Correlation between serum phosphate and all-cause mortality in critically ill patients with coronary heart disease accompanied by chronic kidney disease: a retrospective study using the MIMIC-IV database.

Background: The adverse clinical endpoints of cardiovascular and kidney diseases are correlated with increased serum phosphate levels. However, in critically ill patients with coronary heart disease (CHD) accompanied by chronic kidney disease (CKD), the prognostic value of serum phosphate remains unclear. Methods: Patients' medical records from the Medical Information Mart for Intensive Care IV database who had concomitant CKD and CHD were classified into four distinct groups in this large retrospective observational cohort study based on the quartiles of serum phosphate levels. Vital status and the duration of hospital and ICU stays within the short-term follow-up periods of 30 and 90 days constituted the primary outcomes. All-cause mortality in the intensive care unit (ICU) and hospital constituted the secondary outcomes. Further, the Cox proportional hazard and restricted cubic spline (RCS) regression models were employed to ascertain how serum phosphate levels correlated with the primary outcomes. In addition, the occurrence rate of the secondary outcomes across the four quartiles was determined utilizing the Kaplan-Meier method. Results: Among the total 3,557 patients (67.6% male) included, the hospital and ICU all-cause mortality rates were 14.6% and 10%, separately. Higher quartiles of serum phosphate concentrations were associated with shorter short-term survival rates, as shown by the Kaplan-Meier curves. Additionally, the Cox proportional hazards analysis illustrated that serum phosphate was independently linked to a higher death risk in the hospital [HR, 1.10 (95% CI: 1.03-1.18), P = 0.007] and ICU [HR, 1.14 (95% CI: 1.07-1.22), P < 0.001]. Lastly, the RCS regression models suggested a robust non-linear correlation between serum phosphate concentrations and death risk in the ICU and hospital (both P for non-linearity <0.001). Conclusions: The prognostic value of serum phosphate is significant in critically ill patients with CHD accompanied by CKD. Furthermore, serum phosphate is potentially valuable for identifying patients with this concomitant condition.

Echocardiography-based machine learning algorithm for distinguishing ischemic cardiomyopathy from dilated cardiomyopathy.

BACKGROUND: Machine learning (ML) can identify and integrate connections among data and has the potential to predict events. Heart failure is primarily caused by cardiomyopathy, and different etiologies require different treatments. The present study examined the diagnostic value of a ML algorithm that combines echocardiographic data to automatically differentiate ischemic cardiomyopathy (ICM) from dilated cardiomyopathy (DCM). METHODS: We retrospectively collected the echocardiographic data of 200 DCM patients and 199 ICM patients treated in the First Affiliated Hospital of Guangxi Medical University between July 2016 and March 2022. All patients underwent invasive coronary angiography for diagnosis of ICM or DCM. The data were randomly divided into a training set and a test set via 10-fold cross-validation. Four ML algorithms (random forest, logistic regression, neural network, and XGBoost [ML algorithm under gradient boosting framework]) were used to generate a training model for the optimal subset, and the parameters were optimized. Finally, model performance was independently evaluated on the test set, and external validation was performed on 79 patients from another center. RESULTS: Compared with the logistic regression model (area under the curve [AUC] = 0.925), neural network model (AUC = 0.893), and random forest model (AUC = 0.900), the XGBoost model had the best identification rate, with an average sensitivity of 72% and average specificity of 78%. The average accuracy was 75%, and the AUC of the optimal subset was 0.934. External validation produced an AUC of 0.804, accuracy of 78%, sensitivity of 64% and specificity of 93%. CONCLUSIONS: We demonstrate that utilizing advanced ML algorithms can help to differentiate ICM from DCM and provide appreciable precision for etiological diagnosis and individualized treatment of heart failure patients.

CircRNA mmu_circ_0000021 regulates microvascular function via the miR-143-3p/NPY axis and intracellular calcium following ischemia/reperfusion injury.

