Thus, elevated CRP serum levels indicative of a systemic inflammatory response are associated with a blunted systemic endothelial vasodilator function. The identification of elevated CRP levels as a transient independent risk factor for endothelial dysfunction might provide an important clue to link a systemic marker of inflammation to atherosclerotic disease progression.

Background-Nitric oxide (NO)-and prostacyclin-independent vasodilatation in several vascular beds has been linked to the activation of cytochrome P450 (CYP) epoxygenases expressed in endothelial cells. However, these enzymes, which generate vasodilator epoxyeicosatrienoic acids, may also produce oxygen-derived free radicals, which attenuate the bioavailability of NO. Here, we studied the involvement of CYP 2C9 in modulating endothelium-dependent and -independent changes in forearm blood flow (FBF) in healthy volunteers and in patients with manifest coronary artery disease. Methods and Results-The effects of sulfaphenazole, a selective inhibitor of CYP 2C9, on endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside, SNP) FBF responses were measured by venous occlusion plethysmography in 5 healthy subjects and in 16 patients with angiographically documented stable coronary artery disease. Sulfaphenazole did not modify FBF responses to acetylcholine or SNP in healthy subjects. In contrast, sulfaphenazole markedly and dose-dependently enhanced the FBF response to acetylcholine without affecting the response to SNP. Vitamin C also increased the FBF response to acetylcholine, but this effect was further potentiated by sulfaphenazole. In the presence of N -monomethyl-L-arginine, sulfaphenazole failed to significantly improve acetylcholine-induced vasodilatation. The oxidation of serum proteins was enhanced in patients with coronary artery disease, and this effect was significantly attenuated by sulfaphenazole. Conclusions-The CYP 2C9 inhibitor sulfaphenazole enhances endothelium-dependent vasodilator responses in patients with manifest coronary artery disease. This effect seems to be related to an increase in the bioavailability of NO, probably as a consequence of an attenuated generation of reactive oxygen species by CYP 2C9 in endothelial cells.

Background-Endothelial vasodilator dysfunction may serve as a marker integrating the vascular risk of an individual; however, whether systemic vasodilator function predicts disease progression and cardiovascular event rates in patients with manifest acute coronary syndromes (ACS) is unknown. Methods and Results-In 198 patients with angiographically documented ACS, forearm blood flow (FBF) responses to acetylcholine (ACH; 10 to 50 g/min) and sodium nitroprusside (SNP; 2 to 8 g/min) were measured by venous occlusion plethysmography before hospital discharge within 5 days of an episode of an ACS. Cardiovascular events (cardiovascular death, myocardial infarction, and ischemic stroke) served as outcome variables over a mean follow-up period of 47.7Ϯ15.1 months. Patients who experienced cardiovascular events during follow-up (nϭ31) had a significantly reduced vasodilator response to ACH (PϽ0.05) and SNP (PϽ0.05). By multivariate analysis, vasodilator response to ACH and elevated troponin T serum levels were the only significant (PϽ0.05) independent predictors of a poor prognosis, even after adjustment for traditional cardiovascular risk factors, concurrent medication, invasive treatment strategy, and C-reactive protein serum levels. Recovery of endothelium-dependent vasoreactivity as assessed by repeated FBF assessment 8 weeks after the index measurement after the ACS predicted further event-free survival in a subset of 78 patients. Conclusions-Systemic endothelium-dependent vasoreactivity predicts recurrence of instability and cardiovascular event rates in patients with ACS. Furthermore, the recovery of systemic endothelial function is associated with event-free survival. Assessment of systemic vasoreactivity, measured by a minimally invasive test, provides important prognostic information in addition to that derived from traditional risk factor assessment in patients with ACS.

Background — Anti–tumor necrosis factor (TNF)-α therapy with etanercept, a recombinant TNF receptor that binds to and functionally inactivates TNF-α, was shown to improve the functional status of patients with congestive heart failure (CHF). Because administration of TNF-α has been shown experimentally to depress endothelium-dependent relaxation, we hypothesized that TNF-α antagonism with etanercept might improve the depressed systemic endothelial vasodilator function, which importantly contributes to increased peripheral vascular resistance in patients with advanced CHF. Methods and Results — Endothelium-dependent (acetylcholine, ACH; 10 to 50 μg/min) and endothelium-independent (sodium nitroprusside, SNP; 2 to 8 μg/min) forearm blood flow (FBF) responses were measured by venous occlusion plethysmography in 13 patients with documented CHF (New York Heart Association class III) before, 6 hours after, and 7 days after subcutaneous injection of a single dose of 25 mg etanercept. Maximum ACH-induced FBF increased significantly from 6.9±1.0 to 13.0±1.6 mL/min per 100 mL of forearm tissue ( P <0.05) 6 hours after administration of etanercept and returned to 7.0±1.1 mL/min per 100 mL of forearm tissue after 7 days ( P =NS), whereas SNP-induced FBF responses were not significantly affected. In contrast, FBF responses were not altered in control CHF patients, who did not receive etanercept (n=5). Etanercept-induced increases in ACH-mediated FBF were closely correlated with baseline TNF-α serum levels ( r =0.66; P <0.02). Conclusions — The administration of etanercept profoundly improves systemic endothelial vasodilator capacity in patients with advanced heart failure, suggesting an important role of inflammatory mediators for impaired endothelial vasoreactivity in CHF. Improvement of systemic endothelial function might importantly contribute to the beneficial effects of etanercept on the functional status of patients with CHF.

Thus, increased IL-10 serum levels are associated with improved systemic endothelial vasoreactivity in patients with elevated CRP serum levels, demonstrating that the balance between pro- and anti-inflammatory mediators is a major determinant of endothelial function in patients with CAD.