Potential diagnostic biomarkers: 6 cuproptosis- and ferroptosis-related genes linking immune infiltration in acute myocardial infarction.

The current diagnostic biomarkers of acute myocardial infarction (AMI), troponins, lack specificity and exist as false positives in other non-cardiac diseases. Previous studies revealed that cuproptosis, ferroptosis, and immune infiltration are all involved in the development of AMI. We hypothesize that combining the analysis of cuproptosis, ferroptosis, and immune infiltration in AMI will help identify more precise diagnostic biomarkers. The results showed that a total of 19 cuproptosis- and ferroptosis-related genes (CFRGs) were differentially expressed between the healthy and AMI groups. Functional enrichment analysis showed that the differential CFRGs were mostly enriched in biological processes related to oxidative stress and the inflammatory response. The immune infiltration status analyzed by ssGSEA found elevated levels of macrophages, neutrophils, and CCR in AMI. Then, we screened 6 immune-related CFRGs (CXCL2, DDIT3, DUSP1, CDKN1A, TLR4, STAT3) to construct a nomogram for predicting AMI and validated it in the GSE109048 dataset. Moreover, we also identified 5 pivotal miRNAs and 10 candidate drugs that target the 6 feature genes. Finally, RT-qPCR analysis verified that all 6 feature genes were upregulated in both animals and patients. In conclusion, our study reveals the significance of immune-related CFRGs in AMI and provides new insights for AMI diagnosis and treatment.

Interleukin-18 Expression Increases in the Aorta and Plasma of Patients with Acute Aortic Dissection.

BACKGROUND: Interleukin- (IL-) 18 is a proinflammatory cytokine related to cardiovascular diseases, including hypertension and atherosclerosis. This study is aimed at determining whether IL-18 is related to aortic dissection (AD) and identifying the underlying mechanisms. METHODS: IL-18 expression in human aorta samples from AD (n = 8) and non-AD (NAD, n = 7) patients was measured. In addition, the IL-18, IL-6, interferon- (IFN-) γ, and IL-18-binding protein (IL-18BP) concentrations in plasma samples collected from the NAD and AD patients were detected. The effects of IL-18 on macrophage differentiation and smooth muscle cell (SMC) apoptosis were investigated in vitro. RESULTS: IL-18 expression was significantly increased in the aorta samples from the AD patients compared with those from the NAD patients, especially in the torn section. Aortic IL-18 was mainly derived from macrophages and also partly derived from CD4+ T lymphocytes and vascular SMCs. Plasma IL-18, IFN-γ, and IL-6 levels were significantly higher in the AD group than in the NAD group, and the IL-18 levels were positively correlated with the IFN-γ and IL-6 levels. In addition, plasma IL-18BP and free IL-18 levels were also elevated in the AD group. Linear regression analysis showed that the IL-18 level was independently associated with the presence of AD. In addition, anti-mouse IL-18-neutralizing monoclonal antibodies (anti-IL-18 nAb) inhibited angiotensin II-induced M1 macrophage differentiation and SMC apoptosis in vitro. CONCLUSION: IL-18 may participate in AD by regulating macrophage differentiation and macrophage-induced SMC apoptosis.

The Inhibition of Oxidised Low-Density Lipoprotein-Induced Apoptosis of Macrophages by Recombinant Human Brain Natriuretic Peptide and the Underlying Mechanism.

