Stat3 activation-triggered transcriptional networks govern the early stage of HBV-induced hepatic inflammation.

The chronic carrier state of the hepatitis B virus (HBV) often leads to the development of liver inflammation as carriers age. However, the exact mechanisms that trigger this hepatic inflammation remain poorly defined. We analyzed the sequential processes during the onset of liver inflammation based on time-course transcriptome and transcriptional regulatory networks in an HBV transgenic (HBV-Tg) mice model and chronic HBV-infected (CHB) patients (data from GSE83148). The key transcriptional factor (TF) responsible for hepatic inflammation occurrence was identified and then validated both in HBV-Tg mice and liver specimens from young CHB patients. By time-course analysis, an early stage of hepatic inflammation was demonstrated in 3-month-old HBV-Tg mice: a marked upregulation of genes related to inflammation (Saa1/2, S100a8/9/11, or Il1ß), innate immunity (Tlr2, Tlr7, or Tlr8), and cells chemotaxis (Ccr2, Cxcl1, Cxcl13, or Cxcl14). Within CHB samples, a unique early stage of inflammation activation was discriminated from immune tolerance and immune activation groups based on distinct gene expression patterns. Enhanced activation of TF Stat3 was strongly associated with increased inflammatory gene expression in this early stage of inflammation. Expression of phosphorylated Stat3 was higher in liver specimens from young CHB patients with relatively higher alanine aminotransferase levels. Specific inhibition of Stat3 activation significantly attenuated the degree of liver inflammation, the expression of inflammation-related genes, and the inflammatory monocytes and macrophages in 3-month-old HBV-Tg mice. Stat3 activation is essential for hepatic inflammation occurrence and is a novel indicator of early-stage immune activation in chronic HBV carriers. IMPORTANCE: Until now, it remains a mystery that chronic hepatitis B virus (HBV)-infected patients in the "immune tolerance phase" will transition to the "immune activation phase" as they age. In this study, we reveal that Stat3 activation-triggered hepatic transcriptional alterations are distinctive characteristics of the early stage of immune/inflammation activation in chronic HBV infection. For the first time, we discover a mechanism that might trigger the transition from immune tolerance to immune activation in chronic HBV carriers.

Endothelial TET2 regulates the white adipose browning and metabolism via fatty acid oxidation in obesity.

Obesity is a complex metabolic disorder, manifesting as excessive accumulation of body fat. Ten-Eleven Translocation-2 (TET2) has garnered significant attention in the context of obesity due to its crucial role in epigenetic regulation and metabolic homeostasis. In this study, we aimed to investigate the effect of endothelial TET2 on obesity and explore the potential mechanism. We generated endothelial cell-specific TET2 deficiency mice and investigated endothelial TET2 using transcriptomic and epigenomic analyses. We determined the downregulation of endothelial TET2 in white adipose tissues. Furthermore, we identified that endothelial TET2 loss aggravated high-fat diet-induced obesity by inhibiting vascularization and thus suppressing white adipose tissue browning. Mechanistically, endothelial TET2 modulates obesity by engaging in endothelial fatty acid oxidation and angiocrine-mediated secretion of bone morphogenetic protein 4 (BMP4), in which nuclear factor-erythroid 2-related factor 2 (NRF2) serves as a key mediator. Our study reveals that endothelial TET2 regulates white adipose tissue browning by interacting with NRF2 to facilitate fatty acid oxidation and lipolysis in adipocytes.

TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53.

Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC-MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD+ transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2+ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.

NLRC3 deficiency promotes hypoxia-induced pulmonary hypertension development via IKK/NF-κB p65/HIF-1α pathway.

Hypoxia-induced pulmonary hypertension is a subgroup of type 3 pulmonary hypertension (PH) with the recommended treatment limited to oxygen therapy and lacks potential therapeutic targets. To investigate the role of NLRC3 in hypoxia-induced PH and its potential mechanism, we first collected lung tissues of high-altitude pulmonary hypertension (HAPH) patients. Immunohistochemistry and immunofluorescence showed that NLRC3 was downregulated and was mainly co-localized with the smooth muscle cells of the pulmonary vessels in HAPH patients. Besides, we found that NLRC3 was also expressed in endothelial cells in HAPH patients for the first time. Then, wild type (WT) and NLRC3 knockout (NLRC3-/-) mice were used to construct hypoxia models and primary pulmonary arterial smooth muscle cells (PASMCs) of rats and endothelial cells were cultured for verification. Right heart catheterization and echocardiography suggested that NLRC3 knockout promoted right ventricular systolic pressure (RVSP) up-regulation, right ventricular hypertrophy and fibrosis in hypoxia-induced mice. This study first demonstrated that NLRC3 deficiency promoted hypoxia-stimulated PASMCs proliferation, Human umbilical vein endothelial cells (HUVECs) apoptosis, migration and inflammation through IKK/NF-κB p65/HIF-1α pathway in vitro and in vivo, further promoted vascular remodeling and PH progression, which provided a new target for the treatment of hypoxia-induced PH.

