Background: Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics. Methods: Bone marrow–derived macrophages from control mice and mice with diabetes were grown in physiological glucose (5 mmol/L) and subjected to RNA sequencing (n=6), assay for transposase accessible chromatin sequencing (n=6), and chromatin immunoprecipitation sequencing (n=6) for determination of hyperglycemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into (normoglycemic) Ldlr ^{−/ −} mice was used to assess its functional significance in vivo. Evidence of hyperglycemia-induced trained immunity was sought in human peripheral blood mononuclear cells from patients with diabetes (n=8) compared with control subjects (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection. Results: In macrophages, high extracellular glucose promoted proinflammatory gene expression and proatherogenic functional characteristics through glycolysis-dependent mechanisms. Bone marrow–derived macrophages from diabetic mice retained these characteristics, even when cultured in physiological glucose, indicating hyperglycemia-induced trained immunity. Bone marrow transplantation from diabetic mice into (normoglycemic) Ldlr ^{−/ −} mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity. Integrated assay for transposase accessible chromatin, chromatin immunoprecipitation, and RNA sequencing analyses of hematopoietic stem cells and bone marrow–derived macrophages revealed a proinflammatory priming effect in diabetes. The pattern of open chromatin implicated transcription factor Runt-related transcription factor 1 (Runx1). Similarly, transcriptomes of atherosclerotic plaque macrophages and peripheral leukocytes in patients with type 2 diabetes were enriched for Runx1 targets, consistent with a potential role in human disease. Pharmacological inhibition of Runx1 in vitro inhibited the trained phenotype. Conclusions: Hyperglycemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy.

Background: There is a potential concern about increased bleeding risk in patients receiving omega‐3 polyunsaturated fatty acids (PUFAs). The aims of this study‐level meta‐analysis were to determine the risk of bleeding and to assess whether this relationship is linked to the received dose of omega‐3 PUFAs or the background use of antiplatelet treatment. Methods and Results: Electronic databases were searched through May 2023 to identify randomized clinical trials of patients receiving omega‐3 PUFAs. Overall bleeding events, including fatal and central nervous system events, were identified and compared with those of a control group. A total of 120 643 patients from 11 randomized clinical trials were included. There was no difference in the pooled meta‐analytic events of bleeding among patients receiving omega‐3 PUFAs and those in the control group (rate ratio [RR], 1.09 [95% CI, 0.91–1.31]; P =0.34). Likewise, the incidence of hemorrhagic stroke, intracranial bleeding, and gastrointestinal bleeding were similar. A prespecified analysis was performed in patients receiving high‐dose purified eicosapentaenoic acid (EPA), which demonstrated a 50% increase in the relative risk of bleeding but only a modest increase in the absolute risk of bleeding (0.6%) when compared with placebo. Bleeding risk was associated with the dose of EPA (risk difference, 0.24 [95% CI, 0.05–0.43]; P =0.02) but not the background use of antiplatelet therapy (risk difference, −0.01 [95% CI, −0.02 to 0]; P =0.056). Conclusions: Omega‐3 PUFAs were not associated with increased bleeding risk. Patients receiving high‐dose purified EPA may incur additional bleeding risk, although its clinical significance is very modest.

Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CX₃CL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CX₃CR1. We have shown previously that the fractalkine receptor CX₃CR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CX₃CR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CX₃CR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.

A recently-validated, highly-sensitive T2 mapping magnetic resonance (MRI) technique accurately quantifies carotid plaque lipid. The aims of this study were to determine: (i) the extent of carotid plaque lipid in patients with acute coronary syndromes (ACS); (ii) the effects of initiation of high-intensity statin on plaque lipid content and (iii) whether plaque lipid content is related to standard or 'functional' blood lipid measurements. Statin naïve subjects presenting with ACS underwent carotid artery MRI at 3 T scanner to quantify plaque lipid. Patients were subsequently commenced on high dose statin as part of clinical care and underwent a second MRI after three months. Plaque composition was measured using objective semi-automated techniques. 23 out of 24 patients had measurable lipid. Three months after statin initiation there was a significant reduction in carotid lipid percentage [from 10.3% (7.2-14.2) to 7.4% (5.4-10.0), p = 0.002] and a significant increase in fibrous percentage [from 83.3% ± 6.6-85.5% ± 4.8, p = 0.039]. None of the studied functional blood biomarkers were related to either baseline carotid plaque lipid content or its propensity to change with statin treatment. T2-mapping demonstrated depleted carotid plaque lipid following the initiation of high-intensity statin treatment. Standard or 'functional' blood biomarkers were dissociated from plaque lipid content or changes with treatment. These findings further reinforce the importance of disease characterisation over risk factor assessment. Subject to clinical trial findings, quantification of plaque lipid may provide the basis for an approach to identify patients suitable for intensive lipid reduction regimes.