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CLINICAL RESEARCH: BIOMARKERS

Adipokines, Insulin Resistance, and Coronary Artery Calcification

Atif Qasim, MD^_*, Nehal N. Mehta, MD^_*, Mahlet G. Tadesse, ScD, Megan L. Wolfe, BS^_*, Thomas Rhodes, MSPH, Cynthia Girman, DrPH and Muredach P. Reilly, MB^_*,_*

^_* Cardiovascular Institute and Institute for Translational Medicine and Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Department of Mathematics, Georgetown University, Washington, DC
Department of Epidemiology, Merck Research Laboratories, West Point, Pennsylvania.

Manuscript received January 29, 2008; revised manuscript received April 25, 2008, accepted April 28, 2008.

^_* Reprint requests and correspondence: Dr. Muredach P. Reilly, Cardiovascular Institute, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Boulevard, Philadelphia, Pennsylvania. (Email: muredach{at}spirit.gcrc.upenn.edu).

Objectives: We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary artery calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, metabolic syndrome, and plasma C-reactive protein (CRP).

Background: Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.

Methods: We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, nondiabetic participants in the SIRCA (Study of Inherited Risk of Coronary Atherosclerosis).

Results: Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance, and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjustment for age, gender, traditional risk factors, and Framingham risk scores (tobit regression ratio 2.42 (95% confidence interval [CI]: 1.48 to 3.95; p = 0.002) and further adjustment for metabolic syndrome and CRP (tobit regression ratio: 2.31; 95% CI: 1.36 to 3.94; p = 0.002). In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, interleukin-6, and soluble tumor necrosis factor receptor-2, as well as the homeostasis model assessment of insulin resistance (HOMA-IR) index, predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, metabolic syndrome, and CRP.

Conclusions: In SIRCA, although both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.

Key Words: adiponectin • leptin • coronary artery calcification • atherosclerosis • inflammation

Abbreviations and Acronyms   BMI = body mass index   CAC = coronary artery calcium   CAD = coronary artery disease   CRP = C-reactive protein   CVD = cardiovascular disease   FRS = Framingham risk score   HOMA-IR = homeostasis model assessment of insulin resistance   IL = interleukin   IMT = intima-media thickness   LRT = likelihood-ratio test   sol-TNFR2 = soluble tumor necrosis factor receptor-2

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