Cardiac ischemia-reperfusion (I/R) is associated with a high rate of complications. Restoring microvascular function is crucial for cardiac repair. However, the molecular mechanisms by which the circRNAs repairs microvascular dysfunction are unknown. High-throughput RNA sequencing and quantitative real-time PCR (qRT-PCR) were used to measures circRNA levels in cardiac tissue samples. We found a total of 80 up-regulated and 54 down-regulated differentially expressed circRNAs, of which mmu_circ_0000021 were consistent with bioinformatics predictions. Next, mmu_circ_0000021 knockdown and overexpression were performed to indicate the functional role of mmu_circ_0000021. The interaction of mmu_circ_0000021, miR-143-3p and NPY were evaluated using dual-luciferase assays, RNA pull-down assays and RNA immunoprecipitation (RIP). Immunohistochemistry, transmission electron microscopy, and immunofluorescence were used to determine the presence of leukocytes and changes in microvascular morphology and function. Mechanistically, mmu_circ_0000021 involved in regulating microvascular dysfunction via miR-143-3p by targeting NPY. However, the contraction of microvascular spasm caused by NPY is related to calmodulin. By regulating NPY, Circular RNA (circRNA) further affects microvascular spasm, regulates microcirculation disorders, and restores cardiac function. Our findings highlight a novel role for mmu_circ_0000021 by regulating microvascular function following I/R injury.

E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme.

BACKGROUND: E-cigarette aerosol containing aldehydes, including acetaldehyde, are metabolized by the enzyme aldehyde dehydrogenase 2 (ALDH2). However, little is known how aldehyde exposure from e-cigarettes, when coupled with an inactivating ALDH2 genetic variant, ALDH2*2 (present in 8% of the world population), affects cardiovascular oxidative stress. OBJECTIVES: The study was to determine how e-cigarette aerosol exposure, coupled with genetics, impacts cardiovascular oxidative stress in wild type ALDH2 and ALDH2*2 knock-in mice. METHODS: Using selective ion flow mass spectrometry, we determined e-cigarette aerosol contains acetaldehyde levels 10-fold higher than formaldehyde or acrolein. Based on this finding, we tested how isolated ALDH2*2 primary cardiomyocytes respond to acetaldehyde and how intact ALDH2*2 knock-in rodents instrumented with telemeters respond physiologically and at the molecular level to 10 days of e-cigarette aerosol exposure relative to wild type ALDH2 rodents. RESULTS: For ALDH2*2 isolated cardiomyocytes, acetaldehyde (1 µM) caused a 4-fold greater peak calcium influx, 2-fold increase in ROS production and 2-fold increase in 4-HNE-induced protein adducts relative to wild-type ALDH2 cardiomyocytes. The heart rate in ALDH2*2 mice increased ∼200 beats/min, while, heart rate in ALDH2 mice increased ∼150 beats/min after 10 days of e-cigarette exposure, relative to air-exposed mice. E-cigarette aerosol exposure triggered ∼1.3 to 2-fold higher level of protein carbonylation, lipid peroxidation, and phosphorylation of NF-κB for both strains of mice, with this response exacerbated for ALDH2*2 mice. CONCLUSIONS: Our findings indicate people carrying an ALDH2*2 genetic variant may be more susceptible to increases in cardiovascular oxidative stress from e-cigarette aerosol exposure.

Machine learning to predict no reflow and in-hospital mortality in patients with ST-segment elevation myocardial infarction that underwent primary percutaneous coronary intervention.

