Soluble CD40 Levels in Plasma Are Associated with Cardiovascular Disease and in Carotid Plaques with a Vulnerable Phenotype

Abstract

Background and purpose: CD40 and CD40 ligand (CD40L) are costimulatory molecules of the tumor necrosis factor receptor superfamily and well known for their involvement in inflammatory diseases: atherosclerotic mouse models with disrupted CD40 signalling develop lesions of reduced size with a more stable plaque profile. This study investigated the potential of plasma and intraplaque levels of CD40 and CD40L as markers for cardiovascular disease (CVD) in humans and their association with plaque stability.

Methods: Soluble CD40 and CD40L (sCD40L) were measured in plasma in 1,437 subjects from The SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort. Intra-plaque levels of sCD40 and sCD40L were measured in atherosclerotic plaque homogenates from 199 subjects of the Carotid Plaque Imaging Project (CPIP) cohort.

Results: Both plasma sCD40 and sCD40L levels were elevated in individuals with prevalent stroke, while sCD40 levels also were higher in individuals with a prior acute myocardial infarction. Plasma levels of sCD40 correlated with carotid intima-media thickness and total carotid plaque area and were associated with risk of cardiovascular events over a 3-year follow-up period. Intra-plaque levels of sCD40 and sCD40L were associated with plaque components characteristic for plaque vulnerability and extracellular matrix remodelling.

Conclusions: Higher plasma sCD40 and sCD40L levels are associated with prevalent CVD. Plasma sCD40 levels also correlate with the severity of carotid atherosclerosis and predict future cardiovascular events, while intra-plaque levels correlate with a vulnerable plaque phenotype. Our findings thus demonstrate that elevated levels of sCD40 and sCD40L are markers of CVD.

Keywords: Atherosclerosis; CD40; CD40 ligand; Carotid arteries; Inflammation.

Figure 1.

Flow chart showing the study population of the The SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort, including excluded subjects and subjects with/without cardiovascular disease (CVD).

Figure 2.

CD40 and CD40 ligand (CD40L) localization in endarterectomy plaques. CD40 and CD40L immunoreactivity was found in particular in the shoulder (A, B) and cap (C, D) regions. Squares in insets mark enlarged plaque regions. Scale bars are 50 μm (far left and right image columns), 20 μm (middle column), and 1 mm (insets, far left column) (n=22 plaques).

Figure 3.

Graphic representation of plasma soluble CD40 (sCD40) in cardiovascular disease. Higher plasma sCD40 levels are associated with prevalent cardiovascular disease, severity of carotid atherosclerosis and predict future cardiovascular events (CV events). MI, myocardial infarction.