Introduction: This study aimed to evaluate the relationship between 2-h post-load minus fasting plasma glucose (2hPG-FPG) and 1-year clinical outcomes, such as death, stroke recurrence, and modified Rankin Scale (mRS) ≥2–3 among acute ischemic stroke (AIS) patients without diabetes mellitus (DM) history. Methods: 1,214 AIS patients without DM history, obtained from ACROSS-China, were divided into 4 quartiles, based on 2hPG-FPG measurements obtained 14 days post-admission. Four models were constructed using multivariate Cox and logistic regression analyses, based on the inclusion of age, gender, trial of ORG 10172 in acute stroke treatment, NIH Stroke Scale scores (model 1), plus 10 other clinical parameters (model 2), plus newly diagnosed DM (NDDM) post-admission (model 3), plus 2hPG and FPG (model 4). Associations found from those 4 models between 2hPG-FPG and 1-year clinical outcomes were confirmed via stratification, multiplicative interaction, sensitivity, and restricted cubic spline analyses. Results: The highest quartile of 2hPG-FPG, after adjusting for variables, such as stroke severity (model 2), was independently associated with death, stroke recurrence, and mRS ≥2–3 (odds ratio [OR] = 3.95, 2.96, 4.15, and 4.83, respectively, all p < 0.0001). Increased 2hPG-FPG remained independently associated with mRS ≥2–3 in models 3–4, as well as increased mRS ≥2 under stratification analyses among both non-NDDM and NDDM patients. Conclusion: 2hPG-FPG is a relatively specific indicator of poorer 1-year clinical prognoses among AIS patients, independent of NDDM, 2hPG, and FPG post-hospital admission. Therefore, the oral glucose tolerance test could be a useful approach for detecting a higher likelihood for developing poorer prognoses among patients without DM history.
Background: Thrombosis is the chief culprit in the fatal event of atherosclerotic cardiovascular disease (ASCVDs). Neutrophil extracellular traps (NETs) closely link inflammation and thrombosis. The immune-related GTPase family M protein (IRGM) and its ortholog of mouse IRGM1 are positively correlated with plaque rupture during atherosclerosis process. However, whether and how IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis remains unknown, which will further promote the development of antithrombotic treatment tools.Methods: The thrombi images, platelet activation makers and NETs makers were detected in the serum of 193 STEMI patients and 43 controls. To futher investigate IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis in vivo, ApoE-/- Irgm1+/- and ApoE-/- mice received diets rich in fat and 2.5% FeCl3 was then used to induce experimental arterial thrombosis in an atherosclerosis background. In vitro, PMA and thrombin were used to stimulate neutrophils and platelets, respectively, and the expression of IRGM/IRGM1 were modified. To reveal the molecular mechanisms, MAPK- cPLA2 signals inhibitors were used.Results: Thrombi were observed in the offender lesions in almost all STEMI patients, and serum IRGM was positively correlated with platelet factor 4 and neutrophil elastase. Subsequently, Irgm1 deficient mice have a longer occlusion time and lower growth rate. In vitro, as expected, IRGM/Irgm1 deficiency inhibits platelet activation and platelet-neutrophil interaction. More importantly, IRGM promoted NETs production through activating MAPK-cPLA2 signals in PMA stimulated neuropils, whereas inhibiting the production of NETs eliminated the difference in platelet activation and thrombosis caused by IRGM/Irgm1 modification in vivo and vitro. Similarly, inhibition of platelet activation also eliminated the influence of IRGM/Irgm1 modification on NETs production.Conlusions: Overall, our data indicate that IRGM/Irgm1 deficiency in neuropils inhibits the intense interaction between neutrophils and platelets, and ultimately inhibits thrombosis. Targeting IRGM may represents a new therapeutic strategy that prevents and treats thrombosis during ASCVDs.Funding Information: This work was supported by the National Natural Science Foundation Projects [grant numbers 81870353 and 82170262 to S.F.], the Natural Science Foundation of Heilongjiang Province [grant number LH2020H048 and TD2020H001], and the 2nd Affiliated Hospital of Harbin Medical University, Harbin [grant number CX2016-21].Declaration of Interests: The authors have declared that no competing interest exists.Ethics Approval Statement: All experiments using human subjects were performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board Harbin Medical University. Written informed consent was obtained from participants before inclusion in the study.
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