Vascular endothelial dysfunction (VED) plays a pivotal role in the pathogenesis of atherosclerosis and is associated with insulin resistance and visceral obesity. We examined the predicting factors of VED in uncomplicated premenopausal obese women using analysis of endothelium-dependent vasodilation by radial artery pulse wave obtained through applanation tonometry.
The subjects included a group of 33 obese women body mass index ((BMI)≥25) and another age-matched control group of 25 nonobese women (BMI: 18.5–22.9) of Asian origin. All uncomplicated premenopausal (20–45 y) obese women were sedentary (<1 h/week of physical activity). Anthropometric measurements were performed, and regional distributions of adipose tissue and metabolic variables were measured. Endothelial function was measured by pulse wave analysis after salbutamol administration, which reflects endothelium-mediated vasodilation, contributed partially by nitric oxide release from β2-adrenergic stimulation. Radial artery wave forms were recorded and from a derived aortic wave forms augmentation index (AIx, defined as the pressure difference between the first and second peaks of the central arterial wave form, expressed as a percentage of the pulse pressure) was calculated. The subjects received sublingual nitroglycerine (NTG) (0.6 mg), followed by nebulized salbutamol (2.5 mg).
AIx fell significantly after the administration of salbutamol, which causes endothelium-dependent vasodilatation. This value was significantly reduced in obese women compared with the controls (10.3±6.7 vs 17.2±6.8%, P=0.0003). NTG, which causes endothelium-independent vasodilatation, did not produce significant changes (P=0.917). As for our obese subjects, the visceral adipose tissue area was a significant predictor of VED independent of BMI, percent body fat, and other metabolic variables including high-sensitivity C-reactive protein (ß=−0.141, P=0.002, Adj-R2=0.41).
Increased abdominal adiposity is a powerful independent predictor of VED in uncomplicated obese women. Further studies are warranted to determine the pathophysiological link between visceral adipose tissue and VED.
Obesity has emerged as an independent risk factor of cardiovascular disease in both men and women.1,2 Body fat distribution has been described as the stronger predictor of cardiovascular complications of obesity in the majority of previous studies.2,3,4
Vascular endothelial dysfunction (VED) has been hypothesized to play an important role in the pathogenesis of atherosclerosis. The presence of endothelial dysfunction leads to the formation of coronary artery plaques through inflammatory responses5,6 and enhances the risk of future cardiovascular events.6
Previous studies have shown that VED is related to insulin resistance7,8 and abdominal obesity, that is, excess visceral adipose tissue,9,10 which suggest that VED may be an important link between obesity per se and heightened cardiovascular risk. Accordingly, the study of this association is of great importance because it may provide a new insight for prevention and early diagnostic strategies.
A simple and noninvasive method to evaluate the endothelial function was recently introduced. The pulse wave analysis method measures vascular endothelial function, employing the principle that the β2-agonist induces vasodilation through the L-argine–NO pathway.11,12,13,14,15 Previous studies used invasive methods of intra-arterial infusion of acetylcholine11,16 or the flow-mediated dilatation method,9,10,11,16,17 which measured the changes in the diameter of the brachial artery through reactive hyperemia using 2-D images.
The purpose of this study was to evaluate the association between VED and obesity in uncomplicated premenopausal women. Individuals with conventional cardiovascular risk factors, substantially associated with obesity, were excluded to minimize the confounding effects. VED was measured using the pulse wave analysis method.
The subjects were premenopausal women between the age of 20 and 45 y. The obese subjects with body mass index (BMI) ≥25 kg/m2 were selected among individuals visiting the university hospital obesity clinic. This classification of obesity in Asians adults was adapted from the guideline, ‘The Asia-Pacific Perspective: Redefining Obesity and its Treatment—a joint enterprise of the Regional Office for the Western Pacific of the World Health Organization, the International Association for the Study of Obesity and the International Obesity Task Force’. Among the obese women, those with any significant comorbidities were excluded through a self-report questionnaire, clinical examinations, and blood tests, that is, hypertension, dyslipidemia (low-density lipoprotein (LDL)-cholesterol ≥160 mg/dl, high-density lipoprotein (HDL)-cholesterol <40 mg/dl, or triglyceride ≥200 mg/dl), type II diabetes, coronary heart disease, stroke, thyroid disease, or depression. Also excluded were current smokers and those with experiences of any commercial diet program or antiobesity medications for the past 3 months. In all, 33 obese subjects were finally included for this study. Age-matched 25 premenopausal volunteers with BMI between 18.5 and 22.9 kg/m2 were recruited as a control group. All subjects completed informed consent, and the study protocol was approved by the Institutional Review Board at Ewha Womans University Mokdong Hospital.
