Cardiac proteomic profiling suggests that hypertrophic and dilated cardiomyopathy share a common pathogenetic pathway of the calcium signalling pathway.

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are classified as different diseases but have many similar pathogenic genes and clinical symptoms. Previous research has focused on mutated genes. This study was conducted to identify key molecular mechanisms and explore effective therapeutic targets. METHODS: Myocardial tissue was harvested from patients with HCM (n = 3) or DCM (n = 4) during surgery. Hearts donated by healthy traffic accident victims were treated as controls (n = 4). Total proteins were extracted for liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were annotated via GO and KEGG analyses. Selected distinguishing protein abundance was confirmed by western blotting. RESULTS: Compared with the control group, there were 121 and 76 DEPs in the HCM and DCM groups, respectively. GO terms for these two comparisons are associated with contraction-related components and actin binding. Additionally, the most significantly upregulated and downregulated proteins were periostin and tropomyosin alpha-3 chain in both comparisons. Moreover, when comparing the HCM and DCM groups, we found 60 significant DEPs, and the GO and KEGG terms are related to the calcium signalling pathway. Expression of the calcium regulation-related protein peptidyl-prolyl cis-trans isomerase (FKBP1A) was significantly upregulated in multiple samples. CONCLUSION: HCM and DCM have many mutual pathogenetic pathways. Calcium ion-related processes are among the most significant factors affecting disease development. For HCM and DCM, research on regulating linchpin protein expression or interfering with key calcium-related pathways may be more beneficial than genetic research.

A nomogram prediction model for sternal incision problems.

Presently, the incidence and mortality rates of sternal incision problems (SIPs) after thoracotomy remain high, and no effective preventive measures are available. The data on 23 182 patients at Xinqiao Hospital, Army Medical University treated with median sternotomy from 1 August 2009 to 31 July 2019 were retrospectively reviewed. A prediction model of SIPs after median thoracotomy was established using R software and then validated using the bootstrap method. Next, the validity and accuracy of the model were tested and evaluated. In total, 15 426 cases met the requirements of the present study, among which 309 cases were diagnosed with SIPs, with an incidence rate of 2%. The body mass index (BMI), intensive care unit (ICU) time, diabetes mellitus, and revision for bleeding were identified as independent risk factors for postoperative SIPs. The nomogram model achieved good discrimination (73.9%) and accuracy (70.2%) in predicting the risk of SIPs after median thoracotomy. Receiver operating characteristic curve analysis showed that the area under curve of the model was 0.705 (95% confidence interval [CI]: 0.746-0.803); the Hosmer-Lemeshow test showed that χ2  = 6.987 and P = 0.538, and the fitting degree of the calibration curve was good. Additionally, the clinical decision curve showed that the net benefit of the model was greater than 0, and the clinical application value was high. The nomogram based on BMI, ICU time, diabetes mellitus, and revision for bleeding can predict the individualised risk of SIPs after median sternotomy, showing good discrimination and accuracy, and has high clinical application value. It also provides significant guidance for screening high-risk populations and developing intervention strategies.

Mid-term follow-up of aortic valve replacement for bicuspid aortic valve.

OBJECTIVE: The purpose of this study was to evaluate the mid-term outcome of aortic valve replacement for bicuspid aortic valve and tricuspid aortic valve and the related risk factors. METHODS: From January 2014 to June 2019, 177 tricuspid aortic valve patients and 101 bicuspid aortic valve patients who underwent aortic valve replacement in our hospital were collected. 1:1 propensity score matching analysis was used to control the bias in patient selection. The perioperative and follow-up data between the two groups were compared. Independent risk factors which were associated with the continued dilatation of the ascending aorta were identified by univariate or multivariate logistic regression analysis. RESULTS: After the matching procedure, 160 patients were included in the analysis (80 in each group). Baseline characteristics, intraoperative, and perioperative outcomes were similar between the two groups (all p > 0.05). Moreover, 67 patients in the tricuspid aortic valve group and 70 in the bicuspid aortic valve group completed the follow-up. The ascending aorta change, annual change rate, and the proportion of continuous dilation of ascending aorta in bicuspid aortic valve group were significantly higher than those in the tricuspid aortic valve group (p < 0.05). Multivariate logistic regression analysis showed that type 1 in bicuspid aortic valve (OR 5.173; 95% CI 1.772, 15.101; p = 0.003), aortic regurgitation (OR 3.673; 95% CI 1.133, 11.908; p = 0.030), and aortic valve stenosis with regurgitation (OR 6.489; 95% CI 1.726, 24.404; p = 0.006) were independent risk factors for the continued dilatation of the ascending aorta in all AV patients. Furthermore, the multivariate logistic regression analysis showed that type 1 in bicuspid aortic valve (OR 5.157; 95% CI 1.053, 25.272; p = 0.043), age ≥ 40 years (OR 6.956; 95% CI 1.228, 39.410; p = 0.028), and aortic regurgitation (OR 4.322; 95% CI 1.174, 15.911; p = 0.028) were independent risk factors for the continued dilatation of the ascending aorta in bicuspid aortic valve patients. CONCLUSION: Compared with tricuspid aortic valve patients, the ascending aorta of bicuspid aortic valve patients is more likely to continue to enlarge after aortic valve replacement. Type 1 in bicuspid aortic valve, age ≥ 40 years, and aortic regurgitation were the independent risk factors.

