Why the study?
Development of immunomodulatory interventions in heart failure is hindered by the complexity and redundancies of inflammatory pathways, which remain poorly understood.
Cohort (n=3,713)
Multimarker profiling in heart failure identifies specific immune processes, such as T-cell costimulation, that are associated with mortality and may serve as novel therapeutic targets.
May support immune-based HF risk stratification; hypothesis-generating for T-cell modulation before clinical adoption.
AIMS: The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF. METHODS AND RESULTS: We measured 355 biomarkers in 2022 patients with worsening HF and an independent validation cohort (n = 1691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the gene ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of 'T-cell costimulation' and 'response to interferon-gamma/positive regulation of interferon-gamma production' showed the most consistent positive and negative associations with all-cause mortality, respectively, after external validation. Within T-cell costimulation, inducible costimulator ligand, CD28, CD70, and tumour necrosis factor superfamily member-14 were identified as potential therapeutic targets. CONCLUSIONS: We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF.
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Markousis‐Mavrogenis et al. (2021) conducted a cohort in worsening heart failure (n=3,713). Activation of diverse immune processes was evaluated on all-cause mortality at 2-year follow-up.
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