The American Journal of Medicine
Volume 123, Issue 8 , Pages 727-734, August 2010

Paradoxical Preservation of Vascular Function in Severe Obesity

  • Luigi Marzio Biasucci, MD

      Affiliations

    • Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
    • Corresponding Author InformationReprint requests should be addressed to: Luigi Marzio Biasucci, MD, Institute of Cardiology, Catholic University, Largo Gemelli 8, 00168 Roma, Italy
    • ,
  • Francesca Graziani, MD

      Affiliations

    • Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
    • ,
  • Vittoria Rizzello, MD, PhD

      Affiliations

    • Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
    • ,
  • Giovanna Liuzzo, MD, PhD

      Affiliations

    • Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
    • ,
  • Caterina Guidone, MD

      Affiliations

    • Institute of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
    • ,
  • Alberto Ranieri De Caterina, MD

      Affiliations

    • Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
    • ,
  • Salvatore Brugaletta, MD

      Affiliations

    • Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
    • ,
  • Gertrude Mingrone, MD

      Affiliations

    • Institute of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy
    • ,
  • Filippo Crea, MD

      Affiliations

    • Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy

Article Outline

Abstract 

Background

Obesity is associated with a high risk of coronary artery disease morbidity and mortality. Yet, postmortem studies have shown that severely obese subjects exhibit smooth coronary arteries, thus suggesting that they may be protected from atherosclerosis. We assessed vascular function and its possible determinants in a cohort of normal-weight to severely obese insulin-sensitive subjects (body mass index [BMI] 23.2-49 kg/m2).

Methods

Seventy-one healthy, insulin-sensitive subjects (Homeostasis Model Assessment of Insulin Resistance index <2.5), divided into normal-weight (n = 13; BMI = 23.2 ± 1.6), obese (n = 35; BMI=32.6±2.5), and severely obese (n=23; BMI=49.0±7.9) groups, were enrolled. Vascular function was evaluated by flow-mediated dilation and carotid intima–media thickness. High-sensitivity C-reactive protein, leptin, adiponectin, vascular growth factors, and CD34+KDR+/CD133+ endothelial progenitor cells, known markers of vascular health/protection, also were measured.

Results

Flow-mediated dilation was higher in severely obese than in obese and normal-weight individuals (P=.019 and P=.011 respectively). Intima–media thickness was consistently lower in severely obese than in obese individuals (P=.040) and similar in severely obese and normal-weight individuals (P >.99). Levels of high-sensitivity C-reactive protein and leptin were higher in severely obese than in obese and normal-weight individuals (high-sensitivity C-reactive protein: P=.018 and P=.05, respectively; leptin: P <.001 for both comparisons). CD34+KDR+ endothelial progenitor cells were significantly higher in severely obese versus obese individuals (P=.039).

Conclusion

Our study demonstrates that vascular function is paradoxically better in severely obese than in obese subjects and similar to that found in normal-weight subjects. Despite higher levels of high-sensitivity C-reactive protein and leptin, severely obese individuals may be partially protected from atherosclerosis, possibly by a greater mobilization of endothelial progenitor cells.

Keywords: Endothelial function, Inflammation, Obesity

 

Obesity is a new epidemic associated with a high risk of morbidity and mortality for several diseases, including coronary artery disease.1, 2 Although the increased risk of coronary artery disease in obese subjects is partially explained by higher rates of diabetes, hypertension, and dyslipidemia, it also has been proposed that obesity per se constitutes a risk factor for coronary artery disease.3 However, the role of obesity and, in particular, the degree of obesity in the absence of its metabolic complications are not clear yet. Specifically, it is not known whether the association between obesity and coronary artery disease is linear, as is the case for other risk factors. Furthermore, postmortem data suggest that subjects with severe obesity might have a reduced atherosclerotic burden.4, 5, 6, 7, 8

Clinical Significance

 


•Insulin-sensitive, severely obese subjects exhibit a better vascular function than obese and normal-weight subjects despite higher levels of C-reactive protein and leptin.

•This paradoxical preservation of vascular function in patients with severe obesity is associated with and may be related to higher levels of circulating endothelial progenitor cells.

•Obesity per se, in the absence of insulin resistance, does not seem to affect cardiovascular diseases.

