Cellular and Molecular Insights into the Divergence of Neural Stem Cells on Matrigel and Poly-l-lysine Interfaces.

Poly-l-lysine (PLL) and Matrigel, both classical coating materials for culture substrates in neural stem cell (NSC) research, present distinct interfaces whose effect on NSC behavior at cellular and molecular levels remains ambiguous. Our investigation reveals intriguing disparities: although both PLL and Matrigel interfaces are hydrophilic and feature amine functional groups, Matrigel stands out with lower stiffness and higher roughness. Based on this diversity, Matrigel surpasses PLL, driving NSC adhesion, migration, and proliferation. Intriguingly, PLL promotes NSC differentiation into astrocytes, whereas Matrigel favors neural differentiation and the physiological maturation of neurons. At the molecular level, Matrigel showcases a wider upregulation of genes linked to NSC behavior. Specifically, it enhances ECM-receptor interaction, activates the YAP transcription factor, and heightens glycerophospholipid metabolism, steering NSC proliferation and neural differentiation. Conversely, PLL upregulates genes associated with glial cell differentiation and amino acid metabolism and elevates various amino acid levels, potentially linked to its support for astrocyte differentiation. These distinct transcriptional and metabolic activities jointly shape the divergent NSC behavior on these substrates. This study significantly advances our understanding of substrate regulation on NSC behavior, offering novel insights into optimizing and targeting the application of these surface coating materials in NSC research.

Clinical outcomes of serum potassium in patients with percutaneous coronary intervention: insights from a large single-center registry.

Background: Serum potassium homeostasis plays an important role in myocardial electrical stability, but the impact of altered serum potassium levels on the major adverse cardiovascular and cerebral events (MACCE) in patients with percutaneous coronary intervention (PCI) has not been evaluated. Aim: To evaluate the association between serum potassium level and the risk of MACCE in PCI patients. Materials and methods: This retrospective study involved 8,263 in-patients from a single-center registry who were successfully treated with PCI between January 2003 and December 2020. Clinical data were collected for 24 h after admission. Data were analyzed from June 2003 to December 2021. The primary outcome was MACCE, defined as a composite of all-cause death, myocardial infarction, revascularization, stroke, and heart failure-related hospitalization. Results: The median [interquartile range (IQR)] follow-up for all patients was 4.0 (2.1, 5.8) years, and 1,632 patients (19.7%) were diagnosed with MACCE. High serum potassium levels were associated with a 20% increased risk of MACCE (hazard ratio [HR]: 1.20, 95% confidence interval [CI]: 1.05-1.38, P = 0.008) and 72% increased risk of all-cause death (HR: 1.72, 95% CI: 1.39-2.14, P < 0.001). Multivariate Cox analysis showed that the risk of MACCE was higher in patients at the highest quartile of serum potassium (Q4 vs. Q1: adjusted HR: 1.18, 95% CI: 1.02-1.35, P = 0.026). Moreover, a higher serum potassium level was always associated with a higher risk of all-cause death (Q4 vs. Q1: adjusted HR: 1.50, 95% CI: 1.17-1.91, P = 0.001). A U-shaped relationship between serum potassium levels, MACCE, and all-cause death was derived in patients undergoing PCI. Serum potassium levels, maintained within the range of 3.8-4.0 mmol/L before PCI, exhibited the lowest risk of associated MACCE and all-cause death. Conclusion: Our results demonstrate that the serum potassium level could be associated with higher risks of MACCE and all-cause death in PCI patients. In particular, serum potassium levels maintained at 3.8-4.0 mmol/L before PCI could lower the risk of MACCE and all-cause death.

Risk stratification algorithm for clinical outcomes in anemic patients undergoing percutaneous coronary intervention.