Recent Advances for Dynamic-Based Therapy of Atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease, which may lead to high morbidity and mortality. Currently, the clinical treatment strategy for AS is administering drugs and performing surgery. However, advanced therapy strategies are urgently required because of the deficient therapeutic effects of current managements. Increased number of energy conversion-based organic or inorganic materials has been used in cancer and other major disease treatments, bringing hope to patients with the development of nanomedicine and materials. These treatment strategies employ specific nanomaterials with specific own physiochemical properties (external stimuli: light or ultrasound) to promote foam cell apoptosis and cholesterol efflux. Based on the pathological characteristics of vulnerable plaques, energy conversion-based nano-therapy has attracted increasing attention in the field of anti-atherosclerosis. Therefore, this review focuses on recent advances in energy conversion-based treatments. In addition to summarizing the therapeutic effects of various techniques, the regulated pathological processes are highlighted. Finally, the challenges and prospects for further development of dynamic treatment for AS are discussed.

Arrhythmogenic mechanism of a novel ryanodine receptor mutation underlying sudden cardiac death.

AIMS: The ryanodine receptor 2 (RyR2) is essential for cardiac muscle excitation-contraction coupling; dysfunctional RyR2 participates in the development of inherited arrhythmogenic cardiac disease. In this study, a novel RyR2 mutation A690E is identified from a patient with family inheritance of sudden cardiac death, and we aimed to investigate the pathogenic basis of the mutation. METHODS AND RESULTS: We generated a mouse model that carried the A690E mutation. Mice were characterized by adrenergic-induced ventricular arrhythmias similar to clinical manifestation of the patient. Optical mapping studies revealed that isolated A690E hearts were prone to arrhythmogenesis and displayed frequency-dependence calcium transient alternans. Upon ß-adrenoceptor challenge, the concordant alternans was shifted towards discordant alternans that favour triggering ectopic beats and Ca2+ re-entry; similar phenomenon was also found in the A690E cardiomyocytes. In addition, we found that A690E cardiomyocytes manifested abnormal Ca2+ release and electrophysiological disorders, including an increased sensitivity to cytosolic Ca2+, an elevated diastolic RyR2-mediated Ca2+ leak, and an imbalance between Ca2+ leak and reuptake. Structural analyses reveal that the mutation directly impacts RyR2-FK506 binding protein interaction. CONCLUSION: In this study, we have identified a novel mutation in RyR2 that is associated with sudden cardiac death. By characterizing the function defects of mutant RyR2 in animal, whole heat, and cardiomyocytes, we demonstrated the pathogenic basis of the disease-causing mutation and provided a deeper mechanistic understanding of a life-threatening cardiac arrhythmia.

Macrophage-Specific NLRC5 Protects From Cardiac Remodeling Through Interaction With HSPA8.

Macrophages regulate inflammation and the process of tissue repair. Therefore, a better understanding of macrophages in the pathogenesis of heart failure is needed. In patients with hypertrophic cardiomyopathy, NLRC5 was significantly increased in circulating monocytes and cardiac macrophages. Myeloid-specific deletion of NLRC5 aggravated pressure overload-induced pathological cardiac remodeling and inflammation. Mechanistically, NLRC5 interacted with HSPA8 and suppressed NF-κB pathway in macrophages. The absence of NLRC5 in macrophages promoted the secretion of cytokines such as interleukin-6 (IL-6), which affected cardiomyocyte hypertrophy and cardiac fibroblast activation. Tocilizumab, an anti-IL-6 receptor antagonist, may be a novel therapeutic strategy for cardiac remodeling and chronic heart failure.

Synthesis and Demulsification Properties of Poly (DMDAAC-co-DAMBAC) (9:1) Copolymer.

