Stem cell antigen-1+cell-derived fibroblasts are crucial for cardiac fibrosis during heart failure.

AIMS: Mesenchymal stem cells (MSCs) present in the heart cannot differentiate into cardiomyocytes, but may play a role in pathological conditions. Therefore, the aim of this study was to scrutinise the role and mechanism of MSC differentiation in vivo during heart failure. METHODS AND RESULTS: We performed single-cell RNA sequencing of total non-cardiomyocytes from murine and adult human hearts. By analysing the transcriptomes of single cells, we illustrated the dynamics of the cell landscape during the progression of heart hypertrophy, including those of stem cell antigen-1 (Sca1)+ stem/progenitor cells and fibroblasts. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone marrow-derived Sca1+ cells give rise to fibroblasts. Interestingly, partial depletion of Sca1+ cells alleviated the severity of myocardial fibrosis and led to a significant improvement in cardiac function in Sca1-CreERT2;Rosa26-eGFP-DTA mice. Similar non-cardiomyocyte cell composition and heterogeneity were observed in human patients with heart failure. Mechanistically, our study revealed that Sca1+ cells can transform into fibroblasts and affect the severity of fibrosis through the Wnt4-Pdgfra pathway. CONCLUSIONS: Our study describes the cellular landscape of hypertrophic hearts and reveals that fibroblasts derived from Sca1+ cells with a non-bone marrow source largely account for cardiac fibrosis. These findings provide novel insights into the pathogenesis of cardiac fibrosis and have potential therapeutic implications for heart failure. Non-bone marrow-derived Sca1+ cells differentiate into fibroblasts involved in cardiac fibrosis via Wnt4-PDGFRα pathway.

Right Coronary-Left Ventricular Fistula and Its Course: A Case Report.

BACKGROUND: Coronary fistula is a relatively rare cardiac disease. The incidence of coronary fistula flowing into the right heart structure is much higher than in inflow into the left heart structures. Opportunities for surgical intervention and treatment strategies for these patients still need to build more consensus.  Case presentation: Here, we report a case of right coronary artery-left ventricular fistula combined with a giant coronary artery aneurysm during the treatment course. CONCLUSION: Because of its rarity as well as its specificity of coronary artery fistula, each case requires an individualized evaluation. More consideration also can be given to the choice of surgical approach.

Analysis of clinical distribution and drug resistance of klebsiella pneumoniae pulmonary infection in patients with hypertensive intra cerebral hemorrhage after minimally invasive surgery.

OBJECTIVES: To investigate the clinical distribution and drug resistance of Klebsiella pneumoniae pulmonary infection in patients with hypertensive intracerebral hemorrhage after minimally invasive surgery. METHODS: A total of 658 patients with hypertensive intracerebral hemorrhage who underwent minimally invasive surgery admitted to the intensive care unit (ICU) and the Department of Neurology of Affiliated Hospital of Hebei University from January 2015 to January 2020 were enrolled and divided into two groups: the observation group and the control group. Three hundred and thirty-three cases with postoperative pulmonary infection were included into the observation group, and 325 cases without postoperative pulmonary infection were divided into the control group. The intubation time, neurological deficiency score and Glasgow coma scale (GCS) of the two groups were analyzed and compared. Automatic microbial identification system was utilized to isolate bacteria from patients in the observation group, identify Klebsiella pneumoniae, and analyze Klebsiella pneumoniae infection, clinical department distribution, and age distribution. The Kirby-Bauer method was adopted to carry out the drug susceptibility test of Klebsiella pneumoniae infection. RESULTS: The intubation time and neurological deficiency score of patients with hypertensive cerebral hemorrhage in the observation group were significantly higher than those in the control group (p<0.05), while the GCS score was significantly lower than that in the control group (p<0.05). A total of 403 strains of pathogenic bacteria were isolated from 325 patients in the observation group, of which 52 strains of Klebsiella pneumoniae were detected in 52 patients with postoperative pulmonary infection, accounting for 12.90%. The detection rates of Klebsiella pneumoniae in ICU and neurology department were 53.85% and 46.15%, respectively. Klebsiella pneumoniae had the highest detection rate (40.38%) in people aged 70 years and above. Moreover, fifty-two strains of Klebsiella pneumoniae showed low drug resistance rate (<20%) to cefoperazone/sulbactam, piperacillin/tazobactam, cefoxitin, imipenem, meropenem, amikacin, ciprofloxacin, and levofloxacin. CONCLUSION: For patients with hypertensive cerebral hemorrhage who have pulmonary infection after minimally invasive surgery, risk factors causing infection should be identified in time, their Klebsiella pneumoniae infection should be correctly monitored, and antibiotics should be taken rationally to effectively promote the elimination of brain edema in patients and protect the cranial nerve function of patients.

