Circulating cytokines in relation to the extent and composition of coronary atherosclerosis: Results from the ATHEROREMO-IVUS study
Introduction
Inflammation is known to play a major role in atherosclerosis [1], [2], [3]. The development of atherosclerosis includes, among others, expression of adhesion molecules by inflamed endothelium, migration of leukocytes into the intima, uptake of modified lipoprotein particles, and formation of lipid-laden macrophages [4]. During the evolution of atherosclerotic lesions, T-lymphocytes join the macrophages in the intima [4]. This T-cell infiltrate produces proinflammatory cytokines (including tumor necrosis factors (TNFs), interferons (IFNs), and interleukins (ILs)), but may also stimulate a T helper cell type 2 (Th2) response which can promote anti-inflammatory actions (and cytokines such as IL-10 and transforming growth factor β) [2], [5]. This dual role of cytokines is believed to control the subsequent development and destabilization of arherosclerotic plaques in coronary (among other) arteries [6], potentially leading to plaque rupture or erosion and ultimately resulting in adverse clinical events such as myocardial infarction or sudden cardiac death [7].
While previous research has provided ample insights into the signaling cascades of cytokines and their roles in the pathogenesis of atherosclerosis, studies on the associations of cytokines with in-vivo determined extent and particularly composition of coronary atherosclerosis are currently scarce. Cytokines are located both inside the affected vessel walls and in the circulation [8]. We hypothesize that circulating cytokines are associated with in-vivo measures of plaque burden and features of plaque vulnerability, and consequently may be useful for clinical risk stratification with regard to cardiovascular outcome.
The aim of this study is to examine the associations of the cytokines TNF-α, TNF-β, interferon γ (IFNγ), IL-6, IL-8, IL-10 and IL-18 and of circulating TNF receptor 2 (TNF R2) with the extent and composition of coronary atherosclerosis as determined in-vivo by intravascular ultrasound (IVUS) and IVUS-virtual histology (IVUS-VH), in a non-culprit vessel in patients undergoing coronary angiography.
Section snippets
Study population
The design of The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis – Intravascular Ultrasound (ATHEROREMO-IVUS) study has been described elsewhere [9]. In brief, 581 patients who underwent diagnostic coronary angiography or percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS; n = 309) or stable angina pectoris (SAP; n = 261) have been included from November 2008 to January 2011 in the Erasmus MC, Rotterdam, the Netherlands.
Baseline characteristics
Baseline characteristics are summarized in Table 1. Mean age was 61.5 ± 11.4 years and 75.4% were men. Coronary angiography or PCI was performed for several indications: 159 (27.9%) patients had an acute myocardial infarction, 150 (26.3%) patients had unstable angina pectoris and 261 (45.8%) had SAP. The median length of the imaged coronary segment was 44.1 [33.7–55.4] mm. Based on IVUS-VH, a total of 239 (41.9%) patients had at least 1 TCFA lesion, including 69 (12.1%) patients with at least 1
Discussion
This study examined whether circulating cytokine concentrations are associated with extent and composition of coronary atherosclerosis, as determined by IVUS and IVUS-VH in a non-culprit vessel, in patients with SAP or ACS undergoing coronary angiography. In patients with SAP, higher concentrations of TNF-α were associated with higher coronary plaque burden and with presence of VH-TCFA lesions, and displayed a tendency towards a positive association with presence of VH-TCFA lesion with a plaque
Conflict of interest
All authors have read the final version and approved submission of the manuscript. The manuscript is an original work that has not been published and is not under consideration for publication elsewhere in whole or in part in any language. There was no commercial association that might pose a conflict of interest in connection with this manuscript.
Acknowledgments
We would like to thank the following interventional cardiologists and technical staff for their contribution to this study: Eric Duckers, MD, PhD; Willem van der Giessen, MD, PhD; Peter P.T. de Jaegere, MD, PhD; Jurgen M.R. Ligthart; Evelyn Regar, MD, PhD; Carl Schultz, MD, PhD; Karen T. Witberg and Felix Zijlstra, MD, PhD. We are indebted to Professor Willem van der Giessen, who provided a valuable contribution to the design and completion of the study, but passed away before finalization of
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These authors contributed equally to this work.