Agents targeting inflammatory cytokine pathways have been primarily studied in the context of preventing CV consequences of atherosclerosis. A relevant example is the IL-1β inhibitor canakinumab in the CANTOS trial. [119]low-dose methotrexate in the CIRT trial [120]and a comparison of the vascular safety of the IL-6 inhibitor tocilizumab and the TNF-α inhibitor etanercept in the setting of rheumatoid arthritis in the ENTRACTE trial [121]. The TNF-alpha inhibitor infliximab was studied for 28 weeks in a pilot placebo-controlled trial (ATTACH trial) in patients with moderate to severe heart failure. [122]. Despite reducing CRP and IL-6 levels, infliximab failed to improve clinical status and appeared to be associated with adverse events at the highest doses. Shortly thereafter, the RENEWAL study investigated the effects of the TNF-α inhibitor etanercept in patients with HFrEF, but did not demonstrate any benefit on HF (HHF) mortality or hospitalization. [123]. The effect of the IL-1beta inhibitor canakinumab on his HF outcomes was studied in a prespecified secondary analysis of his CANTOS trial in participants with prior ACS and elevated hs-CRP. [124]. In this exploratory analysis, we noted that canakinumab dose-dependently reduced her HHF and composite mortality of HHF mortality and HF mortality. The same pathway was targeted using the IL-1 receptor antagonist anakinra in a series of small randomized trials in HF patients [125]. Anakinra improved peak oxygen consumption (VO2 max) over 12 weeks compared to placebo in patients with recently decompensated heart failure. [126]. Additionally, in patients with ST-elevation myocardial infarction (STEMI), 14-day treatment with anakinra reduced hs-CRP levels and the incidence of new-onset heart failure or heart failure hospitalization 1 year after STEMI. [127]. Longer and larger studies are needed to examine the effects of anakinra on more challenging heart failure outcomes. Taken together, these exploratory studies seem to suggest a beneficial role for several anti-inflammatory therapies in HF, especially those targeting interleukins close to the IL-6 cascade. [128]. In fact, diltibekimab, a human monoclonal antibody against IL-6, was shown in his RESCUE study to reduce sensitive CRP in participants at high risk of atherosclerosis. [129]. Its effects on CV, heart failure, and mortality outcomes in HF patients and participants at high CV risk are being studied in the HERMES trial (NCT05636176) and ZEUS trial (NCT05021835), respectively.