Utilizing the copolymerization modification of dimethyl diallyl ammonium chloride (DMDAAC), the high positive charge density of the copolymer could be maintained, thereby facilitating the deficiency of its monomer in the application. In this paper, poly (DMDAAC-co-DAMBAC) (9:1) was synthesized with an aqueous polymerization method using DMDAAC and methyl benzyl diallyl ammonium chloride (DAMBAC) as monomers and 2,2'-azobis [2-methylpropionamidine] dihydrochloride (V50) as an initiator. Targeted to the product's weight-average relative molecular mass (Mw), the response surface methodology (RSM) was used to optimize the preparation process. The optimal process conditions were obtained as follows: w (M) = 80.0%, m (V50):m (M) = 0.00700%, m (Na4EDTA):m (M) = 0.00350%, T1 = 50.0 °C, T2 = 60.0 °C, and T3 = 72.5 °C. The intrinsic viscosity ([η]) of the product was 1.780 dL/g, and the corresponding double bond conversion (Conv.) was 90.25 %. Poly (DMDAAC-co-DAMBAC) (9:1) revealed a highest Mw of 5.637 × 105, together with the polydispersity index d (Mw/Mn) as 1.464. For the demulsification performance of simulated crude oil O/W emulsions, the demulsification rate of poly (DMDAAC-co-DAMBAC) (9:1) could reach 97.73%. Our study has illustrated that the copolymerization of DMDAAC and a small amount of DAMBAC with poor reactivity could significantly improve the relative molecular weight of the polymer, enhance its lipophilicity, and thus the application scope of the polymer.

Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation.

OBJECTIVES: To determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy. BACKGROUND: We have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear. METHODS AND RESULTS: Rats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4p.E11K rat atrium. Next, we identified that dysfunctional MYL4 protein impairs autophagy flux in vitro and in vivo. Cardiac lysosome positioning and mobility were regulated by MYL4 in cardiomyocytes, which affected lysosomal acidification and maturation of lysosomal cathepsins. We then examined the effects of MYL4 overexpression via adenoviral gene-transfer on atrial cardiomyopathy induced by MYL4 mutation: MYL4 protein overexpression attenuated atrial structural remodeling and autophagy dysfunction. CONCLUSIONS: MYL4 regulates autophagic flux in atrial cardiomyocytes via lysosomal mobility. MYL4 overexpression attenuates MYL4 p.E11K induced fibrotic atrial cardiomyopathy, while correcting autophagy and lysosomal function. These results provide a molecular basis for MYL4-mutant induced fibrotic atrial cardiomyopathy and identify a potential biological-therapy approach for the treatment of atrial fibrosis.

Hourly Ultrafine Particle Exposure and Acute Myocardial Infarction Onset: An Individual-Level Case-Crossover Study in Shanghai, China, 2015-2020.

Associations between ultrafine particles (UFPs) and hourly onset of acute myocardial infarction (AMI) have rarely been investigated. We aimed to evaluate the impacts of UFPs on AMI onset and the lag patterns. A time-stratified case-crossover study was performed among 20,867 AMI patients from 46 hospitals in Shanghai, China, between January 2015 and December 2020. Hourly data of AMI onset and number concentrations of nanoparticles of multiple size ranges below 0.10 µm (0.01-0.10, UFP/PNC0.01-0.10; 0.01-0.03, PNC0.01-0.03; 0.03-0.05, PNC0.03-0.05; and 0.05-0.10 µm, PNC0.05-0.10) were collected. Conditional logistic regressions were applied. Transient exposures to these nanoparticles were significantly associated with AMI onset, with almost linear exposure-response curves. These associations occurred immediately after exposure, lasted for approximately 6 h, and attenuated to be null thereafter. Each interquartile range increase in concentrations of total UFPs, PNC0.01-0.03, PNC0.03-0.05, and PNC0.05-0.10 during the preceding 0-6 h was associated with increments of 3.29, 2.08, 2.47, and 2.93% in AMI onset risk, respectively. The associations were stronger during warm season and at high temperatures and were robust after adjusting for criteria air pollutants. Our findings provide novel evidence that hourly UFP exposure is associated with immediate increase in AMI onset risk.

Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes.

