The prognostic value of admission lymphocyte-to-monocyte ratio in critically ill patients with acute myocardial infarction.

BACKGROUND: Inflammation plays a critical role in acute myocardial infarction (AMI). Recent studies have shown the value of hematologic indicators in MI risk stratification and prognostic assessment. However, the association between lymphocyte-to-monocyte ratio (LMR) and the long-term mortality of critically ill MI patients remains unclear. METHODS: Clinical data were extracted from the Medical Information Mart for Intensive Care III database. Patients diagnosed with AMI on admission in the intensive care units were include. The optimal cutoff value of LMR was determined by X-tile software. The Cox proportional hazard model was applied for the identification of independent prognostic factors of 1-year mortality and survival curves were estimated using the Kaplan-Meier method. In order to reduce selection bias, a 1:1 propensity score matching (PSM) method was performed. RESULTS: A total of 1517 AMI patients were included in this study. The cutoff value for 1-year mortality of LMR determined by X-Tile software was 3.00. A total of 534 pairs of patients were matched after PSM. Multivariate analysis (HR = 1.369, 95%CI 1.110-1.687, P = 0.003) and PSM subgroups (HR = 1.299, 95%CI 1.032-1.634, P = 0.026) showed that 1-year mortality was significantly higher in patients with LMR < 3.00 than patients with LMR ≥ 3.00 in Cox proportional hazard models. The survival curves showed that patients with LMR < 3.00 had a significantly lower 1-year survival rate before (63.83 vs. 81.03%, Log rank P < 0.001) and after PSM (68.13 vs. 74.22%, Log rank P = 0.041). CONCLUSION: In this retrospective cohort analysis, we demonstrated that a low admission LMR (< 3.00) was associated with a higher risk of 1-year mortality in critically ill patients with AMI.

Sitagliptin on Carotid Intima-Media Thickness in Type 2 Diabetes Mellitus Patients and Anemia: A Subgroup Analysis of the PROLOGUE Study.

INTRODUCTION: Randomized clinical trials have not shown an additional clinical benefit of sitagliptin treatment over conventional treatment alone. However, studies of sitagliptin treatment have not examined the relationship between anemia and treatment group outcomes. METHODS: The PROLOGUE study is a prospective clinical trial of 442 participants with type 2 diabetes mellitus (T2DM) randomized to sitagliptin treatment or conventional treatment which showed no treatment differences [Estimated mean (± standard error) common carotid intima-media thickness (CIMT) was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI -0.028 to 0.011, p = 0.309) at 24 mo of follow-up]. This is a post hoc subanalysis using data obtained from the PROLOGUE study; the study population was divided into anemic groups (n = 94) and nonanemic group (n = 343) based on hemoglobin level. And we analyzed for the changes in each CIMT parameter from baseline to 24 months in subgroups. RESULTS: The treatment group difference in baseline-adjusted mean common carotid artery- (CCA-) IMT at 24 months was -0.003 mm (95% CI -0.022 to 0.015, p = 0.718) in the nonanemic subgroup and -0.007 mm (95% CI -0.043 to 0.030, p = 0.724) in the anemic subgroup. Although there were no significant differences in the other CIMT parameters between the treatment groups in the anemic subgroup, the changes in mean and max ICA-IMT at 24 months in the nonanemic subgroup were significantly lower in the sitagliptin group than the conventional group [-0.104 mm (95% CI -0.182 to -0.026), p = 0.009 and -0.142 mm (-0.252 to -0.033), p = 0.011, respectively]. CONCLUSION: These data suggest that nonanemia may indicate a potentially large subgroup of those with T2DM patients that sitagliptin therapy has a better antiatherosclerotic effect than conventional therapy. Further research is needed to confirm these preliminary observations.

TRIM44 aggravates cardiac fibrosis after myocardial infarction via TAK1 stabilization.

Myocardial infarction (MI) is one of the most dangerous cardiovascular events. Cardiac fibrosis is a common pathological feature of remodeling after injury that is related to adverse clinical results with no effective treatment. Previous studies have confirmed that TRIM44, an E3 ligase, can promote the proliferation and migration of various tumor cells. However, the role of TRIM44 in cardiac fibrosis remains unknown. Models of TGF-ß1 stimulation and MI-induced fibrosis were established to investigate the role and potential underlying mechanism of TRIM44 in cardiac fibrosis. The results showed that cardiac fibrosis was significantly inhibited after TRIM44 knockdown in a mouse model of MI, while it was enhanced when TRIM44 was overexpressed. Furthermore, in vitro studies showed that fibrosis markers were significantly reduced in cardiac fibroblasts (CFs) with TRIM44 knockdown, whereas TRIM44 overexpression promoted the expression of fibrosis markers. Mechanistically, TRIM44 maintains TAK1 stability by inhibiting the degradation of k48-linked polyubiquitination-mediated ubiquitination, thereby increasing phosphorylated TAK1 expression in the fibrotic environment and activating MAPKs to promote fibrosis. Pharmacological inhibition of TAK1 phosphorylation reversed the fibrogenic effects of TRIM44 overexpression. Combined, these results suggest that TRIM44 is a potential therapeutic target for cardiac fibrosis.

