Intima-Media Thickness in Severe Obesity: Links with BMI and metabolic status but not with systemic or adipose tissue inflammation

OBJECTIVE

Obesity is associated with cardiovascular risk and a low-grade inflammatory state in both blood and adipose tissue (AT). Whether inflammation contributes to vascular alteration remains an open question. To test this hypothesis, we measured arterial intima-media thickness (IMT), which reflects subclinical atherosclerosis, in severely obese subjects and explored associations with systemic inflammation and AT inflammation.

RESEARCH DESIGN AND METHODS

IMT of the carotid artery (C-IMT) and IMT of the femoral artery (F-IMT) were measured in 132 nonobese (control) subjects (BMI 22.3 kg/m²; mean age 44.8 years) and 232 subjects who were severely obese without diabetes (OB/ND; n = 146; BMI 48.3 kg/m²; age 38.2 years) or severely obese with type 2 diabetes (OB/D; n = 86; BMI 47.0; age 49.4 years). In 57 OB/ND subjects, circulating soluble E-selectin, matrix metalloproteinase 9, myeloperoxidase, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, tissue plasminogen activator inhibitor 1, cystatin C, cathepsin S, and soluble CD14 were measured in serum. AT macrophages were quantified by CD68 immunochemistry.

RESULTS

Both C-IMT and F-IMT increased in OB/ND and OB/D patients. In OB/ND patients, age was the sole independent determinant of IMT. No significant association was found with circulating inflammation-related molecules, number of CD68⁺ cells, or the presence of crown-like structures in visceral or subcutaneous AT of OB/ND patients.

CONCLUSIONS

IMT increased with severe obesity but was not influenced by the degree of systemic inflammation or AT macrophage accumulation.Obesity is well-recognized as a major risk factor for the development of metabolic disorders and cardiovascular disease (CVD), such as heart failure, myocardial infarction, and stroke (1–4). Two recent studies have identified an increased risk of cardiovascular events in subjects with extreme BMI (4,5), and the number of these subjects is increasing rapidly (6,7). As shown in the Prospective Studies Collaboration (4), cardiovascular risk factors (CV-RFs) increase with BMI. In a French study conducted using the general population (6), the proportion of subjects treated for three CV-RFs (dyslipidemia, diabetes, and hypertension) was 14-fold higher for obese subjects compared with subjects of normal weight. In addition to BMI, altered body-fat distribution and ectopic fat deposition are strongly associated with mortality and morbidity attributable to CVD (8,9). It is well-established that visceral fat accumulation is associated with CV-RFs, such as hypertension, hypertriglyceridemia, or low HDL cholesterol (HDL-c), and with insulin resistance, type 2 diabetes, prothrombotic and proinflammatory states, sleep apnea, and cardiac hypertrophy, which can have potentially deleterious effects on the cardiovascular system.Although the association between obesity and increased CV-RFs is recognized, the pathophysiological pathways that link expansion of fat mass (FM) to atherosclerosis are less clearly established. Growing evidence attributes a major role to the altered biology of adipose tissue (AT) as a cause of comorbidities in obesity. Part of the systemic inflammation that characterizes obesity originates from AT, where inflammatory cells, mainly macrophages, accumulate and create local inflammation (10,11). Adipose-derived inflammatory factors produced by enlarged adipocytes or AT macrophages (or both) are often increased in the serum of obese subjects and thought to contribute to the metabolic complications of obesity, including insulin resistance and liver disease (12). In this context, it is tempting to hypothesize that products released by AT impinge on vascular cells to promote the development of atherosclerotic lesions in obesity. In line with this hypothesis, recent studies of humans report a positive association between AT inflammation, as assessed by the presence of macrophages in crown-like structures (CLS), and endothelial dysfunction, as evaluated by brachial artery flow-mediated dilatation in obese subjects (13,14).The measure of intima-media thickness (IMT) is a noninvasive marker for subclinical atherosclerosis and provides a reliable and predictive value for later cardiovascular events (15–17). Previous studies of humans have shown correlations between BMI and increased IMT (18–22). However, only one previous study (23) has investigated IMT in morbidly obese subjects and only in a limited sample.The objectives of our study were to describe the relationships between obesity-related phenotypes and IMT values at two arterial sites in a large group of massively obese subjects and to assess the potential links between systemic inflammation and AT inflammation.