BACKGROUND: Ischemic diseases represent a major global health care burden. Angiogenesis is critical in recovery of blood flow and repair of injured tissue in ischemic diseases. Ten-eleven translocation protein 2 (TET2), a member of DNA demethylases, is involved in many pathological processes. However, the role of TET2 in angiogenesis is still unrevealed. METHODS: TET2 was screened out from three DNA demethylases involved in 5-hydroxylmethylcytosine (5-hmC) regulation, including TET1, TET2 and TET3. Knockdown by small interfering RNAs and overexpression by adenovirus were used to evaluate the role of TET2 on the function of endothelial cells. The blood flow recovery and density of capillary were analyzed in the endothelial cells-specific TET2-deficient mice. RNA sequencing was used to identify the TET2-mediated mechanisms under hypoxia. Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation-qPCR (ChIP-qPCR) and glucosylated hydroxymethyl-sensitive-qPCR (GluMS-qPCR) were further performed to reveal the interaction of TET2 and STAT3. RESULTS: TET2 was significantly downregulated in endothelial cells under hypoxia and led to a global decrease of 5-hmC level. TET2 knockdown aggravated the hypoxia-induced dysfunction of endothelial cells, while TET2 overexpression alleviated the hypoxia-induced dysfunction. Meanwhile, the deficiency of TET2 in endothelial cells impaired blood flow recovery and the density of capillary in the mouse model of hindlimb ischemia. Mechanistically, RNA sequencing indicated that the STAT3 signaling pathway was significantly inhibited by TET2 knockdown. Additionally, Co-IP, ChIP-qPCR and GluMS-qPCR further illustrated that STAT3 recruited and physically interacted with TET2 to activate STAT3 target genes. As expected, the effects of TET2 overexpression were completely suppressed by STAT3 silencing in vitro. CONCLUSIONS: Our study suggests that the deficiency of TET2 in endothelial cells impairs angiogenesis via suppression of the STAT3 signaling pathway. These findings give solid evidence for TET2 to be a therapeutic alternative for ischemic diseases.

A novel clinical prediction scoring system of high-altitude pulmonary hypertension.

Background: High-altitude pulmonary hypertension (HAPH) is a common disease in regions of high altitude where performing right heart catheterization (RHC) is challenging. The development of a diagnostic scoring system is crucial for effective disease screening. Methods: A total of 148 individuals were included in a retrospective analysis, and an additional 42 residents were prospectively enrolled. We conducted a multivariable analysis to identify independent predictors of HAPH. Subsequently, we devised a prediction score based on the retrospective training set to anticipate the occurrence and severity of HAPH. This scoring system was further subjected to validation in the prospective cohort, in which all participants underwent RHC. Results: This scoring system, referred to as the GENTH score model (Glycated hemoglobin [OR = 4.5], Echocardiography sign [OR = 9.1], New York Heart Association-functional class [OR = 12.5], Total bilirubin [OR = 3.3], and Hematocrit [OR = 3.6]), incorporated five independent risk factors and demonstrated strong predictive accuracy. In the training set, the area under the curve (AUC) values for predicting the occurrence and severity of HAPH were 0.851 and 0.832, respectively, while in the validation set, they were 0.841 and 0.893. In the validation set, GENTH score model cutoff values of ≤18 or >18 points were established for excluding or confirming HAPH, and a threshold of >30 points indicated severe HAPH. Conclusions: The GENTH score model, combining laboratory and echocardiography indicators, represents an effective tool for distinguishing potential HAPH patients and identifying those with severe HAPH. This scoring system improves the clinical screening of HAPH diseases and offers valuable insights into disease diagnosis and management.

Extracellular traps from activated vascular smooth muscle cells drive the progression of atherosclerosis.

Extracellular DNA traps (ETs) represent an immune response by which cells release essential materials like chromatin and granular proteins. Previous studies have demonstrated that the transdifferentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. This study seeks to investigate the interaction between CD68+ VSMCs and the formation of ETs and highlight its function in atherosclerosis. Here we show that ETs are inhibited, and atherosclerotic plaque formation is alleviated in male Myh11CrePad4flox/flox mice undergoing an adeno-associated-virus-8 (AAV8) mediating overexpression of proprotein convertase subtilisin/kexin type 9 mutation (PCSK9) injection and being challenged with a high-fat diet. Obvious ETs generated from CD68+ VSMCs are inhibited by Cl-amidine and DNase I in vitro. By utilizing VSMCs-lineage tracing technology and single-cell RNA sequencing (scRNA-seq), we demonstrate that the ETs from CD68+ VSMCs influence the progress of atherosclerosis by regulating the direction of VSMCs' transdifferentiation through STING-SOCS1 or TLR4 signaling pathway.

Prognostic value of plasma adipokine chemerin in patients with coronary artery disease.