All examinations were completed during the follicular phase within 10 days after menstruation:
(1) Anthropometric measurements and blood pressure: Body weight was measured with light clothing on up to 0.1 kg. Height was measured up to 0.1 cm. Waist circumference was measured at the midpoint between upper iliac and lower costal level up to 0.1 cm at the end of normal expiration. Hip circumference was measured around the largest part of the hip.
Blood pressure was measured with the subjects sitting comfortably using a sphygmomanometer (Yamasu, Japan). Individuals with systolic pressure ≥140 mmHg or diastolic pressure ≥90 mmHg were excluded.
(2) Body fat measurements: Percent body fat (%) was measured in fasting state using the bioelectrical impedance analysis (Inbody 2.0, Biospace., Korea).
Body fat distribution was determined by computed tomography (GE High speed Advantage CT scanner; GE, USA). Abdominal subcutaneous adipose tissue and visceral adipose tissue were evaluated by single-slice scan at the L4–5 level. The attenuation interval was −40 to −140 Hounsfield units. A cursor was used to define the total cross-sectional areas and the area of visceral fat (area inside the rectus abdominis muscle). Data were elaborated using a histogram-based statistical program.
(3) Blood tests: Plasma glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, and nonesterified fatty acid (NEFA) concentrations were measured after overnight fasting for more than 12 h. Plasma insulin was measured using radioimmunoassay. The estradiol level was measured using a microparticle enzyme imunoassay (Axisym, abbott, USA). The level of high-sensitivity C-reactive protein (CRP) was measured with nephelometry using BNII (Dade Behring, Germany), which has the minimum detection concentration of 0.175 mg/l. The Homeostasis Model Assessment (HOMA) score was calculated to evaluate insulin resistance.18
(4) VED Pulse wave analysis with the administration of salbutamol and nitroglycerine (NTG) was carried out to evaluate VED.
(1) Pulse wave analysis (SphygmoCor, AtCor Medical Pty Ltd, Australia): The arterial pressure wave is formed from the combination of the incident wave (ie the pressure wave generated by the left ventricle in systole) and waves reflected back from the periphery.19 The velocity of reflected waves from peripheral vessels is increased in stiff arterial walls. Accordingly, in stiff arteries, systolic pressure augmentation occurs as reflected waves return earlier during the systolic phase. Based on this principle, radial artery pressure was measured using a high-fidelity micromanometer (SPC-301; Millar Instrument, TX, USA). The artery is compressed between the sensor and the underlying structures, and thus the intra-arterial pressure is transmitted through the arterial wall to the sensor. Data were collected directly into a portable computer and, after 20 sequential waveforms had been acquired, the integral software was used to generate an averaged peripheral and corresponding central wave form, which was then subjected to further analysis to determine augmentation index (AIx) and ascending aortic pressure.20,21,22,23
(2) Measurement of AIx with the administration of salbutamol and NTG:12,13,14,15 The AIx was measured after the administration of NTG, which induces vasodilation independent of vascular endothelial cells and salbutamol dependent on vascular endothelial cells.
ΔAIx (NTG, %): AIx was measured at the peak action time of 3 min after the sublingual administration of 0.6 mg NTG (Nitroglycerin Myungmoon tab®), which acts independent of vascular endothelial cells. The difference in AIx before and after drug administration was calculated and depicted in ΔAIx (NTG, %).
ΔAIx (salbutamol,%): 25 min after the administration of NTG, 2.5 mg of nebulized salbutamol (ventolin nebul®), which acts on vascular endothelial cells through L-argine–NO pathway, was inhaled with mask and, 30 min later, pulse wave analysis was carried out to measure the AIx. The difference in Alx before and after drug administration was calculated and depicted in ΔAIx (salbutamol, %).
