IL6/adiponectin/HMGB1 feedback loop mediates adipocyte and macrophage crosstalk and M2 polarization after myocardial infarction.

Background: Differences in border zone contribute to different outcomes post-infarction, such as left ventricular aneurysm (LVA) and myocardial infarction (MI). LVA usually forms within 24 h of the onset of MI and may cause heart rupture; however, LVA surgery is best performed 3 months after MI. Few studies have investigated the LVA model, the differences in border zones between LVA and MI, and the mechanism in the border zone. Methods: The LVA, MI, and SHAM mouse models were used. Echocardiography, Masson's trichrome staining, and immunofluorescence staining were performed, and RNA sequencing of the border zone was conducted. The adipocyte-conditioned medium-treated hypoxic macrophage cell line and LVA and MI mouse models were employed to determine the effects of the hub gene, adiponectin (ADPN), on macrophages. Quantitative polymerase chain reaction (qPCR), Western blot analysis, transmission electron microscopy, and chromatin immunoprecipitation (ChIP) assays were conducted to elucidate the mechanism in the border zone. Human subepicardial adipose tissue and blood samples were collected to validate the effects of ADPN. Results: A novel, simple, consistent, and low-cost LVA mouse model was constructed. LVA caused a greater reduction in contractile functions than MI owing to reduced wall thickness and edema in the border zone. ADPN impeded cardiac edema and promoted lymphangiogenesis by increasing macrophage infiltration post-infarction. Adipocyte-derived ADPN promoted M2 polarization and sustained mitochondrial quality via the ADPN/AdipoR2/HMGB1 axis. Mechanistically, ADPN impeded macrophage HMGB1 inflammation and decreased interleukin-6 (IL6) and HMGB1 secretion. The secretion of IL6 and HMGB1 increased ADPN expression via STAT3 and the co-transcription factor, YAP, in adipocytes. Based on ChIP and Dual-Glo luciferase experiments, STAT3 promoted ADPN transcription by binding to its promoter in adipocytes. In vivo, ADPN promoted lymphangiogenesis and decreased myocardial injury after MI. These phenotypes were rescued by macrophage depletion or HMGB1 knockdown in macrophages. Supplying adipocytes overexpressing STAT3 decreased collagen disposition, increased lymphangiogenesis, and impaired myocardial injury. However, these effects were rescued after HMGB1 knockdown in macrophages. Overall, the IL6/ADPN/HMGB1 axis was validated using human subepicardial tissue and blood samples. This axis could serve as an independent factor in overweight MI patients who need coronary artery bypass grafting (CABG) treatment. Conclusion: The IL6/ADPN/HMGB1 loop between adipocytes and macrophages in the border zone contributes to different clinical outcomes post-infarction. Thus, targeting the IL6/ADPN/HMGB1 loop may be a novel therapeutic approach for cardiac lymphatic regulation and reduction of cell senescence post-infarction.

Association of hyperglycemia ratio and ventricular arrhythmia in critically ill patients admitted to the intensive care unit.

INTRODUCTION: The relationship between relative hyperglycemia and ventricular arrhythmia (VA) in critically ill patients admitted to intensive care units (ICU) remains unclear. This study aims to investigate the association between stress hyperglycemia ratio (SHR) and VA in this population. METHODS: This retrospective and observational study analyzed data from 4324 critically ill patients admitted to the ICU, obtained from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The SHR was calculated as the highest blood glucose level during the first 24 h of ICU admission divided by the admission blood glucose level. Based on the optimal cut-off values under the receiver operating characteristic curve, patients were stratified into high SHR (≥ 1.31) and low SHR (< 1.31) group. To investigate the impact of diabetes mellitus (DM) on the outcome, patients were stratified as low SHR/DM; low SHR/non-DM; high SHR/DM, and high SHR/non-DM. Restricted cubic spline (RCS) and logistic regression analysis were performed to analyze the relationship between SHR and VA. RESULTS: A total of 4,324 critically ill patients were included in this retrospective and observational study. The incidence of VA was higher in the high SHR group. Multiple-adjusted RCS revealed a "J-shaped" correlation between SHR and VA morbidity. The logistic regression model demonstrated that high SHR was associated with VA. The high SHR/non-DM group had a higher risk of VA than other groups stratified based on SHR and DM. Subgroup analysis showed that high SHR was associated with an increased risk of VA in patients with coronary artery disease. CONCLUSION: High SHR is an independent risk factor and has potential as a biomarker of higher VT/VF risk in ICU-admitted patients.