BACKGROUND: The machine learning algorithm (MLA) was implemented to establish an optimal model to predict the no reflow (NR) process and in-hospital death that occurred in ST-elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention (pPCI). METHODS: The data were obtained retrospectively from 854 STEMI patients who underwent pPCI. MLA was applied to predict the potential NR phenomenon and confirm the in-hospital mortality. A random sampling method was used to split the data into the training (66.7%) and testing (33.3%) sets. The final results were an average of 10 repeated procedures. The area under the curve (AUC) and the associated 95% confidence intervals (CIs) of the receiver operator characteristic were measured. RESULTS: A random forest algorithm (RAN) had optimal discrimination for the NR phenomenon with an AUC of 0.7891 (95% CI: 0.7093-0.8688) compared with 0.6437 (95% CI: 0.5506-0.7368) for the decision tree (CTREE), 0.7488 (95% CI: 0.6613-0.8363) for the support vector machine (SVM), and 0.681 (95% CI: 0.5767-0.7854) for the neural network algorithm (NNET). The optimal RAN AUC for in-hospital mortality was 0.9273 (95% CI: 0.8819-0.9728), for SVM, 0.8935 (95% CI: 0.826-0.9611); NNET, 0.7756 (95% CI: 0.6559-0.8952); and CTREE, 0.7885 (95% CI: 0.6738-0.9033). CONCLUSIONS: The MLA had a relatively higher performance when evaluating the NR risk and in-hospital mortality in patients with STEMI who underwent pPCI and could be utilized in clinical decision making.

Overexpression of Activating Transcription Factor 3 Alleviates Cardiac Microvascular Ischemia/Reperfusion Injury in Rats.

Activating transcription factor 3 (ATF3) has been confirmed to be responsive to oxidative stress and to negatively regulate the activity of Toll-like receptor 4 (TLR4). However, the effect of ATF3 on cardiac microvascular ischemia/reperfusion (I/R) injury remains unknown. The GEO2R online tool was employed to obtain differentially expressed genes GSE4105 and GSE122020, in two rat I/R injury microarray datasets. We established a rat myocardial I/R model in vivo, and also generated an in vitro hypoxia/reoxygenation (H/R) model of cardiomyoblast H9c2 cells. Overexpression of ATF3 was achieved by adenoviral-mediated gene transfer (Ad-ATF3). Rats were randomly divided into four groups: sham, I/R, I/R + Ad-Lacz (as a control), and I/R + Ad-ATF3. ELISA, CCK-8, DCFH-DA probe, qRT-PCR and Western blotting were used to determine the expression of ATF3, oxidative indices, cellular injury and TLR4/NF-κB pathway-associated proteins. Transmission electron microscopy, immunohistochemistry and immunofluorescence were used to detect the leukocyte infiltration and the alteration of microvascular morphology and function in vivo. Echocardiographic and hemodynamic data were also obtained. Bioinformatics analysis revealed that ATF3 was upregulated in I/R myocardia in two independent rat myocardial I/R models. Cardiac microvascular I/R injury included leukocyte infiltration, microvascular integrity disruption, and microvascular perfusion defect, which eventually resulted in the deterioration of hemodynamic parameters and heart function. Ad-ATF3 significantly restored microvascular function, increased cardiac microvascular perfusion, and improved hemodynamic parameters and heart function. Mechanistically, Ad-ATF3 ameliorated oxidative stress, inhibited TLR4/NF-κB pathway activation and down-regulated the expression of downstream proinflammatory cytokines in I/R myocardium in vivo and in H/R H9c2 cells in vitro. ATF3 overexpression protects against cardiac microvascular I/R injury in part by inhibiting the TLR4/NF-κB pathway and oxidative stress.

MiR-98-5p promotes ischemia/reperfusion-induced microvascular dysfunction by targeting NGF and is a potential biomarker for microvascular reperfusion.

