Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic 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,Erik S.G Stroes

doi:10.1194/jlr.p600014-jlr200

Abstract

C-reactive protein (CRP) has been suggested to exert direct adverse effects on the vasculature in experimental setups, including endothelial dysfunction and proinflammatory changes. Here, we assessed the consequences of 1.25 mg/kg highly purified recombinant human CRP, administered as an 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 (maximum, 89.2 +/- 30.0% vs. 117.7 +/- 13.1% in normolipidemic subjects; P = 0.037). Procoagulant activity was also higher in FH patients, illustrated by increased prothrombin fragment 1+2 (F(1+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 with normolipidemic subjects (P = 0.009 for F(1+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 evokes augmented procoagulant responses. These findings suggest that particularly in hypercholesterolemia, CRP-lowering strategies should be considered in addition to LDL reduction.

Highlights

C-reactive protein (CRP) has been suggested to exert direct adverse effects on the vasculature in experimental setups, including endothelial dysfunction and proinflammatory changes
To further explore the potential proatherogenic function of CRP in humans, we evaluated the impact of CRP infusion on vascular reactivity, inflammation, and coagulation in subjects with increased Low density lipoprotein-cholesterol (LDL-C) levels [familial hypercholesterolemia (FH)] as well as in normolipidemic subjects
Higher body mass index values were found in the FH patients (P 5 0.025), whereas blood pressure, heart rate, and forearm blood flow (FBF) were not different

Summary

Introduction

C-reactive protein (CRP) has been suggested to exert direct adverse effects on the vasculature in experimental setups, including endothelial dysfunction and proinflammatory changes. Human studies addressing the concept of CRP adversely affecting the vessel wall are warranted In this respect, we recently found that CRP infusion elicits the activation of inflammatory and coagulation pathways in healthy volunteers [12]. We considered that CRP infusion would have a greater impact on endothelial vasoreactivity in humans with hypercholesterolemia The basis for this hypothesis are several observations in different animal species of hypercholesterolemia showing exaggerated responses, including endothelial dysfunction, to experimental endotoxemia [14, 15]. To further explore the potential proatherogenic function of CRP in humans, we evaluated the impact of CRP infusion on vascular reactivity, inflammation, and coagulation in subjects with increased LDL-C levels [familial hypercholesterolemia (FH)] as well as in normolipidemic subjects

Methods

Results

Conclusion