Case report: Novel TBX5-related pathogenic mechanism of Holt-Oram syndrome.

Introduction: Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities. Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS. Case description: We present the case of a 24-year-old female with upper limb alterations (congenital dysplasia in the wrist and elbow joints) and an anomalous left main trunk arising from the right coronary sinus. The patient inherited a base T (reference C) at rs883079 from her mother and base C (reference T) at rs10850326 from her father, both of which belong to the 3'-untranslated region (UTR) of the TBX5 gene; no alterations in TBX5 expression or single-nucleotide polymorphisms (SNPs) in other exon areas were found. We explored the effects of TBX5 on cardiomyocytes using the HL-1 cell line and TBX5-knockdown cells. Discussion: Quantitative polymerase chain reaction analysis demonstrated that TEKT2, TEKT4, and SPTB expression decreased after TBX5 knockdown, while chromatin immunoprecipitation analysis further revealed that TBX5 binds to the TEKT2, TEKT4, and SPTB promoter regions to promote gene transcription. Our findings support a novel TBX5-related pathogenic mechanism in HOS.

Myocardial Infarction-Induced INSL6 Decrease Contributes to Breast Cancer Progression.

Myocardial infarction (MI) induces early-stage breast cancer progression and increases breast cancer patients' mortality and morbidity. Insulin-like peptide 6 (INSL6) overexpression can impede cardiotoxin-induced injury through myofiber regeneration, playing a significant role in MI progression. To investigate the diverse significance of INSL6 in a variety of malignant tumors, we explored INSL6 through MI GEO dataset and multiple omics data integrative analysis, such as gene expression level, enriched pathway analysis, protein-protein interaction (PPI) analysis, and immune subtypes as well as diagnostic value and prognostic value in pancancer. INSL6 expression was downregulated in the MI group, and overall survival analysis demonstrated that INSL6 could be the prognostic biomarkers in the overall survival of breast cancer (BRCA). INSL6 expression differs significantly not only in most cancers but also in different molecular and immune subtypes of cancers. INSL6 might be a potential diagnostic and prognostic biomarker of cancers due to the high accuracy in diagnostic and prognostic value. Furthermore, we focused on BRCA and further investigated INSL6 from the perspective of the correlations with clinical characteristics, prognosis in different clinical subgroups, coexpression genes, and differentially expressed genes (DEGs) and PPI analysis. Overall survival and disease-specific survival analysis of subgroups in BRCA demonstrated that lower INSL6 expression had a worse prognosis. Therefore, INSL6 aberrant expression is associated with the progression and immune cell infiltration of the tumor, especially in KIRP and BRCA. Therefore, INSL6 may serve as a potential prognostic biomarker and the crosstalk between MI and tumor progression.

TSPAN4 and migrasomes in atherosclerosis regression correlated to myocardial infarction and pan-cancer progression.

The migrasomes formation is mediated by the assembly of micron-scale tetraspanin macrodomains and the recruitment of tetraspanin 4 (TSPAN4). However, the physiological functions of TSPAN4 on migrasomes are less known. The TSPAN4 expression in macrophages in single-cell sequencing data, GEO datasets and TCGA database were determined. TSPAN4 expression was highly associated with atherosclerosis regression-related macrophages, intraplaque hemorrhage and ruptured plaques. TSPAN4 expression was upregulated in spontaneous MI and inducible MI mice model. Besides, TSPAN4 expression was highly correlated with tumor-associated macrophages. The study provided a critical role of TSPAN4 aberrant expression in the progression of atherosclerosis and pan-cancer, and the intervention of TSPAN4 and migrasomes may save dying patients' lives and improve their prognosis.

Alpha-lipoic acid impedes myocardial ischemia-reperfusion injury, myocardial apoptosis, and oxidative stress by regulating HMGB1 expression.

