart Study has been published previously [16]. In some cases, r-values differ slightly from those reported by Parikh et al. owing to small differences in the sample size.

  2. b

    CFPWV, carotid femoral pulse wave velocity.

FMD (%)2,735−0.070.0005−0.08a<0.0001−0.10<0.0001−0.10<0.0001
Hyperemic mean flow velocity (cm/s)2,470−0.040.04−0.04a0.03−0.030.10−0.030.19
Peripheral arterial tone ratio1,679−0.22<0.0001−0.27<0.0001−0.25<0.0001−0.23<0.0001
1,000/CFPWVb (ms/mm)2,716−0.21<0.0001−0.29<0.0001−0.22<0.0001−0.24<0.0001
Forward wave amplitude (mmHg)2,7160.070.00070.070.00020.060.00090.060.0009
Mean arterial pressure (mmHg)2,7160.17<0.00010.23<0.00010.24<0.00010.24<0.0001

Thoracic periaortic fat and vascular function measures

TAT was associated with each of the primary measures of vascular function in minimally adjusted models. There was a negative association between TAT and brachial artery vasodilatory measures, peripheral arterial tone ratio, and 1,000/CFPWV and a positive association between TAT and forward wave amplitude and mean arterial pressure (Table 3). These associations remained significant in multivariable models (all P < 0.03) with the exception of the association between TAT and forward wave amplitude (P = 0.66). After additional adjustment for BMI, TAT remained negatively associated with hyperemic mean flow velocity (P = 0.03), peripheral arterial tone ratio (P = 0.02), and 1,000/CFPWV (P = 0.0009). However, after additional adjustment for VAT, TAT was no longer associated with any measure of vascular function (all P > 0.06).

Table 3. Multivariable-adjusteda regression for thoracic periaortic fat with vascular function measures
  Model 1: MV* adjusted Model 2: MV* + BMI adjusted Model 3: MV* + VAT adjusted 
 NRegression coefficient (95% C.I.)P-valueRegression coefficient (95% C.I.)P-valueRegression coefficient (95% C.I.)P-value
  1. Data presented as β-coefficients per one standard deviation increase of thoracic periaortic fat.

  2. BMI, body mass index; VAT, visceral adipose tissue.

  3. a

    Multivariable models adjusted for age, sex, cohort, smoking, alcohol intake, mean arterial pressure (not included in models with mean arterial pressure as dependent variable), heart rate, walk test (no, before, after), total/HDL cholesterol, log triglycerides, fasting glucose level, menopause, hormone replacement therapy, diabetes, hypertension treatment, lipid treatment, and prevalent cardiovascular disease.

  4. b

    CFPWV, carotid femoral pulse wave velocity.

FMD (%)2,735−0.26 (−0.42, −0.10)0.002−0.14 (−0.33, 0.04)0.13−0.15 (−0.37, 0.07)0.19
Hyperemic mean flow velocity (cm/s)2,470−1.03 (−1.94, −0.11)0.03−1.20 (−2.26, −0.15)0.03−1.00 (−2.27, 0.28)0.13
Peripheral arterial tone ratio1,679−0.06 (−0.09, −0.04)<0.0001−0.03 (−0.06, 0.00)0.02−0.01 (−0.04, 0.02)0.46
1,000/CFPWVb (ms/mm)2,716−1.85 (−2.70, −0.99)<0.0001−1.69 (−2.69, −0.69)0.00090.32 (−0.87, 1.51)0.60
Forward wave amplitude (mmHg)2,716−0.11 (−0.62, 0.40)0.660.52 (−0.08, 1.11)0.090.69 (−0.02, 1.40)0.06
Mean arterial pressure (mmHg)2,7161.06 (0.59, 1.53)<0.00010.10 (−0.45, 0.65)0.72−0.12 (−0.78, 0.53)0.71

The association of TAT with baseline brachial artery diameter, baseline mean flow velocity, and baseline peripheral arterial tone is summarized in Supporting Information Table 1. TAT was associated with baseline measures in multivariable models, but not after adjustment for either BMI or VAT.

