Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab.

BACKGROUND: Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size. METHODS: STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24-36, 72-168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months. RESULTS: Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=-0.29, -0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=-0.09,-0.14, respectively). CONCLUSIONS: Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients. TRIAL REGISTRATION NUMBER: NCT03004703.

Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.

BACKGROUND: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. METHODS: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). FINDINGS: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. INTERPRETATION: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage. FUNDING: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).

High levels of interleukin-6 are associated with final infarct size and adverse clinical events in patients with STEMI.

OBJECTIVE: Inflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction (STEMI). We aimed to explore the role of acute and sustained interleukin 6 (IL-6) signalling, including soluble IL-6 receptor (IL-6R), with regard to infarct size, adverse remodelling and future cardiovascular events in patients with STEMI. METHODS: We included 269 patients with first-time STEMI, symptom duration <6 hours and treated with percutaneous coronary intervention. Blood sampling and cardiac MRI were performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12-month and 70-month follow-up, respectively. RESULTS: IL-6 levels above median at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF). IL-6 levels in the highest quartile were at all sampling points associated with an increased risk of having an adverse clinical event during the first 12 months and with long-term all-cause mortality. IL-6R was not associated with infarct size, LVEF, myocardial salvage or long-term all-cause mortality. CONCLUSION: Acute and sustained elevation of IL-6 measured 4 months after STEMI were associated with larger infarct size, reduced LVEF and adverse clinical events including all-cause mortality. The results add important information to the sustained role of inflammation in patients with STEMI and IL-6 as a potential target for long-term intervention. TRIAL REGISTRATION NUMBER: NCT00922675.