Background: Adipokine chemerin was proven to be associated with coronary artery disease (CAD), but its prognostic implications in CAD remain unclear. Methods: This study consists of two parts, one is a basic study and the other is a clinical cohort study. First, we investigated the differential expression of six adipokines in the atherosclerotic mice model compared to mice with milder degrees of atherosclerosis and mice without atherosclerosis using microarray data. We then examined the potential of chemerin as a diagnostic and prognostic indicator in a CAD cohort. A total of 152 patients were enrolled in our study, including 77 patients with angiographically proven CAD and 75 control subjects without cardiovascular disease. Plasma adipokine chemerin levels were measured in all patients, and major adverse cardiovascular events (MACEs) were followed up, including ischemic stroke, non-fatal myocardial infarction, revascularization, and cardiovascular death. Results: In the aortas of atherosclerotic mice, chemerin expression was up-regulated compared to control mice. The plasma chemerin levels of CAD patients were higher than those of non-CAD patients (128.93 ± 37.06 vs. 109.85 ± 27.47 mmol/L, respectively, P < 0.001). High chemerin levels were an independent predictor of CAD (ß = 2.702, 95% CI, 1.344-5.431, P = 0.001). We followed up with patients for a median duration of 5.5 years (3.9-5.6). The Kaplan-Meier curves showed that patients in the high chemerin group had a significantly higher risk of MACEs than the low chemerin group in patients with CAD (log-rank P = 0.003), not with non-CAD (Log-rank P = 0.120). Furthermore, Cox multivariate analysis revealed that high chemerin levels were an independent predictor of MACEs (HR 2.267; 95% CI, 1.139-4.515; P = 0.020). Finally, the cellular study showed that chemerin is predominantly expressed in PBMC-derived macrophages. Conclusion: Plasma chemerin levels were increased in the CAD patients, and a high chemerin level increased the risk of MACEs in CAD patients.

Effect of Substituents on the Homopolymerization Activity of Methyl Alkyl Diallyl Ammonium Chloride.

Among nitrogen-containing cationic electrolytes, diallyl quaternary ammonium salt is a typical monomer with the highest positive charge density, which has attracted the most attention, especially in the research on homopolymers and copolymers of dimethyl diallyl ammonium chloride (DMDAAC), which occupy a very unique and important position. In order to improve the lipophilicity of substituted diallyl ammonium chloride monomers under the premise of high cationic charge density, the simplest, most direct, and most efficient structure design strategy was selected in this paper. Only one of the substituents on DMDAAC quaternary ammonium nitrogen was modified by alkyl; the substituents were propyl and amyl groups, and their corresponding monomers were methyl propyl diallyl ammonium chloride (MPDAAC) and methyl amyl diallyl ammonium chloride (MADAAC), respectively. The effect of substituent structure on the homopolymerization activity of methyl alkyl diallyl ammonium chloride was illustrated by quantum chemical calculation and homopolymerization rate determination experiments via ammonium persulfate (APS) as the initiator system. The results of quantum chemistry simulation showed that, with the finite increase in substituted alkyl chain length, the numerical values of the bond length and the charge distribution of methyl alkyl diallyl ammonium chloride monomer changed little, with the activation energy of the reactions in the following order: DMDAAC < MPDAAC < MADAAC. The polymerization activities measured by the dilatometer method were in the order DMDAAC > MPDAAC > MADAAC. The activation energies Ea of homopolymerization were 96.70 kJ/mol, 97.25 kJ/mol, and 100.23 kJ/mol, and the rate equation of homopolymerization of each monomer was obtained. After analyzing and comparing these results, it could be easily found that the electronic effect of substituent was not obvious, whereas the effect of the steric hindrance was dominant. The above studies have laid a good foundation for an understanding of the polymerization activity of methyl alkyl diallyl ammonium chloride monomers and the possibility of preparation and application of these polymers with high molecular weight.

Learning aerodynamics with neural network.

We propose a neural network (NN) architecture, the Element Spatial Convolution Neural Network (ESCNN), towards the airfoil lift coefficient prediction task. The ESCNN outperforms existing state-of-the-art NNs in terms of prediction accuracy, with two orders of less parameters. We further investigate and explain how the ESCNN succeeds in making accurate predictions with standard convolution layers. We discover that the ESCNN has the ability to extract physical patterns that emerge from aerodynamics, and such patterns are clearly reflected within a layer of the network. We show that the ESCNN is capable of learning the physical laws and equation of aerodynamics from simulation data.

