Abstract
Background
Activation of the inflammatory response in heart failure (HF) may initially serve as a compensatory mechanism. However, on the longer term, this physiological phenomenon can become disadvantageous. Temporal patterns of inflammatory proteins other than CRP have not yet been investigated in patients with stable HF.
Purpose
We aimed to evaluate the association of 17 serially measured cytokines and cytokine receptors with clinical outcome in patients with stable heart failure.
Methods
In 263 patients, 1984 serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (IQR: 1.4–2.5) years. The primary endpoint (PE) composed of cardiovascular mortality, HF-hospitalization, heart transplantation, and LVAD. We selected baseline blood samples in all patients, as well as the two samples closest to the primary endpoint, and the last sample available in event-free patients. Thus, in 567 samples we measured 17 cytokines and cytokine receptors using the Olink Proteomics Cardiovascular III multiplex assay. Associations between biomarkers and PE were investigated by joint modelling.
Results
Median age was 68 (IQR: 59–76) years, with 72% men, 74% NYHA class I-II and a median ejection fraction of 30% (23–38%). 70 patients reached a PE. After adjustment for clinical characteristics (age, sex, diabetes, atrial fibrillation, NYHA class at baseline, diuretics and systolic blood pressure), 7 biomarkers were associated with the PE (Figure). Interleukin-1 receptor type 1 (IL1RT1) showed the strongest association: HR 2.65 [95% CI: 1.78–4.21]) per standard deviation change in level (NPX) at any point in time during follow-up, followed by Tumor necrosis factor receptor 1 (TNF-R1): 2.25 [1.66–3.08], and C-X-C motif chemokine 16 (CXCL16): 2.18 [1.59–3.04]. After adjustment for baseline N-terminal pro–B-type natriuretic peptide, high-sensitive troponin T and C-reactive protein however, only IL1RT1 and TNF-R1 remained significantly associated with the PE.
Conclusion
Repeatedly measured levels of several cytokines and cytokine receptors are independently associated with clinical outcome in stable HF patients. These results suggest that repeated measurements of these biomarkers, in addition to established cardiac biomarkers, may contribute to personalized risk assessment and herewith better identify high-risk patients.
Figure 1. Associations between levels of cytokines and cytokine receptors and the primary endpoint.
Funding Acknowledgement
Type of funding source: Other. Main funding source(s): This work was supported by the Jaap Schouten Foundation and the Noordwest Academie.
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