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Title: Short-term fenofibrate treatment reduces elevated plasma Lp-PLA2 mass and sVCAM-1 levels in a subcohort of hypertriglyceridemic GOLDN participants

Author
item TSAI, ALEXANDER - University Of Minnesota
item STEFFEN, BRIAN - University Of Minnesota
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item STRAKA, ROBERT - University Of Minnesota
item ZHOU, XIA - University Of Minnesota
item HANSON, NAOMI - University Of Minnesota
item ARNETT, DONNA - University Of Alabama
item TSAI, MICHAEL - University Of Minnesota

Submitted to: Translational Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/27/2011
Publication Date: 8/1/2011
Citation: Tsai, A.K., Steffen, B.T., Ordovas, J.M., Straka, R.J., Zhou, X., Hanson, N.Q., Arnett, D.K., Tsai, M.Y. 2011. Short-term fenofibrate treatment reduces elevated plasma Lp-PLA2 mass and sVCAM-1 levels in a subcohort of hypertriglyceridemic GOLDN participants. Translational Research. 58(2):99-105.

Interpretive Summary: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that in humans is encoded by the PLA2G7 gene. In the blood it travels mainly with low-density lipoprotein (LDL) and it is produced by inflammatory cells and hydrolyzes oxidized phospholipids in LDL. High levels of Lp-PLA2 are associated with inflammation, atherosclerosis, and coronary heart disease events. In addition, Lp-PLA2 has been linked to classical markers of endothelial activation, including soluble vascular cell adhesion molecule-1 (sVCAM-1). Although treatment with fenofibrate reduces Lp-PLA2, it is unclear whether fenofibrate reduces sVCAM-1 levels Concentrations of Lp-PLA2 and sVCAM-1 were measured in plasma at before and after 3 weeks of fenofibrate treatment in 96 hypertriglyceridemic (HTG) participants of the Genetics of Lipid-lowering Drugs and Diet Network study. Fenofibrate treatment resulted in approximately 30% increase in Lp-PLA2 and approximately 15% increase in sVCAM-1 levels but only in those with low baseline levels of either target. In contrast, Lp-PLA2 was reduced by approximately 35% in those with high baseline levels. VCAM-1 levels were significantly reduced by approximately 8% and 17% in those with medium and high levels, respectively. In conclusion, fenofibrate treatment in HTG reduced the levels of Lp-PLA2 and sVCAM-1, but only in those with elevated baseline levels of these biomarkers and therefore, at high cardiovascular risk.

Technical Abstract: High levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with inflammation, atherosclerosis, and coronary heart disease events. In addition, Lp-PLA(2) has been linked to classical markers of endothelial activation, including soluble vascular cell adhesion molecule-1 (sVCAM-1). Although treatment with fenofibrate reduces Lp-PLA(2) mass, it is unclear whether fenofibrate reduces sVCAM-1 levels or whether an association exists between any changes observed in Lp-PLA(2) and sVCAM-1. Concentrations of Lp-PLA(2) mass and sVCAM-1 levels were measured in plasma at baseline and after 3 weeks of fenofibrate treatment (160 mg/d) in 96 hypertriglyceridemic participants of the Genetics of Lipid-lowering Drugs and Diet Network study. Lp-PLA(2) and sVCAM-1 were stratified by tertiles as determined by baseline levels of the respective target. Fenofibrate treatment resulted in a 30.1% mean increase in Lp-PLA(2) mass (P = 0.0003) and a 14.7% mean increase in sVCAM-1 levels (P = 0.0096) but only in tertile1 of either target. In contrast, Lp-PLA(2) mass was reduced by 35.3% (P less than 0.0001) in tertile 3. Soluble VCAM-1 levels were significantly reduced by 7.74% (P = 0.0109) and 17.2% (P less than 0.0001) in tertiles 2 and 3, respectively. No associations were observed between Lp-PLA(2) and sVCAM-1 at baseline or post-treatment. In conclusion, fenofibrate treatment in hypertriglyceridemic subjects reduced the levels of Lp-PLA(2) mass and sVCAM-1, but only in those with elevated baseline levels of these biomarkers. The greatest reductions in Lp-PLA(2) levels were observed in individuals with Lp-PLA(2) concentrations indicative of increased cardiovascular disease risk (greater than 200 ng/mL).