Microvasculature and intraplaque hemorrhage in atherosclerotic carotid lesions: a cardiovascular magnetic resonance imaging study

Abstract

Background: The presence of intraplaque haemorrhage (IPH) has been related to plaque rupture, is associated with plaque progression, and predicts cerebrovascular events. However, the mechanisms leading to IPH are not fully understood. The dominant view is that IPH is caused by leakage of erythrocytes from immature microvessels. The aim of the present study was to investigate whether there is an association between atherosclerotic plaque microvasculature and presence of IPH in a relatively large prospective cohort study of patients with symptomatic carotid plaque.

Methods: One hundred and thirty-two symptomatic patients with ≥2 mm carotid plaque underwent cardiovascular magnetic resonance (CMR) of the symptomatic carotid plaque for detection of IPH and dynamic contrast-enhanced (DCE)-CMR for assessment of plaque microvasculature. Ktrans, an indicator of microvascular flow, density and leakiness, was estimated using pharmacokinetic modelling in the vessel wall and adventitia. Statistical analysis was performed using an independent samples T-test and binary logistic regression, correcting for clinical risk factors.

Results: A decreased vessel wall Ktrans was found for IPH positive patients (0.051 ± 0.011 min- 1 versus 0.058 ± 0.017 min- 1, p = 0.001). No significant difference in adventitial Ktrans was found in patients with and without IPH (0.057 ± 0.012 min- 1 and 0.057 ± 0.018 min- 1, respectively). Histological analysis in a subgroup of patients that underwent carotid endarterectomy demonstrated no significant difference in relative microvessel density between plaques without IPH (n = 8) and plaques with IPH (n = 15) (0.000333 ± 0.0000707 vs. and 0.000289 ± 0.0000439, p = 0.585).

Conclusions: A reduced vessel wall Ktrans is found in the presence of IPH. Thus, we did not find a positive association between plaque microvasculature and IPH several weeks after a cerebrovascular event. Not only leaky plaque microvessels, but additional factors may contribute to IPH development.

Trial registration: NCT01208025 . Registration date September 23, 2010. Retrospectively registered (first inclusion September 21, 2010). NCT01709045 , date of registration October 17, 2012. Retrospectively registered (first inclusion August 23, 2011).

Keywords: Atherosclerosis; Cardiovascular Disease; Cerebrovascular Disease/Stroke; DCE-MRI; Intraplaque hemorrhage; Ischemic stroke; Magnetic Resonance Imaging (MRI); Microvasculature; Transient Ischemic Attack (TIA).

Conflict of interest statement

Ethics approval and consent to participate

Approval of the local Institutional Ethical Review Board was obtained and written informed consent was obtained for all patients (Medisch Ethische Toetsingscommissie MUMC+, ref. number METC 09–2-082).

Consent for publication

An institutional consent form has been signed by the two patients whose images have been used in Fig. 1.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

a Transversal cardiovascular magnetic resonance (CMR) images of a patient with carotid plaque in the right carotid artery with intraplaque hemorrhage (IPH). The following CMR sequences were acquired: (A) pre-contrast T1-weighted (T1W) quadruple inversion recovery (QIR) turbo spin echo (TSE), (B) post-contrast T1W QIR TSE, (C) time of flight (TOF), (D) T2W TSE and (E) T1W inversion recovery (IR) turbo field echo (TFE). Three regional saturation slabs were positioned on T1W QIR TSE and T2W TSE sequences; one on the throat to reduce swallowing artefacts and another two on the subcutaneous fat, with an angle of approximately 45 degrees with respect to the regional saturation slab that is positioned on the throat (both left and right) to reduce ghosting. A lipid-rich necrotic core was identified as a region within the bulk of the plaque that does not show contrast enhancement (* on B) on the post-contrast T1W QIR images. On the T1W IR TFE image, a hyper-intense signal in the bulk of the plaque can be clearly observed, indicating the presence of IPH (* on panel E). Panel F shows the plaque contours on the post-contrast T1W QIR TSE images (green = outer vessel wall, red = inner vessel wall, yellow = lipid-rich necrotic core, blue = IPH, orange/brown = calcifications). b Transversal CMR image of a carotid plaque in the right carotid artery without IPH but with a small lipid-rich necrotic core. All panels consist of the same sequences as in Fig. 1a

Fig. 2

a Hematoxylin and eosin (HE) staining (demonstrating the absence of IPH) and the corresponding CD 31 staining (black arrows show presence of microvessels) from a histological specimen obtained during carotid endarterectomy. b Hematoxylin and eosin (HE) staining (demonstrating IPH) and the corresponding CD 31 staining (no presence of microvessels) from a histological specimen obtained during carotid endarterectomy, the black arrow points towards the area were intraplaque hemorrhage is present

Fig. 3

Pre-contrast T1 weighted (T1w) quadruple inversion recovery (QIR) turbo spin echo (TSE) image (a) from a patient with intraplaque hemorrhage (IPH). Note that a Regional Saturation Technique (REST) slab is visible on the right side, which was placed over the subcutaneous fat tissue to prevent ghosting artefacts. Three-dimensional T1w inversion recovery turbo field echo (IR TFE) image (b) from the same patient with IPH. A hyperintense signal is visible within the bulk the plaque compared with the adjacent sternocleidomastoid muscle (*), indicating the presence of IPH. Parametric Ktrans map of the plaque is overlaid on IR TFE image shown in B (c). In this parametric map voxelwise determined Ktrans values are colour encoded from 0 to 0.25 min− 1. Within this plaque, the IPH exhibits low Ktrans values, shown in dark red, while higher Ktrans values (brighter red) are observed in the outer vessel wall (adventitial layer). Pre-contrast T1w QIR TSE image from a patient without IPH (d). 3D T1w IR TFE image (e) from the same patient without IPH. Parametric Ktrans map is overlaid on IR TFE image shown in B (f). In this parametric map voxelwise determined Ktrans values are colour encoded from 0 to 0.25 min− 1. Within this plaque, higher Ktrans values are observed, shown in bright red/yellow/white. Written informed consent for publication of their clinical details and/or clinical images was obtained from the patients. A copy of the consent forms is available for review by the Editor of this journal

Fig. 4

Vessel wall and adventitial Ktrans versus IPH status. Vessel wall and adventitial Ktrans (mean ± standard error) for patients with (IPH+) and without intraplaque haemorrhage (IPH-)