Background: In recent years, attempts have been made to employ various immunomodulatory therapies as new treatment strategies for heart failure, yet the outcomes have been disappointing. Consequently, unveiling the complexity and causal relationships of the immune system's role in heart failure has become imperative. Methods: We first determined the levels of immune cells in failing myocardium using five immune infiltration algorithms: Cibersort, xCell, ssGSEA, MCPcounter, and QuanTIseq. Subsequently, two-sample bidirectional Mendelian Randomization (MR) analysis was conducted between heart failure and 731 immune cell phenotypes using Inverse Variance Weighted (IVW) as the main method, reinforced by MR-Egger, Weighted median, and Weighted mode as secondary analysis methods. Sensitivity analyses were performed to ensure data stability and feasibility. Results: Immune infiltration analysis revealed changes in the levels of immune cell infiltration in failing myocardium, including T cells, Mast cells, B cells, NK cells, and macrophages. MR analysis indicated that 19 immune cell phenotypes from 5 cell types were associated with an increased risk of heart failure, while 12 immune cell phenotypes from 6 cell types were associated with a decreased risk, without heterogeneity and pleiotropy. Reverse MR analysis did not support a causal relationship between HF and any of the 731 immune cell phenotypes. Conclusion: Our study highlights the complex pattern and causal relationship between the immune system and heart failure through immune infiltration and MR analyses. This provides new insights for the exploration of immunocyte therapies for heart failure.

The authors have declared no competing interest.

Our work was supported by the Natural Science Foundation of Shandong Province (CN) [Grant Nos.ZR2023MH053] and National Natural Science Foundation of China [Grant Nos. 81774247 and 81804045].

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Publicly available datasets were analyzed in this study. This data can be found here: GSE57338 and GWAS Catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics)