European Heart Journal Advance Access published online on June 8, 2006
European Heart Journal, doi:10.1093/eurheartj/ehl079
1 Department of Internal Medicine, Section of Vascular Medicine, University Medical Center Utrecht, F02.126, Heidelberglaan 100, PO Box 85500, 3508 GA Utrecht, The Netherlands
* To whom correspondence should be addressed. Aims Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)- Methods and results A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF- Conclusion Pioglitazone treatment can convey direct protection against cytokine (TNF-
Received October 10, 2005
Revised April 24, 2006
Accepted May 19, 2006
Clinical research
TNF-
Fabrice M.A.C. Martens 1,
Ton J. Rabelink 2,
Jos op 't Roodt 2,
Eelco J.P. de Koning 2,
and
Frank L.J. Visseren 1 *
induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-
agonist pioglitazone
2 Department of Nephrology, Leiden University Medical Center, The Netherlands
Frank L.J. Visseren, E-mail: F.L.J.Visseren{at}umcutrecht.nl
Abstract 
, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-
agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF- on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus. (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF- infusion (P=0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF--induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-, interleukin-6, soluble TNF--receptors, or CD40L were observed.)-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes..
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