Emerging opportunities to target inflammation: myocardial infarction and type 2 diabetes

Abstract

After myocardial infarction (MI), patients with type 2 diabetes have an increased rate of adverse outcomes, compared to patients without. Diabetes confers a 1.5-2-fold increase in early mortality and, importantly, this discrepancy has been consistent over recent decades, despite advances in treatment and overall survival. Certain assumptions have emerged to explain this increased risk, such as differences in infarct size or coronary artery disease severity. Here, we re-evaluate that evidence and show how contemporary analyses using state-of-the-art characterization tools suggest that the received wisdom tells an incomplete story. Simultaneously, epidemiological and mechanistic biological data suggest additional factors relating to processes of diabetes-related inflammation might play a prominent role. Inflammatory processes after MI mediate injury and repair and are thus a potential therapeutic target. Recent studies have shown how diabetes affects immune cell numbers and drives changes in the bone marrow, leading to pro-inflammatory gene expression and functional suppression of healing and repair. Here, we review and re-evaluate the evidence around adverse prognosis in patients with diabetes after MI, with emphasis on how targeting processes of inflammation presents unexplored, yet valuable opportunities to improve cardiovascular outcomes in this vulnerable patient group.

Keywords: Diabetes; Inflammation; Myocardial infarction; Trained immunity.

Figure 1

Potential for diabetes-associated adverse outcome after myocardial infarction. Adverse outcomes have been associated with features attached to the myocardium, microvasculature, and coronary arteries. Further differences in inflammatory processes including leukocyte and platelet activation, myelopoiesis, and HITI may contribute to this prognostic gap. CRP, C-reactive protein; HITI, hyperglycaemia-induced trained immunity; IL-1b, interleukin-1 beta; IL-6, interleukin-6; RAGE, receptor for advanced glycation end-products; ROS, reactive oxygen species.

Figure 2

Cellular processes of inflammation relevant to acute MI in diabetes. After acute myocardial infarction (AMI), damaged cardiomyocytes release damage-associated molecular patterns (DAMPs), which activate pattern recognition receptors (PRRs) on macrophages including Toll-like Receptors (TLR) 2 and 4 and the receptor for advanced glycation end products (RAGE). This activation triggers nuclear factor kappa B (NFκB) signalling, subsequently activating the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Reactive oxygen species (ROS) contribute to NLRP3 inflammasome activation, culminating in the production of interleukin-1 beta (IL-1b). Furthermore, injured cardiomyocytes stimulate T cells to produce interferon-gamma (IFN-γ), which in turn activates the Janus kinase/signal-transducer and activator of transcription (JAK-STAT) pathway within macrophages, leading to the production of interleukin-6 (IL-6). Increased glucose entry into the cell induces metabolic reprogramming and modifies epigenetic enzymes such as histone methyltransferases (HMT), histone demethylases (HDM), histone acetyltransferases (HAT), and histone deacetylases (HDAC). This leads to key histone modifications, including histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac). These modifications alter chromatin accessibility at the IL-6 promoter, 'holding it open' to facilitate active transcription. Additionally, these epigenetic marks enhance NFκB activity. Moreover, these epigenetic changes inhibit anti-inflammatory pathways within macrophages, such as interleukin 4 (IL-4) signalling, consequently decreasing the production of anti-inflammatory cytokines such as interleukin 10 (IL-10). Ultimately, hyperglycaemia skews macrophage function away from an M2 anti-inflammatory phenotype towards a pro-inflammatory M1 phenotype. a-KG, a-ketoglutarate; GLUT1, glucose transporter-1; HMGB1, high mobility group protein B1; HSP, heat-shock proteins; IFNGR, interferon-gamma receptor; IL-4R, interleukin-4 receptor. Created with BioRender.com.