Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease

Low-grade chronic inflammation, characterized by elevated plasma concentrat ions of C-reactive protein (CRP), is associated with an increased risk of a therosclerotic cardiovascular disease. Endothelial cell activation is an ea rly event in atherogenesis, and previous studies have reported correlations between indirect markers of endothelial cell activation and CRP concentrat ion. Therefore, in the present study, we measured CRP concentration (and le ptin concentration as an index of fat mass) in nine healthy subjects (mean age 53+/-8.1 years; body mass index 27 +/- 3.2 kg/m(2); mean arterial blood pressure 101 +/- 9.0 mmHg) undergoing measurement of basal endothelial nit ric oxide (NO) synthesis using intra-brachial infusions of N-G-monomethyl-L -arginine (L-NMMA; a substrate inhibitor of endothelial NO synthase) and no radrenaline (a nonspecific control vasoconstrictor). In univariate analysis , CRP concentration was correlated with (i) the percentage decrease in fore arm blood flow (FBF) during L-NMMA infusion (r = 0.85, P = 0.004); and (ii) the serum leptin concentration (r = 0.65, P = 0.05). In multivariate analy sis, the relationship between CRP concentration and the FBF response to L-N MMA remained significant when age and leptin (t = 2.65, P = 0.045), age and BMI (t = 3.69, P = 0.014), or age and low-density-lipoprotein-cholesterol plus high-density-lipoprotein-cholesterol (t = 3.37, P = 0.044), were inclu ded in regression models. In contrast, the response of FBF to noradrenaline was not significantly related to CRP concentration. These data demonstrate for the first time a relationship between low-grade chronic inflammation a nd basal endothelial NO synthesis (measured using an invasive method), and support the notion that endothelial dysfunction is a critical intermediate phenotype in the relationship between inflammation and cardiovascular disea se.