Circulating Biomarkers of Cell Adhesion Predict Clinical Outcome in Patients with Chronic Heart Failure.

Elke Bouwens,Victor A W M Umans,Eric Boersma,Jan Van Ramshorst,Jasper J Brugts,Isabella Kardys,Victor J Van Den Berg,Sara J Baart,Tjeerd Germans,Kadir Caliskan,Henk Mouthaan,K Martijn Akkerhuis

doi:10.3390/jcm9010195

Abstract

Cardiovascular inflammation and vascular endothelial dysfunction are involved in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. We evaluated temporal patterns of 12 blood biomarkers of cell adhesion in patients with CHF. In 263 ambulant patients, serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (1.4–2.5) years. The primary endpoint (PE) was a composite of cardiovascular mortality, HF hospitalization, heart transplantation and implantation of a left ventricular assist device and was reached in 70 patients. We selected the baseline blood samples in all patients, the two samples closest to a PE, or, for event-free patients, the last sample available. In these 567 samples, associations between biomarkers and PE were investigated by joint modelling. The median age was 68 (59–76) years, with 72% men and 74% New York Heart Association class I–II. Repeatedly measured levels of Complement component C1q receptor (C1qR), Cadherin 5 (CDH5), Chitinase-3-like protein 1 (CHI3L1), Ephrin type-B receptor 4 (EPHB4), Intercellular adhesion molecule-2 (ICAM-2) and Junctional adhesion molecule A (JAM-A) were independently associated with the PE. Their rates of change also predicted clinical outcome. Level of CHI3L1 was numerically the strongest predictor with a hazard ratio (HR) (95% confidence interval) of 2.27 (1.66–3.16) per SD difference in level, followed by JAM-A (2.10, 1.42–3.23) and C1qR (1.90, 1.36–2.72), adjusted for clinical characteristics. In conclusion, temporal patterns of C1qR, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A are strongly and independently associated with clinical outcome in CHF patients.

Highlights

In recent decades, chronic heart failure (CHF) has emerged as a complex syndrome that involves a broad array of biological pathways [1,2]
Here, we examined biomarkers from this panel related to the above-described mechanisms (SELP, SELE, Cadherin 5 (CDH5), Intercellular adhesion molecule-2 (ICAM-2), and platelet endothelial cell adhesion molecule 1 (PECAM-1)) and other potentially interesting biomarkers related to cell adhesion processes (complement component C1q receptor (C1qR), chitinase-3-like protein 1 (CHI3L1), contactin-1 (CNTN1), ephrin type-B receptor 4 (EPHB4), epithelial cell adhesion molecule (Ep-cell adhesion molecules (CAMs)), integrin beta-2 (ITGB2), and junctional adhesion molecule A (JAM-A)
Baseline levels of C1qR, CDH5, Chitinase-3-like protein 1 (CHI3L1), Ephrin type-B receptor 4 (EPHB4) and Junctional adhesion molecule A (JAM-A) were significantly higher in patients who later experienced the endpoint compared to patients who remained event-free

Summary

Introduction

Chronic heart failure (CHF) has emerged as a complex syndrome that involves a broad array of biological pathways [1,2]. In this context, CHF has been associated with endothelial dysfunction and low-grade inflammation [3]. Enhanced expression of CAMs has been found within the myocardial microvasculature of patients with severe CHF as compared to healthy subjects [6], providing further support that vascular inflammation might be involved in the propagation and progression of CHF

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