Mannose as a biomarker of coronary artery disease: Angiographic evidence and clinical significance

Highlights

• High mannose concentration is emerging as a novel marker of cardiovascular disease

• In the discovery cohort, mannose was a marker of coronary artery disease (CAD).

• In the validation cohort, mannose was associated with fibrous cap thickness.

• In both cohorts high mannose was an independent predictor of adverse outcomes.

• High mannose might be a signature of CAD with a vulnerable plaque phenotype.

Abstract

Background

High mannose has previously associated with insulin resistance and cardiovascular disease (CVD). Our objective is to establish whether mannose is associated with anatomical evidence of coronary artery disease (CAD).

Methods

Plasma mannose concentrations were measured by liquid chromatography/tandem mass spectrometry in a discovery cohort (n = 513) and a validation cohort (n = 221) of carefully phenotyped individuals. In both cohorts CAD was quantitated using state-of-the-art imaging techniques (coronary computed coronary tomography angiography (CCTA), invasive coronary angiography and optical coherence tomography). Information on subsequent CVD events/death was collected. Associations of mannose with angiographic variables and biomarkers were tested using univariate and multivariate regression models. Survival analysis was performed using the Kaplan-Meier estimator.

Results

Mannose was related to indices of CAD and features of plaque vulnerability. In the discovery cohort, mannose was a marker of quantity and quality of CCTA-proven CAD and subjects with a mannose level in the top quartile had a significantly higher risk of CVD events/death (p = 3.6e-5). In the validation cohort, mannose was significantly associated with fibrous cap thickness < 65 μm (odds ratio = 1.32 per each 10 μmol/L mannose change [95% confidence interval, 1.05–1.65]) and was an independent predictor of death (hazard ratio for mannose≥vs < 84.6 μmol/L: 4.0(95%CI, 1.4–11.3), p = 0.006).

Conclusion

The current data add novel evidence that high mannose is a signature of CAD with a vulnerable plaque phenotype, consistently across measures of severity of vessel involvement and independent of the traditional correlates of CVD, and that it is an independent predictor of incident adverse outcomes.

Introduction

Previous work – using cell-specific analysis of genome-scale metabolic models, transcriptional regulatory networks, and protein-protein interaction networks – identified elevated circulating mannose concentrations as a novel marker of insulin resistance [1]. More recently, studies using the euglycaemic hyperinsulinaemic clamp technique to measure whole-body insulin sensitivity provided direct evidence that plasma mannose – quantitated by liquid chromatography and tandem mass spectrometry (HPLC-MS-MS) – is insulin regulatable and closely tracks in vivo insulin resistance [2]. Moreover, in epidemiological cohorts higher plasma mannose concentrations have been associated not only with insulin resistance but also with risk of developing diabetes, diabetic kidney disease, and cardiovascular disease (CVD) [3]. The mechanisms underlying these associations have not been explored. In particular, it is not clear whether mannose is related to CVD only because it marks insulin resistance or because of some intrinsic biological property. Preliminary to this inquiry is to establish whether circulating mannose concentrations are indeed associated with anatomical evidence of extent and kind of atherosclerotic lesion characteristics of the coronary vasculature.

To address this question, the present study measured plasma mannose concentrations in two large datasets, a discovery cohort and an external validation cohort, in whom coronary atherosclerosis was quantitated using state-of-the-art imaging techniques in carefully phenotyped groups of individuals.