The observation that heart failure with reduced ejection fraction is associated with elevated circulating levels of pro-inflammatory cytokines opened a new area of research that has revealed a potentially important role for the immune system in the pathogenesis of heart failure. However, until the publication in 2019 of the CANTOS trial findings on heart failure outcomes, all attempts to target inflammation in the heart failure setting in phase III clinical trials resulted in neutral effects or worsening of clinical outcomes. This lack of positive results in turn prompted questions on whether inflammation is a cause or consequence of heart failure. This Review summarizes the latest developments in our understanding of the role of the innate and adaptive immune systems in the pathogenesis of heart failure, and highlights the results of phase III clinical trials of therapies targeting inflammatory processes in the heart failure setting, such as anti-inflammatory and immunomodulatory strategies. The most recent of these studies, the CANTOS trial, raises the exciting possibility that, in the foreseeable future, we might be able to identify those patients with heart failure who have a cardio-inflammatory phenotype and will thus benefit from therapies targeting inflammation.
Patients with heart failure with reduced ejection fraction have elevated circulating levels of pro-inflammatory cytokines compared with healthy individuals.
The innate and adaptive immune systems are activated in heart failure and comprise non-cellular and cellular components, including macrophages, mast cells, B cells and T cells.
The repertoire of immunological responses differs in acute and chronic myocardial inflammation.
Initial phase III clinical trials targeting inflammation in the setting of heart failure had neutral results.
In the CANTOS trial, targeted anti-cytokine therapy with a monoclonal antibody against IL-1β resulted in improved heart failure outcomes in patients with myocardial infarction with or without established heart failure.
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We apologize in advance to colleagues whose work was not directly cited in this Review because of the imposed space limitations. The authors receive support research funds from the NIH (R01 HL58081, HL-73017, HL089543, NIH T32 HL007081 and K08 HL1945108).
L.A. and D.L.M. are co-founders of iCordis, a start-up company focused on developing B cell modulating therapies for the prevention and treatment of heart failure. The other authors declare no competing interests.
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Adamo, L., Rocha-Resende, C., Prabhu, S.D. et al. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol 17, 269–285 (2020). https://doi.org/10.1038/s41569-019-0315-x
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