Purpose: We aimed to evaluate the prognostic value of the temporal patterns of blood biomarkers of cell adhesion in stable patients with CHF.
Methods: In 263 patients, a median of 9 (IQR: 5-10) serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (IQR: 1.4-2.5) years. The composite primary endpoint (PE) of cardiovascular mortality, HF-hospitalization, heart transplantation and LVAD was reached in 70 patients. For efficiency, we selected all baseline samples, the two samples closest to a PE, and the last sample available for event-free patients. Thus, in 567 samples we measured twelve biomarkers of cell adhesion using the Olink Proteomics Cardiovascular III multiplex assay. Associations between biomarkers and first PE were investigated by combining linear mixed effect models and Cox regression (so-called joint model).
Results: Median age was 68 (IQR: 59-76) years, with 72% men and 74% NYHA class I-II. Levels of CD93 (Complement component C1q receptor), CDH5 (VE cadherin), CHI3L1 (Chitinase-3-like protein 1), EPHB4 (Ephrin type-B receptor 4) and JAM-A (Junctional adhesion molecule A) differed at baseline already. The average biomarker evolutions of these markers, and additionally of ICAM-2 (Intercellular adhesion molecule-2), showed different patterns in patients approaching the PE versus those who remained event-free (Figure 1). Repeatedly measured levels of these biomarkers were independently associated with the PE. Corresponding HRs [95% CI] per 1SD increase in log2 level (arbitrary unit) were: CD93: 1.85 [1.29-2.70], CDH5: 1.72 [1.23-2.44], CHI3L1: 2.45 [1.73-3.56], EPHB4: 1.83 [1.33-2.55], ICAM2: 1.74 [1.24-2.46] and JAM-A: 2.07 [1.39-3.18], adjusted for clinical characteristics (age, sex, diabetes, atrial fibrillation, baseline NYHA class, diuretics, systolic blood pressure and eGFR).
Conclusion: CD93, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A show different patterns as adverse events approach in CHF patients, and their temporal patterns strongly predict clinical outcome. These findings demonstrate the incremental value of repeated measurements of biomarkers of cell adhesion in stable patients with CHF.
Figure 1: Average temporal patterns of cell adhesion biomarkers during follow-up.