OBJECTIVE: Macrophage apoptosis plays a key role in atherosclerotic plaque rupture. This study investigated the effects of recombinant human brain natriuretic peptide (BNP) on oxidised low-density lipoprotein (ox-LDL)-induced macrophage apoptosis and explored the underlying mechanism. METHODS: A model of ox-LDL-induced macrophage injury was established to evaluate the role of BNP. Flow cytometry was employed to detect apoptosis and changes in mitochondrial membrane potential (x0394;x03A8;m), and confocal microscopy was used to determine cellular reactive oxygen species (ROS) levels. Additionally, reverse transcription-polymerase chain reaction and colourimetry were used to detect the mRNA expression and activity, respectively, of superoxide dismutase (SOD) and malondialdehyde (MDA). RESULTS: Ox-LDL induced macrophage apoptosis in a concentration-dependent manner, and maximum apoptosis occurred at 100 µg/ml ox-LDL (45.62 ± 2.76 vs. 6.84 ± 1.94%; p < 0.05). Conversely, BNP suppressed macrophage apoptosis, with a maximal effect at 10-9 mol/l (18.56 ± 1.79%; p < 0.05). Compared with the control group, intracellular ROS levels increased, x0394;x03A8;m decreased, SOD mRNA expression and activity decreased and MDA mRNA expression and content increased in the 100-µg/ml ox-LDL group (527.30 ± 36.20 vs. 100.00 ± 0.00%, 3.01 ± 0.52 vs. 9.67 ± 0.51%, 0.53 ± 0.18 vs. 1.00 ± 0.00, 256.6 ± 8.20 vs. 355.8 ± 9.58 U/ml, 1.59 ± 0.23 vs. 1.00 ± 0.00 and 29.4 ± 1.68 vs. 5.94 ± 0.51 nmol/ml; p < 0.05); these effects were significantly counteracted by 10-9 mol/l BNP (237.30 ± 30.62%, 6.55 ± 1.57%, 0.90 ± 0.07, 310.4 ± 2.97 U/ml, 1.14 ± 0.10, 20.54 ± 1.55 nmol/ml; p < 0.05). CONCLUSION: BNP attenuates ox-LDL-induced macrophage apoptosis by suppressing oxidative stress and preventing x0394;x03A8;m loss.

Chemerin15-Ameliorated Cardiac Ischemia-Reperfusion Injury Is Associated with the Induction of Alternatively Activated Macrophages.

Chemerin15 (C15), an endogenous anti-inflammatory component, inhibits the activity of neutrophils and macrophages through G protein-coupled receptor ChemR23; however, its role as well as functional mechanism in mouse myocardial ischemia/reperfusion (I/R) injury remains unknown. Methods. Sham or I/R operations were performed on C57BL/6J mice. The I/R mice received an injection of C15 immediately before reperfusion. Serum troponin T levels, infarct size, cardiomyocyte apoptosis, reactive oxygen species (ROS) production, and infiltration of neutrophils were assessed 24 h after reperfusion, while the macrophage phenotypes, macrophage infiltration, and inflammatory cytokine levels were assessed 48 h after reperfusion. Results. Compared with the control group, the C15-treated mice showed an obvious amelioration of I/R injury and displayed less ROS, accompanied by reduced neutrophil recruitment. C15 decreased the tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6 levels and increased the IL-10 levels in the serum of the I/R mice, which suggested a suppressed inflammatory response that could be related to elevated alternatively activated M2 macrophages with characteristic skewed expression of M2 markers and inhibition of classically activated M1 marker expression. Conclusion. C15 may induce alternatively activated M2 macrophage polarization and suppress the inflammatory response to protect against myocardial I/R injury in mice.

Non-linear association between aspartate aminotransferase to alanine aminotransferase ratio and mortality in critically ill older patients: A retrospective cohort study.

BACKGROUND: The aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio has been shown to be associated with poor clinical outcomes across various patient groups. However, little is unclear about the association between the two in critically ill older patients. Therefore, we aim to investigate the association of the AST/ALT ratio with hospital mortality in this special population. METHODS: In this retrospective cohort study, we extracted elderly patients (age ≥ 65 years) from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The primary outcome was in-hospital mortality. The association between the AST/ALT ratio and hospital mortality was studied using univariable and multivariable Cox regression analysis, as well as restricted cubic splines (RCS). Survival analysis was performed using the Kaplan-Meier (KM) method according to the AST/ALT ratio. RESULTS: Among the 13,358 eligible patients, the mean age was 77.6 years, 7,077 patients (52.9%) were male, and 2,511 patients (18.8%) died in hospital. The AST/ALT ratio was found to be independently associated with in-hospital mortality (HR = 1.05, 95% CI: 1.01-1.09, P = 0.022) after adjusting for potential confounders. Furthermore, a non-linear relationship and saturation effect were observed between them, with the inflection point being 1.80. When the AST/ALT ratio was less than 1.80, we found that every 1 unit increase in the AST/ALT ratio resulted in a 39% increased risk of in-hospital mortality (HR = 1.39, 95% CI: 1.18-1.64, P < 0.001). However, when the AST/ALT ratio was greater than 1.80, the association became saturated (HR = 1.01, 95% CI: 0.96-1.07, P = 0.609). Sensitivity and subgroup analyses showed the results were robust. CONCLUSION: In critically ill older patients, the association between the AST/ALT ratio and in-hospital mortality was non-linear and showed a saturation effect. An elevated AST/ALT ratio was significantly associated with increased in-hospital mortality when the AST/ALT ratio was less than 1.80.

