Utility of USPIO-enhanced MR imaging to identify inflammation and the fibrous cap: A comparison of symptomatic and asymptomatic individuals

Abstract

Background and purpose

Inflammation is a risk factor the vulnerable atheromatous plaque. This can be detected in vivo on high-resolution magnetic resonance (MR) imaging using a contrast agent, Sinerem™, an ultra-small super-paramagnetic iron oxide (USPIO). The aim of this study was to explore whether there is a difference in the degree of MR defined inflammation using USPIO particles, between symptomatic and asymptomatic carotid plaques. We report further on its T₁ effect of enhancing the fibrous cap, which may allow dual contrast resolution of carotid atheroma.

Methods

Twenty patients with carotid stenosis (10 symptomatic and 10 asymptomatic) underwent multi-sequence MR imaging before and 36 h post-USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant was calculated following USPIO administration. Mean signal change across all quadrants were compared between the two groups.

Results

Symptomatic patients had significantly more quadrants with a signal drop than asymptomatic individuals (75% vs. 32%, p < 0.01). Asymptomatic plaques had more quadrants with signal enhancement than symptomatic ones (68% vs. 25%, p < 0.05); their mean signal change was also higher (46% vs. 15%, p < 0.01) and this appeared to correlate with a thicker fibrous cap on histology.

Conclusions

Symptomatic patients had more quadrants with signal drop suggesting larger inflammatory infiltrates. Asymptomatic individuals showed significantly more enhancement possibly suggesting greater stability as a result of thicker fibrous caps. However, some asymptomatic plaques also had focal areas of signal drop, suggesting an occult macrophage burden. If validated by larger studies, USPIO may be a useful dual contrast agent able to improve risk stratification of patients with carotid stenosis and inform selection for intervention.

Introduction

It is well recognised that the risk of thrombo-embolic stroke in the presence of symptomatic carotid stenosis is high. Studies have shown a definite benefit of carotid endarterectomy (CEA) in those patients with a stenosis of 70% or more [1], [2]. The asymptomatic carotid surgery trial revealed that there is almost certainly a sub-group of asymptomatic patients who also harbour vulnerable plaque who may be at increased risk of stroke and would benefit from surgical intervention [3].

It is increasingly accepted that conventional clinical measures of luminal stenosis such as X-ray angiography, magnetic resonance angiography (MRA), CT angiography or ultrasound, are inadequate modalities to determine the risk of plaque rupture and subsequent ischemic sequelae. Furthermore, they underestimate “plaque load” due to the process of arterial remodelling [4], which may give rise to normal luminal measurements despite a large atheroma burden. We also know from studies of the coronary circulation that plaque rupture occurs at low degrees of luminal stenosis and the degree of narrowing predicts events poorly [5], [6]. Often the culprit lesion is found to be unrecognised at angiography.

The concept of the vulnerable plaque initially derived from the coronary circulation is increasingly accepted for the carotid circulation. It has been shown that vulnerable plaque has a thin fibrous cap, extensive lipid core and an associated inflammatory infiltrate [7]. In contrast, stable or “safe” plaque is fibrous, with little lipid and no inflammation. These detailed aspects of plaque morphology and physiology have been impossible to detect in vivo until recently.

High-resolution magnetic resonance (MR) imaging allows accurate quantification of plaque components [8], [9], and the use of Sinerem™, an ultra-small super-paramagnetic iron oxide (USPIO) has allowed the direct visualisation of macrophage infiltration of carotid atheroma in vivo [10], [11], [12]. USPIO is taken up by activated macrophages and when concentrated in the phagolysosomes produces a strong ${\text{T}}_2^{*}$ susceptibility effect, visible as signal voids. In addition, we have observed a T₁ shortening effect post-USPIO infusion in asymptomatic carotid plaques [13], [14]. This may allow better visualisation of the fibrous cap suggesting that this contrast agent could be used not only to detect inflammation within vulnerable lesions but also aid in the identification of “safer” plaques with a significant fibrous component.

The aim of this study was to explore whether there is a difference in the degree of MR defined inflammation using USPIO particles, between symptomatic and asymptomatic carotid plaques and report further on the T₁ effect of enhancing the fibrous cap, which may allow dual contrast resolution of carotid atheroma.