Visceral adipose tissue and vascular function measures

In minimally adjusted models, VAT was negatively associated with peripheral arterial tone ratio and 1,000/CFPWV and positively associated with forward wave amplitude and MAP. The significant associations between VAT, peripheral arterial tone ratio, and 1,000/CFPWV persisted in multivariable models are summarized in Table 4. After additional adjustment for BMI, associations were no longer significant except for peripheral arterial tone ratio (P = 0.0007), and 1,000/CFPWV (P < 0.0001). In multivariable models containing both fat depots, the associations of VAT with peripheral arterial tone and tonometry measures (1,000/CFPWV, forward wave amplitude and mean arterial pressure) were significant, whereas the associations of TAT with these parameters were no longer significant. For these measures, there was no attenuation of the regression coefficients for VAT after adjustment of multivariable models for TAT. Variance inflation factor was <3.2 for each of these associations, suggesting the lack of severe multicollinearity. The association of VAT with baseline peripheral arterial tone amplitude is summarized in Supporting Information Table 1. VAT was positively associated with baseline peripheral arterial tone in multivariable models that included BMI.

Table 4. Multivariable-adjusteda regression for VAT with vascular function measures. Data presented as β-coefficients per one standard deviation increase of VATb
  Model 1: MV* adjusted Model 2: MV* + BMI adjusted 
 nRegression coefficient (95% C.I.)P-valueRegression coefficient (95% C.I.)P-value
  1. Multivariable models adjusted for age, sex, cohort, smoking, alcohol intake, mean arterial pressure (not included in models with mean arterial pressure as dependent variable), heart rate, walk test (no, before, after), total/HDL cholesterol, log triglycerides, fasting glucose level, menopause, hormone replacement therapy, diabetes, hypertension treatment, lipid treatment, and prevalent cardiovascular disease.

  2. a

    The association of VAT and FMD and hyperemic mean flow velocity in the Framingham Heart Study has been published previously [16].

  3. b

    CFPWV, carotid femoral pulse wave velocity.

Peripheral arterial tone ratio1,679−0.08 (−0.11, −0.06)<0.0001−0.05 (−0.08, −0.02)0.0007
1,000/CFPWVb (ms/mm)2,716−2.93 (−3.79, −2.07)<0.0001−3.83 (−4.98, −2.68)<0.0001
Forward wave amplitude (mmHg)2,716−0.67 (−1.18, −0.16)0.01−0.05 (−0.74, 0.64)0.88
Mean arterial pressure (mmHg)2,7161.64 (1.17, 2.11)<0.00010.63 (0.00, 1.26)0.05

Secondary analyses

Association of TAT and VAT with augmentation index

TAT was positively associated with augmentation index in multivariable models and this association remained significant after adjustment for either BMI or VAT (all P < 0.05, Supporting Information Table 1). There was no association between VAT and augmentation index in either multivariable-adjusted or multivariable and BMI-adjusted models (allP > 0.05, Supporting Information Table 1).

Mean values of peripheral arterial tone ratio and 1,000/CFPWV on the basis of tertiles of TAT within tertiles of VAT

To further investigate the association between higher TAT relative to VAT with vascular function measures, we compared mean peripheral arterial tone ratio values and mean 1,000/CFPWV values stratified by sex-specific VAT and TAT tertiles (Figure 1). Mean peripheral arterial tone ratio values were lower across TAT tertiles within VAT tertiles 1 and 3 (P < 0.05). For 1,000/CFPWV, levels across TAT tertiles were also lower in VAT tertiles 1 and 3.

image

Figure 1. Sex- and age-specific tertiles of VAT by tertiles of TAT for mean peripheral arterial tone ratio and mean 1,000/carotid femoral pulse wave velocity. Age-adjusted P-value for linear trend is shown. Error bars reflect standard errors. Peripheral arterial tone ratio is natural log transformed.