Small Cavity of Left Ventricle Does Not Affect Short-term Outcome in Patients with Rheumatic Mitral Valve Stenosis Undergoing Mitral Valve Replacement.

BACKGROUND: Small cavity left ventricle (SCLV) may affect the clinical outcomes of patients undergoing mitral valve replacement (MVR). This study aims to investigate the incidence of SCLV in patients with rheumatic mitral valve stenosis undergoing MVR and analyze its effect on short-term patient outcomes. METHODS: We retrospectively examined all consecutive patients with isolated or concomitant MVR for rheumatic mitral valve stenosis in our center from 2013 to 2018. SCLV was defined as end-diastolic volume index ≤ 50 ml/m2. After inclusion and exclusion, a total of 1,437 patients were analyzed. The baseline information was collected and compared between SCLV and non-SCLV patients. Multivariate logistic regression analysis was conducted to determine the effect of SCLV on early mortality. RESULTS: A total of 1,437 patients were included in the study. SCLV was detected in 13.57% of the patients. Compared with the non-SCLV group, patients with SCLV were smaller-sized and primarily female. There were no significant differences between SCLV and non-SCLV patients regarding major postoperative complications, nor were there incidence of prosthesis-patient mismatch. Logistic regression analysis showed that SCLV was not a risk factor for short-term mortality (P = 0.998). CONCLUSIONS: Our results demonstrated that SCLV was not associated with poorer early outcomes after MVR surgery in patients with rheumatic mitral valve stenosis.

Right atrium hemangioma in patient with history of mixed-thrombus surgery.

Primary cardiac neoplasms are rare, cardiac hemangiomas are even rarer, and a mixed thrombus followed by a primary cardiac hemangioma is exceptionally rare epidemiology. Here, we report the case of a man with a right atrium mixed-thrombus surgical history who went on to develop a cardiac hemangioma.

Giant Left Atrial Appendage Aneurysm: Surgical Treatment to Prevent Potential Complications.

Left atrial appendage aneurysm (LAAA) is a rare anomaly, which predisposes to hazardous cardiovascular events. We present a rare case of a 26-year-old female with a giant left atrial appendage aneurysm. The left atrial appendage was incidentally detected during her pregnancy. Six months later after her parturition, the patient was referred to our department and successfully received surgical treatment prophylactically to prevent potential complications. To the best of our knowledge, only about 100 cases of LAAA have been reported.

[Intraoperative autologous based blood conservation strategies in mitral valve replacement].

OBJECTIVE: To evaluate whether intraoperative autologous donation (IAD) can reduce perioperative blood transfusion for patients underwent mitral valve replacement (MVR). METHODS: A total of 318 patients received implementation of IAD from January 2011 to December 2013 were analyzed retrospectively, and compared with 517 patients of the previous 36-month period (from January 2008 to December 2012). The method of small-volume retrograde autologous priming, strict blood transfusion standard along with IAD together constituted a progressive blood-saving strategy. Statistical methods including Students' t-test, Pearson's χ(2) test, Kruskal-Wallis analysis and multivariate Logistic regression model were used for comparisons of the data. RESULTS: There were no significant difference between IAD group and non-IAD group considering preoperative patient demographics, characteristics and preoperative comorbidities. However, IAD group significantly reduced number of patients transfused with intra/post-operative packed red-blood cell (PRBC) (55(17.0%) vs. 215 (42.1%), χ(2)=53.0, P=0.000), and had significantly reduced postoperative chest tube output (150(380) ml vs. 700(660) ml, H=195.648, P=0.000), length of stay ((16±6) d vs. (20±8)d, t=9.60, P=0.000). But hematocrit were lower in IAD group (30%±5% vs.33%±4% at end of operation, t=7.76, P=0.000; 30%±4% vs. 32%±5% at discharge, P=0.000, t=3.86). Multivariate logistic aggression analysis revealed that age, IAD and smoking history were factors influencing the probability of intra or postoperative blood transfusion. CONCLUSION: Implementation of blood conservation strategies based on intraoperative autologous donation in mitral valve replacement surgery can significantly reduce intra/postoperative blood transfusion as well as postoperative complications.