BACKGROUND: To explore the crosstalk between baseline or visit hemoglobin and major adverse cardiovascular and cerebral events (MACCE) in percutaneous coronary intervention (PCI) patients and to construct risk stratification models to predict MACCE amongst these patients. MATERIALS AND METHODS: We conducted a retrospective cohort in patients undergoing PCI procedures at Beijing Friendship Hospital between January 2013 and December 2020. Multivariate Cox proportional hazards models were employed for data analyses. The composite MACCE was the primary endpoint and we used machine learning algorithms to evaluate risk factors associated with MACCE. Model performance was measured using Brier scores and receiver-operating characteristic curves. The association between risk factors and MACCE probability was examined using partial dependency plots. RESULTS: 8,298 PCI-treated patients were enrolled in the study. 1,919 of these patients had anemia. During a four-year median follow-up period, 1,636 patients (19.71%) had MACCE. The visit hemoglobin and hemoglobin change was associated with higher risk of MACCE respectively (visit hemoglobin: hazard ratio [HR]: 0.98; 95% confidence interval [CI]: 0.98-0.99; p < 0.001; hemoglobin change: HR: 0.99; 95%CI: 0.98-0.99; p < 0.001). Gradient Boosting (GB) was the BPM, with a mean C-statistic value of 0.78 (95% CI: 0.76-0.80) for predicting MACCE (Brier score: 0.26). The best indicator for MACCE was a low estimated glomerular filtration rate [eGFR] (71 mL/min/1.73m2) at admission, followed by a high serum HbA1c (6.6%) level. A simple risk tree successfully classified patients (17-40.5%) with increased risks of MACCE. The high- vs. low-risk HR for MACCE was 2.04 (95% CI: 1.48-2.82). CONCLUSIONS: Visit hemoglobin and long-term hemoglobin changes were more predictive of MACCE risk than baseline hemoglobin levels. Our findings indicated that increasing hemoglobin levels might improve the long-term prognosis of anemia patients. We established a new risk stratification model for MACCE, which may more efficiently prioritize targeted screening for at-risk anemic patients undergoing PCI.

Visit hemoglobin and long-term hemoglobin changes predicted the risk of MACCE better than baseline hemoglobin.Patients with anemia will benefit from increasing hemoglobin levels.A new risk stratification model for MACCE was established to identify at-risk anemic patients undergoing PCI.

Abnormal plasma ceramides refine high-risk patients with worsening heart failure.

Background: Worsening heart failure (WHF) is a heterogeneous clinical syndrome with poor prognosis. More effective risk stratification tools are required to identify high-risk patients. Evidence suggest that aberrant ceramide accumulation can be affected by heart failure risk factors and as a driver of tissue damage. We hypothesized that specific ceramide lengths and ratios serve as biomarkers for risk stratification in WHF patients by reflecting pathological changes of distinct organ dysfunctions. Medthods: We measured seven plasma ceramides using liquid chromatography-mass spectrometry (LC-MS) in 1,558 patients, including 1,262 participants in retrospective discovery set and 296 WHF patients in prospective validation set in BIOMS-HF study (Registry Study of Biomarkers in Heart Failure). Univariable and multivariable logistic regression models were constructed to identify associations of ceramides with organ dysfunctions. Results: We constructed three ceramide-based scores linked independently to heart, liver, and kidney dysfunction, with ceramides and ratios included in each score specifying systemic inflammation, chronic metabolic disorder, and water-sodium retention. The combined ceramide heart failure score (CHFS) was independently associated with adverse outcomes [Hazard Ratio, 2.80 (95% CI: 1.78-4.40; P < 0.001); 2.68 995% CI: 1.12-6.46; P = 0.028)] and improved the predictive value of Acute Decompensated Heart Failure National Registry score and BNP [net reclassification index, 0.34 (95% confidence interval, CI: 0.19-0.50); 0.42 (95% CI: 0.13-0.70)] in the discovery and validation set, respectively. Lower BNP levels, but higher CHFS had the highest hazard of future adverse events in WHF patients. Conclusion: Abnormal plasma ceramides, associated with heart and peripheral organ dysfunctions, provide incremental prognostic information over the ADHERE score and brain natriuretic peptide concentration for risk stratification in WHF patients. This may facilitate the reclassification of high-risk patients in need of aggressive therapeutic interventions.

Aldosterone dysregulation predicts the risk of mortality and rehospitalization in heart failure with a preserved ejection fraction.

