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Circulating immune checkpoints predict heart failure outcomes
Elles M Screever1,2, Laura I E Yousif2, Javid J Moslehi3
1Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands.
Insights
Immune checkpoint ligands are elevated in heart failure (HF) patients, correlating with disease severity and predicting worse outcomes. These findings suggest immune checkpoint ligands play a role in HF development and progression.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Limited data exist on immune checkpoint (IC) ligands in heart failure (HF) pathophysiology.
- Investigating IC ligands in HF is crucial for understanding disease mechanisms.
Purpose of the Study:
- To explore the role of IC ligands in HF using animal models and human cohorts.
- To determine the association of IC ligands with HF severity and prognosis.
Main Methods:
- Transcriptomic analysis of cardiac tissue in HF mouse models.
- Measurement of serum levels of sPD-L1, sPD-L2, and galectin-9 in stable and worsening HF patients.
- Association analysis with clinical parameters (NYHA classification, galectin-3, hs-troponin-T) and prognostic outcomes.
Main Results:
- IC ligands (sPD-L1, sPD-L2, galectin-9) were differentially expressed in HF models and elevated in HF patients.
- Serum levels of these ligands correlated with NYHA classification, galectin-3, and hs-troponin-T.
- Higher sPD-L1 and galectin-9 levels predicted increased HF hospitalization and mortality risk; sPD-L2 and galectin-9 predicted outcomes in worsening HF.
Conclusions:
- IC ligands are expressed in cardiac disease models and elevated in HF patients.
- Elevated IC ligand levels are associated with HF disease severity and significantly predict prognosis.
- These findings suggest a potential role for IC ligands in the pathogenesis of HF.
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.
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