Interleukin‐1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST‐Segment–Elevation Myocardial Infarction

Abstract

Background ST ‐segment–elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin‐1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C‐reactive protein) levels during the first 14 days in patients with ST ‐segment–elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo‐controlled, double‐blind, clinical trial in 99 patients with ST ‐segment–elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39–120] versus 214 [interquartile range, 131–394] mg·day/L; P <0.001), without significant differences between the anakinra arms. No significant differences were found between anakinra and placebo groups in the interval changes in left ventricular end‐systolic volume (median, 1.4 [interquartile range, −9.8 to 9.8] versus −3.9 [interquartile range, −15.4 to 1.4] mL; P =0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, −1.6% to 10.2%] versus 2.7% [interquartile range, −1.8% to 9.3%]; P =0.61) at 12 months. The incidence of death or new‐onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [ P =0.046] and 0% versus 11.4% [ P =0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; P =0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; P =0.016). Conclusions In patients presenting with ST ‐segment–elevation myocardial infarction, interleukin‐1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 01950299.

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

“…Also, IL-1β has been associated with a reduced expression of genes involved in the regulation of calcium homeostasis, including phospholamban, sarcoplasmic reticulum calcium ATPase [ 72 , 73 ]. IL-1 is largely produced during the inflammatory phase of cardiac repair [ 74 , 75 ]. Beside its pro-inflammatory functions, IL-1 induces increased synthesis and production of MMPs by cardiac fibroblasts [ 76 , 77 ].…”

Deciphering post-infarct inflammation: Should it heal, would it hurt?

“…10 The use of experimental parabiosis surgery in animals has shown that IL-1b increase bone marrow hematopoietic stem cell proliferation after AMI and contributes to myocardial inflammation leading to heart failure after AMI 11 . A clinical trial with an IL-1 blocker, anakinra, showed prevention of heart failure in patients with ST-segment elevation AMI when treated for 14 days during the index event 12 . Whether and how the treatment affected the recruitment of inflammatory cells within the heart of the patients with AMI remains unexplored.…”

Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II–III Systolic Heart Failure

“… 30 Phase 2 studies with an IL-1 receptor antagonist, anakinra, showed improved cardiac function and/or cardiorespiratory fitness in patients with HF and a reduced incidence of new onset HF in patients with ST-segment elevation MI. 9 – 11 , 31 – 36 …”

“…The lack of effect of dapansutrile on CRP levels is unlikely to depend on baseline CRP levels that were rather similar to those observed in the CANTOS trial 28 and also in other trials with an IL-1 blocker—anakinra—conducted by our group. 11 , 31 , 35 , 38 It is also possible that despite the NLRP3 inflammasome inhibition, a residual IL-6 signaling in HFrEF may persist because of NLRP3-independent pathways. These aspects will require being investigated in future studies.…”