Abstract
BackgroundThere is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Patients with lower neutrophil counts following acute coronary syndromes tend to have a greater coronary flow reserve, which is a strong predictor of long-term cardiovascular health. But so far, no data are available regarding the impact of neutrophil inhibition on cardiovascular clinical or surrogate endpoints. Therefore, the aim of this study is to investigate the effects of AZD5069, a cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibitor, on coronary flow reserve and coronary structure and function in patients with coronary artery disease.Methods/DesignNinety subjects with coronary artery disease undergoing percutaneous coronary intervention will be included in this investigator-driven, randomised, placebo-controlled, double-blind, phase IIa, single-centre study. Participants will be randomised to receive either AZD5069 (40 mg) administered orally twice daily or placebo for 24 weeks. Change in coronary flow reserve as determined by 13N-ammonia positron emission tomography-computed tomography will be the primary outcome. Change in the inflammatory component of coronary plaque structure and the backward expansion wave, an invasive coronary physiological measure of diastolic function, will be assessed as secondary outcomes.DiscussionCardiovascular surrogate parameters, such as coronary flow reserve, may provide insights into the potential mechanisms of the cardiovascular effects of CXCR2 inhibitors. Currently, ongoing trials do not specifically focus on neutrophil function as a target of intervention, and we therefore believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease.Trial registrationEudraCT, 2016-000775-24. Registered on 22 July 2016.International Standard Randomised Controlled Trial Number, ISRCTN48328178. Registered on 25 February 2016.
Highlights
There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture
Ongoing trials do not focus on neutrophil function as a target of intervention, and we believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease
Secondary objective The secondary objectives of the study are to ascertain, in patients undergoing percutaneous coronary intervention (PCI) for atherosclerotic coronary disease, if 24 weeks of Cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibition therapy will result in a reduction in the inflammatory component of coronary plaque, a decrease in the degree of in-stent restenosis and improvements in coronary microvascular function compared with placebo
Summary
There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Atherosclerosis involves recruitment of leucocytes (predominantly neutrophils and monocytes) to sites of vascular injury. This is triggered by the accumulation of oxidised low-density lipoprotein (LDL) within the intima, which stimulates endothelial cells to express an atherosclerotic phenotype and leads to the adherence of leucocytes on their surface. Neutrophils are over-represented in the vasculature of patients with unstable atherosclerotic plaque [4] and are associated with histologic features of plaque vulnerability [5, 6] In addition to these established structural changes, a high-fat meal has been shown to elicit a mild neutrophilia along with endothelial dysfunction [7]. Colchicine, a known neutrophil chemotaxis inhibitor, has been shown to reduce vascular events in patients with coronary heart disease [8]
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