We assessed flow-mediated dilation and carotid intima–media thickness in healthy, insulin-sensitive subjects, divided into 3 groups according to body mass index (BMI): normal-weight, obese, and severely obese. To elucidate the potential mechanisms of an association between different degrees of obesity and vascular function, we also measured high-sensitivity C-reactive protein,9 as a marker of inflammation, and leptin, the prototypic adipokine, known to be associated with a worse vascular function;10 and adiponectin11 and endothelial progenitor cells (and their putative mobilizing factors), known to be associated with a better vascular function.12

Back to Article Outline

Materials and Methods 

Study Design 

We designed an observational cohort study to assess the effect of the degree of obesity on vascular function. The study was conducted from October 2007 to September 2008, at the Catholic University, Rome, Italy.

Study Population 

As shown in Figure 1, a total of 173 subjects were screened, 60 of whom were excluded for the following reasons: cancer, renal failure, known diabetes,13 thyroid dysfunction, chronic lung disease, weight change or treatment for obesity, and known or suspected cardiovascular disease. The remaining 113 subjects were further screened with a 75-g oral glucose tolerance test, 42 of whom were excluded for the following reasons: diabetes,13 impaired fasting glucose, impaired glucose tolerance, or insulin resistance, defined as Homeostasis Model of Insulin Resistance Index greater than 2.514 (Figure 1).

  • View full-size image.
  • Figure 1. 

    †Initial exclusion criteria were: weight change of 3 kg or more in the last 6 months or any kind of treatment for obesity, known diabetes, chronic lung disease, thyroid dysfunction, myocardial infarction, or angina pectoris assessed on the basis of medical history or history of coronary revascularization procedures or the presence of left bundle branch block, Q or QS waves on the electrocardiogram, renal failure (defined as serum creatinine levels >1.3 mg/dL), or cancer in the previous 5 years. ‡Oral glucose tolerance test excluded individuals with diabetes7 (fasting plasma glucose >7.0 mmol/L or 2-hour plasma glucose >11 mmol/L), impaired fasting glucose (fasting plasma glucose 6.1-6.9 mmol/L), impaired glucose tolerance (2-hour plasma glucose: 7.8-11.0 mmol/L), and insulin resistance determined using the Homeostasis Model Assessment of Insulin Resistance with the equation: Homeostasis Model Assessment of Insulin Resistance = (FPI × FPG)/22.5, where FPI is fasting plasma insulin concentration (mU/L) and FPG is fasting plasma glucose (mmol/L); the cutoff value for insulin resistance was 2.5.8 BMI = Body mass index; EKG = electrocardiogram; HOMA-IR = Homeostasis Model of Insulin Resistance; OGTT = oral glucose tolerance test.

Seventy-one subjects were finally enrolled (35 men and 36 women aged 43-62 years). These subjects were divided into 3 categories according to BMI (kilograms/meters squared): normal-weight (n=13, BMI 23.2±1.6 kg/m2), obese (n=35, BMI 32.6±2.5 kg/m2), and severely obese (n=23, BMI 49.0±7.9 kg/m2) (Table 1). All participants were comparable in age and gender, and none were receiving medical treatment. When present, hypertension or hyperlipidemia was a new diagnosis. All individuals were enrolled from the Catholic University of the Sacred Heart. Obese and severely obese individuals were enrolled from the obesity clinic, severely obese individuals were under evaluation for bariatric surgery, and normal-weight individuals were volunteers chosen from hospital employees. Informed consent was obtained from each subject.

Table 1. Characteristics of Study Groups
N (N=13)O (N=35)SO (N=23)
Gender (F/M)8/515/2013 /10
Age, mean±SD (y)48.4±5.651.0±6.252.0±9.9
Weight, mean±SD (kg)64.5±9.692.7±12.2‡132.9±31⁎†
Waist circumference, mean±SD (cm)79.5±9.9106.7±10.9‡142.8±20.9⁎†
BMI, mean±SD (kg/m2)23.2±1.632.6±2.5‡49±7.9⁎†
% body fat, mean±SD (%)17±5.425.8±9.561.1±15.1⁎†
Family history of IHD, n (%)5(38%)15(43%)9(39%)
Hypertension, n (%)5(38%)14(40%)9(39%)
Smokers, n (%)4(30.7%)11(31%)7(30.4%)
Total cholesterol, mean±SD (mg/dL)207±60210±57204±43
LDL cholesterol, mean±SD (mg/dL)129±39139±35128±36
HDL cholesterol, mean±SD (mg/dL)49±1250±1148±13
Triglycerides, mean±SD (mg/dL)119±63115±68141±39
FPG, median-range (mmol/L)4.36(3.81-5.14)4.53(3.92-5.25)4.59(4.25-5.25)
FPI, median-range (mU/L)3.81(2.63-8.15)5.71(2.26-7.82)5.87(3.49-9.03)
HOMA-IR index, median-range0.70(0.46-1.70)1.16(0.41-1.55)‡1.21(0.67-1.73)⁎

BMI = Body mass index; FPG = fasting plasma glucose; FPI = fasting plasma insulin; HDL = high-density lipoprotein; HOMA-IR = Homeostasis Model Assessment of Insulin Resistance; IHD = ischemic heart disease; LDL = low-density lipoprotein; N = normal-weight; O = obese; SD = standard deviation; SO = severely obese.

