Highlights
- •The extension of atherosclerosis cannot be accurately predicted using clinical variables.
- •This holds true particularly in populations at high/very-high cardiovascular risk.
- •Several circulating proteins have been evaluated, but none proved powerful enough.
- •19 plausible biomarkers were ranked in terms of strength and predictive power.
- •CD40R emerged as a the most powerful biomarker of carotid atherosclerosis extension.
Abstract
Background and aims
The severity of the atherosclerotic burden is hardly quantifiable in subjects at high
cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules
have been proposed as circulating biomarkers of atherosclerosis, but none has emerged
as clinically meaningful.
Methods
Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell
migration, apoptosis and endothelial activity were measured by Proximity Extension
Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes
(66%) and established CV disease (50%), who underwent ultrasound assessment of carotid
atherosclerosis with total plaque area quantification.
Results
In patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers
were identified as the more closely related to atherosclerosis extension. Compared
with a multivariable model including major traditional CV risk factors, the percentage
gain of explained variability in total plaque area was the greatest (33%) after inclusion
of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1
(15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R,
PDGF was hyperbolic. In the whole study cohort, including subjects without carotid
plaques, CD40R was the strongest predictor of the presence and extension of carotid
atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater
atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally
higher load of CV risk factors.
Conclusions
CD40R stands among an extended set of plausible atherosclerosis-related biomarkers
as the most powerful predictor of carotid atherosclerosis burden in a high CV risk
cohort.
Graphical abstract
Graphical Abstract
Keywords
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Article Info
Publication History
Published online: January 17, 2022
Accepted:
January 13,
2022
Received in revised form:
November 25,
2021
Received:
August 19,
2021
Identification
Copyright
© 2022 Elsevier B.V. All rights reserved.
