Effects of CRP-infusion on endothelial function and coagulation in normo- and hypercholesterolemic subjects

Radjesh J. Bisoendial, John J. P. Kastelein, Stephan L. M. Peters, Johannes H. M. Levels, Rakesh Birjmohun, Joris I. Rotmans, Daniel Hartman, Joost C. M. Meijers, Marcel Levi, and Erik S.G. Stroes

vascular medicine, Academic Medical Center, Amsterdam 1105 AZ

Corresponding Author: r.j.bisoendial{at}amc.uva.nl

C-reactive protein (CRP) has been suggested to exert direct adverse effects on the vasculature in experimental setups, including endothelial dysfunction and pro-inflammatory changes. Here, we assessed the consequences of 1·25 mg/kg highly purified recombinant human (rh)CRP, administered as a intravenous bolus, in six patients with familial hypercholesterolemia (FH) and six normocholesterolemic subjects. Endothelium-dependent and –independent vasoreactivity to serotonin and nitroprusside, respectively, were assessed using venous occlusion plethysmography before and after CRP-infusion. For biochemical analyses, blood was drawn at different time-points. At baseline, FH-patients showed blunted endothelium-dependent vasodilation (max 89·2±30·0% versus 117·7±13·1% in normolipidemic subjects; p=0·037). Procoagulant activity was also higher in FH-patients, illustrated by elevated prothrombin fragment 1+2 (F1+2) levels (p=0·030) and plasminogen activator inhibitor type-1 (PAI-1) activity (p=0·016). Upon CRP-challenge, endothelium-dependent vasodilator capacity further deteriorated in FH-patients (p=0·029), whereas no change in vascular reactivity was observed in normolipidemic subjects. Additionally, coagulation activation was augmented in FH-patients compared to normolipidemic subjects (p=0·009 for F1+2 levels; p=0·018 and p=0·003 for PAI-1 antigen and activity, respectively). No difference in inflammatory responses was observed between groups. In hypercholesterolemic patients, CRP aggravates endothelial dysfunction and also evoke augmented procoagulant responses. These findings suggest that particularly in hypercholesterolemia, CRP-lowering strategies should be considered in addition to LDL-reduction.

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