Serum aldosterone is associated with cardiac remodeling, which contributes to morbidity and mortality in heart failure (HF); however, the prognostic value of aldosterone in HF with a preserved ejection fraction (HFpEF) is unclear. We used liquid chromatography-tandem mass spectrometry to quantify serum aldosterone in 873 patients with HFpEF in a Registry Study of Biomarkers for HF. The retrospective study was conducted at Beijing Anzhen Hospital from May 2017 to October 2019. The primary endpoint was a composite of all-cause mortality and rehospitalization for HF. Aldosterone concentrations in patients with and without events were 124.22 pmol L-1 (interquartile range (IQR): 48.62-256.20) and 96.33 pmol L-1 (IQR: 37.33-215.76), respectively (P=0.023). Aldosterone independently predicted all-cause mortality (adjusted hazard ratio (aHR), 1.55; 95% confidence interval (95%CI), 1.06-2.27; P=0.024) and the primary endpoint (aHR, 1.43; 95%CI, 1.11-1.85; P=0.006). Patients with high aldosterone concentrations were at higher risk of concentric remodeling (adjusted odds ratio (aOR), 1.45; 95% CI, 1.03-2.04; P=0.034). Patients with high aldosterone and B-type natriuretic peptide concentrations were at a higher risk of the primary endpoint (hazard ratio (HR), 1.85; 95%CI, 1.29-2.66; P=0.001). We conclude that elevated aldosterone is associated with a risk of rehospitalization with HF and all-cause mortality in patients with HFpEF.

TMAO: how gut microbiota contributes to heart failure.

An increasing amount of evidence reveals that the gut microbiota is involved in the pathogenesis and progression of various cardiovascular diseases. In patients with heart failure (HF), splanchnic hypoperfusion causes ischemia and intestinal edema, allowing bacterial translocation and bacterial metabolites to enter the blood circulation via an impaired intestinal barrier. This results in local and systemic inflammatory responses. Gut microbe-derived metabolites are implicated in the pathology of multiple diseases, including HF. These landmark findings suggest that gut microbiota influences the host's metabolic health, either directly or indirectly by producing several metabolites. In this review, we mainly discuss a newly identified gut microbiota-dependent metabolite, trimethylamine N-oxide (TMAO), which appears to participate in the pathologic processes of HF and can serve as an early warning marker to identify individuals who are at the risk of disease progression. We also discuss the potential of the gut-TMAO-HF axis as a new target for HF treatment and highlight the current controversies and potentially new and exciting directions for future research.

Flow evaluation of STA-MCA bypass using quantitative ultrasonography: An alternative to standard angiography for follow up of bypass graft.

PURPOSE: To date, digital subtraction angiography (DSA) has been considered as the gold imaging modality for assessing graft patency after extracranial-intracranial bypass. The utility of a noninvasive and quantitative method of assessing graft flow postoperatively was evaluated by using quantitative ultrasonography. METHOD: All STA-MCA bypass surgery performed over a 5-year period at a single institution were reviewed. Measured by duplex ultrasonography, pre-operative (day1) and post-operative (day1, day7, 3month and 6 month) graft blood flow rates were recorded and analyzed. Results were correlated to Matsushima grade determined by DSA performed within 24 h when ultrasonography was conducted to confirm the graft function. RESULTS: 100 patients with 131 operated hemispheres were included in this study. The mean flow rates in the STA graft on pre-operative day1, post-operative day 1 and 7, at 3- and 6-month postoperatively were 24.1, 106.7, 112.6, 97.4 and 79.7 ml/min respectively. The mean post-operative flow in the STA graft graded as A/B/C were significantly different (168.0 ± 34.8 ml/min, 91.0 ± 15.5, 42.1 ± 17.2 ml/min, respectively, p = 0.000). 124.5 ml/min and 65.5 ml/min are good cut-off value for predicting post-operative graft Matsushima grade. The analysis also showed excellent agreement between ultrasonography and DSA for assessing bypass function (κ = 0.78). CONCLUSIONS: The patency of the STA grafts can be assessed noninvasively by quantitative ultrasonography, which results are comparable to those of conventional DSA. This, therefore, suggest that quantitative ultrasonography may be an alternative method to standard DSA for serial follow up of STA grafts.