⁎Severely obese versus normal-weight: P <.001 for weight, waist circumference, BMI, and percent body fat; P=.007 for HOMA-IR index.

†Severely obese versus obese: P <.001 for weight, waist circumference, BMI, and percent body fat.

‡Obese versus normal-weight: P <.001 for weight, waist circumference, and BMI; P=.043 for HOMA-IR index.

Anthropometric Measurements 

Body weight and waist circumference were measured in the morning, before breakfast. Weight and percent body fat were evaluated by the Tanita bioimpedance balance (Tanita International Division, West Dryton, UK). Waist circumference was measured just above the uppermost lateral border of the right ileum using the National Health and Nutrition Examination Survey protocol.15 Subjects were requested to refrain from physical activity 24 hours before every test.

Ultrasound Studies 

Carotid intima–media thickness and brachial artery flow-mediated dilation were performed using a Duplex ultrasound system (Aplio, Toshiba SSA-770 A, Tochigi-Ken, Japan) equipped with a high-resolution 7.5-MHz linear phase-array vascular transducer. B-mode real-time imaging was used. All ultrasound scans were performed by a single experienced operator. All examinations were digitized and analyzed offline by an independent reader. Both operators were blinded to all clinical and laboratory data.

Measurement of Flow-Mediated Dilation 

Flow-mediated dilation was analyzed on the brachial artery.16 Subjects fasted for more than 4 hours before the evaluation. Cigarettes and caffeine intake were prohibited on the morning of the study. Examinations were performed in a quiet room, with subjects in a supine position. The right arm was immobilized by 2 cushions supporting the elbow and wrist. A blood pressure cuff was placed at 10 cm distal to the site of the measurement (above the antecubital fossa). After 15 minutes of rest, B-mode imaging of the brachial artery in the longitudinal section was obtained. Internal brachial artery diameter was measured according to the leading-to-leading edge approach from the near to the far wall at the R wave of the electrocardiogram signal. All measurements were averaged from 3 consecutive cardiac cycles. After 6 baseline measurements were obtained, ischemia was induced by the inflation of the cuff to 100 mm Hg greater than the systolic arterial pressure to occlude flow for 4 minutes. After the deflation of the cuff, diameter measurements were performed for 5 minutes, starting 40 seconds after deflation, at 20-second intervals. Maximal obtained diameter during ischemia-induced hyperemia was used to calculate the percentage flow-mediated dilation ([maximum diameter-baseline diameter]/baseline diameter×100%). The coefficients of variation for baseline and hyperemia diameters were 0.5% and 0.7%, respectively. Repeated analyses of baseline and deflation flow measurements were highly reproducible, with correlations greater than 0.98.

Measurement of Carotid Intima–Media Thickness 

Intima–media thickness measurement was performed at the carotid level with subjects in a supine position. A minimum of 3 frames (taken at the tip of the R-wave on the electrocardiogram) of the far wall of the right and left common carotid arteries (longitudinal section), 1 cm proximal to the carotid bifurcation, were digitized and measured. Measurements were done by tracing the leading edge of the lumen–intima and the media–adventitia interfaces. Three to 6 measurements at both common carotid arteries were taken, yielding mean intima–media thickness (the average thickness across the 1-cm segment of each carotid arteries) and maximum intima–media thickness (the single highest measurement).17 The measurement of the intima–media thickness was conducted in plaque-free areas; a plaque was defined as an intima–media thickness greater than 1.5 mm.18 The intraobserver coefficient of variation was 3.9% (mean ± standard deviation of the difference, 0.018±0.031 mm), and the interobserver value was 5.6% (0.028±0.032 mm).

Blood Sampling 

Peripheral blood samples were taken in the morning, with the patient resting for at least 30 minutes after an overnight fast. Twenty milliliters of blood were taken after minimal venostasis; plasma and serum were snap-frozen and stored at −80°C after being divided in aliquots.

Measurements in Plasma and Serum 

Plasma high-sensitivity C-reactive protein levels were measured with a high-sensitivity immunonephelometric assay (Siemens Diagnostic BN, Dearfield, Del); plasma leptin and adiponectin were assayed by radioimmunoassay (Phoenix Pharmaceuticals, Phoenix, Ariz; Linco, St Charles, Mo, respectively). Platelet-derived growth factor, hepatocyte growth factor, fibroblast growth factor, and vascular endothelial growth factor were measured by Enzyme-Linked Immunosorbent Assay (SearchLight Human Angiogenesis Array, Thermo Fisher Scientific, Rockford, Ill).

