Abstract 16901: Leukotriene Production by the 5-lipoxygenase Pathway is Linked to Microvascular Dysfunction
Introduction: 5-lipoxygenase (5-LO) and 5-lipoxygenase activating protein (FLAP) are essential for production of leukotrienes (LTs), lipid mediators with inflammatory and vasoactive actions. Inhibition of 5-LO (VIA-2291) reduced atherosclerosis in a Ph2 study and both 5-LO and FLAP inhibition reduce atherosclerosis in animal disease models. Coronary flow velocity reserve (CFVR) reflects coronary artery stenosis and microvascular function.
Hypothesis: LTs are related to CFVR after acute coronary syndrome (ACS) and inhibition of LT production will improve CFVR.
Methods: Clinical - the relationship between CFVR and LTB4 production in blood was examined in 50 patients 4 months post ACS. Preclinical - the effect of treatment with the FLAP inhibitor AZD6642 was assessed in 30 NZW rabbits. Prior to treatment rabbits were challenged with high fat diet (HFD) for seven weeks. Plasma cholesterol, LTs and atherosclerosis (IMT assessed with ultrasound) were measured after the HFD priming period and served as baseline. After 12 weeks ± treatment with AZD6642, cholesterol, atherosclerosis and CFVR were evaluated. Biomarkers of FLAP inhibition (LTB4, LTC4) were followed during the treatment time. Chow diet was given during the treatment period to mimic the effect of lipid lowering treatment and to focus on the anti-inflammatory and microvascular benefits of AZD6642. At termination, histological analyses and vessel mRNA expression analyses were performed. All statistical tests are one-sided in accordance with the hypotheses.
Results: Clinical - there was an inverse correlation between LTB4 and CFVR (p=0.026, r=-0.30) four months post ACS. Preclinical - AZD6642 reduced LTB4 & LTC4 production in blood (p<0.05) and in aortic tissue homogenates (p<0.001). Atherosclerosis progressed slowly during the treatment period and was not affected by AZD6642 when measured either as IMT change or by histology. However, CFVR was improved by AZD6642 at 12 weeks (p=0.037) and there was an inverse relationship between LTB4 production in blood and CFVR (p=0.004, r=-0.48).
Conclusions: LTB4 and CFVR was inversely correlated in patients following an ACS and in atherosclerotic rabbits. AZD6642 efficiently reduced LTs and improved CFVR in rabbits.
Author Disclosures: J. Wikström: Employment; Significant; AstraZeneca RnD. D. Karlsson: Employment; Significant; AstraZeneca RnD. M. Behrendt: Employment; Significant; AstraZeneca RnD. S. Swedlund: None. H. Westergren: Employment; Significant; AstraZeneca RnD. D. Hovdal: Employment; Significant; AstraZeneca RnD. M. Sundquist: Employment; Significant; AstraZeneca RnD. A. Andréasson: Employment; Significant; AstraZeneca RnD. A. Jönsson-Rylander: Employment; Significant; AstraZeneca RnD. M. Månsson: Ownership Interest; Modest; Owns stock in AstraZeneca plc. C. Whatling: Employment; Significant; AstraZeneca RnD. L. Gan: Employment; Significant; AstraZeneca RnD.
- © 2016 by American Heart Association, Inc.