Elsevier

Atherosclerosis

Volume 235, Issue 2, August 2014, Pages 606-612
Atherosclerosis

The relationship of novel adipokines, RBP4 and omentin-1, with carotid atherosclerosis severity and vulnerability

https://doi.org/10.1016/j.atherosclerosis.2014.05.957Get rights and content

Highlights

  • Elevated RBP4 levels in patients with established carotid atherosclerosis.

  • Serum RBP4 levels parallels the degree of carotid stenosis.

  • Positive and independent association of RBP4 with carotid total plaque area.

  • Low omentin-1 levels are associated with established carotid atherosclerosis.

  • Univariate association of low omentin-1 serum levels with GSM score and symptoms.

Abstract

Objective

We investigated the relationship of circulating novel adipokines, retinol-binding protein 4 (RBP4) and omentin-1, with advanced carotid atherosclerosis and ultrasound indexes of severity (total plaque area-TPA) and plaque echogenicity and vulnerability (Gray-Scale median – GSM score).

Methods

We enrolled 225 patients with high-grade carotid stenosis (HGCS) who underwent carotid revascularization (73 Symptomatic patients, 152 asymptomatic patients) and 75 age- and sex-matched, asymptomatic individuals with low-grade (<50%) carotid stenosis (LGCS). Seventy-three individuals without current manifestations of atherosclerotic disease served as control group (COG). All participants underwent carotid ultrasound with TPA and GSM score assessment. Moreover, clinical parameters, metabolic profile, and circulating levels of hsCRP and adipokines were assessed.

Results

RBP4 was significantly elevated in HGCS (51.44 ± 16.23 mg/L) compared to LGCS (38.39 ± 8.85 mg/L), independent of symptoms existence, whereas RBP4 levels in COG were even lower (25.74 ± 10.72 mg/L, p < 0.001 compared to either HGCS or LGCS). Inversely, serum omentin-1 levels were significantly lower across HGCS (490.41 ± 172 ng/ml) and LGCS (603.20 ± 202.43 ng/ml) than COG (815.3 ± 185.32, p < 0.001). Moreover, the considerable difference between HGCS and LGCS (p < 0.001) was exclusively attributed to the excessive suppression of omentin-1 concentrations in symptomatic versus asymptomatic (p = 0.004) patients. HGCS and LGCS did not differ in the rest of clinical and biochemical parameters. In multiple regression analysis, RBP4 (beta = 0.232, p = 0.025) and hsCRP (beta = 0.300, p = 0.004) emerged as independent determinants of TPA in patients with carotid atherosclerosis. Low serum levels of omentin-1 correlated with GSM score and symptoms but that association was lost in multivariate analysis..

Conclusion

RBP4 serum levels were significantly elevated in patients with established carotid atherosclerosis and were positively associated with atherosclerosis severity. The association of low serum omentin-1 with carotid plaque echolucency requires further investigation..

ClinicalTrials.gov Identifier: NCT00636766.

Introduction

Cerebral ischemia is one of the most important causes of morbidity and mortality in industrialized countries, associated with considerable medical and socio-economic burden [1]. Carotid artery stenosis as a causative factor of ischemic strokes or transient ischemic attacks (TIAs) constitutes a major therapeutic target of primary and secondary prevention strategies [2]. Randomized controlled trials and subsequent meta-analyses have demonstrated the degree of carotid stenosis as the gold-standard criterion for effective carotid revascularization in combination with best medical treatment in patients with symptoms (≥50% stenosis) and some selected patients without symptoms (≥80% stenosis) [3]. In addition to the magnitude of atherosclerosis, emerging evidence supports the prognostic power of plaque vulnerability in carotid atherosclerosis evolution [4]. Thereby, insights into the quantitative evaluation of both total plaque area (TPA) and texture would help to identify potentially high risk atherosclerotic lesions that would most benefit from intervention [5].

We know from numerous clinical and experimental trials that inflammation plays a pivotal role in the development and destabilization of carotid plaques [6], [7]. In vivo, the inflammatory process can easily be monitored by serum inflammatory biomarkers assay. Novel pro-inflammatory and anti-inflammatory derivatives from adipose tissue, known as adipokines, have recently been associated with carotid atherosclerosis [8]. Among them, retinol-binding protein 4 (RBP4) has emerged as a potential mediator of the interplay between obesity, insulin resistance, and inflammation [9], [10]. A growing body of evidence supports the positive relationship of RBP4 with the presence of either coronary artery disease (CAD) [11], [12] or subclinical carotid atherosclerosis [13]. However, the role of RBP4 in established carotid atherosclerosis is still obscure.

Another newly identified adipokine, omentin-1, has been intimately linked with protective mechanisms against obesity and insulin resistance [14]. Moreover, low plasma levels of omentin-1 have been measured in patients with extended CAD [15], or carotid atherosclerosis [16]. Nevertheless, no previous study has examined the interaction of omentin-1 with carotid atherosclerosis severity and vulnerability.

Taken together, the primary aim of the current study was to investigate the relationship of both RBP4 and omentin-1 serum levels with the presence and the ultrasonographically quantified severity of established carotid atherosclerosis. We also tested the hypothesis that these biomarkers correlate with ipsilateral neurological symptoms and valid ultrasound indices of plaque vulnerability.

Section snippets

Patients

In the present study we enrolled patients with established carotid atherosclerosis and individuals without current manifestations of atherosclerotic diseases. All participants underwent ultrasound examination of both carotids. Carotid atherosclerosis was characterized by the presence of at least one atherosclerotic plaque localized at the internal carotid artery (ICA) or the common carotid artery (CCA). Atherosclerotic plaque was defined as a focal structure encroaching into the arterial lumen

Comparison between established carotid atherosclerosis and controls

Results are depicted in Table 1. Patients with established carotid atherosclerosis showed significantly higher frequency of major cardiovascular risk factors, such as smoking habit, diabetes, hypertension and dyslipidemia, than individuals in the control group. Moreover, they appeared with higher concentrations of RBP4 and inflammatory markers (hsCRP and white blood cells count) (p < 0.05) and lower concentrations of omentin-1 (p < 0.001) than control counterparts.

Subgroup analysis revealed

Discussion

To our knowledge this is the first study evaluating the relationship of novel adipokines, RBP-4 and omentin-1, with ultrasonographically assessed carotid TPA and density. Our cross-sectional study showed significantly higher RBP4 and lower omentin-1 circulating levels in patients with carotid atherosclerosis compared to individuals without atherosclerotic manifestations. Moreover, serum RBP-4 levels were positively related to plaque area scoring (TPA), independent of traditional cardiovascular

Conflict of interest

All authors declare no conflict of interest.

Acknowledgments

Co-funded by the Operational Program “Competitiveness and Entrepreneurship” and Regional Operational Programmes of the National Strategic Reference Framework (NSRF) 2007-2013. “SYNERGASIA”: “Collaborative projects of small and medium scale” (09ΣΥΝ-12-1054).

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