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Alternative Complement Pathway in Carotid Atherosclerosis: Low Plasma Properdin Levels Associate With Long-Term
Mieke C Louwe1, Chrysostomi Gialeli2, Annika E Michelsen1,3
1Research Institute of Internal Medicine, Oslo University Hospital Oslo Norway.
Insights
Low plasma properdin levels are linked to increased cardiovascular mortality in patients with carotid atherosclerosis. Conversely, high properdin within plaques suggests local complement activation and plaque vulnerability.
Area of Science:
- Cardiovascular Research
- Immunology
- Complement System Biology
Background:
- Complement activation is implicated in atherosclerosis pathogenesis.
- Limited data exists on alternative complement pathway activation in carotid atherosclerosis and its prognostic value.
Purpose of the Study:
- To investigate the extent of alternative complement pathway activation in patients with carotid atherosclerosis.
- To determine the association of complement factors with adverse outcomes, specifically cardiovascular mortality.
Main Methods:
- Measured plasma levels of factor D, properdin, C3bBbP, and factor H using ELISA in two cohorts (Discovery and Validation).
- Correlated plasma complement factor levels with adverse outcomes, including cardiovascular mortality, over a mean follow-up of 7 years.
- Assessed intraplaque properdin levels and their correlation with plaque vulnerability markers.
Main Results:
- Patients with carotid atherosclerosis exhibited increased plasma levels of factor D, properdin, and C3bBbP compared to controls.
- Low plasma properdin levels (
- High intraplaque properdin levels correlated with markers of plaque vulnerability and symptomatology.
Conclusions:
- Low plasma properdin levels are a strong, independent predictor of cardiovascular mortality in carotid atherosclerosis patients.
- Elevated intraplaque properdin suggests local alternative complement pathway activation and is linked to plaque vulnerability.
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,
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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