Download figure to PowerPoint

Additional adjustment of models for C-reactive protein

We performed exploratory analyses to examine the effect of additional adjustment for C-reactive protein (CRP) levels in multivariable models of both TAT and VAT with vascular function measures that had retained significance after BMI adjustment. We found that the negative association between VAT and peripheral arterial tone ratio was no longer significant after CRP adjustment (regression estimate 0.03, P = 0.10), whereas the negative association of VAT and 1,000/CFPWV remained significant (regression estimate: −3.58, P = 0.0002). TAT remained significantly negatively associated with hyperemic mean flow velocity (regression estimate: −1.14, P = 0.02), pulse arterial tone ratio (regression estimate: −0.03, P = 0.03), and 1,000/CFPWV (regression estimate: −1.54, P = 0.003) after adjustment for CRP.

Age and sex interactions

In multivariable models, there was no evidence of effect modification by sex in the associations of either fat depot with vascular function measures. Evidence of effect modification by age was found in the negative associations of both fat depots with peripheral arterial tone ratio and forward wave amplitude in multivariable models; the negative association between TAT and forward wave amplitude was stronger in older participants, whereas the negative association between VAT and forward wave amplitude was stronger in younger individuals. In contrast, the positive associations of both fat depots with mean arterial pressure were consistently stronger in younger individuals (data not shown).

Analyses limited to the Third-Generation cohort

In analyses of the association of TAT with vascular function measures limited to the Third-Generation cohort (in whom MDCT scans and vascular function measures were performed at the same study visit), the results were generally similar (Supporting Information Table 2). TAT was associated with most vascular measures in multivariable models, with some residual association after adjustment for BMI, and full attenuation of the associations upon VAT adjustment. The results for the association of VAT and vascular function, limited to the Third Generation, were also generally similar. It is worth noting that the estimated β-coefficient of the association of VAT and mean arterial pressure was higher in the Third-Generation cohort. This may reflect the previously documented age interaction (P, interaction <0.0001) in which results for the association of VAT and mean arterial pressure were stronger in younger as opposed to older individuals.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

In our community-based sample, TAT, a local perivascular fat depot, and VAT, a measure of central adiposity, were associated with multiple measures of vascular function that are believed to reflect distinct biologic pathways that may contribute to the development of cardiovascular disease. TAT, which may serve as a marker of perivascular fat throughout the vasculature, was negatively associated with hyperemic mean flow velocity and peripheral arterial tone response (measures of microvascular function) as well as 1,000/CFPWV (a measure of aortic stiffness with a lower value of 1,000/CFPWV corresponding to a stiffer aorta). In addition, VAT was negatively associated with peripheral arterial tone and inverse CFPWV. These findings suggest an association of both of these fat depots with microvascular function and aortic stiffness beyond that of generalized adiposity.

Our findings are largely consistent with the small number of previous studies that have examined either perivascular or visceral adiposity and measures of vascular function. Perivascular fat surrounding the brachial artery has been previously found to be associated with hyperemic mean flow volume, but not FMD [30]. Hyperemic mean flow volume is closely related to our measure of hyperemic mean flow velocity. In contrast to our findings with TAT, the association of peribrachial adipose tissue and hyperemic mean flow volume persisted after adjustment for VAT. We extend these findings by examining TAT, a different subtype of perivascular fat and also examining the association with the measures of pulse arterial tone and arterial stiffness. Similarly, prior studies, including those from the Framingham Heart Study as well as the Health ABC study, found associations between VAT and both brachial artery FMD and CFPWV. We now additionally describe the association of VAT and both pulse arterial tone and various measures of arterial stiffness.

Contrary to our hypothesis, we did not observe an association between TAT and vascular function measures after accounting for VAT. These findings have multiple potential explanations. First, TAT and VAT are highly correlated; although statistical testing was not consistent with severe multicollinearity, we cannot rule out the possibility that conjoint statistical adjustment may still attenuate true associations. In an attempt to disentangle the specific associations of TAT versus VAT with measures of vascular function, we examined the association of TAT with 1,000/CFPWV and peripheral arterial tone within VAT tertiles, and observed a trend of lower pulse arterial tone ratio (more adverse microvascular function) and lower 1,000/CFPWV (higher stiffness) across tertiles of TAT. These findings are of particular interest, given TAT directly surrounds the thoracic aorta and CFPWV is a measure of aortic stiffness.