Efficacy of mitral valve repair as an adjunct procedure to coronary artery bypass grafting in moderate ischemic mitral regurgitation: a meta-analysis of randomized trials.

OBJECTIVE: Whether moderate ischemic mitral regurgitation (IMR) should be repaired during coronary artery bypass grafting (CABG) is still uncertain. This meta-analysis of randomized controlled trials (RCTs) evaluated the efficacy of adding mitral valve repair (MVR) to CABG in patients with moderate IMR. METHODS: We searched PubMed, the Cochrane Library, and the Web of Science for RCTs that compared the efficacy of CABG plus MVR with CABG alone. Four RCTs that included 505 patients met the eligibility criteria. RESULTS: CABG + MVR significantly reduced the risk of intermediate residual mitral regurgitation (MR) grade ≥2+ compared with CABG alone (risk ratio [RR] = 0.20, 95% confidence interval [CI] 0.04-0.92, p = 0.04), but did not have advantages on 30-day/in-hospital mortality (RR = 1.06, 95% CI 0.37-3.09, p = 0.91), intermediate mortality (RR = 0.90, 95% CI 0.48-1.67, p = 0.73), risk of intermediate NYHA class ≥II (RR = 0.62, 95% CI 0.24-1.62, p = 0.33), intermediate left ventricular ejection fraction (LVEF) (SMD = 0.04%, 95% CI -0.35 to 0.42, p = 0.84), and intermediate LV end-systolic volume index (LVESVI) (SMD = -0.20 mL/m(2) , 95% CI -0.92 to 0.51, p = 0.58). CONCLUSION: Compared with CABG alone, adding MVR to CABG in patients with moderate IMR reduces the residual MR grade, but has no significant effect on mortality, intermediate NYHA class, LVEF, and LVESVI. Further RCTs with larger sample size and longer follow-up are needed to more clearly elucidate the efficacy of MVR as an adjunct procedure to CABG in patients with moderate IMR.

Fibroblasts facilitate lymphatic vessel formation in transplanted heart.

Rationale: Lymphangiogenesis plays a critical role in the transplanted heart. The remodeling of lymphatics in the transplanted heart and the source of newly formed lymphatic vessels are still controversial, especially the mechanism of lymphangiogenesis remains limited. Methods: Heart transplantation was performed among BALB/c, C57BL/6J, Cag-Cre, Lyve1-CreERT2;Rosa26-tdTomato and Postn(2A-CreERT2-wpre-pA)1;Rosa26-DTA mice. scRNA-seq, Elisa assay, Western blotting, Q-PCR and immunohistochemical staining were used to identify the cells and cell-cell communications of allograft heart. Cell depletion was applied to in vivo and in vitro experiments. Whole-mount staining and three-dimensional reconstruction depicted the cell distribution within transparent transplanted heart. Results: Genetic lineage tracing mice and scRNA-seq analysis have revealed that these newly formed lymphatic vessels mainly originate from recipient LYVE1+ cells. It was found that LECs primarily interact with activated fibroblasts. Inhibition of lymphatic vessel formation using a VEGFR3 inhibitor resulted in a decreased survival time of transplanted hearts. Furthermore, when activated fibroblasts were ablated in transplanted hearts, there was a significant suppression of lymphatic vessel generation, leading to earlier graft failure. Additional investigations have shown that activated fibroblasts promote tube formation of LECs primarily through the activation of various signaling pathways, including VEGFD/VEGFR3, MDK/NCL, and SEMA3C/NRP2. Interestingly, knockdown of VEGFD and MDK in activated fibroblasts impaired cardiac lymphangiogenesis after heart transplantation. Conclusions: Our study indicates that cardiac lymphangiogenesis primarily originates from recipient cells, and activated fibroblasts play a crucial role in facilitating the generation of lymphatic vessels after heart transplantation. These findings provide valuable insights into potential therapeutic targets for enhancing graft survival.

