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.

Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor κB

“…Our results do not address the potential therapeutic efficacy of longer-term, lower-dose salsalate treatment in this or other groups. In contrast to short-term salsalate administration in the present study and previous investigation in overweight/obese adults [16], recent work in patients with type 2 diabetes [30] and coronary artery disease [37] found no improvements in FMD with longer-term administration of salicylate-based compounds (salsalate and sulfasalazine, respectively). These differences may result from differences in compounds and dosing, concurrent use of medications such as statins, ACE inhibitors and/or metformin that improve endothelial dysfunction, or different etiologies of endothelial dysfunction among these groups.…”

Angiopoietin‐Like 2 Promotes Atherogenesis in Mice

“…The relative contribution of inflammation versus hypercholesterolemia in atherogenesis is a recurrent question in the field of atherosclerosis . Short‐term intervention with sulfasalazine, an inhibitor of NFκB, in patients with coronary artery disease has not been successful in reversing endothelial dysfunction, whereas in a small group of patients with recent acute coronary syndrome, inhibition of the leukotriene‐generating enzyme 5‐lipoxygenase reduced inflammation and plaque progression . More studies are ongoing to further decipher the exact contribution of inflammation in atherogenesis …”

The Effect of Salsalate Therapy on Endothelial Function in a Broad Range of Subjects

“…Salsalate therapy has had conflicting results on endothelial function in patients with HIV . Tabit and colleagues found no effect of sulfasalazine therapy on endothelial function in patients with coronary artery disease . Similarly, Goldfine et al found no difference in FMD in diabetic subjects treated with high‐dose salsalate therapy .…”