Association of age-adjusted Charlson comorbidity index with adverse outcomes in patients undergoing transcatheter aortic valve replacement: A retrospective cohort study.

Patients undergoing transcatheter aortic valve replacement (TAVR) have a high comorbid burden. Our objective was to assess the association between the age-adjusted Charlson comorbidity index (Age-CCI) and mortality and readmission rates within 1-year post-TAVR. Data were extracted from the Medical Information Mart for Intensive Care IV database (MIMIC-IV version 2.0). The primary endpoint was a composite outcome of all-cause mortality or readmission within 1-year after TAVR. To examine the associations of Age-CCI with outcomes, we used multivariable Cox proportional hazards regression, restricted cubic spline (RCS), and Kaplan-Meier curves. A total of 785 patients (52.9% male) with a median age of 84.0 years were assessed. More than half of our patients had an Age-CCI ≥ 7. After adjustment for potential confounders, we found that a 1 unit increase in Age-CCI was associated with a 10% increase in mortality and readmission rates after TAVR (HR = 1.10, 95% CI: 1.04-1.17, P < .001). High Age-CCI (Age-CCI ≥ 7) compared with the low Age-CCI (Age-CCI < 7) showed a 36% increase of mortality and readmission rates (HR = 1.36, 95% CI: 1.07-1.73, P = .013). The RCS curve analysis showed a continuous linear relationship between Age-CCI and the composite outcome risk (P for non-linearity = .671). The Kaplan-Meier survival analysis showed that patients with Age-CCI ≥ 7 had a poorer prognosis than those with Age-CCI < 7 (log-rank P < .001). Subgroup analyses showed the results remained stable. Age-CCI is independently associated with all-cause mortality and readmission in patients treated with TAVR, which may help clinicians risk-stratify patients and offer an opportunity to improve patient outcomes.

Association of red blood cell distribution width-to-albumin ratio with mortality in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Frailty is associated with poor prognosis in patients undergoing transcatheter aortic valve replacement (TAVR). The red blood cell distribution width (RDW)-to-albumin ratio (RAR) reflects key components of frailty. This study aimed to evaluate the relationship between RAR and all-cause mortality in patients undergoing TAVR. METHODS: The data were extracted from the Medical Information Mart for Intensive Care IV database. The RAR was computed by dividing the RDW by the albumin. The primary outcome was all-cause mortality within 1-year following TAVR. The association between RAR and the primary outcome was evaluated using the Kaplan-Meier survival curves, restricted cubic spline (RCS), and Cox proportional hazard regression models. RESULTS: A total of 760 patients (52.9% male) with a median age of 84.0 years were assessed. The Kaplan-Meier survival curves showed that patients with higher RAR had higher mortality (log-rank P < 0.001). After adjustment for potential confounders, we found that a 1 unit increase in RAR was associated with a 46% increase in 1-year mortality (HR = 1.46, 95% CI:1.22-1.75, P < 0.001). According to the RAR tertiles, high RAR (RAR > 4.0) compared with the low RAR group (RAR < 3.5) significantly increased the risk of 1-year mortality (HR = 2.21, 95% CI: 1.23-3.95, P = 0.008). The RCS regression model revealed a continuous linear relationship between RAR and all-cause mortality. No significant interaction was observed in the subgroup analysis. CONCLUSION: The RAR is independently associated with all-cause mortality in patients treated with TAVR. The higher the RAR, the higher the mortality. This simple indicator may be helpful for risk stratification of TAVR patients.

Serum irisin correlates to the severity of acute myocardial infarction and predicts the postoperative major adverse cardiovascular events.

Irisin is a myogenic cytokine which plays an important role in the cardiovascular system. The aim of this study was to investigate the correlation between serum irisin levels and major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). A total of 207 patients with AMI who underwent PCI were selected as research subjects. Serum irisin levels at admission were measured, and patients were stratified according to the receiver operating characteristic curve to assess differences in MACE within one year after PCI. After one year of follow-up, 207 patients were divided into two groups, 86 with MACE and 121 without MACE. There were significant differences in age, Killip grade, left ventricular ejection fraction, cardiac troponin I, creatine kinase-muscle/brain, and serum irisin between the two groups. Serum irisin level at admission in AMI patients significantly correlated with the occurrence of MACE after PCI, and could be used as an effective marker for predicting the occurrence of MACE in AMI patients after PCI.