Doxorubicin-induced cardiotoxicity is maturation dependent due to the shift from topoisomerase IIα to IIß in human stem cell derived cardiomyocytes.

Doxorubicin (DOX) is widely used to treat various cancers affecting adults and children; however, its clinical application is limited by its cardiotoxicity. Previous studies have shown that children are more susceptible to the cardiotoxic effects of DOX than adults, which may be related to different maturity levels of cardiomyocyte, but the underlying mechanisms are not fully understood. Moreover, researchers investigating DOX-induced cardiotoxicity caused by human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown that dexrazoxane, the recognized cardioprotective drug for treating DOX-induced cardiotoxicity, does not alleviate the toxicity of DOX on hiPSC-CMs cultured for 30 days. We have suggested that this may be ascribed to the immaturity of the 30 days hiPSC-CMs. In this study, we investigated the mechanisms of DOX induced cardiotoxicity in cardiomyocytes of different maturity. We selected 30-day-old and 60-day-old hiPSC-CMs (day 30 and day 60 groups), which we term 'immature' and 'relatively mature' hiPSC-CMs, respectively. The day 30 CMs were found to be more susceptible to DOX than the day 60 CMs. DOX leads to more ROS (reactive oxygen species) production in the day 60 CMs than in the relatively immature group due to increased mitochondria number. Moreover, the day 60 CMs mainly expressed topoisomerase IIß presented less severe DNA damage, whereas the day 30 CMs dominantly expressed topoisomerase IIα exhibited much more severe DNA damage. These results suggest that immature cardiomyocytes are more sensitive to DOX as a result of a higher concentration of topoisomerase IIα, which leads to more DNA damage.

Midrange ejection fraction as a risk factor for deterioration of cardiofunction after permanent pacemaker implantation.

PURPOSE: To determine whether the midrange ejection fraction (mrEF) is associated with increased risk of deterioration of cardiac function (DCF) after dual chamber permanent pacemaker (PPM) implantation. METHODS: We performed a prospective cohort study of relevance in patients with EF ≥ 40% and indications for PPMs. Patient characteristics were recorded at baseline and 1 day, 1 month, 3 months, and 6 months after PPM implantation with leads placed in the right ventricular apex. These included clinical symptoms, signs, biochemical parameters, BNP, echocardiography and ECG parameters, and pacing-related parameter changes. The patients were followed-up for 6 months. Univariate and multivariable Cox regression analyses were performed. RESULTS: A total of 879 patients were included, aged 35 to 88 years (mean age 67.2 ± 9.6); a total of 81 patients (9.2%) developed DCF after PPM implantation, including LVEF < 40% (57 cases) and increased NYHA class (24 cases). Cox models demonstrated that age ≥ 75 years (HR 2.273 [95% CI, 1.541-3.626]), OMI (HR 2.078 [95% CI, 1.275-3.604]), mrEF (HR 2.762 [95% CI, 1.558-4.769]), moderate mitral regurgitation (HR 2.819 [95% CI, 1.604-4.153]), and right ventricular pacing ≥ 50% (HR 2.311 [95% CI, 1.478-3.937]) were strong predictors for DCF, and NT-proBNP > 1000 ng/L and paced QRS duration ≥ 180 ms were also the independent predictors of DCF. CONCLUSIONS: MrEF was associated with increased risk of deterioration of cardiac function after PPM implantation. Moderate mitral regurgitation and increased NT-proBNP levels are also potential independent predictors for deterioration of cardiac function after PPM implantation.

Uric acid: a potent molecular contributor to pluripotent stem cell cardiac differentiation via mesoderm specification.