TRIM38 protects H9c2 cells from hypoxia/reoxygenation injury via the TRAF6/TAK1/NF-κB signalling pathway.

Tripartite motif (TRIM) 38 is a ubiquitin E3 protein ligase that is involved in various intracellular physiological processes. However, the role of TRIM38 in myocardial ischaemia/reperfusion (I/R) injury remains to be elucidated. We aimed to establish an in vitro cellular hypoxia/reperfusion (H/R) model to explore the role and potential mechanisms of TRIM38 in H9c2, a rat cardiomyoblast cell line. Recombinant adenoviruses for silencing or overexpressing TRIM38 were constructed and transfected into H9c2 cells. Western blotanalysisshowed that TRIM38 expression was significantly decreased after H/R injury. Functionally, TRIM38 expression relieved inflammatory responses and oxidative stress, and inhibited H/R-induced apoptosis in H9c2 cells. Mechanistically, TRIM38 overexpression inhibited H/R-induced transforming growth factor beta-activated kinase 1 (TAK1)/nuclear factor-kappa B (NF-κB) pathway activity in H9c2 cells. The opposite results were observed after TRIM38 knockdown. Furthermore, H/R-induced injury aggravated by TRIM38 deficiency in H9c2 cells was reversed upon treatment with 5Z-7-oxozeaenol, a TAK1 inhibitor. Therefore, TRIM38 reduction attenuated the anti-apoptotic capacity and anti-inflammatory potential of H/R-stimulated H9c2 cells by activating the TAK1/NF-κB signalling pathway. Specifically, TRIM38 alleviated H/R-induced H9c2 cell injury by promoting TNF receptor-associated factor 6 degradation, which led to the inactivation of the TAK1/NF-κB signalling pathway. Thus, our study provides new insights into the molecular mechanisms underlying H/R-induced myocardial injuries.

Tripartite motif 38 attenuates cardiac fibrosis after myocardial infarction by suppressing TAK1 activation via TAB2/3 degradation.

The role of tripartite motif (TRIM) 38, a ubiquitin E3 ligase regulating various pathophysiological processes, in cardiac fibrosis remains unclear. Here, a model of angiotensin II and myocardial infarction (MI)-induced fibrosis was established to explore its role in cardiac fibrosis and its underlying mechanisms. Cardiac fibrosis in the mouse MI model was mitigated by TRIM38 overexpression, but aggravated by its depletion. Consistently, in vitro overexpression or knockdown of TRIM38 ameliorated or aggravated the proliferation and secretion of cardiac fibroblasts (CFs) exposed to fibrotic stimulation, respectively. Mechanistically, TRIM38 suppressed cardiac fibrosis progression by attenuating TAK1/MAPK signaling. Inhibiting TAK1/MAPK signaling with a pharmacological inhibitor greatly reversed the effects of TRIM38 knockdown on CF secretion. Specifically, TRIM38 interacted with and "targeted" TAB2 and TAB3 for degradation, subsequently inhibiting TAK1 phosphorylation and negatively regulating MAPK signaling. These findings can help develop therapeutic strategies to treat and prevent cardiac fibrosis.

Development and Validation of a Nomogram of In-hospital Major Adverse Cardiovascular and Cerebrovascular Events in Patients With Acute Coronary Syndrome.

Background and Objective: This study aims to develop and validate a nomogram for the occurrence of in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) in acute coronary syndrome (ACS) patients. Methods: A total of 1,360 ACS patients admitted between November 2014 and October 2019 from Zhongda Hospital and Yancheng Third People's Hospital were included. Patients admitted in Zhongda Hospital before 2018 were split into the training cohort (n = 793). Those admitted after 2018 in Zhongda Hospital and patients from Yancheng Third People's Hospital were split into the validation cohort (n = 567). Twenty eight clinical features routinely assessed including baseline characteristics, past medical history and auxiliary examinations were used to inform the models to predict in-hospital MACCE (all-cause mortality, reinfarction, stroke, and heart failure) in ACS patients. The best-performing model was tested in the validation cohort. The accuracy and clinical applicability were tested by the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analyses (DCA). Results: The in-hospital MACCE occurred in 93 (6.83%) patients. The final prediction model consists of four variables: age, Killip grading, fasting blood-glucose (FBG) and whether percutaneous coronary intervention (PCI) was performed at early stage. A nomogram was used to present the final result. Individualized nomogram exhibited comparable discrimination to the Global Registry of Acute Coronary Events (GRACE) score [AUC: 0.807 (95% CI 0.736-0.878) vs. 0.761 (95% CI 0.69-0.878)], P = 0.10) and a better discrimination than the Evaluation of the Methods and Management of Acute Coronary Events (EMMACE) score [AUC: 0.807 (95% CI 0.736-0.878) vs. 0.723(95% CI 0.648-0.798), P = 0.01] in predicting the risk of in-hospital MACCE in ACS patients. A good prediction performance was maintained in the validation cohort (AUC =0.813, 95% CI 0.738-0.889). The prediction model also exhibited decent calibration (P = 0.972) and clinical usefulness. Conclusion: The nomogram may be a simple and effective tool in predicting the occurrence of in-hospital MACCE in ACS patients. Further longitudinal studies are warranted to validate its value in guiding clinical decision-making and optimizing the treatment of high-risk patients.