The Action and Mechanism of Trehalose on GATA4 Autophagy Degradation and Ventricular Remodeling.

OBJECTIVE: To probe the effect of trehalose on myocardial hypertrophy and its specific molecular mechanism. METHODS: C57BL/6J male mice were divided into four subgroups: Sham operation subgroup (Sham), negative sham subgroup (Sham+Trehalose), transverse aortic constriction (TAC), and trehalose treatment subgroup (TAC+Trehalose). Immediately after the TAC operation, trehalose at a dose of 10 mg/kg was given daily via gavage. After four weeks, changes in cardiac function were evaluated using ultrasound to measure EF (ejection fraction), FS (fractional shortening), IVRT (isovolumic relaxation time), MPI (myocardial performance index), Tau (isovolumic relaxation time constant), LVESP (left ventricular end-systolic pressure), and EDPVR (end-diastolic pressure-volume relationship). The profiles of autophagy-associated proteins (p62, LC3II/I, and Beclin-1) and GATA4 protein in mice myocardial tissues were assessed by Western blotting (WB). Myocardial cells were classified from TAC mice into five groups: Control, Trehalose, Phenylephrine (PE), PE+Trehalose, and PE+Trehalose+autophagy inhibitor chloroquine groups. In the PE group, cardiomyocytes were treated with 50 µmol/L PE. Then, the cells were treated with trehalose (100 µmol/L), trehalose (100 µmol/L)+autophagy (20 µmol/L) for 24 hours respectively. The Control group was treated with the same amount of normal saline. Flow cytometry was utilized to detect myocardial cell apoptosis in each subgroup. The alterations in apoptosis and autophagy-correlated proteins (p62, LC3II/I, and Beclin-1) were assessed by WB. Additionally, the level of GATA4 protein upstream of autophagy was estimated. Furthermore, the expression levels of pro-apoptotic proteins Bad, BAX, Cleaved-caspase-3, and anti-apoptotic protein Bcl-2 were examined by WB. RESULTS: The TAC operation significantly augmented myocardial hypertrophy, heart weight-to-body weight ratio, and myocardial cell apoptosis in mice (p < 0.05). Trehalose significantly improved cardiac hypertrophy, cardiomyocyte apoptosis, and cardiac function decline in mice. Additionally, it also significantly enhanced autophagy in mouse cardiac tissues (p < 0.05). At the cellular level, trehalose significantly decreased PE-elicited apoptosis and promoted the protein expressions of Beclin-1 and LC3 II/I in cardiomyocytes while significantly dampening the profiles of p62 and GATA4 in cells. The effect of trehalose and chloroquine treatment was significantly greater than that of the trehalose group. CONCLUSIONS: Trehalose significantly abates myocardial hypertrophy and pressure overload-induced cardiomyocyte apoptosis in mice. The cardioprotective effect of trehalose on enhanced autophagy is attributed, at least in part, to the promotion of autophagic degradation of GATA4.

Effects of first-line antidiabetic drugs on the improvement of arterial stiffness: A Bayesian network meta-analysis.

BACKGROUND: Changes in vascular function are closely associated with the development of cardiovascular disease (CVD). Pulse wave velocity (PWV) is a potential indicator of vascular dysfunction; it allows noninvasive assessment of arterial stiffness. Currently, evidence for the effects of different classes of antidiabetic drugs on arterial stiffness remains limited. In this study, a network meta-analysis (NMA) was performed to explore the associations between changes in arterial stiffness and first-line antidiabetic drugs by evaluating PWV in patients with different metabolic abnormalities. METHODS: We systematically searched several electronic databases for randomized controlled trials (RCTs) published from inception until 25 August 2022, without language restrictions. The primary outcome was the change in PWV (ΔPWV) in all included studies; subgroup analysis was performed for patients with abnormal glucose metabolism, including prediabetes and diabetes mellitus. NMA was performed to calculate the mean differences (MDs) with 95% confidence intervals (CIs) as effect sizes to evaluate the ΔPWV. RESULTS: Among the 2257 candidate articles identified in the initial search, 18 RCTs were eventually included in the analysis. In all studies, two classes of new antidiabetic drugs, glucagon-like peptide-1 receptor (GLP-1R) agonists and sSodium-glucose co-transporter 2 (SGLT-2) inhibitors, improved arterial stiffness by decreasing PWV compared with placebo (MD = -1.11, 95% CI: -1.94 to 0.28) and (MD = -0.76, 95% CI: -1.45 to -0.08). A conventional antidiabetic drug, metformin, also showed similar efficacy compared with placebo (MD = -0.73, 95% CI: -1.33 to -0.12). Finally, in subgroup studies of patients with abnormal glucose metabolism diseases, GLP-1R agonists (MD = -1.06, 95% CI: -2.05 to -0.10) significantly decreased PWV compared with placebo. CONCLUSION: Three classes of antidiabetic drugs-GLP-1R agonists, SGLT-2 inhibitors, and metformin-have the potential to improve arterial stiffness. Among the six classes of antidiabetic drugs analyzed, GLP-1R agonists constitute the only class of drugs that improves arterial stiffness in patients with abnormal glucose metabolism diseases.