Tricuspid-regurgitation-mediated flow-driven right-to-left cardiac shunting caused systemic hypoxemia in a patient with patent foramen ovale without elevated right atrial pressure.

The prevalence of patent foramen ovale (PFO) is 20-25% among adults. The role of right-to-left shunting through the PFO in systemic hypoxemia remains poorly understood. Right-to-left shunting through the PFO can occur either due to elevated right atrial pressure (pressure-driven) or directed venous flow toward the PFO (flow-driven). Herein, we report a rare case of flow-driven right-to-left shunting via the PFO in a patient with traumatic tricuspid regurgitation. A 45-year-old Chinese woman was admitted due to progressive dyspnea for 3 years, presenting with cyanosis and digital clubbing. She was hypoxic, with an oxygen saturation of 83% on room air, and arterial blood gas showed an oxygen tension of 53 mmHg. Echocardiography showed severe tricuspid regurgitation with ruptured chordae tendinea, causing regurgitant jet flow directed toward the interatrial septum, leading to intermittent right-to-left shunting between the septa primum and secundum. Swan-Ganz catheterization revealed normal-high right atrial pressure and excluded pulmonary hypertension. The patient underwent tricuspid valve repair and PFO closure. Her oxygen saturation returned to 95% and her symptoms resolved. Right-to-left shunting through the PFO could cause systemic hypoxemia via a flow-driven mechanism, occasionally manifesting as cyanosis and clubbing digits. PFO closure and treatment of underlying disease are effective in improving hypoxemia.

Pulsed field ablation as a precise approach for cardiac arrhythmia treatment via cardiac microenvironment remodeling.

PFA uses short-duration, high-voltage electrical pulses to induce transient or irreversible electroporation on cell membranes, causing cell death. Selective inhibition of chaotic electrical signals in morbid cardiomyocytes significantly aids the treatment of atrial fibrillation, ventricular tachycardia, and other heart arrhythmias. Recent preclinical and clinical studies have only investigated physical changes, such as lesion size and myocardial scar. Compared to radiofrequency ablation and cryoballoon ablation, PFA causes less postoperative myocardial cell fibrosis and inflammatory reaction and does not result in myocardial necrosis or tissue scar formation. However, the regulatory mechanism of cellular stress following PFA treatment remains unknown. This study aimed to analyze the transcriptome of the mouse ventricle after PFA treatment. The animals were subjected to a 225-V electric pulse with a 1.5-mm gap between the positive and negative electrodes. Hearts were harvested at 3, 6, 12, 24 h, and 2, 5 days for myocardial zymogram testing. PFA-treated ventricular regions were selected for single-nucleus sequencing. We discovered that PFA remodeled the cardiac microenvironment as a whole. Further, we discussed the possible stress response and wound-healing mechanism in non-targeted cells. In conclusion, PFA allowed effective and selective ventricular myocardium ablation with controllable inflammation.

Prognostic biomarkers for sepsis mortality based on the literature and LC-MS-based metabolomics of sepsis patients.