Measurements of Endothelial Progenitor Cells 

To evaluate endothelial progenitor cells, 100 μL of fresh venous blood in ethylene diamine tetraacetic acid were incubated with fluorescein isothiocyanate-, phycoerythrin-, or peridinin chlorophyll- conjugated monoclonal antibodies: CD34 (8G12 clone, IgG1), KDR (R&D Systems, Abingdon, Oxon, UK), or CD133 (AC133 clone, IgG1; Miltenyi Biotec, Bergisch Gladbach, Germany).19 Endothelial progenitor cells were considered as CD34+KDR+ cells at flow cytometry. The percentage of the immature subset of endothelial progenitor cells, identified as CD34+ CD133+ cells, also was evaluated.

Statistical Analysis 

Because the Homeostasis Model Assessment of Insulin Resistance, high-sensitivity C-reactive protein, leptin, endothelial progenitor cells, fibroblast growth factor, hepatocyte growth factor, platelet-derived growth factor, and vascular endothelial growth factor showed a skewed distribution, we used the Kruskal–Wallis test with multiple-comparison procedures (Dunn's method) for comparisons among groups. Waist circumference, weight, BMI, adiponectin, intima–media thickness, and flow-mediated dilation had a normal distribution and were evaluated by analysis of variance for repeated measures with the Bonferroni correction. Chi-square statistics were used for categoric variables. Results were adjusted for age, gender, hypertension, and smoking status by multivariate linear regression analysis. A P value of less than .05 (2-tailed) was considered statistically significant. A power calculation considering a 50% increase in flow-mediated dilation showed that 10 subjects per group were required for a P value less than .05 with 80% power. Data are reported as medians and ranges or as means ± standard deviation, as appropriate. Statistical analysis was performed by using the Statistical Package for the Social Sciences version 15.0 (SPSS Inc, Chicago, Ill).

Back to Article Outline

Results 

Anthropometric data consistently differed among the 3 groups with their differences in BMI. However, the prevalence of hypertension, family history of coronary artery disease, and levels of triglycerides and total, high-density, and low-density lipoprotein-cholesterol were similar among the groups. Notwithstanding the differences among the groups, all participants were insulin-sensitive (Table 1).

Ultrasound Studies 

Data are shown in Table 2. Flow-mediated dilation was significantly higher in the severely obese group versus the obese and normal-weight groups (P=.019 and P=.011, respectively) and was similar between the latter 2 groups (P >.99) (Figure 2A). Maximum intima–media thickness was consistently and significantly lower in severely obese versus obese subjects (P=.04), whereas it did not differ between severely obese and normal-weight subjects (P>.99) and between normal-weight and obese subjects (P=.17) (Figure 2B). No differences were found in mean intima–media thickness among groups. At multivariate linear regression analysis, flow-mediated dilation was independent of age, gender, hypertension, and smoking status, but was associated with BMI (R=0.31; P=.014), whereas intima–media thickness was associated with male gender (R=0.27; P=.036). When adjusted for BMI, the difference of flow-mediated dilation in severely obese versus normal-weight subjects and in severely obese versus obese subjects was confirmed (P=.001 and P=.03, respectively).

Table 2. Results of Ultrasound Studies and Biological Parameters in Different Groups
N (n=13)O (n=35)SO (n=23)
Brachial diameter, mean±SD (mm)3.56±0.643.90±0.734.05±0.71
Peak FMD, mean±SD (%)7.33±3.687.53±5.4713.02±6.50⁎†
Mean IMT, mean±SD (mm)0.54±0.120.66±0.210.58±0.15†
Maximum IMT, mean±SD (mm)0.70±0.200.89±0.380.66±0.14
Subjects carotid plaques, n (%)1/13(8%)11/35(31%)3/23(13%)
hs-CRP, median-range (mg/L)2.13(0.15-5.50)2.38(0.37-35.84)7.42(0.95-37.44)⁎†
Leptin, median-range (ng/L)9.04(1.90-25.70)13.10(2.00-55.50)71.95(28.10-100)⁎†
Adiponectin, mean±SD (μg/mL)10.51±6.4112.42±6.9013.66±6.96
CD34+CD133+, median-range (%)0.075(0.00-0.37)0.070(0.00-1.15)0.17(0.00-1.87)
CD34+ KDR+, median-range (%)0.14(0.02-0.59)0.16(0.00-3.32)0.29(0.01-2.44)†
PDGF, median-range (pg/mL)1722(1101-23,080)1986(665-3204)2127(590-3529)
HGF, median-range (pg/mL)3118(2232-9459)6997(2362-14,632)4905(1959-16,983)‡
FGF, median-range (pg/mL)175(82-403)255(127-660)318(155-719)⁎
VEGF, median-range (pg/mL)575(276-849)835(394-2195)ʃ976(369-2221)⁎‡