Triglyceride to High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio, a Simple but Effective Indicator in Predicting Type 2 Diabetes Mellitus in Older Adults.

Background: A simple and readily available biomarker can provide an effective approach for the surveillance of type 2 diabetes mellitus (T2DM) in the elderly. In this research, we aim to evaluate the role of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as an indicator for new-onset T2DM in an elderly Chinese population aged over 75 years. Methods: This longitudinal retrospective cohort study was conducted using a free database from a health check screening project in China. Participants with baseline TG and HDL measurements were enrolled, and the data of T2DM development were collected. The cumulative incident T2DM rates in different quintile groups of TG/HDL-C ratio (Q1 to Q5) were calculated and plotted. The independent effect of baseline TG/HDL-C ratio on T2DM risk during the follow-up period was tested by the Cox proportional hazard model. Subgroup analysis was also conducted to clarify the role of TG/HDL-C ratio in specific populations. Results: A total of 231 individuals developed T2DM among 2,571 subjects aged over 75 years during follow-up. Regardless of adjustment for potential confounding variables, elevated TG/HDL-C ratio independently indicated a higher risk of incident T2DM [hazard ratio (HR) = 1.29; 95% confidence interval (CI), 1.14-1.47; P < 0.01. As compared with the lowest quintile (Q1), elevated TG/HDL-C ratio quintiles (Q2 to Q5) were associated with larger HR estimates of incident T2DM [HR (95% CI), 1.35 (0.85-2.17), 1.31 (0.83-2.06), 1.85 (1.20-2.85), and 2.10 (1.38-3.20), respectively]. In addition, a non-linear correlation was found between TG/HDL-C ratio and the risk of T2DM, and the slope of the curve decreased after the cutoff point of 2.54. Subgroup analysis revealed a stronger positive correlation among male individuals and those with body mass index <24 kg/m2. Conclusions: Increased TG/HDL-C ratio indicates a greater risk of new-onset T2DM regardless of confounding variables. TG/HDL-C ratio is a simple but effective indicator in predicting T2DM in older adults. More future investigations are warranted to further promote the clinical application of TG/HDL-C ratio.

Combined glycoprotein IIb/IIIa inhibitor therapy with ticagrelor for patients with acute coronary syndrome.

This study was to compare the efficacy and safety of combined glycoprotein IIb/IIIa inhibitor (GPI) and ticagrelor versus ticagrelor in patients with acute coronary syndrome (ACS). An observational study was conducted using the Improving Care for Cardiovascular Disease in China-ACS project. Totally, 13,264 patients with ACS and received combination therapy or ticagrelor therapy were analyzed. The primary outcome was the composite of major cardiovascular events (MACE: all-cause mortality, myocardial infarction [MI], stent thrombosis, cardiogenic shock, and ischemic stroke), and secondary outcomes included all-cause mortality, MI, stent thrombosis, cardiogenic shock, and ischemic stroke. The multivariable adjusted analysis indicated that combination therapy was associated with an increased risk of major cardiovascular events (MACE) (P = 0.001), any bleeding (P<0.001), and major bleeding (P = 0.005). Moreover, the multivariable adjusted for propensity score-matched (PSM) analysis suggested that combination therapy produced additional risk of MACE (P = 0.014), any bleeding (P<0.001), and major bleeding (P = 0.005). Moreover, PSM analysis suggested that combination therapy was associated with greater risk of stent thrombosis (P = 0.012) and intracranial bleeding (P = 0.020). Combined GPI and ticagrelor therapies did not have any beneficial effects on MACE, stent thrombosis, intracranial bleeding, any bleeding, or major bleeding.