OBJECTIVES: The management of sepsis, a potentially lethal overreaction to infection, is limited by the lack of prognostic tools to guide its treatment. Our aim is to identify a novel metabolic biomarker panel for predicting sepsis mortality based on a literature review and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. METHODS: In the literature, we found metabolomics biomarkers reported to predict sepsis mortality. We determined the classifications, reported frequency, and KEGG pathway enrichment of these markers. Using serum samples from 20 sepsis survivors and 20 non-survivors within 28 days after admission to the intensive care unit (ICU), we performed LC-MS-based metabolomics. Based on the literature review and metabolomics, a prognostic biomarker panel for sepsis was identified and its area under the curve (AUC) values was assessed. RESULTS: Kynurenate, caffeine, and lysoPC 22:4 were selected as a prognostic biomarker panel for sepsis. The panel had an area under the curve (AUC) of 0.885 (95% CI, 0.694-1) evaluated by linear support vector machine (SVM) and 0.849 (0.699-1) by random forest (RF), which was higher than that of the Sequential Organ Failure Assessment (SOFA). A combination of kynurenate, caffeine, and lysoPC 22:4 and SOFA provided the best discriminating performance, with AUCs of 0.961 (0.878-1) for SVM and 0.916 (0.774-1) for RF. CONCLUSIONS: The prognostic biomarker panel consisting of kynurenate, caffeine, and lysoPC 22:4 may aid in the identification of sepsis patients at a high risk of death, leading to personalized therapy in clinical practice that will improve sepsis survival.

Overexpression of KCNJ2 enhances maturation of human-induced pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: Although human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are a promising cell resource for cardiovascular research, these cells exhibit an immature phenotype that hampers their potential applications. The inwardly rectifying potassium channel Kir2.1, encoded by the KCNJ2 gene, has been thought as an important target for promoting electrical maturation of iPSC-CMs. However, a comprehensive characterization of morphological and functional changes in iPSC-CMs overexpressing KCNJ2 (KCNJ2 OE) is still lacking. METHODS: iPSC-CMs were generated using a 2D in vitro monolayer differentiation protocol. Human KCNJ2 construct with green fluorescent protein (GFP) tag was created and overexpressed in iPSC-CMs via lentiviral transduction. The mixture of iPSC-CMs and mesenchymal cells was cocultured with decellularized natural heart matrix for generation of 3D human engineered heart tissues (EHTs). RESULTS: We showed that mRNA expression level of KCNJ2 in iPSC-CMs was dramatically lower than that in human left ventricular tissues. KCNJ2 OE iPSC-CMs yielded significantly increased protein expression of Kir2.1 and current density of Kir2.1-encoded IK1. The larger IK1 linked to a quiescent phenotype that required pacing to elicit action potentials in KCNJ2 OE iPSC-CMs, which can be reversed by IK1 blocker BaCl2. KCNJ2 OE also led to significantly hyperpolarized maximal diastolic potential (MDP), shortened action potential duration (APD) and increased maximal upstroke velocity. The enhanced electrophysiological maturation in KCNJ2 OE iPSC-CMs was accompanied by improvements in Ca2+ signaling, mitochondrial energy metabolism and transcriptomic profile. Notably, KCNJ2 OE iPSC-CMs exhibited enlarged cell size and more elongated and stretched shape, indicating a morphological phenotype toward structural maturation. Drug testing using hERG blocker E-4031 revealed that a more stable MDP in KCNJ2 OE iPSC-CMs allowed for obtaining significant drug response of APD prolongation in a concentration-dependent manner. Moreover, KCNJ2 OE iPSC-CMs formed more mature human EHTs with better tissue structure and cell junction. CONCLUSIONS: Overexpression of KCNJ2 can robustly enhance maturation of iPSC-CMs in electrophysiology, Ca2+ signaling, metabolism, transcriptomic profile, cardiomyocyte structure and tissue engineering, thus providing more accurate cellular model for elucidating cellular and molecular mechanisms of cardiovascular diseases, screening drug-induced cardiotoxicity, and developing personalized and precision cardiovascular medicine.

Case Report: Using Medtronic AP360 mechanical prosthesis in mitral valve replacement for patients with mitral insufficiency after primum atrial septal defect repair to reduce left ventricular outflow tract obstruction risk.

