Prognostic value of IL-22 levels and the TH17 pathway in patients with acute myocardial infarction

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Abstract Introduction Acute myocardial infarction (AMI) induces a surge in inflammatory cytokines and cells including T helper cells (TH). TH17 cells are activated by pro-inflammatory cytokines such as IL-1, IL-6, and IL-21; they secrete IL-17 and IL-22 to promote neutrophil chemotaxis and to induce pro-inflammatory cytokine secretion from macrophages. Purpose We aimed to explore the prognostic value of the TH17 pathway and its component cytokines in AMI patients. Methods Patients with AMI (STEMI and NSTEMI) were included from the SPUM-ACS cohort (total N=4,787) selecting a time window <24 h from symptom onset to blood sampling before PCI. Patients with malignancies or immunosuppressive therapies were excluded. 160 patients who experienced death (N=85) or recurrent AMI (N=75) within 1-year follow-up (AMI-case) were compared to 152 counterparts with favorable outcome matched for age, sex, AMI subtype, and onset time (AMI-control). 45 healthy blood donors (HD) without cardiovascular disease were added as a reference group. Cytokine levels were reported as median + IQR and were analyzed with multivariate linear regression. Group comparisons were made using the Mann-Whitney U test or Kruskal-Wallis test and multiple comparisons corrected with Dunn’s test. Kaplan-Meier curves were cut off at a median IL-22 level and tested with Log-rank test. Results Our measurement showed correlation among components in TH17 pathway. IL-22 was significantly associated with IL-1β (β=-3.027e-1, p=0.0164), IL-6 (β=5.413e-3, p<0.0001), and IL-21 (β=3.567e-2, p<0.0001), but not with IL-1α or IL-1RA. IL-22 was not correlated with IL-17. Age (median=71.45 vs 71.30 years, p>0.05), percentage of women (23.8% vs 19.7%, p>0.05), and percentage of STEMI (70.6% vs 69.7%, p>0.05) did not differ between AMI-case and AMI-control. AMI-case and AMI-control both showed higher plasma IL-22 levels than HD, whereas there was no difference between AMI groups (Figure 1A). AMI patients who died within 1-year follow-up had higher IL-22 levels than those with recurrent AMI (Figure 1B). Regarding TH17 activation, patients who died had higher IL-17 levels (Figure 1C). Median IL-22 (4.86 pg/mL) levels were tested for predicting outcome: Patients with higher IL-22 levels had more risk for death or recurrent AMI (p=0.0253, Figure 2A). The mortality of patients above median IL-22 levels was higher than those below (p=0.0126); The KM-curves diverged early in less than 1 month after the initial event (Figure 2B). Conclusions Upstream regulators (IL-1β, IL-6) correlated with downstream effectors (IL-22, IL-17) within the pathways involving TH17 cells. Both IL-22 and Il-17 were higher in AMI patients who died within one year than in similar patients who survived. Investigating TH-17- and IL-22-related pathways may be of interest for further investigation in patients with AMI.