BACKGROUND: Inflammation, oxidative stress, and apoptosis contribute to myocardial ischemia/reperfusion injury (I/RI). Alpha-lipoic acid (ALA) plays a critical role in I/RI by impeding apoptosis and inflammation. Here, we aimed to explore the underlying mechanisms of ALA after I/RI. METHODS: The left anterior descending coronary artery (LAD) was ligated, and H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to establish an I/RI model. Prior to this, H9c2 cells and rats were treated using an appropriate amount of ALA. The cardiac function, inflammatory factors, and myocardial pathology were assessed in vitro. We detected cell viability, apoptosis, and oxidative stress-related factors in vivo. Moreover, proteins of the HMGB1/TLR4/NF-κB signaling pathway were detected both in vivo and in vitro. RESULTS: We observed that ALA increased cell viability in vitro and decreased apoptosis in vitro and in vivo. ALA inhibited reactive oxygen species production, decreased malondialdehyde, and increased superoxide dismutase activity to resist oxidative stress in vitro. ALA also reduced the expression of inflammatory cytokines (IL-6, IL-1ß, and TNF-α) in vivo. ALA also suppressed the levels of the apoptotic protein, Bax, and increased the expression of the anti-apoptotic protein Bcl-2, in vitro and in vivo. Moreover, we observed that ALA significantly inhibited the cytoplasmic localization of HMGB1, which might attenuate MI/RI or H/R via HMGB1/TLR4/NF-κB pathway. CONCLUSION: ALA regulates HMGB1 translocation and attenuates I/R via the HMGB1/TLR4/NF-κB signaling pathway, thus impeding apoptosis, oxidation, and inflammation, and might be a potential target for myocardial ischemia/reperfusion injury.

Anticoagulation with nafamostat mesilate during extracorporeal life support.

Nafamostat mesylate (NM) affects coagulation and fibrinolysis and impedes obesity-associated protein demethylase activity, which regulates Na+/K+ transport properties and the NF-κB signaling pathway. NM significantly decreases macrophage, neutrophil, and T lymphocyte infiltration, thereby reducing inflammation and apoptosis after reperfusion and promoting recovery in patients with severe conditions such as near-fatal asthma and cardiac arrest. Extracorporeal life support (ECLS) devices are used for cardiac and/or pulmonary support as a bridge to recovery, decision, surgery, or transplant in patients with refractory cardio-circulatory or respiratory diseases and provide essential opportunities for organ support and patient survival. However, they can lead to some potential adverse events such as hemorrhage and thrombosis. NM provides a sustained innate immune response of coagulation and anti-inflammation in extracorporeal circuits, principally due to its activation of the contact and complement systems. Heparin is the main anticoagulant used in extracorporeal circuits; however, it may cause massive bleeding and heparin-induced thrombocytopenia. Although no antidote is available, NM has a very short half-life of approximately 8-10 min and might have positive effects on patients who require coagulation and anti-inflammation. NM has been used for anticoagulation in continuous renal replacement therapy, extracorporeal membrane oxygenation, hemodialysis, and left ventricular assist devices. In this review, we focused on the pharmacology, monitoring parameters, and considerations for the special use of NM in patients receiving ECLS. Our findings suggest that systemic anticoagulation with NM during ECLS might be a feasible and safe alternative with several advantages for critically ill patients with high-risk bleeding and might improve their prognosis.

Macrophage-Related Genes Biomarkers in Left Ventricular Remodeling Induced by Heart Failure.

