IL-6 Receptor Blockade with Tocilizumab Reduces Monocyte-Mediated Myocardial Injury in STEMI
In this ASSAIL-MI substudy, tocilizumab attenuated the post-STEMI monocyte surge, with lower monocyte counts at 24 hours correlating with reduced peak troponin T and improved myocardial salvage index. RNA sequencing revealed tocilizumab-modulated gene expression in pathways related to myocardial remodeling, apoptosis, and chemotaxis, potentially through SOCS3 downregulation. In vitro experiments confirmed that tocilizumab limited cardiomyocyte apoptosis under ischemia/reperfusion and reduced IL-6-driven monocyte chemotaxis, suggesting a mechanistic basis for the cardioprotective effects observed in the main trial.
The original study
The effects of interleukin-6-receptor inhibition on monocytes in STEMI: a substudy of the ASSAIL-MI trial.
- Authors
- Huse C, Murphy SL, Yang K, Balzer NR, Stokke MK, Anstensrud AK, et al.
- Journal
- EBioMedicine
- Type
- Journal Article, Randomized Controlled Trial
- PMID
- 41076990
Original abstract
BACKGROUND: Interleukin-6 receptor (IL-6R) inhibition by tocilizumab improves myocardial salvage index (MSI) in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect remain unclear. METHODS: This pre-defined exploratory sub-study of the ASSAIL-MI trial enumerated circulating monocytes and examined their transcriptome profile in relation to the MSI and peak troponin T (TnT) in STEMI patients randomiseded to tocilizumab (n = 101) or placebo (n = 98). RNA sequencing was performed on peripheral monocytes in 14 patients. To elaborate the in vivo findings, in vitro chemotaxis and apoptosis assays were performed on THP-1 monocytes and cardiomyocyte (HL-1) cell lines, respectively. FINDINGS: STEMI patients had increased monocyte counts at 24 h and 3-7 days after hospitalisation/PCI and this increase was attenuated by tocilizumab. Lower monocyte levels at 24 h were associated with lower TnT levels and higher MSI. Monocyte gene expression suggested that tocilizumab modulated cytokine signalling pathways related to myocardial remodelling, apoptosis, and chemotaxis, potentially through a decrease in suppressor of cytokine signalling 3 (SOCS3). In vitro, tocilizumab limited apoptosis of cardiomyocytes exposed to ischemia/reperfusion and reduced chemotaxis in monocytes exposed to IL-6. INTERPRETATION: These findings suggest that IL-6R inhibition by tocilizumab during STEMI is associated with reduced monocyte counts and cardioprotective alterations in monocyte signalling potentially linked to the downregulation of SOCS3. FUNDING: This work was supported by the South-Eastern Norway Regional Health Authority (no. 2019067) and The Research Council of Norway (no. 282867) The ASSAIL-MI main study was supported by an independent grant from ROCHE who also provided drugs/placebo for infusion.