Hyperglycaemia-induced trained immunity alters monocyte function in type 2 diabetes patients after myocardial infarction

Abstract Background After myocardial infarction (MI), patients with type 2 diabetes (T2D) have an increased rate of adverse outcomes. Innate immune processes of inflammation likely play an important role(1). We have previously shown how hyperglycaemia induces trained immunity i.e. primes innate immune cells for pro-inflammatory gene expression and function(2). Hence, we hypothesise that following MI, innate immune cells in patients with T2D will display exaggerated and prolonged inflammatory responses and suppression of pathways of inflammation resolution, which are all manifestations of hyperglycaemia-induced trained immunity (HITI). Methods In 10 patients with ST-segment-elevation myocardial infarction (5 with T2D and 5 without), blood samples were collected at presentation and at 48 hours and 3 months after MI. Single-cell RNA sequencing was undertaken on peripheral leukocytes. Results CD14+ monocytes showed the greatest number of differentially expressed genes. Gene set enrichment analysis of Hallmark pathways identified changes in the response to MI. Compared with patients without T2D, CD14+ monocytes at all 3 time points showed positive enrichment of the Interferon Alpha Response (adj. p-value = 4.0 x 10-2 and 2.5 X 10-4 and 3.9 x 10-2 respectively). In addition, a time-course analysis of the acute response to MI revealed negative enrichment of oxidative phosphorylation in CD14+ monocytes from patients with T2D (adj. p-value = 2.9 x 10-2) but positive enrichment in patients without T2D (adj. p value =2.1 x 10-7). Conclusions Our findings suggest that after MI, patients with T2D exhibit altered (i) inflammatory and (ii) metabolic profiles in CD14+ monocytes, characterised by enhanced interferon alpha signalling, a pathway that has been shown to mediate adverse outcomes after MI(3), and impaired oxidative phosphorylation. These changes may account for the adverse prognosis in T2D patients.