BACKGROUND: Elevated left ventricular mass index contributes to morbidity and mortality induced by heart failure and M2 macrophages play a critical role in left ventricular remodeling. Here, our aim was to investigate the roles of M2 macrophage-related genes in heart failure. METHODS: GSE10161 was downloaded and the abundance of immune cells were estimated utilizing the CIBERSORT algorithm. Using the limma test and correlation analysis, differentially expressed plasm B cells and M2 macrophages-related genes (DEBRGs and DEMRGs) were documented. Functional pathways and the protein-protein interaction network were analyzed and the hub DEMRGs were obtained. The hub DEMRGs and their interactions were analyzed using NetworkAnalyst 3.0 and for validation, the hub DEMRGs expressions were analyzed using the GSE135055, GSE116250 and GSE74144 datasets. RESULTS: 103 differentially expressed genes were correlated with the abundance of M2 Macrophages and were identified as DEMRGs (PCC >0.4), which were mainly enriched in extracellular matrix organization, cell adhesion molecule binding and postsynaptic membrane. After screening out, 5 hub DEMRGs were obtained, including FN1 (degree = 21), COL3A1 (degree = 13), COL1A2 (degree = 13), FBN1 (degree = 12), and MMP2 (degree = 11). However, no hub DEBRGs were obtained in the network. The expression patterns of the screened DEMRGs were further validated in the patients with heart failure, dilated cardiomyopathy, ischemic cardiomyopathy or hypertension. CONCLUSIONS: The results can improve our understanding of the macrophages-associated molecular mechanisms in heart failure induced by dilated cardiomyopathy, ischemic cardiomyopathy or hypertension and 5 hub DEMRGs may help prevent the adverse left ventricular remodeling to decrease mortality and morbidity.

TSPAN4 is a prognostic and immune target in Glioblastoma multiforme.

Background: Atherosclerosis can impact cancer progression due to the cholesterol and calcium metabolism, illustrating the links between atherosclerosis and cancer metastasis. Tetraspanin 4 (TSPAN4) may help understand migrasomes in diseases and provide novel targets for treatment. Methods: TSPAN4 expression in atherosclerosis Gene Expression Omnibus (EO) dataset and multiple omics data were explored, such as enriched pathways analysis, protein-protein interaction analysis, immune subtypes as well as diagnostic and prognostic value in pan-cancer. The relationship between Glioblastoma multiforme (GBM) and TSPAN4 was further investigated. Results: Compared to control, TSPAN4 expression was upregulated in foam cells from patients with atherosclerosis and survival analysis demonstrated high TSPAN4 expression contributes to poor prognosis. TSPAN4 expression differs significantly in immune subtypes of cancers, which can be a diagnostic and prognostic target of cancers due to the high accuracy. Overall survival analysis of subgroups demonstrated that higher TSPAN4 expression had a worse prognosis and the univariate analysis and multivariate analysis demonstrated age, TSPAN4 expression, WHO grade, IDH status and histological types were independent risk factors of Glioblastoma multiforme. Conclusion: The TSPAN4 expression was associated with atherosclerosis progression and pan-cancer, especially in Glioblastoma multiforme and GBMLGG. Therefore, TSPAN4 may serve as a potential biomarker and the crosstalk between atherosclerosis and tumor progression. The results are not fully validated and further studies are still needed to validate in vivo and in vitro.

RNA-binding protein CELF1 promotes cardiac hypertrophy via interaction with PEBP1 in cardiomyocytes.

Cardiac hypertrophy is considered as a common pathophysiological process in various cardiovascular diseases. CUG triplet repeat-binding protein 1 (CELF1) is an RNA-binding protein that has been shown to be an important post-transcription regulator and involved in several types of cancer, whereas its role in cardiac remodeling remains unclear. Herein, we found that the expression of CELF1 was significantly increased in pressure overload-induced hypertrophic hearts and angiotensin II (Ang II)-induced neonatal cardiomyocytes. Based on transverse aortic constriction-induced cardiac hypertrophy model, CELF1 deficiency markedly ameliorated cardiac hypertrophy, cardiac fibrosis, oxidative stress, and apoptosis. Accordingly, CELF1 deficiency alleviated the production of reactive oxygen species (ROS) and apoptosis of neonatal cardiomyocytes via inhibition of Raf1, TAK1, ERK1/2, and p38 phosphorylation. Mechanistically, depletion or overexpression of CELF1 negatively regulated the protein expression of phosphatidylethanolamine-binding protein 1 (PEBP1), while the mRNA expression of PEBP1 remained unchanged. RNA immunoprecipitation revealed that CELF1 directly interacted with PEBP1 mRNA. Biotin pull-down analysis and dual-luciferase assay showed that CELF1 directly bound to the fragment 1 within 3'UTR of PEBP1. Moreover, knockdown of PEBP1 partially enhanced the production of ROS and apoptosis of neonatal cardiomyocytes inhibited by CELF1 deficiency. In conclusion, CELF1 binds to the 3'UTR of PEBP1 and acts as an endogenous activator of MAPK signaling pathway. Inhibition of CELF1 attenuates pathological cardiac hypertrophy, oxidative stress, and apoptosis, thus could be a potential therapeutic strategy of pathological cardiac hypertrophy.