Background: Atrial septal defect is one of the most common congenital heart diseases in adults. Primum atrial septal defect (PASD) accounts for 4%-5% of congenital heart defects. Patients with PASD frequently suffer mitral insufficiency (MI), and thus, mitral valvuloplasty (MVP) or mitral valve replacement (MVR) is often required at the time of PASD repair. Unfortunately, recurrent unrepairable severe mitral regurgitation can develop in many patients undergoing PASD repair plus MVP in either short- or long-term after the repair surgery, requiring a re-do MVR. In those patients, the risk of left ventricular outflow tract obstruction (LVOTO) has increased. Case presentation: We present five such cases, ranging in age from 24 to 47 years, who had a PASD repair plus MVP or MVR for 14-40 years while suffering moderate to severe mitral regurgitation. Using Medtronic AP360 mechanical mitral prostheses, only one patient experienced mild LVOTO. Conclusions: The use of Medtronic AP360 mechanical mitral prostheses to perform MVR in patients with MI who had a history of PASD repair can potentially reduce the risk of LVOTO. Long-term follow-up is required to further confirm this clinical benefit associated with AP360 implantation in patients with PASD.

Comparative analysis of thoracic and abdominal aortic aneurysms across the segment and species at the single-cell level.

Introduction: Aortic aneurysm is a life-threatening disease resulted from progressive dilatation of the aorta, which can be subdivided into thoracic and abdominal aortic aneurysms. Sustained subcutaneous angiotensin II infusion can induce aortic aneurysms in mice. However, the relevance of using angiotensin II induction model to study aneurysm disease and the degree of commonality between species remain elusive. Methods: We utilized scRNA-seq to infer aortic cell sub-structures and transcriptional profiles in clinical patient TAAs and AAAs, as well as mouse models of corresponding diseases (Ang II induction) and in healthy mouse aorta. Unbiased comparison between mice and humans explored the possible reasonability and utility of mouse Ang II-induced aortic aneurysm as a model for human aortic aneurysm diseases. Meanwhile, we performed comparative analysis of aortic aneurysms between TAA and AAA in both organisms. Results and Discussion: We demonstrated similarities and differences of changes in the components of human and mouse cell types, and our unbiased comparison between mouse and human identified well conserved subpopulations of SMCs and macrophages. Furthermore, the results of our comparative analyses suggested different biological functions and distinct potential pathogenic genes for thoracic and abdominal aortic aneurysms. MIF and SPP1 signaling networks participated in aortic aneurysm in both organisms. This study maps aortic aneurysm and offers opportunities for future researches to investigate the potential of subpopulations or marker genes as therapy targets.

Identification of PDCD1 as a potential biomarker in acute rejection after kidney transplantation via comprehensive bioinformatic analysis.

Background: Acute rejection is a determinant of prognosis following kidney transplantation. It is essential to search for novel noninvasive biomarkers for early diagnosis and prompt treatment. Methods: Gene microarray data was downloaded from the Gene Expression Omnibus (GEO) expression profile database and the intersected differentially expressed genes (DEGs) was calculated. We conducted the DEGs with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Distribution of immune cell infiltration was calculated by CIBERSORT. A hub gene marker was identified by intersecting the rejection-related genes from WGCNA and a selected KEGG pathway-T cell receptor signaling pathway (hsa04660), and building a protein-protein interaction network using the STRING database and Cytoscape software. We performed flow-cytometry analysis to validate the hub gene. Results: A total of 1450 integrated DEGs were obtained from five datasets (GSE1563, GSE174020, GSE98320, GSE36059, GSE25902). The GO, KEGG and immune infiltration analysis results showed that AR was mainly associated with T cell activation and various T-cell related pathways. Other immune cells, such as B cells, Macrophage and Dendritic cells were also associated with the progress. After utilizing the WGCNA and PPI network, PDCD1 was identified as the hub gene. The flow-cytometry analysis demonstrated that both in CD4+ and CD8+ T cells, PD1+CD57-, an exhausted T cell phenotype, were downregulated in the acute rejection whole blood samples. Conclusions: Our study illustrated that PDCD1 may be a candidate diagnostic biomarker for acute kidney transplant rejection via integrative bioinformatic analysis.

Novel Plasma Biomarker-Based Model for Predicting Acute Kidney Injury After Cardiac Surgery: A Case Control Study.

