title: 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.
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Corey E
authors.initials: CE
authors.lastname: Tabit
authors.forename: Monica
authors.initials: M
authors.lastname: Holbrook
authors.forename: Sherene M
authors.initials: SM
authors.lastname: Shenouda
authors.forename: Mustali M
authors.initials: MM
authors.lastname: Dohadwala
authors.forename: Michael E
authors.initials: ME
authors.lastname: Widlansky
authors.forename: Alissa A
authors.initials: AA
authors.lastname: Frame
authors.forename: Brian H
authors.initials: BH
authors.lastname: Kim
authors.forename: Mai-Ann
authors.initials: MA
authors.lastname: Duess
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Kluge
authors.forename: Aaron
authors.initials: A
authors.lastname: Levit
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Vita
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Hamburg
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001900:Boston; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D005385:Fingers / Q000098:blood supply*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008365:Manometry; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011237:Predictive Value of Tests; D012460:Sulfasalazine / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D018608:Ultrasonography, Doppler; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D018836:Inflammation Mediators; D016328:NF-kappa B; D012460:Sulfasalazine