The dosage and timing of administrations for these drugs were based on pilot studies and our own previous experiences. Pilot studies have confirmed that 15 min was sufficient for the hemodynamic changes by NTG to return to baseline but a longer period of time was required for salbutamol. Therefore, NTG was always administered first, followed by salbutamol 25 min later.
(3) Coefficient of variation (CV) of the pulse wave analysis: The coefficient of variance (CV) for the repeatability of Alx was 10.3±5.5% according to previous studies.27,28 Repeated measurements of the pulse wave analysis with 1-week interval in 10 nonobese volunteers showed a CV of 1.4± 2.3 % for Alx.
Data are presented as means±s.d. Independent t-test was used to compare both ΔAIx (NTG,%) and ΔAIx (salbutamol,%) between the obese and control subjects.
To determine the related parameters affecting ΔAIx (salbutamol,%) while considering the correlation coefficient between each independent variable, a multiple linear regression model was constructed by a step-wise method, with BMI-adjusted ΔAIx (salbutamol,%) as the dependent variable.
Baseline mean arterial pressure (MAP), heart rate and AIx, and also changes in MAP and heart rate were entered into the model to investigate the potential confounding effect of these factors.
A log transformation of high-sensitivity CRP, fasting insulin, and HOMA score were carried out to achieve normal distribution. The level of significance was set at P<0.05 (two-tailed). Statistical calculations were performed using SAS systems for Windows version 8.0 (SAS Inc.).
The baseline characteristics of the subjects are summarized in Table 1. The mean BMI of the obese and control groups was 28.8 (±3.6) and 20.4 (±1.5) kg/m2, respectively. There were no significant differences with regard to changes in age, blood pressure, fasting plasma glucose levels, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride, estradiol, and NEFA (Table 1).
Fasting insulin, HOMA score, and high-sensitivity CRP levels were significantly higher in the obese group compared to the control.
Pulse wave analysis
There were no significant differences with regard to changes in baseline heart rate, baseline AIx, and baseline MAP. The result showed no significant change in heart rate by the administration of either NTG or salbutamol, neither did it show any change in MAP after the administration of NTG or salbutamol. AIx after NTG also did not alter (Table 2).
In contrast, ΔAIx (salbutamol, %) was significantly reduced in the obese group (10.3±6.7%) compared to the control group (17.2±6.8%, P=0.0003), suggesting that endothelium-dependent vasodilatation was impaired in the obese group (Table 2).
Both NTG and salbutamol produced changes in heart rate and MAP in the obese and control groups (P<0.05) (Table 2).
Regression models in the obese group
Within the obese group, ΔAIx (salbutamol,%) showed the highest correlation with visceral adipose tissue area (r=−0.640,. P<0.001), followed by percent body fat (r=−0.477, P=0.006), BMI(r=−0.432, P=0.014), and fasting insulin (r=−0.359, P=0.044). The value of ΔAIx (salbutamol, %) was not correlated with high-sensitivity CRP (r=−0.305, P=0.089), neither were age, blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride, fasting glucose, NEFA, HOMA, or change in heart rate in the obese women .
When multiple regression analysis was performed by step-wise method to determine whether variables are significantly related to BMI-adjusted ΔAIx (salbutamol,%), visceral adipose tissue area was the only independent variable in the obese group, which revealed that 41% of the variance of ΔAIx (salbutamol,%) was predicted by visceral adipose tissue area (Adj-R2=40.6%) (Table 3).
The present study showed that VED was correlated with visceral adipose tissue in premenopausal obese women without conventional cardiovascular risk factors. The correlation between visceral adipose tissue and endothelial dysfunction was independent of BMI and body fat mass. The results suggest that an increased visceral adiposity can be an independent predictor of VED, which leads to cardiovascular disease. This reinforces many previous studies, suggesting that the development of visceral adipose tissue is linked to major complications of obesity.
High-sensitive CRP, NEFA, and HOMA, that is, obesity-related factors that may affect endothelial dysfunction, were not correlated with endothelial dysfunction in this study and previously Brook et al29 showed similar results.
