Vascular consequences of metabolic syndrome in early life.

The presence of the metabolic syndrome, a clustering of metabolic risk factors closely associated with abdominal obesity, is accompanied by an increased risk for the development of cardiovascular diseases and type 2 diabetes mellitus. It is now generally accepted that insulin resistance together with abdominal obesity are key features in the pathophysiology of the metabolic syndrome. As a result of total body energy dysbalance, adipocytes in abdominal adipose tissue enlarge and start producing chemotactic factors, such as monocyte chemoattractant protein-1 (MCP-1) attracting monocytes/macrophages. This dysfunctional abdominal adipose tissue produces large quantities of free fatty acids, adipokines, and inflammatory cytokines, e.g. interleukin-6 (IL-6) and tumour necrosis factor-a (TNF-a), that are secreted into the systemic circulation and contribute to pathophysiological processes leading to cardiovascular diseases and type 2 diabetes mellitus. Abdominal adipose tissue has a unique anatomical relationship with the liver. Cytokines produced by abdominal adipose tissue are released into the portal circulation, influencing liver production of haemostatic and proinflammatory proteins and cytokines [C-reactive protein (CRP), IL-6], further increasing systemic inflammation and activating haemostasis. The cardiovascular risk associated with the metabolic syndrome has been shown in cohorts of middle-aged patients with and without clinically manifest vascular diseases. The study of Mattson et al. extends our knowledge of the vascular risk of metabolic syndrome to young adults. In their study, using different definitions of metabolic syndrome, it was shown that the presence of metabolic syndrome in early life is already associated with increased carotid intima-media thickness (cIMT) and decreased carotid artery compliance, established measures of subclinical atherosclerosis. Compared with young adults without metabolic syndrome, the subjects with metabolic syndrome were abdominally obese and, as a result, had higher blood pressure and triglycerides and lower high-density lipoprotein (HDL)-cholesterol plasma concentrations. In a recent study by Baker et al., it was shown that overweight in childhood was associated with an increased cardiovascular risk in later life. It is conceivable that overweight children have a high chance of developing metabolic syndrome in young adulthood, accompanied by subclinical atherosclerosis, and develop clinical manifestations of atherosclerosis in later life. The implications of these studies are that treatment of metabolic syndrome may need to be started in early life by reducing weight and increasing physical activity. Ideally, development of overweight is prevented by starting at a young age. This is not only the domain of clinical medicine but more a matter for society. Although the case for metabolic syndrome is building up, there are several issues that still need to be addressed. First, there are several definitions for the ‘diagnosis’ of metabolic syndrome. In general, all definitions are based on similar clinical criteria but differ in the cut-off values used. In the study of Mattson et al., there was no difference between the different definitions of metabolic syndrome as to the presence of subclinical atherosclerosis. In studies with clinical vascular end-points, the metabolic syndrome based on criteria defined by ATPIII was associated with the highest risk for developing (recurrent) cardiovascular diseases. Although fairly arbitrary cut-off values have been used in the ATPIII-defined metabolic syndrome, this definition seems to work very well in identifying patients at high risk for developing cardiovascular diseases. Modification of diagnostic criteria for metabolic syndrome by advanced modelling using continuous variables rather than dichotomized criteria may further increase the prognostic abilities of the ATPIII definition. Critics point towards the lack of additive prognostic information for the syndrome compared with the individual components of metabolic syndrome. From a prognostic standpoint that may be the case, but from an aetiological point of view metabolic syndrome adds important information as to the cause of the clustering of important