Serum endocan as a predictive biomarker of cardiovascular risk in obese pediatric patients

Endocan, formerly called endothelial cell-specific molecule-1 (ESM-1), is a soluble dermatan sulfate proteoglycan (50 kDa) expressed by endothelial cells of dermal, coronary, pulmonary and adipose tissue microvasculature. It is secreted into the bloodstream, where it is found at concentrations of 0.5–1 ng/ml in the plasma of healthy subjects [1, 2].

Endocan may be involved in molecular interactions with a variety of biologically active modalities essential for the regulation of biological processes related to cell adhesion, migration, proliferation, leukocyte migration, and neovascularization [3]. Endocan also plays a role in the development of vascular disease, inflammation process, and endothelial dysfunction [4]. Moreover it acts on endothelial cells, promoting the action of vascular endothelial growth factor-A (VEGF-A) on its receptor (VEGFR-2) and inducing endothelial permeability [2]. Endocan level is significantly increased in various diseases such as cancer, sepsis, pneumonia, pulmonary thromboembolism, diabetes mellitus, rheumatoid arthritis, osteoarthritis and cardiovascular diseases [3, 4]. In addition, Endocan may have prognostic role for these diseases and patient outcomes [4, 5].

Endocan has been proposed in several studies as a novel endothelial mediator that stimulates the proliferation and migration of vascular smooth muscle cells, and may contribute to neointima formation during atherogenesis, leading to the thickening of the intima-media layer [6]. Thus, endocan with its inflammatory and pro-angiogenic effects may play a role in the process of atherosclerosis [7]. Furthermore endocan levels may reflect a condition of vascular inflammation [8], with possible implications in the pathophysiology of hypertension, as demonstrated in a cohort of adult patients [9]. It is well known that children with obesity are at increased risk of developing hypertension, dyslipidemia, impaired glucose tolerance, insulin resistance or type2 diabetes mellitus and early atherosclerosis, with a consequent increased risk for cardiovascular disease over time [9, 10]. In clinical practice, it would be desirable to stratify this risk with a noninvasive and easy tool in order to obtain prognostic marker and endocan would own all these features.

The aims of present study were 1) to compare fasting serum endocan levels between children with obesity and healthy controls and 2) to investigate the relationships of endocan with body mass index (BMI) and other indices of cardiometabolic risk.

Thirty-eight children were consecutively recruited, including 19 Caucasian children with obesity and 19 normal-weight controls, matched for age (11.94 ± 0.52 vs 10.32 ± 0.96 years; p = 0.07), sex (9 males/10 females vs 9 males/10 females). Liver and kidney function tests were normal in the entire population. Table 1 shows the physical and biochemical features of the total sample.

Children with obesity had higher LDL, n-HDL, insulin, HOMA and alanine aminotransferase (ALT) values than healthy controls; conversely, HDL levels were lower in children with obesity (Table 1).

Fasting endocan concentration was significantly higher in children with obesity compared to controls (2.03 ± 0.15 vs 1.51 ± 0.12 ng/ml; p = 0.02) (Table 1).

Correlation analysis revealed a positively association only with insulin level (rho = 0.47; p = 0.04). No significant correlation with BMI values, fasting glucose and lipid profile was found. However, our data showed the association, with a trend toward the statistical significance, between endocan and HOMA-IR (rho 0.43; p = 0.07) ( Fig. 1).

Only 12 children with obesity underwent abdomen ultrasound (informed consent was not obtained in 7 cases). The presence of steatosis was reported in 5 cases. No significant correlation between presence and grade of steatosis and endocan levels was found (Table 2 and Fig. 2).

Childhood obesity is one of the major public health problems worldwide rising due to sedentary lifestyles and unhealthy diets. It is important to emphasize that a child with obesity is very likely to become an adult with obesity: the rate of probability increases with age and is directly proportional to the degree of obesity [15]. For a preschooler child with obesity, the probability of becoming an adult with obesity ranges from 26 to 41%; for school-aged children, this percentage reaches 69% and for adolescents with obesity 83% [16]. The association between obesity and increased risk of serious long-term adult complications such as arterial hypertension, dyslipidemia, impaired glucose tolerance, IR, pre-diabetes or type 2 diabetes mellitus and early atherosclerosis is well established [15]. IR is an important link between obesity and associated cardiovascular risk and it has been suggested as one of the early mechanisms for the development of endothelial dysfunction in young individuals with obesity [17, 18]. Indeed, IR is associated with specific central body fat distribution in adolescents with obesity and the onset of metabolic syndrome in childhood [18, 19]. Moreover, recent studies have shown that HOMA-IR levels are closely related to the lipid profile of the pediatric population and that the initial changes in glucose metabolism, found in prepubertal children with obesity, may be one of the factors leading to increased arterial intima thickness [17, 18]. In addition, some studies have shown that adolescents with obesity, with higher levels of intrahepatic steatosis (despite comparable levels of obesity in their peers), have increased fasting glucose levels and systemic IR, and most have significant cardiovascular risk [14, 20, 21].

Furthermore, obesity leads to low-grade chronic inflammation and in obese individuals, in addition to the synthesis of pro-inflammatory cytokines (such as IL-6 and TNFα), a reduction of anti-inflammatory cytokines (such as adiponectin) is observed in adipose tissue [3, 4, 22]. These conditions lead to chronic inflammation and endothelial dysfunction, which form the basis of the atherosclerotic process and increase cardiovascular risk factors [23, 24].

Thus, the close correlation between childhood obesity and cardiovascular risk is well established. For this reason is very important to find an easily accessible marker to stratify cardiovascular risk also for children with obesity. Several studies, as already mentioned, in the medical literature have shown that Endocan plays an important role in the development of vascular disease, inflammation process, and endothelial dysfunction [3, 4, 22]. In our research, in agreement with previous ones, we demonstrated that Endocan serum levels were higher in subjects with obesity compared to the healthy group, moreover, we also found that plasma Endocan levels were significantly related to insulinemia levels. Our results also showed the association, with a trend toward the statistical significance, between endocan and HOMA-IR. We also looked at the relationship between Endocan levels and hepatic steatosis; unfortunately, the small sample size was the main limitation of our research, and not all patients underwent abdominal ultrasound scans, which affected the statistical significance of the data obtained. To date, only another study has examined the association between Endocan and hepatic steatosis in a population of children with obesity, and the results are similar to ours [7]. A previous study in adult patients with obesity, with or without steatosis, reported reduced plasma levels of Endocan compared with healthy lean subjects [10]. The different results between our study and this study may be due to a possible fluctuation in the expression of Endocan during physiological development in children [7]. To date, few studies have been conducted in pediatric populations. This study may provide a basis for future studies.

Our study demonstrates that Endocan levels are significantly increased in subjects with obesity and that can be correlated with the major metabolic disorders associated with obesity. Although preliminary, our data suggested that Endocan has an important diagnostic and prognostic role that could be used to improve the future management of children with obesity at increased cardio-metabolic risk.