OBJECTIVE: This study examined the correlation between serum miR-98-5p levels and indices of microvascular reperfusion in patients undergoing primary percutaneous coronary intervention (pPCI) after ST-segment elevation myocardial infarction (STEMI). Additionally, we evaluated the mechanisms by which miR-98-5p promoted ischemia/reperfusion (I/R)-induced injury in both cultured cell lines and an animal model. METHODS: Circulating miR-98-5p levels were measured and compared from 171 STEMI patients undergoing pPCI, who were divided into two groups: no-reflow and reflow. The levels of miR-98-5p, nerve growth factor (NGF), and transient receptor potential vanilloid 1 (TRPV1) were analyzed in cultured human coronary endothelial cells (HCECs) exposed to hypoxia/reoxygenation (H/R). The effects of antagomir-98-5p on myocardial I/R-induced microvascular dysfunction in vivo were evaluated. Target gene expression and activity were assessed. RESULTS: Higher miR-98-5p levels were associated with compromised indices of microvascular reperfusion. In vitro experiments on HCECs showed that exposure to H/R significantly increased miR-98-5p levels. We identified NGF as a novel target of miR-98-5p. Further, antagomir-98-5p relieved microvascular dysfunction and enhanced the expression of NGF and TRPV1 in the rat myocardial I/R model. CONCLUSIONS: MiR-98-5p promotes microvascular dysfunction by targeting the NGF-TRPV1 axis. Serum miR-98-5p serves as a potential biomarker for microvascular reperfusion.

Prevalence, Virulence, Antimicrobial Resistance, and Molecular Characterization of Pseudomonas aeruginosa Isolates From Drinking Water in China.

Pseudomonas aeruginosa is an important opportunistic pathogen and remains a major threat to the microbial safety of drinking water. There is a lack of comprehensive data on P. aeruginosa contamination in drinking water in China. Therefore, this study aimed to determine the prevalence, genetic diversity, virulence genes, and antimicrobial resistance of P. aeruginosa isolated from mineral water and spring water in China. From January 2013 to January 2014, 314 drinking water samples were collected from 23 cities in China. Of the collected samples, 77 (24.5%) were contaminated with P. aeruginosa, and these comprised 34 raw water (30.4%), 39 activated carbon-filtered water (30.6%), and four final water product (3.9%). A total of 132 P. aeruginosa isolates were obtained, and all of them showed the presence of virulence genes, with the detection rates of ExoU, ExoS, phzM, toxA, and lasB genes being 7.6, 86.3, 95.5, 89.4, and 100%, respectively. All isolates were sensitive to the 14 antibiotics (ciprofloxacin, levofloxacin, ofloxacin, norfloxacin, gentamicin, tobramycin, amikacin, polymyxin B, imipenem, meropenem, aztreonam, ceftazidime, cefepime, and piperacillin/tazobactam) tested. The 132 isolates were categorized into 42 sequence types according to multilocus sequence typing, and ST235 accounted for 8.3% (11) of the total isolates. Thus, this study provides comprehensive data on the prevalence and characteristics of P. aeruginosa in drinking water in China and can aid in developing preventive measures against contamination during the drinking water treatment process.

miR-190a-5p participates in the regulation of hypoxia-induced pulmonary hypertension by targeting KLF15 and can serve as a biomarker of diagnosis and prognosis in chronic obstructive pulmonary disease complicated with pulmonary hypertension.

PURPOSE: miR-190a-5p expression alters dynamically in response to hypoxia. However, the role of miR-190a-5p expression in hypoxia-induced pulmonary hypertension (PH) remains unclear. We sought to correlate the miR-190a-5p expression levels with the severity, diagnosis, and prognosis of PH in relation to chronic obstructive pulmonary disease (COPD-PH). Additionally, we evaluated the effect of miR-190a-5p through in vitro experiments on human pulmonary endothelial cells (HPECs) that were exposed to hypoxia and in vivo experiments using an animal model of hypoxia-induced PH. METHODS: Circulating miR-190a-5p levels were measured from 73 patients with PH and 32 healthy controls through quantitative real-time PCR. The levels of miR-190a-5p and the expression of Krüppel-like factor 15 (KLF15) were analyzed in HPECs that were exposed to hypoxia, and the effects of antagomir-190a-5p in mice with chronic hypoxia-induced PH were tested. Target gene analysis was performed by Western blot and luciferase assay. RESULTS: The miR-190a-5p level was significantly higher in patients with COPD-PH than in the healthy controls. Higher miR-190a-5p levels were associated with a greater severity of COPD-PH. In vitro experiments on HPECs showed that exposure to hypoxia increased the miR-190a-5p levels significantly. KLF15 was validated as a target of miR-190a-5p. Transfection with miR-190a-5p mimicked inhibition of KLF15 expression in HPECs. In the mouse model of PH, antagomir-190a-5p reduced right ventricular systolic pressure and enhanced the KLF15 expression levels in lung tissue. CONCLUSION: miR-190a-5p regulates hypoxia-induced PH by targeting KLF15. The circulating levels of miR-190a-5p correlate with the severity of COPD-PH, thereby confirming the diagnostic and prognostic value of this parameter in COPD-PH.