Congenital heart disease (CHD) is the most common cause of congenital anomaly and a leading cause of morbidity and mortality worldwide. Generation of cardiomyoctyes derived from pluripotent stem cells (PSCs) has opened new avenues for investigation of human cardiac development. Here we report that uric acid (UA), a physiologically abundant compound during embryonic development, can consistently and robustly enhance cardiac differentiation of human PSCs including hESCs and hiPSCs, in replacement of ascorbic acid (AA). We optimized treatment conditions and demonstrate that differentiation day 0-2, a period for specification of mesoderm cells, was a critical time for UA effects. This was further confirmed by UA-induced upregulation of mesodermal markers. Furthermore, we show that the developing mesoderm may be by directly promoted by SNAI pathway-mediated epithelial-mesenchymal transition (EMT) at 0-24 h and a lengthened G0/G1 phase by increasing the ubiquitination degradation in 24-48 h. These findings demonstrate that UA plays a critical role in mesoderm differentiation, and its level might be a useful indicator for CHD in early fetal ultrasound screening.

Novel oral anticoagulants in the preoperative period: a meta-analysis.

The purpose of this study is to evaluate the efficacy and safety of novel oral anticoagulant (NOAC) versus warfarin therapy in patients undergoing different operations. We performed a systematic review of MEDLINE, EMBASE, Cochrane Controlled Trials Register, and reports presented at scientific meetings. The efficacy and safety of NOACs during the perioperative period was compared to that using warfarin. Of the 2652 studies initially reviewed, we identified 9 that included 15,880 patients for the meta-analysis. Compared to warfarin, dabigatran increased the risk of major bleeding (RR 1.37, 95% CI 1.06-1.78, P = 0.02). Apixaban (RR 0.63, 95% CI 0.40-0.99, P = 0.04) reduced thrombotic events. NOAC therapy decreased thrombotic events in patients undergoing non-cardiac surgery (RR 0.68, 95% CI 0.50-0.92, P = 0.02). Compared to warfarin, the administration of NOACs in the perioperative period has the same risk of thromboembolism and major bleeding. But patients undergoing non-cardiac surgery may benefit more from perioperative NOAC therapy. Apixaban may reduce thrombotic events and dabigatran increases the risk of major bleeding during the perioperative period.

Perioperative management of antithrombotic therapy in patients receiving cardiovascular implantable electronic devices: a network meta-analysis.

PURPOSE: Network meta-analysis (NMA) has advantages including being able to simultaneously compare and rank multiple treatments over traditional meta-analysis. We evaluated by a NMA the optimal antithrombotic strategy during the perioperative period of implantation of cardiovascular implantable electronic devices (CIEDs). METHODS: We performed a network meta-analysis of observational studies (cohort and case-control studies). The eligible studies tested the following antithrombotic therapy during the CIED placement: aspirin, clopidogrel, warfarin, novel oral anticoagulants (NOACs), and heparin bridging. RESULTS: Thirty-one observational studies with 119 study arms were included (41,174 patients receiving long-term antithrombotic therapy; median age, 72.6 years; 70.1% males; median follow-up, 3.6 years). Aspirin (4.26 [2.88-7.22]), warfarin (3.37 [2.17-5.23]), and clopidogrel (3.30 [1.49-5.88]) reduced the risk of bleeding as compared with heparin bridging, and there was no significance difference between continued NOACs and heparin bridging (0.67 [0.21-2.18]). The comparison of commonly used protocols in the management of anticoagulant therapy revealed that continued warfarin (0.38 [0.20-0.74]), continued NOACs (0.19 [0.04-0.89]), and heparin bridging therapy (0.01 [0.05-0.21]) increased the risk of bleeding as compared that of control, and continued warfarin (3.74 [1.96-7.16]), interrupted warfarin (4.89 [2.20-10.88]), and interrupted NOACs (12.5 [1.25-100]) reduced the risk of bleeding compared with that of heparin bridging. CONCLUSIONS: Among various antithrombotic drugs, aspirin had the lowest bleeding risk, followed by warfarin, clopidogrel and NOACs, and heparin, with the greatest bleeding risk. NOACs therapy appears safe and effective, and interrupted NOACs may be the optimal anticoagulation protocol for use during the perioperative period of CIED implantation.