Metabolic Syndrome and Early Death: Getting to the Heart of the Problem
P. W. Franks, T. Olsson
T his editorial appraises an article in the current issue of Hypertension that examines the prospective relationships between features of the metabolic syndrome (MetS) and early death in a population-based cohort form Northern Italy. 1 We also discuss, in light of that study's findings, how relevant conventional definitions of the MetS are for identifying individuals at high risk of early death. The MetS describes a constellation of metabolic and cardiovascular disease risk factors. Although
... ying definitions of the MetS exist, all of the commonly used definitions include a measure of obesity, hyperglycemia, hypertension, and dyslipidemia. 2-4 These definitions are based on "expert" opinion and not on evidence derived from prospective studies, which would be preferable. Thus, it remains uncertain whether the component features of the MetS or the thresholds at which each component is defined as present or absent are informative and optimal for predicting risk of disease or early death. It is also undetermined whether MetS represents a distinct pathophysiological entity. Notwithstanding these issues, the syndrome is extensively used in research studies, and many advocate its use in clinical practice 5 to identify people at high risk of cardiovascular disease and early death. The idea that cardiovascular risk factors with a common etiology cluster in certain individuals at high risk of cardiovascular disease was first popularized by Reaven 6 in the 1980s, although the origins of the MetS date back much earlier. 7 Reaven's 6 emphasis was on elucidating the underlying pathophysiology of cardiovascular disease, for which he postulated that insulin resistance plays a pivotal role, and not on developing a diagnosis of MetS, which could be used in clinical practice. Superficially, at least, MetS relates strongly with cardiovascular morbidity and early death 8 ; this is perhaps unsurprising, because so too do each of the component features of the syndrome. However, for the MetS to have greater clinical or scientific utility than the singular components requires that the level of risk conveyed by MetS exceeds the total level of risk conferred when all of the MetS components are considered simultaneously; in other words, the whole should exceed the sum of its parts. If this were true, it would support the view that the components of the MetS have a common etiology and that Ն2 of the components positively interact. If, however, the level of risk was equal for the syndrome and the sum of its components, a common etiology might exist, but the components could not, on average, be said to interact. Alternatively, if the total risk was less for MetS compared with the sum of its components, the likely explanation would be that the risk conveyed by Ն2 of the components overlap. In this last example, using MetS to identify high-risk individuals would be inefficient and could unnecessarily complicate the choice of treatments. Whether the objective is to test the validity of existing definitions of MetS or to define a new evidence-based definition, large prospective studies of population-based cohorts with baseline measures of the MetS components and welldefined end points are necessary. In this issue of Hypertension, Mancia et al 1 report data from the Pressioni Arteriose Monitorate E Loro Associazioni Study, a longitudinal observation cohort study of cardiovascular risk factors and mortality conducted in a population-based cohort of 2013 adults from the town of Monza in Northern Italy. The main objective of this study was to assess the relationship between MetS and early death during 12 years of follow-up. Sixteen percent of the cohort fulfilled the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS. 3 The adjusted hazard rate ratios for cardiovascular and all-cause mortality associated with MetS in the entire study population were Ϸ1.7 and 1.4, respectively, which were both of modest statistical significance. Mancia et al 1 determined that not all of the components of the MetS significantly contribute to the prediction of mortality. For those that do (ie, blood pressure and hyperglycemia), the pathological processes that link elevations in these traits with fatal events are well described elsewhere, and it is clear that both factors can independently and, in combination, severely damage vital organs and tissues. Mancia et al 1 also examined the contributory role of cardiac function assessed using echocardiography (left ventricular hypertrophy and left ventricular mass index) and elevated ambulatory blood pressure to mortality risk, both of which were present to a greater degree in people with MetS than in those without. When the risk of death associated with MetS was calculated only in people with left ventricular hypertrophy (nϭ266), the hazard rate ratios increased to 3.0 and for all-cause death to 8.2. These estimates were highly statistically significant. This observation suggests that in people with left ventricular hypertrophy, MetS results in a substantial increase in the risk of dying from noncardiovascular causes, which would include neoplasms, neurodegenera-The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.