Tocilizumab attenuated the post-PCI increase in monocyte counts and modulated cytokine signaling pathways related to myocardial remodeling, apoptosis, and chemotaxis in patients with STEMI.
RCT (n=199)
Placebo-controlled
1:1
Yes
Does a single dose of intravenous tocilizumab reduce monocyte counts and alter monocyte signaling in patients with acute STEMI undergoing PCI?
IL-6 receptor inhibition with tocilizumab in STEMI patients attenuates the acute increase in monocytes and modulates cardioprotective signaling pathways, providing a potential mechanism for its benefit on myocardial salvage.
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.
Huse et al. (Sat,) conducted a rct in ST-elevation myocardial infarction (STEMI) (n=199). Tocilizumab vs. Placebo was evaluated on Monocyte counts and transcriptome profile (exploratory sub-study). Tocilizumab attenuated the post-PCI increase in monocyte counts and modulated cytokine signaling pathways related to myocardial remodeling, apoptosis, and chemotaxis in patients with STEMI.