Elsevier

Atherosclerosis

Volume 230, Issue 1, September 2013, Pages 106-109
Atherosclerosis

Lipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: A flag for non-HDL-C

https://doi.org/10.1016/j.atherosclerosis.2013.06.024Get rights and content

Abstract

Objective

We investigated the association between cholesterol across the LDL density range and in the VLDL and IDL particles with the prevalence of inflammatory cells in plaques of patients with severe carotid artery stenosis.

Methods

Forty-five patients undergoing carotid endarterectomy were studied. Plaque specimens were analyzed for cellular composition by immunocytochemistry using monoclonal antibodies. Lipoprotein subclasses were separated by gradient ultracentrifugation.

Results

We found no correlations between LDL-C, HDL-C and plasma triglyceride levels with plaque cellular composition. On the other hand, macrophage content was significantly related to cholesterol in the dense LDL subclasses (r = 0.30, p < 0.01) and in the triglyceride-rich lipoprotein remnants, namely dense VLDL and IDL particles (r = 0.46, p < 0.01). HDL subclasses were not correlated with plaque cellular composition. In a mirror manner, smooth muscle cells were inversely associated with cholesterol levels of the dense LDL subclasses (r = −0.32, p < 0.01 fraction 10; r = −0.26, p < 0.05 fraction 11) while only a non-significant trend was observed with the cholesterol in the VLDL-IDL fractions. These results provide the pathophysiological background to account for the relevance of non-HDL-C as the only lipid parameter, aside LDL density, significantly associated (β = 0.351, p = 0.021) with carotid plaque macrophage content.

Conclusions

We provide evidence that lipoprotein subclasses, specifically cholesterol in the dense LDL fractions and in the triglyceride-rich lipoprotein remnants, significantly affect carotid plaque cellular composition, in particular macrophages content.

Introduction

The degree of carotid artery stenosis has long been considered the most reliable predictor of stroke-risk in patients with carotid artery disease. However, factors other than the degree of stenosis determine whether a carotid plaque will result in acute neurologic events or not, in particular the presence of a vulnerable plaque [1], [2]. While LDL-C is a strong risk factor for coronary events, the association is definitely weaker when the focus is on cerebrovascular events. Despite the inconsistent association between cholesterol levels and the risk of stroke, statin therapy, the mainstay LDL-C lowering approach, is associated with a significant reduction of stroke incidence in both primary and secondary prevention [3]. Although these data do not support a role of LDL-C as risk factor for ischemic stroke, they also leave plausible the contribution of LDL-C independent, anti-inflammatory mechanisms of statins on plaque stability [4]. On the other hand, recent trials based on drugs that raise HDL-C have failed in preventing “hard” endpoints [5] and genetic studies have found that higher HDL-C due to known genetic polymorphisms are not associated to a decreased risk of myocardial infarction [6]. Finally, there is evidence that quality (i.e. size and density) of LDL particles rather than their plasma concentration may play a role in modulating atherosclerotic plaque cellular composition and stability [7], [8].

Here we present novel data on the potential contribution of each single lipoprotein subclass, including dense LDL and triglycerides-rich lipoprotein remnants as compared to standard components of the lipid profile, on cellular composition of carotid plaques retrieved from patients undergoing endarterectomy [9].

Section snippets

Patients

We studied 45 consecutive patients, undergoing endarterectomy for significant narrowing (>70%) of the internal carotid artery. The specimens of primary lesion retrieved at surgery were immediately placed in an optimal cutting temperature compound (OCT compound), frozen in liquid nitrogen and stored at −80 °C as previously described [9]. At the time of endarterectomy, all patients were already taking anti-platelet therapy (acetylsalicylic acid 100 mg/day), and 9 out of 45 patients were on

Results

The 45 patients (35 males, 10 female) were aged 68 ± 8 years. Plasma lipoprotein profile at the time of surgery was characterized by plasma total cholesterol concentration of 233 ± 37 mg/dl, LDL-C 153 ± 35 mg/dl, HDL-C 53 ± 14 mg/dl, non-HDL-C 180 ± 39 mg/dl, triglycerides (TG) 144 ± 61 mg/dl, Lp(a) 22 ± 22 mg/dl. The cholesterol distribution across lipoprotein density range is presented in the panel A of the Fig. 1. Lipoprotein (a) density range overlaps with the densest LDL particles

Discussion

This study, for first the first time, provides evidence of a direct association between carotid macrophage content, a marker of unstable plaque, and cholesterol carried in the dense LDL particles and in the TG-rich IDL and VLDL. Moreover, we confirmed the pathophysiological relevance of the non-HDL-C as compared to the routine lipid parameters in accounting for the inflammatory cellular component of the carotid plaque.

The causal relationship between cholesterol levels and stroke is complex and

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