Elsevier

Vascular Pharmacology

Volume 51, Issues 5–6, November–December 2009, Pages 331-336
Vascular Pharmacology

Diminished omega-3 fatty acids are associated with carotid plaques from neurologically symptomatic patients: Implications for carotid interventions

https://doi.org/10.1016/j.vph.2009.08.003Get rights and content

Abstract

The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are prevalent in fish oil and their cardioprotective effects are thought to be mediated by anti-inflammatory mechanisms. The aim of this study is to determine whether omega-3 fatty acids are associated with carotid plaques from neurologically symptomatic patients. Plaques were obtained from 41 patients (mean age 62 [44–84]; 24-asymptomatic, 17-symptomatic). Intra-plaque lipids were assessed with mass spectrometry. Compared to asymptomatic patients, significantly diminished omega-3 fatty acids DHA (545.8 ± 98 ng/g vs. 270.7 ± 19.6 ng/g, p = 0.0096) and EPA (385.9 ± 68 ng/g vs. 216.4 ± 17.6 ng/g, p = 0.0189) were found in carotid plaques from neurologically symptomatic patients. However, no differences were found in the levels of the omega-6 fatty acid arachidonic acid (p = 0.2003). Immunohistochemistry and ELISA analysis (CD68+ cells, 0.461 ± 0.04 vs. 0.312 ± 0.03, p = 0.003) demonstrated an increased inflammatory infiltrate in plaques from neurologically symptomatic, compared to asymptomatic, patients. Carotid plaques from neurologically symptomatic patients are inflammatory and have decreased intra-plaque levels of omega-3 fatty acids. Future trials will determine whether interventions that increase omega-3 fatty acid incorporation into carotid plaques prevent stroke and improve the safety of carotid interventions.

Graphical abstract

A, B) Omega-3 (EPA and DHA) but not C) omega-6 (AA) fatty acids are decreased in unstable carotid plaques. Mean with 10th–90th percentile shown; ⁎P-value  .05 denotes significance; two-tailed unpaired t-test was used.

Introduction

Increasing evidence suggests that consumption of long-chain omega-3 polyunsaturated fatty acids (PUFAs) protects against cardiovascular disease, especially fatal myocardial infarction and sudden cardiac death (Kromhout et al., 1985, Tavani et al., 2001, Lemaitre et al., 2003). Since humans cannot synthesize the omega-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), intake comes predominantly from consumption of fish or fish oil. The cardiovascular protection of omega-3 PUFAs may occur independently of their lipid-lowering effect (Leaf et al., 2005). Omega-3 fatty acids have anti-inflammatory (Calder, 2006) and anti-arrhythmic effects (Leaf et al., 2005, Kang and Leaf, 2000), and may improve endothelial function (Schiano et al., 2008).

Atherosclerotic plaques arise in the vessel intima and are thought to be a result of cholesterol deposition, hemodynamic strain, and inflammation (Libby et al., 2002). Rupture of the fibrous cap leads to a transition from a stable or asymptomatic to an unstable or symptomatic atherosclerotic plaque. This plaque rupture results in clinically relevant sequelae; in the coronary bed, atherosclerotic plaque rupture leads to a myocardial ischemic event and, in the carotid artery, atherosclerotic plaque rupture leads to an ocular or cerebral ischemic event. These latter events manifest as amaurosis fugax, transient ischemic attacks, or stroke. The mechanisms leading to atherosclerotic plaque rupture are not completely understood and various inflammatory molecules have been hypothesized to play a role (Miller et al., 2007). One set of molecules purported to be involved with carotid plaque instability are omega-3 PUFAs (Thies et al., 2003). Thies et al. demonstrated that supplementation with fish oil can lead to PUFAs incorporation into carotid atherosclerotic plaques, thickening the fibrous caps, potentially stabilizing them (Thies et al., 2003). Patients undergoing carotid endarterectomy (CEA) are ideally suited for studying the biochemical mechanisms involved in the transition from an asymptomatic to a symptomatic atherosclerotic plaque primarily due to the ease of harvesting the tissue samples.