Modified apple polysaccharide influences MUC-1 expression to prevent ICR mice from colitis-associated carcinogenesis.

The present study tried to assess the effects of modified apple polysaccharide (MAP) on colitis associated carcinogenesis and the expression of Mucin 1(MUC1). One hundred and twenty 5-week-old male ICR mice were used. The control mice were just administrated with saline, and the rest mice were injected intraperitoneally with 1, 2-dimethyl-hydrazine (DMH) and dextran sodium sulfate (DSS). In the 7th week, the mice in MAP-treated groups were bred with the basal diets mixed with different doses of MAP (w/w: 1.25%, 2.5% and 5%) for 13 weeks. The pathological findings demonstrated that: in the 20th week, adenocarcinoma and/or adenoma occurred in the colons of all the mice in model group. MAP treatment decreased the incidence of colorectal cancer significantly. In the early phase of inflammation, MUC1 expression in colonic mucosa had no significant changes. However, when the inflammation developed and tumor formed, MUC1 expression increased remarkably (P < 0.01). And the MAP treatment (especially at the dose of 5%) reduced MUC1 expression significantly. These data suggested that MAP could prevent against colitis associated colorectal cancer in ICR mice effectively, and MUC1 may be a potential therapeutic target in colorectal cancer prevention and treatment.

Modified apple polysaccharide prevents colitis through modulating IL-22 and IL-22BP expression.

Chronic intestinal inflammation enhances cell proliferation, angiogenesis, and migration, then promotes the development of colorectal cancer (CRC). Many ingredients of apples have been proven to have anti-inflammatory properties, and show benefits for colitis treatment. In our previous studies, we found modified apple polysaccharide (MAP) could prevent colitis associated colorectal carcinogenesis effectively. Herein, we further our study to observe the effect of MAP on dextran sodium sulfate (DSS)-induced colitis and to investigate the possible mechanisms. IL-22 has both pathogenic and protective effects during intestinal tissue damage. It could be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP). A DSS-induced colitis mouse model, a mouse CRC cell line MCA-38 and a mouse dendritic cell line DC2.4 were treated with MAP. Western blot, ELISA, BrdU staining and a co-culture system were used to detect the expression of IL-22 and IL-22BP. MAP significantly protected ICR mice against DSS-induced colitis, and inhibited the growth of MCA-38 cells. The mechanisms may be that MAP down-regulated IL-22 level and up-regulated expression of IL-22BP. These data may provide another molecular basis for understanding how apples act to prevent colitis and suggest that MAP has a potential to treat colitis and prevent CRC.

Growth-differentiation factor 15 as a predictor of mortality in patients with heart failure: a meta-analysis.

