The metabolic syndrome: more than the sum of its parts?

The prevalence of obesity has risen dramatically in the United States.1 This has led to a marked increase in the metabolic syndrome (MetSyn), a clustering of atherosclerotic cardiovascular disease risk factors characterized by visceral adiposity, insulin resistance, low HDL cholesterol (HDL-C), and a systemic proinflammatory state.2 In the United States, the MetSyn affects roughly 25% of adults over the age of 20 and up to 45% of the population over 50. These observations have focused attention on the role of metabolic derangements in the development of cardiovascular disease. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines highlighted the key features of this syndrome and proposed a clinical definition to facilitate diagnosis and preventive interventions.3 This binary definition is based on having at least 3 of 5 criteria (Table). The diagnosis of the MetSyn appears to identify substantial additional cardiovascular risk above and beyond the individual risk factors.4 Therefore, the clinical diagnosis of MetSyn may be a valuable tool for identification of the elusive high-risk patient. Distinct pathophysiological components of the MetSyn need to be defined if we are to identify the life-style and pharmacological interventions that will succeed in modulating the primary abnormalities of the disorder. Factor analysis has been applied to data from epidemiological studies to reduce the large number of related metabolic variables into a smaller set of core factors.5 Such studies suggest that key components of the MetSyn include central obesity, insulin resistance, dyslipidemia, and hypertension, in addition to chronic inflammation, procoagulation, and impaired fibrinolysis.6 However, current clinical MetSyn guidelines do not incorporate inflammatory or hemostatic factors. In fact, a situation is evolving in clinical practice in which the use of traditional risk factors, absolute risk quantification, diagnosis of the MetSyn, and consideration of inflammatory biomarkers are being considered without global integration of their impact on cardiovascular risk. One approach to dealing with these apparently conflicting needs is to build a broad and inclusive framework of the underlying molecular mechanisms of the MetSyn and to use this as a point of reference for patient-oriented experiments, epidemiological and genetic studies, randomized clinical trials, and clinical practice.