PIK3R1, SPNB2, and CRYAB as Potential Biomarkers for Patients with Diabetes and Developing Acute Myocardial Infarction.

BACKGROUND: Young patients with type 2 diabetes mellitus (DM) and acute myocardial infarction (AMI) have high long-term all-cause and cardiovascular mortality rates. We aimed to investigate the differentially expressed genes (DEGs) that might be potential targets for DM patients with AMI. METHODS: Gene datasets GSE775, GSE19322, and GSE97494 were meta-analyzed to obtain DEGs of the left ventricle myocardium in infarcted mice. Gene datasets including GSE3313, GSE10617, and GSE136948 were meta-analyzed to identify DEGs in diabetes mice. A Venn diagram was used to obtain the overlapping DEGs. KEGG and GO pathway analyses were performed, and hub genes were obtained. Pivotal miRNAs were predicted and validated using the miRNA dataset in GSE114695. To investigate the cardiac function of the screened genes, a MI mouse model was constructed; echocardiogram, qPCR, and ELISA of hub genes were performed; ELISA of hub genes in human blood samples was also utilized. RESULTS: A total of 67 DEGs were identified, which may be potential biomarkers for patients with DM and AMI. GO and KEGG pathway analyses were performed, which were mainly enriched in response to organic cyclic compound and PI3K-Akt signaling pathway. The expression of PIK3R1 and SPNB2 increased in the MI group and was negatively correlated to left ventricular ejection fraction (LVEF), whereas that of CRYAB decreased and was positively correlated to LVEF. Patients with high CRYAB expression demonstrated a short hospital stay and the area under the curves of the three protein levels before and after treatment were 0.964, 0.982, and 0.918, suggesting that PIK3R1, SPNB2, and CRYAB may be diagnostic and prognostic biomarkers for the diabetes patients with AMI. CONCLUSION: The screened hub genes, PIK3R1, SPNB2, and CRYAB, were validated as credible molecular biomarkers and may provide a novel therapy for diabetic cardiac diseases with increased proteotoxic stress.

The Key Genes Underlying Pathophysiology Association between Plaque Instability and Progression of Myocardial Infarction.

Young patients with type 2 diabetes and myocardial infarction (MI) have higher long-term all-cause and cardiovascular mortality. In addition, the observed increased, mildly abnormal baseline lipid levels, but not lipid variability, are associated with an increased risk of atherosclerotic cardiovascular disease events, particularly MI. This study investigated differentially expressed genes (DEGs), which might be potential targets for young patients with MI and a high-fat diet (HFD). GSE114695 and GSE69187 were downloaded and processed using the limma package. A Venn diagram was applied to identify the same DEGs, and further pathway analysis was performed using Metascape. Protein-protein interaction (PPI) network analysis was then applied, and the hub genes were screened out. Pivotal miRNAs were predicted and validated using the miRNA dataset in GSE114695. To investigate the cardiac function of the screened genes, an MI mouse model, echocardiogram, and ELISA of hub genes were applied, and a correlation analysis was also performed. From aged mice fed HFD, 138 DEGs were extracted. From aged mice fed with chow, 227 DEGs were extracted. Pathway enrichment analysis revealed that DEGs in aging mice fed HFD were enriched in lipid transport and lipid biosynthetic process 1 d after MI and in the MAPK signaling pathway at 1 w after MI, suggesting that HFD has less effect on aging with MI. A total of 148 DEGs were extracted from the intersection between plaques fed with HFD and chow in young mice and MI_1d, respectively, which demonstrated increased inflammatory and adaptive immune responses, in addition to myeloid leukocyte activation. A total of 183 DEGs were screened out between plaques fed with HFD vs. chow in young mice and MI_1w, respectively, which were mainly enriched in inflammatory response, cytokine production, and myeloid leukocyte activation. After validation, PAK3, CD44, CD5, SOCS3, VAV1, and PIK3CD were demonstrated to be negatively correlated with LVEF; however, P2RY1 was demonstrated to be positively correlated. This study demonstrated that the screened hub genes may be therapeutic targets for treating STEMI patients and preventing MI recurrence, especially in young MI patients with HFD or diabetes.

