Abstract 15501: The 5-Lipoxygenase Inhibitor Zileuton Improves Endothelial Function in Carriers of Coronary Heart Disease Risk Haplotypes in the ALOX5AP and LTA4H Leukotriene Pathway Genes
Background: Genome wide linkage studies have identified variants in the leukotriene synthesis pathway as conferring risk of coronary heart disease (CHD) and are associated with greater levels of the inflammatory mediator leukotriene B4 (LTB4). We sought to determine whether therapy with an orally active 5-lipoxygenase (5-LO) inhibitor in CHD patients carrying the risk haplotypes would reduce LTB4 synthesis and improve endothelial function.
Methods: A subset of 10 patients (Caucasian males; mean age 60.5±4.5) undergoing coronary angiography were identified and recruited from the Emory Cardiology Biobank, based on carriage of at least one copy of a leukotriene risk haplotype (Hap A, B or K). We measured (1) endothelial function as flow mediated dilatation (FMD) of the brachial artery, (2) ex vivo LTB4 production in isolated and ionomycin-stimulated neutrophils, (3) plasma aminothiol markers of oxidant stress, and (4) markers of inflammation including CRP and interleukin 6 (IL6) at baseline; after 2 and 4 weeks of continuous Zileuton therapy (600mg, 4 times daily) and again after discontinuing the drug at 6, 8 and 20 weeks.
Results: After 4 weeks of drug therapy there was a statistically significant increase in FMD compared to baseline (p=0.02) suggesting improved endothelial function, which reached a peak 2 weeks after drug discontinuation (p=0.007). LTB4 production mirrored these changes, decreasing over 4 weeks, and was significantly lower than baseline at 6 weeks (p=0.01). Both FMD and LTB4 levels returned to baseline values at 20 weeks after drug discontinuation (p=NS for both) (Figure 1). There were no significant trends in plasma markers of oxidative stress, CRP or IL-6 levels.
Conclusions: Administration of a 5-LO inhibitor in subjects selected for leukotriene risk haplotypes reduces LTB4 levels and in parallel improves endothelial dysfunction in patients with CAD. Further randomized trials are needed to explore the implications of these findings.
- © 2011 by American Heart Association, Inc.