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Alternative Complement Pathway in Carotid Atherosclerosis : Low Plasma Properdin Levels Associate With Long-Term Cardiovascular Mortality

Louwe, Mieke C ; Gialeli, Chrysostomi LU ; Michelsen, Annika E ; Holm, Sverre ; Edsfeldt, Andreas LU orcid ; Skagen, Karolina ; Lekva, Tove ; Olsen, Maria Belland ; Bjerkeli, Vigdis and Schjørlien, Therese , et al. (2025) In Journal of the American Heart Association 14(3).
Abstract

BACKGROUND: Complement activation may promote atherosclerosis. Yet, data on the to which extent complement, and more specifically the alternative complement pathway, is activated in patients with carotid atherosclerosis and related to adverse outcome in these patients, are scarce.

METHODS AND RESULTS: We measured, by ELISA, plasma levels of factor D, properdin, C3bBbP (C3 convertase), and factor H in patients with advanced carotid atherosclerosis in a
Discovery (n=324) and in a
Validation (n=206) cohort in relation to adverse outcome (mean follow-up 7.8 and 6.6 years, respectively). Our major findings were as follows. Compared with healthy controls, patients with carotid atherosclerosis had increased plasma levels of... (More)

BACKGROUND: Complement activation may promote atherosclerosis. Yet, data on the to which extent complement, and more specifically the alternative complement pathway, is activated in patients with carotid atherosclerosis and related to adverse outcome in these patients, are scarce.

METHODS AND RESULTS: We measured, by ELISA, plasma levels of factor D, properdin, C3bBbP (C3 convertase), and factor H in patients with advanced carotid atherosclerosis in a
Discovery (n=324) and in a
Validation (n=206) cohort in relation to adverse outcome (mean follow-up 7.8 and 6.6 years, respectively). Our major findings were as follows. Compared with healthy controls, patients with carotid atherosclerosis had increased plasma levels of factor D, properdin, and C3bBbP (
P<0.001), but not factor H, an inhibitor of the alternative complement pathway, compared with controls. Although patients with carotid atherosclerosis had elevated levels of properdin compared with controls, within these patients, low plasma levels of properdin (ie, <median levels of properdin in the patient group) were significantly associated with cardiovascular mortality. This was seen in both the
Discovery (HR 2.31,
P=0.019) and the
Validation cohort (hazard ratio [HR], 2.81,
P=0.014). In contrast to the low circulating levels, high intraplaque properdin levels (assessed by ELISA) correlated with markers of plaque vulnerability and symptomatology.

CONCLUSIONS: We show a strong and independent association of low plasma properdin levels with cardiovascular mortality in 2 cohorts. Conversely, the plaque properdin levels linked to features of plaque vulnerability, potentially reflecting increased deposition at the site of inflammation or local production of properdin in the atherosclerotic lesion indicating local enhanced alternative complement pathway activation.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Properdin, Male, Female, Carotid Artery Diseases/blood, Complement Pathway, Alternative, Aged, Middle Aged, Biomarkers/blood, Case-Control Studies, Enzyme-Linked Immunosorbent Assay, Time Factors, Complement Factor D/metabolism, Complement Factor H/metabolism, Risk Factors, Prognosis, alternative complement pathway, carotid atherosclerosis, complement, plaque vulnerability, stroke
in
Journal of the American Heart Association
volume
14
issue
3
article number
e038316
pages
14 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:39868499
  • scopus:85218032619
ISSN
2047-9980
DOI
10.1161/JAHA.124.038316
language
English
LU publication?
yes
id
3ee25797-1200-4da1-94cb-b49b7cbbd158
date added to LUP
2025-02-11 23:11:25
date last changed
2025-06-13 05:20:49
@article{3ee25797-1200-4da1-94cb-b49b7cbbd158,
  abstract     = {{<p>BACKGROUND: Complement activation may promote atherosclerosis. Yet, data on the to which extent complement, and more specifically the alternative complement pathway, is activated in patients with carotid atherosclerosis and related to adverse outcome in these patients, are scarce.</p><p>METHODS AND RESULTS: We measured, by ELISA, plasma levels of factor D, properdin, C3bBbP (C3 convertase), and factor H in patients with advanced carotid atherosclerosis in a <br>
 Discovery (n=324) and in a <br>
 Validation (n=206) cohort in relation to adverse outcome (mean follow-up 7.8 and 6.6 years, respectively). Our major findings were as follows. Compared with healthy controls, patients with carotid atherosclerosis had increased plasma levels of factor D, properdin, and C3bBbP (<br>
 P&lt;0.001), but not factor H, an inhibitor of the alternative complement pathway, compared with controls. Although patients with carotid atherosclerosis had elevated levels of properdin compared with controls, within these patients, low plasma levels of properdin (ie, &lt;median levels of properdin in the patient group) were significantly associated with cardiovascular mortality. This was seen in both the<br>
 Discovery (HR 2.31, <br>
 P=0.019) and the <br>
 Validation cohort (hazard ratio [HR], 2.81,<br>
 P=0.014). In contrast to the low circulating levels, high intraplaque properdin levels (assessed by ELISA) correlated with markers of plaque vulnerability and symptomatology.<br>
 </p><p>CONCLUSIONS: We show a strong and independent association of low plasma properdin levels with cardiovascular mortality in 2 cohorts. Conversely, the plaque properdin levels linked to features of plaque vulnerability, potentially reflecting increased deposition at the site of inflammation or local production of properdin in the atherosclerotic lesion indicating local enhanced alternative complement pathway activation.</p>}},
  author       = {{Louwe, Mieke C and Gialeli, Chrysostomi and Michelsen, Annika E and Holm, Sverre and Edsfeldt, Andreas and Skagen, Karolina and Lekva, Tove and Olsen, Maria Belland and Bjerkeli, Vigdis and Schjørlien, Therese and Stø, Kristine and Kong, Xiang Yi and Dahl, Tuva B and Nilsson, Per H and Libby, Peter and Aukrust, Pål and Mollnes, Tom Eirik and Ueland, Thor and Skjelland, Mona and Gonçalves, Isabel and Halvorsen, Bente}},
  issn         = {{2047-9980}},
  keywords     = {{Humans; Properdin; Male; Female; Carotid Artery Diseases/blood; Complement Pathway, Alternative; Aged; Middle Aged; Biomarkers/blood; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Time Factors; Complement Factor D/metabolism; Complement Factor H/metabolism; Risk Factors; Prognosis; alternative complement pathway; carotid atherosclerosis; complement; plaque vulnerability; stroke}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{3}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of the American Heart Association}},
  title        = {{Alternative Complement Pathway in Carotid Atherosclerosis : Low Plasma Properdin Levels Associate With Long-Term Cardiovascular Mortality}},
  url          = {{http://dx.doi.org/10.1161/JAHA.124.038316}},
  doi          = {{10.1161/JAHA.124.038316}},
  volume       = {{14}},
  year         = {{2025}},
}