FGF = Fibroblast growth factor; FMD = flow-mediated dilation; HGF = hepatocyte growth factor; hs-CRP = high-sensitivity C-reactive protein; IMT = intima–media thickness; N = normal-weight; O = obese; PDGF = platelet-derived growth factor; SD = standard deviation; SO = severely obese; VEGF = vascular endothelial growth factor.

⁎Severely obese versus normal-weight: FMD (P=.011); hs-CRP (P=.018); leptin (P <.001); FGF (P=.012); VEGF (P=.01).

†Severely obese versus obese: FMD (P=.019); IMT (P=.04); hs-CRP (P=.05); leptin (P <.001); CD34+KDR+ (P=.039).

‡Obese versus normal-weight: HGF (P=.04); VEGF (P=.04).

  • View full-size image.
  • Figure 2. 

    A, B, Ultrasound studies: assessment of flow-mediated dilation by brachial artery ultrasound and measurement of carotid intima–media thickness by 2-dimensional carotid ultrasound. Subjects were subgrouped according to BMI as normal-weight (n = 13), obese (n = 35), and severely obese (n = 23). A, Maximal diameter during ischemia-induced hyperemia was used to calculate the percentage of flow-mediated dilation: ([maximum diameter-baseline diameter]/baseline diameter × 100%). Flow-mediated dilation was significantly higher in severely obese subjects than in obese and normal-weight subjects (13.02% ± 6.50% vs 7.53% ± 5.47%, P = .019, and 13.02% ± 6.50% vs 7.33% ± 3.68%, P = .011, respectively). No differences were found in flow-mediated dilation between normal-weight and obese subjects (7.33% ± 3.68% vs 7.53% ± 5.47%, respectively, P >.99) (P for trend = .005). B, Three to six measurements at both common carotid arteries were taken, yielding mean intima–media thickness (the average thickness across the 1-cm segment of each carotid arteries) and maximum intima–media thickness (the single highest measurement). Maximum carotid intima–media thickness was significantly lower in severely obese subjects versus obese subjects (0.66 ± 0.14 mm vs 0.89 ± 0.38 mm, P = .04). No differences in maximum intima–media thickness were found between severely obese and normal-weight subjects (0.66 ± 0.14 mm vs 0.70 ± 0.20 mm, P >.99) and between normal-weight and obese subjects (0.70 ± 0.20 mm vs 0.89 ± 0.38 mm, P = .17) (P for trend = .028). No differences were found in mean intima–media thickness among groups (P for trend .08). C-E, Biological parameters: measurement of high-sensitivity C-reactive protein, leptin and endothelial progenitor cells. C, High-sensitivity C-reactive protein was higher in severely obese versus obese subjects (7.42 mg/L [0.95-37.44 mg/L] vs 2.38 mg/L [0.37-35.84 mg/L], P = .05) and in severely obese versus normal-weight subjects (7.42 mg/L [0.95-37.44 mg/L] vs 2.13 mg/L [0.15-5.50 mg/L], P = .018]. No differences were found between normal-weight and obese subjects (P for trend = .012). D, Leptin levels were significantly higher in severely obese versus obese subjects (71.95 ng/L [28.10-100 ng/L] vs 13.10 ng/L [2.00- 55.50 ng/L], P <.001) and in severely obese versus normal-weight subjects (71.95 ng/L [28.10-100 ng/L] vs 9.04 ng/L [1.90-25.70 ng/L], P <.001). No differences were found between normal-weight and obese subjects (P for trend = .0001). E, Endothelial progenitor cells. CD34+KDR+ endothelial progenitor cells were higher in severely obese versus obese subjects (0.29% [0.01%-2.44%] vs 0.16% [0.00%-1.15%], P = .039). No differences were found between normal-weight versus obese subjects (0.14% [0.02%-0.59%] vs 0.16% [0.00%-1.15%] P >.99) or between normal-weight versus severely obese subjects (0.14% [0.02%-0.59%] vs 0.29% [0.01%-2.44%] P = .056) (P for trend = .019). No differences were found in the percentage of CD34+CD133+among groups (P for trend = .28). Dots represent outliers. EPC = Endothelial progenitor cell; IMT = intima–media thickness; N = normal-weight; O = obese; SO = severely obese.

