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

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.

Keywords: biomarkers; cell adhesion molecule; heart failure; repeated measurements.

Figure 1

Average temporal patterns of adhesion molecule biomarkers during follow-up approaching the primary endpoint (PE) or last sample moment. X-axis: time remaining to the PE (for patients who experienced incident adverse events) or time remaining to last sample moment (for patients who remained event-free). Therefore, ‘time zero’ is defined as the occurrence of the endpoint or last sample moment and is depicted on the right side of the x-axis, so that the average marker trajectory can be visualized as the endpoint approaches. Y-axis: biomarker levels in arbitrary, relative units (Normalized Protein Expression, NPX). Solid red line: Average temporal pattern of biomarker levels in patients who reached the primary endpoint during follow-up. Solid blue line: Average temporal pattern of biomarker levels in patients who remained endpoint free (solid blue line). Dashed lines: 95% confidence interval. Abbreviations: Complement component C1q receptor: C1qR, Cadherin 5: CDH5, Chitinase-3-like protein 1: CHI3L1, CNTN1: Contactin-1, Ep-CAM: Epithelial cell adhesion molecule, EPHB4: Ephrin type-B receptor 4, ICAM2: Intercellular adhesion molecule-2, ITGB2: Integrin beta-2, JAM-A: Junctional adhesion molecule A, NPX: Normalized Protein Expression, PE: primary endpoint, PECAM-1: Platelet endothelial cell adhesion molecule 1, SELE: E-selectin, and SELP: P-selectin.