A second explanation for the lack of association of TAT and measures of vascular function after adjustment for VAT is that our measure of TAT captures only fat in the descending aorta; it is possible that the lack of inclusion of periaortic fat surrounding the ascending aorta may have precluded identification of an association of TAT and vascular function after adjustment for VAT. Third, the aorta is an elastic artery that does not directly supply metabolically active tissues [31]. Although TAT may serve as a marker of the total volume of perivascular fat elsewhere in the body, it is possible that associations of TAT with vascular function do not reflect associations of smaller perivascular fat depots with vascular function. Smaller muscular arteries and arterioles undergo greater dynamic modulation, and are likely most important in regulating blood flow [31]. In contrast to TAT, VAT encases small muscular arteries and arterioles of the mesentery, and may actually itself serve as a marker of perivascular fat. Therefore, taken together, our findings do not rule out the existence of a local effect of perivascular fat.

The evidence for a role of perivascular fat in vascular regulation stems largely from basic science and small clinical studies [11, 12, 32, 33]. In both mice and humans, obesity leads to perivascular fat inflammation and changes in adipokine secretion, both of which have been associated with vascular dysfunction [12, 32, 33]. In addition, perivascular fat in lean individuals appears to convey anticontractile properties on the vasculature that are lost with the development of obesity [11, 34]. Consistent with a potential local influence of periaortic fat on the vasculature, inflammation in abdominal periaortic fat has been shown to be associated with angiotensin II-induced aortic aneurysm formation in obese mice [35], and TAT was associated with clinical lower extremity peripheral artery disease in humans despite adjustment for VAT [36].

Strengths and limitations

Strengths of our study include the large community-based nature of the cohort and sophisticated assessment of fat depots and vascular function measures. In addition, detailed assessment of covariates strengthened our multivariable analysis. Certain limitations warrant discussion. The cross-sectional design of the analysis prevents inferences of causality or temporality. The Framingham Heart Study is predominantly white and the results may not be generalizable to other ethnic/racial groups. There were temporal differences between the CT scans and the vascular measures. However, our sensitivity analysis limited to the Third-Generation cohort (in which MDCT scans and vascular function measures occurred during the same study visit) demonstrated overall similar findings. In addition, our primary aim was to assess whether there were differential associations between VAT as compared to TAT with vascular function. Importantly, VAT and TAT were measured at the same time, reducing the risk of affecting our ability to examine the relative association of each with vascular function. Nitroglycerin was not administered to this community-based cohort, preventing us from having a measure of nonendothelium-dependent brachial artery vasodilation. Our measure of periaortic fat is limited to the descending thoracic aorta. Forward wave amplitude and mean arterial pressure rely on the properties of the ascending aorta, and this limitation may explain the lack of association of TAT and these measures. We were not able to measure abdominal periaortic fat, and this prevents us from speculating whether differences in the association between TAT and VAT with vascular function measures were related to different anatomical locations (chest versus abdomen) versus the different structures they surround (aorta versus viscera). Finally, adjustment of multivariable models for CRP does not exclude inflammation as a potential mediator of the association of ectopic fat and vascular function as circulating levels of CRP do not necessarily reflect local inflammatory mediators.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Thoracic periaortic fat and VAT are associated with microvascular function and aortic stiffness after adjustment for BMI, suggesting a role for both local ectopic and central fat depots in vascular dysfunction beyond that of generalized adiposity. Associations of TAT and vascular function measures did not persist after adjustment for VAT, but this does not exclude a role for perivascular fat in vascular function. Our results overall support the growing recognition of a potentially adverse association of perivascular fat and vascular function.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Disclosures: Dr. Mitchell is owner of Cardiovascular Engineering Inc., a company that designs and manufactures devices that measure vascular stiffness. The company uses these devices in clinical trials that evaluate the effects of diseases and interventions on vascular stiffness. The remaining authors declared no conflicts of interest.

References

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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oby20166-sup-0002-SuppInfo.doc65KSupporting Information Table

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