Abstract
Aims: There are limited data examining the role of immune checkpoint (IC) ligands in the pathophysiology of heart failure (HF). Therefore, we explore this in three HF animal models and in three different human cohorts (healthy, stable, and worsening HF). Methods and results: Transcriptomic analyses of cardiac tissue of three different HF mouse models revealed differentially expressed IC receptors and their ligands compared with control mice. Based on this observation, serum levels of three well-known IC ligands (i.e. sPD-L1, sPD-L2 and galectin-9) were measured in stable HF patients from the Vitamin D Chronic Heart Failure (VitD-CHF) study (n = 101), as well as healthy individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (n = 58). sPD-L1, sPD-L2, and galectin-9 were all associated with New York Heart Association classification. In multivariate linear regression analyses, all three IC ligands were associated with galectin-3 (β = 0.230, β = 0.283, and β = 0.304, respectively). sPD-L1 and galectin-9 were also associated with hs-troponin-T (β = 0.386 and β = 0.314). Regarding prognosis, higher serum levels of sPD-L1 and galectin-9 were significantly associated with increased risk for HF hospitalization and all-cause mortality [hazard ratio 1.69 (1.09–2.59) and hazard ratio 1.50 (1.06–2.12)]. Furthermore, the importance of IC ligands was tested in another stage of HF, namely worsening HF patients. In the worsening HF cohort (The BIOlogy Study to Tailored Treatment in Chronic Heart Failure) (n = 2032), sPD-L2 and galectin-9 were associated with New York Heart Association classification and significantly predicted outcome with an increased relative risk of 15% and 20%, after multivariable adjustment, respectively. Conclusions: IC ligands are expressed in cardiac disease models, and serum levels of IC ligands are elevated in HF patients, are associated with disease severity, and significantly predict prognosis. These data indicate a potential role for IC ligands in HF pathogenesis.
| Original language | English |
|---|---|
| Pages (from-to) | 2330-2337 |
| Number of pages | 8 |
| Journal | ESC heart failure |
| Volume | 10 |
| Issue number | 4 |
| Early online date | 25 Apr 2023 |
| DOIs | |
| Publication status | Published - Aug 2023 |
Bibliographical note
Funding Information:This work was supported by grants from the Dutch Heart Foundation (CVON SHE‐PREDICTS‐HF, grant number 2017‐21; CVON RED‐CVD, grant number 2017‐11; CVON PREDICT2, grant number 2018‐30; CVON DOUBLE DOSE, grant number 2020B005; and grant number 2000Z003), by a grant from the LeDucq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure‐PLaN)], and by a grant from the European Research Council (ERC CoG 818715, SECRETE‐HF), all to R.A.d.B., and De Cock‐Hadders Foundation to E.M.S. W.C.M. is supported by the Mandema‐Stipendium of the Junior Scientific Masterclass 2020‐10 of the University Medical Center Groningen and by the Dutch Heart Foundation (Dekker grant 03‐005‐2021‐T005). BIOSTAT‐CHF was funded by a grant from the European Commission (FP7‐242209‐BIOSTAT‐CHF).
Funding Information:
This work was supported by grants from the Dutch Heart Foundation (CVON SHE-PREDICTS-HF, grant number 2017-21; CVON RED-CVD, grant number 2017-11; CVON PREDICT2, grant number 2018-30; CVON DOUBLE DOSE, grant number 2020B005; and grant number 2000Z003), by a grant from the LeDucq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN)], and by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF), all to R.A.d.B., and De Cock-Hadders Foundation to E.M.S. W.C.M. is supported by the Mandema-Stipendium of the Junior Scientific Masterclass 2020-10 of the University Medical Center Groningen and by the Dutch Heart Foundation (Dekker grant 03-005-2021-T005). BIOSTAT-CHF was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF).
Publisher Copyright:
© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