AIMS: Measurement of the biomarker growth-differentiation factor 15 (GDF-15) in patients with heart failure may help in risk stratification. We assessed the relationship between GDF-15 and mortality in patients with heart failure by conducting a meta-analysis. METHODS: PubMed, Embase, ISI Web of Science, SCOPUS, and Cochrane Library databases were searched for studies that reported data on the baseline GDF-15 levels and all-cause or cardiovascular mortality. Pooled hazard ratios for mortality were calculated and presented with 95% confidence intervals (CIs). Potential sources of heterogeneity were assessed by meta-regression, subgroup, and sensitivity analyses. RESULTS: Eight studies with a total of 4126 heart failure patients were included. Pooled results showed that overexpression of GDF-15 was associated with poor survival in heart failure patients (log unit GDF-15: hazard ratio = 1.86, 95% CI = 1.37-2.52). Subgroup analyses revealed similar results. However, there was evidence of heterogeneity and publication bias. The association disappeared after correction using the trim-and-fill method (log unit GDF-15: hazard ratio 1.07, 95% CI 0.80-1.42). CONCLUSION: The results of this meta-analysis indicate an association of elevated GDF-15 levels with increased risk of mortality in patients with heart failure. However, the results should be interpreted with caution due to substantial heterogeneity and publication bias among the studies included in the meta-analysis.

Telmisartan protects against microvascular dysfunction during myocardial ischemia/reperfusion injury by activation of peroxisome proliferator-activated receptor γ.

BACKGROUND: We investigated the potential of telmisartan to improve microvascular dysfunction induced by myocardial ischemia/reperfusion (I/R) injury by activating the peroxisome proliferator-activated receptor gamma (PPARG) pathway. METHODS: Forty-eight male rabbits were randomly allocated into sham-operated, I/R, GW9662, telmisartan, telmisartan-GW9662, or candesartan groups. Rabbits were anesthetized, and the left anterior descending coronary artery (LAD) was ligated for 60 minutes. Following reperfusion for 6 hours, angiotensin II content of the heart was determined using radioimmunoassay. Myocardial neutrophil accumulation and microvessel cross-sectional area were examined histologically. Myocardial capillaries were examined with transmission electron microscopy. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the myocardium were measured using enzyme-linked immunosorbent assay. Western blot was utilized for investigating the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and PPARG. RESULTS: Angiotensin II concentration was significantly increased in all treatment groups compared with the sham-operated group (P < 0.05, all). Accumulation of polymorphonuclear neutrophils was significantly lower, while microvessel cross-sectional area was significantly higher in the telmisartan, telmisartan-GW9662, and candesartan groups compared with the I/R group (P < 0.05). ICAM-1 and VCAM-1 levels were also significantly lower, and correlated with lower NF-κB expression in these groups. The effects were the most significant in the telmisartan group compared with the telmisartan-GW9662 and candesartan groups. Telmisartan significantly increased PPARG protein expression compared with all other groups (P < 0.05, all). CONCLUSIONS: Except for the typical effects of angiotensin II-receptor blocker, telmisartan improved microvascular dysfunction during myocardial I/R injury via the PPARG pathway.

The prognostic value of N-terminal pro-brain natriuretic peptide in non-ST elevation acute coronary syndromes: a meta-analysis.

BACKGROUND: Precise risk stratification is important in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) on determination for hospitalization and intensity of treatment. A meta-analysis was performed in studies of patients with NSTE-ACS to evaluate the predictive nature of elevated N-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS: Online searches were conducted using database to identify suitable studies. A summary of relative risks (RRs) for death and myocardial infarction (MI) was calculated using random-effects modeling. We also calculated the pooled sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: Thirteen studies were included. Elevated NT-proBNP levels were significantly associated with mortality [RR 4.89; 95% confidence interval (CI) 3.85­6.22] and incidence of MI (RR 1.66; 95% CI 1.24­2.22). The sensitivity and specificity for MI was 69.1% (95% CI 66.6%­71.6%) and 43.6% (95% CI 42.9%­44.3%), respectively, along with the positive and negative predictive values for MI of 8.2% (95% CI 7.7%­8.7%) and 95.1% (95% CI 94.6%­95.5%), respectively. CONCLUSIONS: Meta-analysis suggests that elevated NT-proBNP levels were associated with an increased risk for MI or death in patients with NSTE-ACS. Normal levels of NT-proBNP are certainly more helpful when selecting NSTE-ACS patients with likelihood for favorable outcomes.