Biological Parameters 

Data are reported in Table 2. High-sensitivity C-reactive protein and leptin levels were higher in the severely obese group than in the obese and normal-weight groups (high-sensitivity C-reactive protein, mg/L: P=.05 and P=.018, respectively; leptin, ng/L: P <.001 for both comparisons), whereas they did not differ between the latter 2 groups (Figure 2C, D). No significant differences were found in adiponectin levels among groups.

Hepatocyte growth factor was higher in obese versus normal-weight subjects (P=.04), and fibroblast growth factor levels were higher in severely obese versus normal-weight subjects (P=.012). Vascular endothelial growth factor levels were higher in severely obese versus normal-weight subjects (P=.01) and in obese versus normal-weight subjects (P=.04).

CD34+KDR+ cells were significantly higher in severely obese versus obese groups (P = .039), whereas they were similar in normal-weight versus obese groups (P >.99) and in normal-weight versus severely obese groups (P = .056) (Figure 2E). No differences were found in the percentage of CD34+ CD133+ among groups.

Back to Article Outline

Discussion 

Our study demonstrates that otherwise healthy, insulin-sensitive, severely obese subjects show paradoxically higher flow-mediated dilation and lower intima–media thickness than obese individuals and values comparable to those found in normal-weight individuals, despite higher levels of high-sensitivity C-reactive protein and leptin. Moreover, severely obese subjects show, on average, increased circulating levels of growth factors, such as fibroblast growth factor and vascular endothelial growth factor, together with significantly higher levels of CD34+KDR+ endothelial progenitor cells. These findings suggest that severely obese subjects may be partially protected from atherosclerosis and generate a number of challenging hypotheses.

Previous Studies 

Although several observational studies reported an association between increasing BMI and cardiovascular death,20, 21 absent or mild coronary atherosclerosis has been observed in severely obese patients in several postmortem studies.4, 5, 6, 7, 8 In particular, Duflou et al7 investigated the mechanisms of sudden cardiac death in 28 severely obese subjects. They found that only 25% of subjects showed coronary atherosclerosis and that even in these cases coronary lesions were not responsible for sudden death. Similarly, in 166 forensic autopsies of severely obese subjects, Kortelainen8 found that a sizeable proportion of patients did not exhibit coronary stenosis, even at an advanced age, nor coronary thrombosis. The apparent discrepancies between epidemiologic and postmortem studies may be because death certificates usually attribute any cause of unexplained sudden death to myocardial infarction. However, sudden death is a quite common event in severe obesity and not necessarily related to an ischemic mechanism.7 Furthermore, the association between the increase in fat tissue and coronary artery disease risk has been questioned by the observation that risk of death after myocardial infarction or coronary revascularization procedures is lower in obese than in normal-weight subjects. This finding led to the formulation of the so-called “obesity paradox,” for which there is increasing evidence22 that cannot be fully explained.23, 24

Few studies have explored vascular function in severe obesity, obtaining conflicting results. Arkin et al25 found that endothelial function worsened with increasing BMI; however, they included patients with diabetes or insulin resistance, which were exclusion criteria in our study. On the other hand, Faintuch et al26 found that pulse-wave velocity, a marker of vascular stiffness, is lower in severely obese than in obese subjects, which is in agreement with our results. However, both of these studies differ considerably from our study. To dissect out the “pure” effect of increasing fat amount on vascular function, we focused for the first time on nondiabetic or insulin-resistant obese subjects and severely obese individuals.

Inflammation and Adipokines 

Previous studies have established a link between inflammation and endothelial dysfunction,9, 27 proposing a causative role for high-sensitivity C-reactive protein. Therefore, our finding that higher levels of high-sensitivity C-reactive protein in severely obese subjects are associated with higher flow-mediated dilation and lower intima–media thickness is unexpected and intriguing, representing an apparent discrepancy between inflammation and endothelial dysfunction. These data, which are in agreement with a recent report,26 suggest that high-sensitivity C-reactive protein is not causative of endothelial dysfunction, as already proposed,28 or that a more potent protective mechanism occurs.

We also found higher levels of leptin in severely obese individuals than in obese and normal-weight individuals. Leptin acts as a proinflammatory adipokine and has been shown to induce endothelial dysfunction in obese mice.10 However, our findings might be partially explained by recent ex vivo studies showing a vasodilatatory action of leptin,29 an effect that is not blunted in patients with increased adiposity, thus suggesting that leptin resistance may be tissue-specific and may not affect vascular function.30 Moreover, leptin receptor has been found to be expressed in endothelial cells, where it is functionally active for leptin-dependent angiogenic activity,31 an observation that would help to explain our results.

