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Carotid plaque macrophage burden and inflammatory lipid-associated macrophage markers predict secondary major adverse cardiovascular events after endarterectomy

Prange, Koen H.M. ; Bel-Bordes, Gemma ; Depuydt, Marie A.C. LU ; Barlampas, Panos ; Reif, Moritz J. ; Grönloh, Max L.B. ; Kempkes, Rosalie W.M. ; Griffith, Guillermo R. ; van Roomen, Cindy and Zhu, Yayuan , et al. (2026) In European Heart Journal 47(28). p.3821-3836
Abstract

Background and Aims: Atherosclerosis is a chronic lipid-driven inflammatory disease and one of the leading underlying causes of cardiovascular morbidity and mortality in Western society. Macrophages are key players in atherosclerotic development. Although the cellular composition of carotid atherosclerotic lesions has been determined, macrophage population definitions lack granularity and lineage data. Moreover, to date no direct link has been established between cellular content of atherosclerotic lesions and secondary clinical outcome. This study is aimed at characterization of atherosclerotic lesion macrophages and identification of plaque cell types and marker genes that predict the risk of secondary major adverse cardiovascular... (More)

Background and Aims: Atherosclerosis is a chronic lipid-driven inflammatory disease and one of the leading underlying causes of cardiovascular morbidity and mortality in Western society. Macrophages are key players in atherosclerotic development. Although the cellular composition of carotid atherosclerotic lesions has been determined, macrophage population definitions lack granularity and lineage data. Moreover, to date no direct link has been established between cellular content of atherosclerotic lesions and secondary clinical outcome. This study is aimed at characterization of atherosclerotic lesion macrophages and identification of plaque cell types and marker genes that predict the risk of secondary major adverse cardiovascular events in a clinical setting. Methods: Single-cell RNA sequencing on blood and plaques from 46 carotid endarterectomy patients enrolled in the AtheroExpress cohort. Deconvolution was done on bulk transcriptome data from 656 AtheroExpress patients, and findings were validated in 82 patients enrolled in the Carotid Plaque Imaging Project. Results: Four major archetypes of plaque macrophages were identified: inflammatory macrophages, lipid-associated macrophages (LAMs), tissue-resident-like LAMs, and inflammatory LAMs. Cellular trajectory and fate analyses revealed that these are derived from both classical and non-classical monocytes. Functionally, this study demonstrated the capacity of monocytes to differentiate into inflammatory LAMs via inflammatory- or resident-like LAM and LAM stages. Next, the AtheroExpress bulk RNA-seq cohort was deconvoluted. Macrophages were shown to be the only cell population significantly associated with both symptoms at time of surgery and increased risk of major adverse cardiovascular events during a 3-year follow-up period. Within the macrophage population, mostly LAM and inflammatory LAM foam cell markers such as PLIN2 and TREM1 were associated with an increased risk of major adverse cardiovascular events after 3-year follow-up. These associations were validated in the Carotid Plaque Imaging Project cohort. Conclusions: Together, these findings provide critical insights into the functional differences and origin of macrophage subpopulations in human atherosclerosis and show their clinical significance and risk prediction value in relation to future cardiovascular events.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
atherosclerosis, biomarkers, CVD, iLAM, inflammation, Macrophages, PLIN2, TREM1
in
European Heart Journal
volume
47
issue
28
pages
3821 - 3836
publisher
Oxford University Press
external identifiers
  • pmid:41758068
  • scopus:105045367522
ISSN
0195-668X
DOI
10.1093/eurheartj/ehag117
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2026. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
id
39cabe95-f2d4-4069-9be9-11e7addef1c1
date added to LUP
2026-08-11 14:23:08
date last changed
2026-09-08 18:22:25
@article{39cabe95-f2d4-4069-9be9-11e7addef1c1,
  abstract     = {{<p>Background and Aims: Atherosclerosis is a chronic lipid-driven inflammatory disease and one of the leading underlying causes of cardiovascular morbidity and mortality in Western society. Macrophages are key players in atherosclerotic development. Although the cellular composition of carotid atherosclerotic lesions has been determined, macrophage population definitions lack granularity and lineage data. Moreover, to date no direct link has been established between cellular content of atherosclerotic lesions and secondary clinical outcome. This study is aimed at characterization of atherosclerotic lesion macrophages and identification of plaque cell types and marker genes that predict the risk of secondary major adverse cardiovascular events in a clinical setting. Methods: Single-cell RNA sequencing on blood and plaques from 46 carotid endarterectomy patients enrolled in the AtheroExpress cohort. Deconvolution was done on bulk transcriptome data from 656 AtheroExpress patients, and findings were validated in 82 patients enrolled in the Carotid Plaque Imaging Project. Results: Four major archetypes of plaque macrophages were identified: inflammatory macrophages, lipid-associated macrophages (LAMs), tissue-resident-like LAMs, and inflammatory LAMs. Cellular trajectory and fate analyses revealed that these are derived from both classical and non-classical monocytes. Functionally, this study demonstrated the capacity of monocytes to differentiate into inflammatory LAMs via inflammatory- or resident-like LAM and LAM stages. Next, the AtheroExpress bulk RNA-seq cohort was deconvoluted. Macrophages were shown to be the only cell population significantly associated with both symptoms at time of surgery and increased risk of major adverse cardiovascular events during a 3-year follow-up period. Within the macrophage population, mostly LAM and inflammatory LAM foam cell markers such as PLIN2 and TREM1 were associated with an increased risk of major adverse cardiovascular events after 3-year follow-up. These associations were validated in the Carotid Plaque Imaging Project cohort. Conclusions: Together, these findings provide critical insights into the functional differences and origin of macrophage subpopulations in human atherosclerosis and show their clinical significance and risk prediction value in relation to future cardiovascular events.</p>}},
  author       = {{Prange, Koen H.M. and Bel-Bordes, Gemma and Depuydt, Marie A.C. and Barlampas, Panos and Reif, Moritz J. and Grönloh, Max L.B. and Kempkes, Rosalie W.M. and Griffith, Guillermo R. and van Roomen, Cindy and Zhu, Yayuan and Edsfeldt, Andreas and Sun, Jiangming and de Jong, Maaike J.M. and Mol, Barend M. and Slütter, Bram and Bot, Ilze and Neele, Annette E. and de Kleijn, Dominique P.V. and de Borst, Gert J. and Kroon, Jeffrey and Wezel, Anouk and Smeets, Harm J. and Stroes, Erik S.G. and van Buul, Jaap D. and Goossens, Pieter and Kuiper, Johan and Goncalves, Isabel and Pasterkamp, Gerard and Mokry, Michal and de Winther, Menno P.J.}},
  issn         = {{0195-668X}},
  keywords     = {{atherosclerosis; biomarkers; CVD; iLAM; inflammation; Macrophages; PLIN2; TREM1}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{28}},
  pages        = {{3821--3836}},
  publisher    = {{Oxford University Press}},
  series       = {{European Heart Journal}},
  title        = {{Carotid plaque macrophage burden and inflammatory lipid-associated macrophage markers predict secondary major adverse cardiovascular events after endarterectomy}},
  url          = {{http://dx.doi.org/10.1093/eurheartj/ehag117}},
  doi          = {{10.1093/eurheartj/ehag117}},
  volume       = {{47}},
  year         = {{2026}},
}