Effect of sulfasalazine on inflammation and endothelial function in patients with established coronary artery disease

Abstract

Inflammation is critical for atherosclerosis development and may be a target for risk-reduction therapy. In experimental studies, activation of the inflammatory regulator, nuclear factor kappa B (NFlB), contributes to endothelial activation and reduced nitric oxide production. We treated patients with coronary artery disease with sulfasalazine, an inhibitor of NFκB, and placebo in a randomized, double-blind, crossover study design. Brachial artery flow-mediated dilation (FMD) and digital vascular function were measured at baseline and after each 6-week treatment period. Of the 53 patients enrolled in the crossover study, 32 (age 60 ± 10, 22% female) completed all the visits, with a high rate of study withdrawal due to gastrointestinal side effects. In a subset of 10 participants, we compared the effects of 4 days of sulfasalazine treatment (n = 5) to no treatment (n = 5) on NFκB-regulated gene expression in peripheral blood mononuclear cells. Tumor necrosis factor α-stimulated expression of CD69 and NFlB subunit p50 was significantly blunted after 4 days of sulfasalazine treatment but not after no treatment. However, FMD and digital vasodilator response did not significantly change from baseline with long-term sulfasalazine treatment. Short-term sulfasalazine inhibited NFlB activity; however, long-term treatment was poorly tolerated and did not improve endothelial function. Our findings suggest that sulfasalazine therapy is not the optimal anti-inflammatory treatment for reversing endothelial dysfunction in cardiovascular disease. Further studies are warranted to investigate the potential for NFlB inhibition to reduce cardiovascular risk.

Trial registration: ClinicalTrials.gov NCT00554203.

Figures

Figure 1

Study Design. For the crossover study, participants were randomized to sulfasalazine treatment first (top row) or placebo first (bottom row) and received the assigned treatment for 6 weeks (one 500mg or placebo pill twice daily for one week, then two 500mg or placebo pills twice daily for 5 weeks). After a two-week rest period, the participants crossed over to the alternate treatment.

Figure 2

Consolidated Standards of Reporting Trials (CONSORT) flow diagram.

Figure 3

Effect of sulfasalazine on NFκB mediated inflammatory activity. Peripheral blood mononuclear cells were isolated as described in the methods section before and after 4 days of sulfasalazine treatment (1000mg twice daily) in 5 patients with coronary artery disease. Expression levels of NFκB-regulated genes were assessed with quantitative PCR after two hours of treatment with TNFα at 0, 1, and 10ng/ml. P value shown for comparison of overall gene expression before and after sulfasalazine treatment.