Elsevier

Atherosclerosis

Volume 236, Issue 1, September 2014, Pages 18-24
Atherosclerosis

Circulating cytokines in relation to the extent and composition of coronary atherosclerosis: Results from the ATHEROREMO-IVUS study

https://doi.org/10.1016/j.atherosclerosis.2014.06.010Get rights and content

Highlights

  • Grayscale and VH-IVUS was performed in 581 patients undergoing coronary angiography.

  • We measured TNF-α, TNF-β, TNF receptor 2, interferon-γ, IL-6, IL-8, IL-10 and IL-18.

  • TNF-α was positively associated with coronary plaque burden and VH-TCFA lesions.

  • IL-10 was inversely associated with coronary plaque burden and large VH-TCFA lesions.

Abstract

Objective

We investigated whether concentrations of TNF-α, TNF-β, TNF-receptor 2, interferon-γ, IL-6, IL-8, IL-10 and IL-18 are associated with extent and composition of coronary atherosclerosis determined by grayscale and virtual histology (VH)- intravascular ultrasound (IVUS).

Methods

Between 2008 and 2011, IVUS(-VH) imaging of a non-culprit coronary artery was performed in 581 patients (stable angina pectoris (SAP), n = 261; acute coronary syndrome (ACS), n = 309) undergoing coronary angiography from the ATHEROREMO-IVUS study. Plaque burden, presence of VH-IVUS-derived thin-cap fibroatheroma (TCFA) lesions, and presence of VH-TCFA lesions with plaque burden ≥70% were assessed. Blood samples for cytokine measurement were drawn from the arterial sheath prior to the angiography procedure. We applied linear and logistic regression.

Results

TNF-α levels were positively associated with plaque burden (beta (β) [95%CI]: 4.45 [0.99–7.91], for highest vs lowest TNF-α tertile) and presence of VH-TCFA lesions (odds ratio (OR) [95%CI] 2.30 (1.17–4.52), highest vs lowest TNF-α tertile) in SAP patients. Overall, an inverse association was found between IL-10 concentration and plaque burden (β [95%CI]: −1.52 [−2.49 to −0.55], per Ln (pg/mL) IL-10) as well as IL-10 and VH-TCFA lesions with plaque burden ≥70% (OR: 0.31 [0.12–0.80],highest vs lowest IL-10 tertile). These effects did not reach statistical significance in the separate SAP and ACS groups.

Conclusion

Higher circulating TNF-α was associated with higher plaque burden and VH-TCFA lesions in SAP patients. Lower circulating IL-10 was associated with higher plaque burden and large VH-TCFA lesions. These in-vivo findings suggest a role for these cytokines in extent and vulnerability of atherosclerosis.

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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