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Plasma Cytokines, Metabolic Syndrome, and Atherosclerosis in Humans
  1. Muredach P. Reilly*,
  2. Anand Rohatgi*,
  3. Kimberly McMahon,
  4. Megan L. Wolfe,
  5. Shailesh C. Pinto,
  6. Thomas Rhodes,
  7. Cynthia Girman,
  8. Daniel J. Rader
  1. From the Cardiovascular Institute and Institute of Translational Medicine and Therapeutics (M.P.R., K.M., M.L.W., S.C.P., D.J.R.), Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; Division of Cardiology (A.R.), University of Texas Southwestern Medical Center; and Department of Epidemiology (T.R., C.G.), Merck Research Laboratories, West Point, PA.
  1. *Authors who contributed equally to this work.
  2. This work was supported by grant M01-RR00040 from the National Center for Research Resources (NCRR)/National Institutes of Health supporting the University of Pennsylvania General Clinical Research Center and in part by a research grant to Dr. Rader from Merck Research Laboratories. Dr. Reilly is supported by the National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and NCRR and by the W.W. Smith Charitable Trust (#H0204), as well as by research funding or honoraria from GlaxoSmithKline, Merck & Co., Ely Lilly Inc, and KOS Pharmaceuticals; Dr Rader is supported by grants from the NHLBI, NIDDK, and NCRR and is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and a recipient of a Doris Duke Distinguished Clinical Investigator Award. Dr. Rader is involved as a consultant to or is in receipt of research funding or honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, KOS Pharmaceuticals, Merck & Co, Merck/Schering-Plough, Pfizer, Schering-Plough, and Takeda; Drs. Rohatgi and Pinto and Ms. McMahon and Ms. Wolfe have no conflict of interest; Drs. Rhodes and Girman are employees of Merck & Co.
  3. This article was presented in abstract form at the 54th Annual Scientific Session, American College of Cardiology, Orlando, FL, March 8, 2005.
  4. Address correspondence to: Dr. Muredach P. Reilly, Cardiovascular Division, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Blvd, Philadelphia, PA 19104-6160; e-mail: muredach{at}spirit.gcrc.upenn.edu.

Abstract

Background Interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) integrate inflammatory and adipose signaling but also have direct vascular effects. We hypothesized that plasma levels of IL-6 and soluble tumor necrosis factor α receptor 2 (sol-TNFR2) would be related to coronary atherosclerosis beyond established risk factors and the metabolic syndrome.

Methods We examined the association of IL-6 and sol-TNFR2 with metabolic syndrome, C-reactive protein (CRP), and coronary artery calcification (CAC) in 875 asymptomatic participants in the Study of Inherited Risk of Coronary Atherosclerosis.

Results IL-6 levels were 56% higher (p < .001) and sol-TNFR2 levels 16% higher (p < .001) in subjects with metabolic syndrome compared with those without. Both cytokines were associated with CAC beyond age, gender, Framingham risk scores, family history, metabolic syndrome, and CRP (odds ratio and 95% confidence interval of higher CAC for 1 SD increase in log-transformed cytokine levels: 1.23 [1.06-1.43], p = .006 for IL-6 and 1.15 [1.01-1.31], p = .04 for sol-TNFR2). In fact, cytokine levels were independently associated with CAC scores in the subgroup with metabolic syndrome and were additive to the homeostasis model assessment of insulin resistance in predicting CAC.

Conclusions Plasma IL-6 and sol-TNFR2 levels were independently associated with CAC, suggesting a role in integrating innate immune and adipose signaling in promoting atherosclerosis and cardiovascular risk. Measurement of their levels may facilitate cardiovascular risk prediction and targeting of therapeutic strategies.

Key words
  • atherosclerosis
  • cytokines
  • metabolic syndrome

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