A miRNA cassette reprograms smooth muscle cells into endothelial cells.

Cellular reprogramming through targeting microRNAs (miRNAs) holds promise for regenerative therapy due to their profound regulatory effects in proliferation, differentiation, and function. We hypothesized that transdifferentiation of vascular smooth muscle cells (SMCs) into endothelial cells (ECs) using a miRNA cassette may provide a novel approach for use in vascular disease states associated with endothelial injury or dysfunction. miRNA profiling of SMCs and ECs and iterative combinatorial miRNA transfections of human coronary SMCs revealed a 4-miRNA cassette consisting of miR-143-3p and miR-145-5p inhibitors and miR-146a-5p and miR-181b-5p mimics that efficiently produced induced endothelial cells (iECs). Transcriptome profiling, protein expression, and functional studies demonstrated that iECs exhibit high similarity to ECs. Injected iECs restored blood flow recovery even faster than conventional ECs in a murine hindlimb ischemia model. This study demonstrates that a 4-miRNA cassette is sufficient to reprogram SMCs into ECs and shows promise as a novel regenerative strategy for endothelial repair.

Predictors and prognostic impact of left ventricular ejection fraction trajectories in patients with ST-segment elevation myocardial infarction.

BACKGROUND: There is little evidence on left ventricular ejection fraction (LVEF) trajectories after ST-segment elevation myocardial infarction (STEMI). AIM: We aim to identify the LVEF trajectories after STEMI and explore their predictors and association with prognosis. METHODS: This is a retrospective, observational study of STEMI patients. The LVEF trajectories were identified by the latent class trajectory model in patients with baseline LVEF < 50%. We used logistic regression analysis to investigate the predictors for LVEF trajectories. The Cox proportional hazard model was used to assess the impact of LVEF trajectories on prognosis. The primary outcomes were cardiovascular mortality and heart failure (HF) rehospitalization. RESULTS: 572 of 1179 patients presented with baseline normal LVEF (≥ 50%) and 607 with baseline reduced LVEF (< 50%). Two distinct LVEF trajectories were identified in patients with baseline reduced LVEF: recovered LVEF group and persistently reduced LVEF group. Higher baseline LVEF, lower peak troponin T, non-anterior MI, and lower heart rates were all found to be independently associated with LVEF recovery. After multivariate adjustments, patients with persistently reduced LVEF experienced an increased risk of cardiovascular mortality (HR 7.49, 95% CI 1.94-28.87, P = 0.003) and HF rehospitalization (HR 3.54, 95% CI 1.56-8.06 P = 0.003) compared to patients with baseline normal LVEF. Patients with recovered LVEF, on the other hand, showed no significant risk of cardiovascular mortality and HF rehospitalization. CONCLUSION: Our study indicated two distinct LVEF trajectories after STEMI and that the persistently reduced LVEF trajectory was related to poor prognosis. In addition, several baseline characteristics can predict LVEF recovery.

High complement protein C1q levels in pulmonary fibrosis and non-small cell lung cancer associated with poor prognosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial pneumonia. Lung cancer, mainly non-small cell lung cancer (NSCLC), is a complication of idiopathic pulmonary fibrosis. IPF is also an independent risk factor of lung cancer. Some studies have shown that the complement system can promote the progression of interstitial pulmonary fibrosis. In addition, C1q has also demonstrated to exert a tumor-promoting effect in many tumors. However, the role of C1q in idiopathic pulmonary fibrosis and lung cancer still remain unclear. METHODS: We selected common differentially expressed genes in IPF and non-small cell lung cancer using datasets from GEO, and investigated common hub gene. The hub genes were validated in IPF by establishing mouse model of IPF and using another four datasets from the GEO. Multiple databases were analyzed including those of Kaplan-Meier Plotter, Tumor Immune Estimation Resource (TIMER2.0) and the Human Protein Atlas (HPA) for NSCLC. RESULTS: In this study, 37 common DEGs were identified in IPF and NSCLC including 32 up-regulated genes and 5 down-regulated genes, and C1q was identified as common hub gene. The methylation status of C1q decreased and the expression levels of C1q increased in both lung cancer and idiopathic pulmonary fibrosis. The prognosis of non-small cell lung cancer and IPF patients with high levels of C1q is poor. CONCLUSIONS: These results show that C1q participates in pulmonary fibrosis and non-small cell lung cancer, and may be a potential diagnostic / prognostic biomarker or a therapeutic target.