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(Circulation. 2007;116:984-992.)
© 2007 American Heart Association, Inc.

Epidemiology

Multimarker Approach to Evaluate the Incidence of the Metabolic Syndrome and Longitudinal Changes in Metabolic Risk Factors

The Framingham Offspring Study

Erik Ingelsson, MD, PhD; Michael J. Pencina, PhD; Geoffrey H. Tofler, MD; Emelia J. Benjamin, MD, ScM; Katherine J. Lanier, MA; Paul F. Jacques, MD; Caroline S. Fox, MD, MPH; James B. Meigs, MD, MPH; Daniel Levy, MD; Martin G. Larson, ScD; Jacob Selhub, PhD; Ralph B. D’Agostino, Sr, PhD; Thomas J. Wang, MD^*; Ramachandran S. Vasan, MD^*

From the Framingham Heart Study, Boston University School of Medicine, Framingham, Mass (E.I., M.J.P., E.J.B., C.S.F., D.L., M.G.L., R.B.D., T.J.W., R.S.V.); Department of Mathematics (M.J.P., K.J.L., R.B.D.) and Cardiology Division and Preventive Medicine (E.J.B., R.S.V.), Boston University School of Medicine, Boston, Mass; Royal North Shore Hospital, Sydney, Australia (G.H.T.); Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Mass (P.F.J., J.S.); Division of Endocrinology, Brigham and Women’s Hospital, Boston, Mass (C.S.F.); Department of Medicine (J.B.M.) and Cardiology Division (T.J.W.), Massachusetts General Hospital, Boston (T.J.W.); and National Heart, Lung, and Blood Institute, Bethesda, Md (D.L.).

Correspondence to Ramachandran S. Vasan, MD, FACC, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702–5803. E-mail vasan{at}bu.edu

Received April 10, 2007; accepted June 15, 2007.

Background— The metabolic syndrome (MetS) is associated with increased cardiovascular risk. We evaluated the relative contributions of circulating biomarkers representing distinct biological pathways to the incidence of MetS and to longitudinal changes of its constituent risk factors.

Methods and Results— We measured 8 circulating biomarkers reflecting inflammation (C-reactive protein), hemostasis (plasminogen activator inhibitor-1, fibrinogen), neurohormonal activity (aldosterone, renin, B-type natriuretic peptide, N-terminal proatrial natriuretic peptide), and endothelial dysfunction (homocysteine) in 2292 Framingham Offspring Study participants (mean age, 57 years; 56% women). We related the biomarker panel to incidence of MetS on follow-up initially and then related biomarkers associated with incident MetS to longitudinal change in its components. On follow-up (mean, 2.9 years), 282 participants (of 1473 participants without prevalent MetS at baseline) developed MetS. After adjustment for clinical risk factors, the biomarker panel was associated with incident MetS (P=0.008). On backward elimination, plasminogen activator inhibitor-1 and aldosterone remained associated with incident MetS (multivariable-adjusted odds ratio per 1-SD increment log marker, 1.31 [P=0.004] and 1.21 [P=0.015], respectively). In multivariable analyses evaluating longitudinal change in MetS components (analyzed as continuous variables), plasminogen activator inhibitor-1 was significantly and positively associated with changes in fasting glucose, systolic blood pressure, and triglycerides (all P<0.05). Serum aldosterone was associated positively with change in systolic blood pressure (P=0.023) and inversely with change in high-density lipoprotein cholesterol (P=0.001).

Conclusions— Higher circulating plasminogen activator inhibitor-1 and aldosterone levels are associated with the development of MetS and with longitudinal change of its components, suggesting that these biomarkers and related pathways play a key role in mediating metabolic risk.

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