There are several possible mechanisms for correlation between visceral adipose tissue and NO-induced VED: (1) insulin resistance associated with visceral adipose tissue,7,8 (2) elevated circulatory NEFA levels,32 associated with the impairment of endothelial vasodilatation, and (3) increased synthesis of inflammatory markers such as CRP produced in the liver by the IL-6 or adhesion molecules such as P-selectin, and cytokines such as TNF-α and IL-6, secreted by visceral adipose tissue.33,34,35,36
Previous studies have shown that insulin and IGF-1 stimulate the secretion of NO in vascular endothelial cells.37 Insulin induces NO release and the expression of endothelial nitric oxide synthase (eNOS).38 This is thought to be mediated by phosphatidylinositol3-kinase (PI3-kinase), probably via an increase in eNOS mRNA transcription.39 Also, TNF-α inhibits eNOS and blocks insulin action on endothelial cells.40 Moreover, it was found that insulin sensitization by troglitazone in the obese subjects restores normal endothelium-mediated vasodilation, which is abnormal in the obese subjects.41 In this study, however, no significant relationship could be observed between HOMA and ΔAIx (salbutamol%).
Vascular endothelial cell function was measured through the pulse wave analysis. Chowienczyk et al14 demonstrated that salbutamol, a β2-agonist, reduces wave reflection by activation of the L-arginine–NO pathway. It was proven by observing the blunted effect of salbutamol after the coadministration of salbutamol and N(G)-monomethyl-L-arginine (L-NMMA), NO synthase blocker.
Recently, Lind et al15 investigated the mechanism behind the reduction in terbutaline-induced wave reflection by systemic interventions with both L-NMMA and noradrenalin (NA), NO-independent vasoconstricter.
Pulse wave analysis with the administration of the salbutamol and NTG has been proven to have a correlation with invasive methods using intra-arterial acetylcholine infusion, using the standard method of endothelial function measurement.12 Compared to previous studies, pulse wave analysis with the drug administration is an easier and noninvasive method.15 In the future, it could be a useful method to measure VED.
The baseline AIx showed no significant difference between the two groups. However, ΔAIx (salbutamol,%) was significantly reduced in the obese group. This result suggests that the endothelial function in vasodilation through L-arginine–NO appears to be affected in the obese group compared to the control group, while there is no difference in vascular wall stiffness between the two groups.
We included in the multiple regression the variables of the baseline MAP, AIx and heart rate, and changes in MAP and heart rate to investigate the potential confounding effect of these factors, because the changes in HR and MAP and baseline HR and MAP influence central wave reflection and AIx.23,42 However, they were not significantly correlated with AIx in this study.
NEFA contributes to the induction of reactive oxygen species (ROS) generation in the endothelial and vascular smooth muscle cells.43 Moreover, as an evidence of increased oxidative stress, vitamin C, an antioxidant, has been shown to reverse the NEFA-induced endothelial dysfunction in healthy subjects.44 A recent study showed that obesity is associated with oxidative stress, which decreases with dietary restriction.45 However, there was no correlation between free fatty acids and ΔAIx (salbutamol,%). This is unlikely to be the mechanistic link in our subjects between elevated free fatty acid levels and endothelial dysfunction.
In obese premenopausal women with no known cardiovascular risk parameters, high-sensitivity CRP was significantly higher compared to the control group. If no other complications were accompanied, the difference in CRP, synthesized in the liver by IL-6 in fat tissues, would not significantly affect vascular wall stiffness. Recent studies have shown that CRP not only reflects the inflammatory state of vascular endothelial cells but also directly decreases the synthesis of NO, which results in VED and cardiovascular disease.46
Increased visceral adipose tissue mass and serum CRP levels could lead to VED through L-arginine–NO pathway by the previously described mechanisms. However, there was no correlation between high-sensitivity CRP and ΔAIx (salbutamol, %) in this study.
In conclusion, increased visceral adipose tissue, calculated by a single-slice CT scan, can be a strong independent predictor of VED, measured by pulse wave analysis method in obese premenopausal women without any other cardiovascular risk factors. In the future, this simple and noninvasive method can be a useful and effective tool in the area of research related with obesity and endothelial dysfunction.
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The pulse analyzer (Pulse Wave Analysis, SphygmoCor) used in the present study was donated by AtCor Medical Pty Ltd. The present study was funded by a research grant provided by Ewha Womans University.
About this article
- visceral adipose tissue area
- vascular endothelial dysfunction
- pulse wave analysis
- augmentation index
- high-sensitivity CRP (C-reactive protein)
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