Extracorporeal membrane oxygenation for near fatal asthma with sudden cardiac arrest.

INTRODUCTION: Near fatal asthma is a life-threatening disorder that requires mechanical ventilation. Near fatal asthma and COPD with sudden cardiac arrest can worsen the outcomes. Previous studies demonstrated that ECMO is a live-saving measure for near fatal asthma that does not respond to traditional treatment. CASE STUDY: A patient with near fatal asthma (NFA) and COPD presented with high airway resistance, life-threatening acidemia and severe hypoxemia that failed to respond to conventional therapy. His hospital course was complicated by sudden cardiac arrest when preparing to initiate V-V mode extracorporeal membrane oxygenation (ECMO). The mode immediately changed from V-V to V-A, then to V-AV and finally to V-V mode in order to improve cardiac function and promote recovery of lung function. RESULTS: On the sixth day, ECMO was removed and on the ninth day, he was extubated and transferred to the ward. Finally, the patient was discharged home on the nineteenth day after admission to be followed up in the pulmonary clinic. CONCLUSIONS: The early application of ECMO and mode changing plausibly resulted in dramatic improvement in gas exchange and restoration of cardiac function. This case illustrates the critical role of ECMO mode changing as salvage therapy in NFA and COPD with sudden cardiac arrest.

LncRNA Oprm1 overexpression attenuates myocardial ischemia/reperfusion injury by increasing endogenous hydrogen sulfide via Oprm1/miR-30b-5p/CSE axis.

AIMS: Ischemia/reperfusion (I/R) injury largely limits the efficacy of revascularization in acute myocardial infarction. Long noncoding RNA (lncRNA) Oprm1 is protective in cerebral I/R injury. This study aimed to investigate the effect of lncRNA Oprm1 on myocardial I/R injury and its mechanism. MAIN METHODS: We ligated and then released the left anterior descending coronary artery of adult male rats to build the I/R model in vivo. At the same time, an H9c2 cardiomyocytes hypoxia-reoxygenation (H/R) model was also used. Myocardial infarction area, cardiac function, histology, TUNEL staining, cell viability, and vital protein expression was conducted and compared. KEY FINDINGS: LncRNA Oprm1 was significantly down-regulated in the I/R injury model. When administered with the AAV9-Oprm1 vector, the myocardial injury and cardiac function were mitigated and preserved, with apoptosis reduced. The cystathionine-γ-lyase (CSE) expression and hydrogen sulfide (H2S) expression were increased. The dual-luciferase reporter gene revealed the targeted relationship between lncRNA Oprm1 and miR-30b-5p. In H9c2 cardiomyocytes models, the miR-30b-5p blocked the protective effect of lncRNA Oprm1 on H/R injury, when Bcl-2, Bcl-xl was down-regulated, and HIF-1α, Bnip-3, Caspase-3, and Caspase-9 up-regulated. SIGNIFICANCE: LncRNA Oprm1can competitively combines with miR-30b-5p, which down-regulates the expression of CSE. When administered with lncRNA Oprm1, increased endogenous H2S can reduce apoptosis and protect the myocardium from I/R injury via activating PI3K/Akt pathway and inhibiting HIF1-α activity.

Downregulation of circFASTKD1 ameliorates myocardial infarction by promoting angiogenesis.

