Our results show that in men with obesity both RYGB and SG induce an amelioration of inflammation and endothelial dysfunction that drives a decrease in cIMT compared to obese men submitted to diet and exercise. Although circulating testosterone was inversely correlated with this decrease in cIMT and some inflammatory markers, multivariate analysis did not confirm this finding. Indeed, the association of low circulating testosterone in males with cardiovascular disease and cIMT has not been consistently demonstrated in previous studies. Although one study showed that cIMT was negatively correlated with TT in 115 men younger than 70 years without a history of cardiovascular events (23), many other studies failed to show an association of circulating androgens with cIMT (24, 25). Therefore, it seems that the increase in circulating testosterone after obesity surgery is the result of weight loss and the amelioration of insulin and leptin resistance (26, 27). This in turn produces a concomitant increase in kisspeptin concentration that restores the hypothalamic-pituitary-gonadal axis (26), but it has no direct association with the decrease in cardiovascular risk as measured by the cIMT.
Chronic low-grade inflammation plays a well-recognized role as a link between obesity and cardiovascular disease (11, 12) and cIMT is a strong predictor of the latter (6). Although the exact mechanism of this low-grade inflammation is not fully understood, there is clear evidence that infiltrating immune cells in adipose tissue, mainly macrophages, play a significant role in this process (28). Physiologically, immune cells from both main lines, myeloid and lymphoid, contribute to tissue repair and apoptosis of damaged or infected cells, with the production of different cytokines and other pro-inflammatory factors such as free radicals, nitric oxide and others (29). With adipose tissue expansion and its dysregulation, together with the occurrence of ectopic fat depot, increased circulating concentration of inflammatory cytokines occurs, and this can potentially modulate atheroma development. Endothelium expresses adhesion molecules, such as ICAM and VCAM, which recruit inflammatory cells including monocytes and lymphocytes and can further propagate inflammation in the vessel wall. This eventually promotes the development of the atherosclerotic lesion by inducing a proliferation of vascular smooth muscle cells and the secretion of pro-coagulant factors such as PAI-1 (13). Therefore we hypothesized that the observed decrease in cIMT after obesity surgery in men could be mainly associated with an amelioration of inflammation and endothelial dysfunction. Despite many studies showing in the past a decrease of several inflammatory markers after obesity surgery (15, 30, 31), to our best knowledge ours is the first one that explores this association with cIMT and circulating androgens in a prospective design in men directly comparing the effects of RYGB with SG.
Among the different inflammatory markers analyzed in the present study, IL-18 has been associated with increased cardiovascular risk (32), obesity (33, 34) and insulin resistance (35). It can be secreted in adipose tissue (36), up-regulated by other inflammatory cytokines (37), and able to stimulate the production of both tumor necrosis factor-α and IL-6, which in turn can induce the production of CRP in the liver (38). IL-6 may cause progression of atherosclerosis by induction of endothelial dysfunction and lipoprotein oxidation, and it is an independent risk factor for coronary artery disease (29). CRP is also associated with higher risk of cardiovascular disease as those individuals with obesity and higher CRP show higher coronary artery calcium scores and increased cIMT (39). All these cytokines have been shown to decrease after obesity surgery (15, 30, 31, 40) and to be associated with a postsurgical decrease in cIMT (14, 41). In our present study, we have been able to confirm a decrease of IL-18 and CRP after both RYGB and SG, but multivariate analysis retained only CRP together with sTWEAK and PAI-1 as those variables associated with the observed changes in cIMT.
TWEAK is a cytokine belonging to the tumor necrosis factor superfamily that induces a high number of physiological and pathological processes depending on cell type through its receptor fibroblast growth factor inducible 14 (Fn14) (42). Both TWEAK and Fn14 are expressed in the arterial wall, both in healthy arteries and atherosclerotic plaques (43), and participate in different stages of atherosclerotic plaque development (44). sTWEAK is a 156-aa proteolytic product derived from the full-length, membrane-bound TWEAK and binds the Fn14 receptor (45). Under pathological conditions such as atherosclerosis, arterial Fn14 expression is upregulated, thus favoring sTWEAK binding and retention in the pathological tissues and decreasing its circulating levels. Therefore, low levels of sTWEAK are found in different atherosclerotic states such as stable coronary artery disease, chronic kidney disease or peripheral artery disease (46). In our study, the increase in sTWEAK after both RYGB and SG compared to controls was associated, after the multivariate analysis, with the decrease in cIMT in men, in agreement with previously reported data of our own from a cohort of women submitted to obesity surgery (17).
PAI-1 is a member of the serine protease inhibitor superfamily that regulates the fibrinolytic system through inhibition of tissue plasminogen activator and urokinase-type plasminogen activator, and it is considered the main inhibitor of fibrinolysis (47). Elevated plasma levels of PAI-1 have been associated with obesity, the metabolic syndrome and cardiovascular disease. PAI-1 is produced by a variety of cells contained in adipose tissue: pre-adipocytes, mature adipocytes, stromal cells, endothelial cells, smooth muscle cells and macrophages (48); and therefore PAI-1 levels directly correlate with cIMT both in young and adult obese subjects (49). Moreover, high circulating concentrations of PAI-1, together with insulin resistance and the presence of the metabolic syndrome, predicted higher cIMT and/or carotid atherosclerotic plaque (50). We previously reported a decrease in PAI-1 after obesity surgery in women, but failed to demonstrate a correlation with the decrease in cIMT (17). Conversely, our present data show that in men, PAI-1 decreases after both RYGB and SG and it is associated with the decrease in cIMT after surgery.
Our present study has the major limitation of the lack of randomization in the allocation of the patients to the different groups of interventions. In addition, the generalizability of the results is limited because we here evaluated the patients after a short-term period of 6 months, so long-term beneficial effects of obesity surgery on cIMT and cardiovascular events could not be evaluated.
In conclusion, both RYGB and SG induce an amelioration of inflammation and endothelial dysfunction that drives a decrease in cIMT compared to men with obesity submitted to diet and exercise. Although circulating testosterone was inversely correlated with this decrease in cIMT, multivariate analysis did not confirm this finding.