De-Ritis Ratio Is Associated with Mortality after Cardiac Arrest.

INTRODUCTION: The aim of our study was to explore the associations of the aspartate transaminase/alanine transaminase (De-Ritis) ratio with outcomes after cardiac arrest (CA). METHODS: This retrospective study included 374 consecutive adult cardiac arrest patients. Information on the study population was obtained from the Dryad Digital Repository. Patients were divided into tertiles based on their De-Ritis ratio. The logistic regression hazard analysis was used to assess the independent relationship between the De-Ritis ratio and mortality. The Kaplan-Meier method and log-rank test were used to estimate the survival of different groups. Receiver operating characteristic (ROC) curve analysis was utilized to compare the prognostic ability of biomarkers. A model combining the De-Ritis ratio was established, and its performance was evaluated using the Akaike information criterion (AIC). RESULTS: Of the 374 patients who were included in the study, 194 patients (51.9%) died in the intensive care unit (ICU), 213 patients (57.0%) died during hospitalization, and 226 patients (60.4%) had an unfavorable neurologic outcome. Logistic regression analysis including potentially confounding factors showed that the De-Ritis ratio was independently associated with mortality, yielding a more than onefold risk of ICU mortality (OR 1.455; 95% CI 1.088-1.946; p = 0.011) and hospital mortality (OR 1.378; 95% CI 1.031-1.842; p = 0.030). Discriminatory performance assessed by ROC curves showed an area under the curve of 0.611 (95% CI 0.553-0.668) for ICU mortality and 0.625 (0.567-0.682) for hospital mortality. Further, the likelihood ratio test (LRT) analysis showed that the model combining the De-Ritis ratio had a smaller AIC and higher likelihood ratio χ 2 score than the model without the De-Ritis ratio. The Kaplan-Meier curves showed that the CA patients in the De-Ritis ratio tertile 3 group clearly had a significantly higher incidence of ICU mortality (log - rank = 0.007). CONCLUSION: An elevated De-Ritis ratio on admission was significantly associated with ICU mortality and hospital mortality after CA. Assessment of the De-Ritis ratio might help identify groups at high risk for mortality.

Overexpression of GATA4 enhances the antiapoptotic effect of exosomes secreted from cardiac colony-forming unit fibroblasts via miRNA221-mediated targeting of the PTEN/PI3K/AKT signaling pathway.

BACKGROUND: GATA4 is an early cardiac-specific transcription factor, and endogenous GATA4-positive cells play a critical role in cardioprotection after myocardial injury. As functional paracrine units of therapeutic cells, exosomes can partially reproduce the reparative properties of their parental cells. Here, we investigated the cardioprotective capabilities of exosomes derived from cardiac colony-forming unit fibroblasts (cCFU-Fs) overexpressing GATA4 (cCFU-FsGATA4) and the underlying mechanism through which these exosomes use microRNA (miRNA) delivery to regulate target proteins in myocardial infarction (MI). METHODS: Exosomes were harvested from cCFU-Fs by ultracentrifugation. miRNA arrays were performed to determine differential miRNA expression between exosomes derived from cCFU-FsGATA4 (GATA4-Exo) and control cCFU-Fs (NC-Exo). A dual-luciferase reporter assay confirmed that miR221 directly targets the 3' untranslated region (UTR) of the phosphatase and tensin homolog on chromosome ten (PTEN) gene. Cardiac function and myocardial infarct size were evaluated by echocardiography and Masson trichrome staining, respectively. RESULTS: Compared with NC-Exo, GATA4-Exo increased the survival and reduced the apoptosis of H9c2 cells. Direct intramyocardial transplantation of GATA4-Exo at the border of the ischemic region following ligation of the left anterior descending (LAD) coronary artery significantly restored cardiac contractile function and reduced infarct size. Microarray analysis revealed significantly increased miR221 expression in GATA4-Exo. qPCR confirmed higher miR221 levels in H9c2 cells treated with GATA4-Exo than in those treated with NC-Exo. miR221 mimic-transfected H9c2 cells demonstrated a significantly higher survival rate following exposure to hypoxic conditions than those transfected with miR221 inhibitor. A dual-luciferase reporter gene assay confirmed the PTEN gene as a target of miR221. Western blot analysis showed that H9c2 cells treated with GATA4-Exo exhibited lower PTEN protein expression and higher p-Akt expression. CONCLUSION: GATA4 overexpression enhances the protective effect of cCFU-F-derived exosomes on myocardial ischemic injury. In terms of the mechanism, it is at least partly due to the miR221 transferred by GATA4-Exo, which inhibits PTEN expression, activates the phosphatidylinositol 3 kinase (PI3K)/AKT signaling pathway, and subsequently alleviates apoptosis of myocardial cells (CMs).