One potential mechanism leading to decreased cardiovascular events is via atherosclerotic plaque stabilization through the anti-inflammatory effects of omega-3 PUFAs. We sought to determine whether patients with advanced carotid plaques, undergoing CEA, had differential levels of omega-3 PUFAs incorporated into the plaques, and whether these levels of PUFAs were correlated with plaque symptomatology and inflammation.

Section snippets

Study design

Patients with at least 50% internal carotid artery stenosis undergoing carotid endarterectomy were included in this study. Informed consent was obtained after approval through the Louisiana State University Health Sciences Center Institutional Review Board and the Veterans Affairs Connecticut Healthcare System. For each enrolling patient, the age, sex, history of cardiac disease, chronic renal insufficiency (defined as a serum creatinine  1.6 mg/dL), diabetes, hypertension, and history of

Results

Carotid atherosclerotic plaques were obtained from 41 patients (35 male; mean age 62, ages 44–84); 24 (59%) were considered asymptomatic and 17 (41%) symptomatic (Table 1). There were no significant differences in the distribution of patient comorbidities, including cardiac disease, chronic renal insufficiency, diabetes mellitus, hypertension, and tobacco use; no differences in overall atherosclerotic burden could be assessed between the two groups. Of those patients with symptomatic carotid

Discussion

We demonstrate that carotid plaques from neurologically symptomatic patients are more inflammatory and composed of diminished omega-3, but not omega-6, polyunsaturated fatty acids compared to asymptomatic carotid plaques. We found a significant correlation between symptomatic carotid atherosclerotic plaques, reduced omega-3 PUFA content, and increased inflammation, as evidenced by CD68+ staining and quantification. Though not statistically significant, we observed a trend towards an increased

Acknowledgment

We thank the LSUHSC Gene Therapy Morphology and Imaging Core for technical assistance with the immunohistochemistry and Frank Abbruscato, BS, for his technical assistance with protein extraction and performance of ELISA assays.

This material is the result of work partially supported by National Institutes of Health–National Center for Research Resources (NIH-NCRR), NIH P20 RR018766 ‘Mentoring in Cardiovascular Biology’ (HAB) , NIH Career Development Award K08-HL079927, the American Vascular

References (20)

There are more references available in the full text version of this article.

Cited by (15)

  • Profiling of lipid mediators in atherosclerotic carotid plaques from type 2 diabetic and non-diabetic patients.

    2022, Prostaglandins Leukotrienes and Essential Fatty Acids
    Citation Excerpt :

    Thus, it has been suggested that a reduction of inflammatory pathways within the atheroma plaque may contribute to the beneficial impact of omega 3 FAs in cardiovascular diseases. Moreover, the omega 3 content of the plaque has been associated with higher plaque stability [18,19]. Recently two large clinical trials of omega 3 supplementation (REDUCED-IT and STRENGHT), that have included a majority of type 2 diabetic patients at high cardiovascular risk, have yielded divergent results with regards to the occurrence of cardiovascular events [20,21].

  • Circulating inflammation-resolving lipid mediators RvD1 and DHA are decreased in patients with acutely symptomatic carotid disease

    2017, Prostaglandins Leukotrienes and Essential Fatty Acids
    Citation Excerpt :

    Supplementation with ω3 docosahexaenoic acid (DHA)-rich fish oil results in fibrous cap thickening and stabilization [5]. We previously demonstrated that carotid plaques from neurologically symptomatic patients are inflammatory and have decreased intra-plaque levels of ω3 fatty acids, including DHA [4]. Consistent with this observation, resolvin D1 (RvD1, 7S, 8R, 17S-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-docosahexaenoic acid), a potent inflammation-resolving lipid mediator biosynthesized from DHA, was reported recently to promote plaque stability, including decreased lesion oxidative stress and necrosis, improved efferocytosis, and fibrous caps thickening [2].

View all citing articles on Scopus

Presented at the 33rd Annual Meeting for the Southern Association for Vascular Surgery, Tucson, AZ, January 14–17, 2009.

View full text