INTRODUCTION: Acute kidney injury (AKI) after cardiac surgery is independently associated with a prolonged hospital stay, increased cost of care, and increased post-operative mortality. Delayed elevation of serum creatinine (SCr) levels requires novel biomarkers to provide a prediction of AKI after cardiac surgery. Our objective was to find a novel blood biomarkers combination to construct a model for predicting AKI after cardiac surgery and risk stratification. METHODS: This was a case-control study. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to Gene Expression Omnibus (GEO) dataset GSE30718 to seek potential biomarkers associated with AKI. We measured biomarker levels in venous blood samples of 67 patients with AKI after cardiac surgery and 59 control patients in two cohorts. Clinical data were collected. We developed a multi-biomarker model for predicting cardiac-surgery-associated AKI and compared it with a traditional clinical-factor-based model. RESULTS: From bioinformatics analysis and previous articles, we found 6 potential plasma biomarkers for the prediction of AKI. Among them, 3 biomarkers, such as growth differentiation factor 15 (GDF15), soluble suppression of tumorigenicity 2 (ST2, IL1RL1), and soluble urokinase plasminogen activator receptor (uPAR) were found to have prediction ability for AKI (area under the curve [AUC] > 0.6) in patients undergoing cardiac surgery. They were then incorporated into a multi-biomarker model for predicting AKI (C-statistic: 0.84, Brier 0.15) which outperformed the traditional clinical-factor-based model (C-statistic: 0.73, Brier 0.16). CONCLUSION: Our research validated a promising plasma multi-biomarker model for predicting AKI after cardiac surgery.

Gut microbes enlarged the protective effect of transplanted regulatory B cells on rejection of cardiac allografts.

BACKGROUND: Regulatory B cells (Bregs) play an important role in maintaining immune homeostasis and have the potential to induce tolerance. Previous work has found that Breg cells are involved in heart transplantation tolerance. However, the effect of Breg on the transplantation tolerance and the underlying mechanisms remain to be clarified. METHODS: Using a within-species heart transplantation model, we aimed to investigate the role of CD19+CD5+CD1dhigh Bregs isolated from transplanted mice in preventing transplant rejection in vivo. We also explored the effects of CD40 and tumor necrosis factor receptor-associated factor 6 (TRAF6) ubiquitin ligase on Breg-mediated prolongation of survival in heart transplant (HT) mice, and the regulatory effects of downstream Cdk4 and Cdk6 proteins on dendritic cells (DCs), which clarified the function and molecular mechanism of Breg cells in HT mice. RESULTS: Our data suggest that adoptive transfer of the transplanted Bregs served as an effective tolerance-inducing mechanism in HT mice and was involved in the CD40-TRAF6 signaling pathway in DCs. Moreover, DCs collected from the Breg treated HT mice also prolonged the survival of HT mice. Furthermore, DC-specific knockout of TRAF6 diminished Breg-mediated prolongation of survival in HT mice. Interestingly, gut microbes from donors increased the survival of cardiac allografts both in both the absence and presence of Bregs but were not implicated in CD40-TRAF6 signaling. CONCLUSIONS: These findings reveal a role of Breg cells in the induction of transplantation tolerance through the blockade of the CD40-TRAF6 signaling pathway, which might be used in the treatment of HT in the clinic.

Proteasome inhibitors enhance endothelial thrombomodulin expression via induction of Krüppel-like transcription factors.

OBJECTIVE: Impairment of the thrombomodulin-protein C anticoagulant pathway has been implicated in pathological thrombosis associated with malignancy. Patients who receive proteasome inhibitors as part of their chemotherapeutic regimen appear to be at decreased risk for thromboembolic events. We investigated the effects of proteasome inhibitors on endothelial thrombomodulin expression and function. METHODS AND RESULTS: Proteasome inhibitors as a class markedly induced the expression of thrombomodulin and enhanced the protein C activating capacity of endothelial cells. Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. These effects were confirmed in vivo, where systemic administration of a proteasome inhibitor enhanced thrombomodulin expression that was paralleled by changes in the expression of KLF2 and KLF4. CONCLUSIONS: These findings identify a novel mechanism of action of proteasome inhibitors that may help to explain their clinically observed thromboprotective effects.