Circulating Immune Checkpoints Predict Heart Failure Outcomes

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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.
Funding Information
  • Hartstichting (2017-21)
  • Hartstichting (2017-11)
  • Hartstichting (2018-30)
  • Hartstichting (2020B005)
  • Hartstichting (2000Z003)
  • Hartstichting (03-005-2021-T005)
  • Leducq Foundation
  • European Research Council (ERC CoG 818715)
  • De Cock--Hadders Foundation
  • University Medical Center Groningen
  • European Commission (FP7-242209-BIOSTAT-CHF)
  • Hartstichting (2017‐21)
  • Hartstichting (2017‐11)
  • Hartstichting (2018‐30)
  • Hartstichting (2020B005)
  • Hartstichting (2000Z003)
  • Hartstichting (03‐005‐2021‐T005)
  • Fondation Leducq
  • European Research Council (ERC CoG 818715)
  • Stichting De Cock-Hadders
  • Universitair Medisch Centrum Groningen
  • European Commission (FP7‐242209‐BIOSTAT‐CHF)

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