Adiponectin, an adipokine considered to be protective for vascular endothelium,11 has been shown to negatively correlate with BMI. Conversely, our study found that adiponectin levels were similar across the different BMI groups. Although we do not have an explanation for this finding, it must be underlined that recent studies failed to demonstrate a significant association of adiponectin with cardiovascular risk.32

Endothelial Progenitor Cells and Vascular Growth Factors 

Fat tissue is not only a source of inflammatory mediators, including adipokines but also a recognized source of stem cells.33, 34 In our study, CD34+KDR+ endothelial progenitor cells were higher in severely obese than in obese and normal-weight individuals. Therefore, their increase might partially explain our finding of preserved vascular function and integrity in severely obese patients. However, although endothelial progenitor cells have been proven to be directly related to endothelial function,35 their clinical and pathophysiologic significance is still unclear and needs to be further investigated. Although some authors have suggested that endothelial progenitor cells might simply be markers of preserved endothelium,36 others consider them protective and reparative for the vascular wall.37

Furthermore, we found slightly increased levels of fibroblast growth factor and vascular endothelial growth factor in severely obese individuals. This may lead to the hypothesis that growth factors protect the endothelium in severe obesity through mobilization of endothelial progenitor cells, leading to improved vascular homeostasis. Because our study population is small, these data must be interpreted cautiously, as hypothesis-generating, and should be confirmed in a larger, specifically designed study.

Back to Article Outline

Limitations 

The cross-sectional design and limited number of individuals enrolled do not allow definitive conclusions to be drawn. As such, the study is more hypothesis-generating than hypothesis-testing, and the results would require confirmation in a larger, ethnically diverse group of individuals before any general conclusions can be drawn. Furthermore, to investigate the pure effect of fat tissue and its products on vascular function, we studied highly selected subjects, with no insulin-resistance, which may not represent the overall population of obese and severely obese individuals. Consequently, our results may not be applicable to the whole population of obese individuals. Another limitation of the study is that catecholamine levels and sympathetic tone were not assessed, which might influence the results because of their link to obesity and vascular reactivity.

Our data do not deny that severe obesity is a condition associated with increased total and cardiovascular mortality, but they do suggest a possible mechanism of protection versus atherosclerosis that may help to explain some unresolved issues on obesity.22

Back to Article Outline

Conclusions 

Our study demonstrates that otherwise healthy, insulin-sensitive, severely obese subjects exhibit a better vascular function than obese and normal-weight subjects, despite higher levels of C-reactive protein and leptin. Our findings challenge the paradigm that fat is necessarily associated with reduced vascular function. On the contrary, abnormally expanded fat tissue per se and its products, including endothelial progenitor cells, may have a protective effect against atherosclerosis in severe obesity. Because the search of protective mechanisms in coronary artery disease is at least as important as that of novel risk factors, our observations might open new avenues to research.

