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Dilated microvessel with endothelial cell proliferation involves intraplaque hemorrhage in unstable carotid plaque

  • Original Article - Vascular Neurosurgery - Ischemia
  • Published:
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Abstract

Background

The purpose of the present study was to clarify the characteristics of endothelial cell (EC) proliferation in intraplaque microvessels in vulnerable plaques and impact on clinical results.

Methods

The present study included 76 patients who underwent carotid endarterectomy. Patients were classified into three groups based on their symptoms: asymptomatic, symptomatic without recurrent ischemic event, and symptomatic with recurrent ischemic event. MR plaque imaging was performed and surgical specimens underwent immunohistochemical analysis. The number of CD31+ microvessels, and Ki67+ and CD105+ ECs in the carotid plaques was quantified, as measurements of maximum CD31+ microvessel diameter.

Results

MR plaque imaging yielded 41 subjects (54.0%) diagnosed with plaque with intraplaque hemorrhage (IPH), 14 subjects (18.4%) diagnosed with fibrous plaques, and 21 (27.6%) subjects diagnosed with lipid-rich plaques. The average largest diameter of microvessel in fibrous plaques, lipid-rich plaques, and plaque with IPH was 12.7 ± 4.1 μm, 31.3 ± 9.3 μm, and 56.4 ± 10.0 μm, respectively (p < 0.01). Dilated microvessels (>40 μm) were observed in 9.6% of plaques with IPH but only in 2.8% of lipid-rich plaques and 0% of fibrous plaques (p < 0.01). Ki67+/CD31+ ECs were identified in 2.8 ± 1.2% of fibrous plaques, 9.6 ± 6.9% of lipid-rich plaques, and in 19.5 ± 5.9% of plaques with IPH (p < 0.01). The average largest diameter of microvessels in the asymptomatic group was 17.1 ± 8.7 μm, 32.3 ± 10.8 μm in the symptomatic without recurrence group, and 55.2 ± 13.2 μm in the symptomatic with recurrence group (p < 0.01).

Conclusion

Dilated microvessels with proliferative ECs may play a key role in IPH pathogenesis. Furthermore, dilated microvessels are likely related to clinical onset and the recurrence of ischemic events. The purpose of the present study was to clarify the characteristics of EC proliferation in intraplaque microvessels in vulnerable plaques and their impact on clinical results, focusing on dilated intraplaque microvessels.

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Funding

D.K. provided financial support in the form of JSPS KAKENHI (grant number JP20K09342).

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Authors and Affiliations

  1. Department of Neurosurgery, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Daina Kashiwazaki, Shusuke Yamamoto, Naoki Akioka, Emiko Hori, Takashi Shibata, Naoya Kuwayama & Satoshi Kuroda

  2. Department of Radiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Kyo Noguchi

Authors
  1. Daina Kashiwazaki
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Correspondence to Daina Kashiwazaki.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institution of Toyama University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Comments

This is a fascinating study from the expert carotid group in Toyama. These authors have previously reported that microvessel formation and vessel dilatation were strongly associated with unstable plaques in human carotid stenosis. In the present submission, the investigators performed an immunohistochemical analysis of microvessels, endothelial cell (EC) proliferation in microvessels, endoglin, and hemoglobin in 76 surgically removed carotid plaques, specifically seeking to correlate intraplaque vessel morphology with MR imaging and clinical correlates. The results are fascinating and instructive. Dilated plaque microvessels were significantly correlated with clinical symptomatology and with intraplaque hemorrhage (IPH). Specifically, the results of the present study suggest that dilated microvessels (>40 μm) are accompanied by active proliferation of ECs in unstable plaques. Furthermore, the results also suggest that IPH is present in proximity to intraplaque dilated neovessels with EC proliferation in unstable carotid plaques. Other findings of note were that ECs in dilated microvessels were positive for CD105, a marker of cell proliferation often found in cells in pathological conditions, and that dilated intraplaque microvessels were correlated with symptom onset and recurrence. The authors demonstrate with authority that dilated microvessels are often accompanied by proliferative ECs and suggest that this could play a key role in developing IPH. High ratios of Ki67+/CD105+ ECs in dilated microvessels suggest that these dilated microvessels formed under pathological conditions. In addition, dilated microvessels are related to the clinical onset and recurrence of ischemic events in carotid stenosis.

This is a significant report that supports the rationale that plaque neovascularization and intraplaque hemorrhage (IPH) are important factors in plaque instability and clinically symptomatic carotid disease.

Christopher Miranda Loftus,

PA, USA

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Kashiwazaki, D., Yamamoto, S., Akioka, N. et al. Dilated microvessel with endothelial cell proliferation involves intraplaque hemorrhage in unstable carotid plaque. Acta Neurochir 163, 1777–1785 (2021). https://doi.org/10.1007/s00701-020-04595-0

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