Circular RNAs (circRNAs), a novel class of endogenous long non-coding RNAs, have attracted considerable attention due to their closed continuous loop structure and potential clinical value. In this study, we investigated the function of circFASTKD1 in vascular endothelial cells. CircFASTKD1 bound directly to miR-106a and relieved its inhibition of Large Tumor Suppressor Kinases 1 and 2, thereby suppressing the Yes-Associated Protein signaling pathway. Under both normal and hypoxic conditions, the ectopic expression of circFASTKD1 reduced the viability, migration, mobility and tube formation of vascular endothelial cells, whereas the downregulation of circFASTKD1 induced angiogenesis by promoting these processes. Moreover, downregulation of circFASTKD1 in mice improved cardiac function and repair after myocardial infarction. These findings indicate that circFASTKD1 is a potent inhibitor of angiogenesis after myocardial infarction and that silencing circFASTKD1 exerts therapeutic effects during hypoxia by stimulating angiogenesis in vitro and in vivo.

Spermine on Endothelial Extracellular Vesicles Mediates Smoking-Induced Pulmonary Hypertension Partially Through Calcium-Sensing Receptor.

Objective- This study aims to determine whether and how the enriched metabolites of endothelial extracellular vesicles (eEVs) are critical for cigarette smoke-induced direct injury of endothelial cells and the development of pulmonary hypertension, rarely explored in contrast to long-investigated mechanisms secondary to chronic hypoxemia. Approach and Results- Metabonomic screen of eEVs from cigarette-smoking human subjects reveals prominent elevation of spermine-a polyamine metabolite with potent agonist activity for the extracellular CaSR (calcium-sensing receptor). CaSR inhibition with the negative allosteric modulator Calhex231 or CaSR knockdown attenuates cigarette smoke-induced pulmonary hypertension in rats without emphysematous changes in lungs or chronic hypoxemia. Cigarette smoke exposure increases the generation of spermine-positive eEVs and their spermine content. Immunocytochemical staining and immunogold electron microscopy recognize the spermine enrichment not only within the cytosol but also on the outer surface of eEV membrane. The repression of spermine synthesis, the inhibitory analog of spermine, N1-dansyl-spermine, Calhex231, or CaSR knockdown profoundly suppresses eEV exposure-mobilized cytosolic calcium signaling, pulmonary artery constriction, and smooth muscle cell proliferation. Confocal imaging of immunohistochemical staining demonstrates the migration of spermine-positive eEVs from endothelium into smooth muscle cells in pulmonary arteries of cigarette smoke-exposed rats. The repression of spermine synthesis or CaSR knockout results in attenuated development of pulmonary hypertension induced by an intravascular administration of eEVs. Conclusions- Cigarette smoke enhances eEV generation with spermine enrichment at their outer surface and cytosol, which activates CaSR and subsequently causes smooth muscle cell constriction and proliferation, therefore, directly leading to the development of pulmonary hypertension.

External Validation of Survival-Predicting Models for Acute Myocardial Infarction with Extracorporeal Cardiopulmonary Resuscitation in a Chinese Single-Center Cohort.

BACKGROUND This study was designed as an external evaluation of potentially relevant models for acute myocardial infarction (AMI) with extracorporeal cardiopulmonary resuscitation (E-CPR). MATERIAL AND METHODS Twenty AMI adults that met criteria were retrospectively analyzed from January 2009 to January 2015. Six possible models - ENCOURAGE, SAVE, ECPR, GRACE, SHOCK, and a simplified risk chart - were identified by literature review and model scores calculated based on original data. Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment, commonly used in intensive care units, served as controls. A receiver operating characteristic curve was used to compare the models' discriminative power for predicting survival to discharge. RESULTS The ECPR model showed the best discriminative performance, with an area under the curve (AUC) of 0.893 (95% confidence interval [CI], 0.733-1.530, p=0.006); the cutoff was 12.5 points, with 66.7% sensitivity and 100% specificity. The "clinical" SHOCK model (including infarct site) showed weaker but still good discriminative power, with an AUC of 0.804 (95% CI, 0.580-1.027, p=0.035); the cutoff was 45.5 points, with 83.3% sensitivity and 71.4% specificity. The remaining models did not show significant discriminative power for predicting survival to discharge. Risk stratifications indicated that a statistically significant difference was observed in the distribution of patients into the ECPR group with different prognoses when stratified by its cutoff (p=0.003), while a trend of significant difference was shown when applied to the SHOCK model (p=0.05). CONCLUSIONS The ECPR and SHOCK models possess important abilities to predict intrahospital outcomes of AMI patients treated with E-CPR.