Back to Article Outline

References 

  1. Haslam DW, James WP. Lancet. 2005;366:1197–1209
  2. Allison DB, Fontaine KR, Manson JE, et al. Annual deaths attributable to obesity in the United States. JAMA. 1999;282:1530–1538
  3. Fontaine KR, Redden DT, Wang C, et al. Years of life lost due to obesity. JAMA. 2003;289:187–193
  4. Melinek J, Livingston E, Cortina G, Fishbein MC. Autopsy findings following gastric bypass surgery for morbid obesity. Arch Pathol Lab Med. 2002;126:1091–1095
  5. Cummings PM, Le BH, Lopes MBS. Postmortem findings in morbidly obese individuals dying after gastric bypass procedures. Hum Pathol. 2007;38:593–597
  6. Ahmed Q, Chung-Park M, Tomashefski JF. Cardiopulmonary pathology in patients with sleep apnea/obesity hypoventilation syndrome. Hum Pathol. 1997;28:264–269
  7. Duflou J, Virmani R, Rabin I, et al. Sudden death as a result of heart disease in morbid obesity. Am Heart J. 1995;130:306–313
  8. Kortelainen ML. Myocardial infarction and coronary pathology in severely obese people examined at autopsy. Int J Obes Relat Metab Disord. 2002;26:73–79
  9. Pasceri V, Willerson JT, Yeh ET. Direct pro-inflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102:2165–2168
  10. Knudson JD, Dincer DU, Zhang C, et al. Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction. Am J Physiol Heart Circ Physiol. 2005;289:H48–H56
  11. Kumada M, Kihara S, Sumitsuji S, et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol. 2003;23:85–89
  12. He T, Smith LA, Harrington S, et al. Transplantation of circulating endothelial progenitor cells restores endothelial function of denuded rabbit carotid arteries. Stroke. 2004;35:2378–2384
  13. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006;29(Suppl 1):S43–S48
  14. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419
  15. Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, et al. Prevalence of cardiovascular disease risk factors in U.S. children and adolescents with diabetes: the SEARCH for diabetes in youth study. Diabetes Care. 2006;29:1891–1896
  16. Donald AE, Charakida M, Cole TJ, et al. Non-invasive assessment of endothelial function (Which technique?). J Am Coll Cardiol. 2006;48:1846–1850
  17. Handa N, Matsumoto M, Maeda H, et al. Ultrasonic evaluation of early carotid atherosclerosis. Stroke. 1990;21:1567–1572
  18. Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim intima-media thickness consensus (2004-2006) (An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004 and Brussels, Belgium, 2006). Cerebrovasc Dis. 2007;23:75–80
  19. Leone AM, Rutella S, Bonanno G, et al. Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function. Eur Heart J. 2005;26:1196–1204
  20. Mc Tigue K, Larson JC, Valoski A. Mortality and cardiac and vascular outcome in extremely obese women. JAMA. 2006;296:79–86
  21. Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet. 2006;368:666–678
  22. Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox and impact of weight loss. J Am Coll Cardiol. 2009;53:1925–1932
  23. Reeves BC, Ascione R, Chamberlain MH, Angelini GD. Effect of body mass index on early outcomes in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol. 2003;42:668–676
  24. Gurm HS, Brennan DM, Booth J, et al. Impact of body mass index on outcome after percutaneous coronary intervention (the obesity paradox). Am J Cardiol. 2002;90:42–45
  25. Arkin JM, Alsdorf R, Bigornia S, et al. Relation of cumulative weight burden to vascular endothelial dysfunction in obesity. Am J Cardiol. 2008;10:98–101
  26. Faintuch J, Marques PC, Bortolotto LA, et al. Systemic inflammation and cardiovascular risk factors: are morbidly obese subjects different?. Obes Surg. 2008;18:854–862
  27. Esteve E, Castro A, Lopez-Bermejo A, et al. Divergent relationships among soluble tumor necrosis factor-α receptors 1 and 2, insulin resistance, and endothelial function. Diabetes Care. 2006;29:1460–1461
  28. Pepys MB. C-reactive protein is neither a marker nor a mediator of atherosclerosis. Nat Clin Pract Nephrol. 2008;4:234–235
  29. Lembo G, Vecchione C, Fratta L. Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes. 2000;49:293–297
  30. Momin AU, Melikian N, Shah AM, et al. Leptin is an endothelial independent vasodilator in humans with coronary artery disease: evidence for tissue specificity of leptin resistance. Eur Heart J. 2006;27:2294–2299
  31. Wolk R, Deb A, Caplice NM, Somers VK. Leptin receptor and functional effects of leptin in human endothelial progenitor cells. Atherosclerosis. 2005;183:131–139
  32. Sattar N, Wannamethee G, Sarwar N, et al. Adiponectin and coronary heart disease: a prospective study and meta-analysis. Circulation. 2006;114:623–629
  33. Sengenes C, Lolmede K, Zakaroff-Girard A, et al. Preadipocytes in the human subcutaneous adipose tissue display distinct features from the adult mesenchymal and hematopoietic stem cells. J Cell Physiol. 2005;205:114–122
  34. Gimble JM, Guilak F. Differentiation potential of adipose derived adult stem (ADAS) cells. Curr Top Dev Biol. 2003;58:137–160
  35. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593–600
  36. Leone AM, Valgimigli M, Giannico MB, et al. From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells. Eur Heart J. 2009;30:890–899
  37. Leor J, Marber M. Endothelial progenitors: a new Tower of Babel?. J Am Coll Cardiol. 2006;48:1588–1590

 Funding: The study was funded by grant 70200400 from Catholic University of the Sacred Heart, Rome, Italy.

 Conflict of Interest: None of the authors have any conflicts of interest associated with the work presented in this manuscript.

 Authorship: All authors had access to the data and played a role in writing this manuscript.

PII: S0002-9343(10)00345-1

doi:10.1016/j.amjmed.2010.02.016

The American Journal of Medicine
Volume 123, Issue 8 , Pages 727-734, August 2010

Article Tools

* Image Usage & Resolution