Multinucleated polyploid cardiomyocytes undergo an enhanced adaptability to hypoxia via mitophagy.

AIMS: There is a large subpopulation of multinucleated polyploid cardiomyocytes (M*Pc CMs) in the adult mammalian heart. However, the pathophysiological significance of increased M*Pc CMs in heart disease is poorly understood. We sought to determine the pathophysiological significance of increased M*Pc CMs during hypoxia adaptation. METHODS AND RESULTS: A model of hypoxia-induced cardiomyocyte (CM) multinucleation and polyploidization was established and found to be associated with less apoptosis and less reactive oxygen species (ROS) production. Compared to mononucleated diploid CMs (1*2c CMs), tetraploid CMs (4c CMs) exhibited better mitochondria quality control via increased mitochondrial autophagy (mitophagy). RNA-seq revealed Prkaa2, the gene for AMPKα2, was the most obviously up-regulated autophagy-related gene. Knockdown of AMPKα2 increased apoptosis and ROS production and suppressed mitophagy in 4c CMs compared to 1*2c CMs. Rapamycin, an autophagy activator, alleviated the adverse effect of AMPKα2 knockdown. Furthermore, silencing PINK1 also increased apoptosis and ROS in 4c CMs and weakened the adaptive superiority of 4c CMs. Finally, AMPKα2-/- mutant mice exhibited exacerbation of apoptosis and ROS production via decreases in AMPKα2-mediated mitophagy in 4c CMs compared to 1*2c CMs during hypoxia. CONCLUSIONS: Compared to 1*2c CMs, hypoxia-induced 4c CMs exhibited enhanced mitochondria quality control and less apoptosis via AMPKα2-mediated mitophagy. These results suggest that multinucleation and polyploidization allow CM to better adapt to stress via enhanced mitophagy. In addition, activation of AMPKα2 may be a promising target for myocardial hypoxia-related diseases.

Risk Factors for Permanent Neurological Dysfunction and Early Mortality in Patients with Type A Aortic Dissection Requiring Total Arch Replacement.

BACKGROUND: Surgery is a definitive treatment for patients with type A aortic dissection. The aim of this study was to identify and analyze the risk factors for permanent neurological dysfunction (PND) and 30-day mortality in patients following total arch replacement and stented elephant trunk implantation in the descending aorta. Methods: The clinical data of 85 consecutive patients who underwent this surgical procedure between December 2013 and May 2017 were reviewed. Multivariate logistic regression analysis was performed to determine the independent predictors of postoperative PND and 30-day mortality. Results: There were 62 males and 23 females, with a mean age of 47.6 ± 11.7 years (range, 26-73 years). Ten patients (11.76%) developed PND after surgery. Postoperative 30-day mortality was 11.76% (10/85), including one death during hospitalization and nine deaths after discharge. Multivariate analysis showed that hypertension was independently associated with postoperative PND (OR = 4.407, 95% CI: 1.021-19.023, P = .047), and age and postoperative PND were independent predictors for 30-day mortality (OR, 1.120; 95% CI, 1.026-1.221; P = .011 and OR, 7.503; CI, 1.290-43.634; P = .025, respectively). Conclusion: Hypertension was independently associated with postoperative PND, and age and postoperative PND were predictors for early mortality in patients who underwent total arch replacement and stented elephant trunk implantation.

A novel approach for characterizing variations in serum peptides in rheumatic heart disease.

BACKGROUND & OBJECTIVES: Acute rheumatic fever and rheumatic heart disease (RHD) are important public health problems in developing countries. In this study, peptidomic analyses on RHD patients and healthy individuals were performed to characterize variations in serum peptide levels using label-free quantitation approaches. METHODS: Blood samples were obtained from 160 healthy controls and 160 RHD patients. Of the 448 identified peptides, 272 were analyzed by two label-free mass spectrometry methods, the spectral count and spectral index. RESULTS: There were 38 proteins and 95 peptides with significant (adjusted P<0.001) differences in the abundance of peptides between healthy controls and RHD patients, including multiple peptides derived from histone H2B, villin-like protein, complement C4-B and motile sperm domain containing protein-2. The levels of 10 peptides were upregulated, and 85 peptides were downregulated in patients compared to controls. In addition, in patients, the levels of four proteins were upregulated and 34 were downregulated compared to controls. INTERPRETATION & CONCLUSIONS: This study shows that detection of significant changes in serum peptides reflects the difference between RHD patients and healthy controls. This label-free method may be helpful for clinicians to treat RHD patients during the perioperative period.

Surgical Management and Postoperative Outcomes of Mechanical Valve Dysfunction: A Six-Year, Single-Center Study.

BACKGROUND: Although many mechanical heart valves are replaced worldwide each year, mechanical valve dysfunction (MVD) remains one of the most common complications following this surgery. In an attempt to improve the postoperative and surgical management of MVD, the study plan was to investigate a group of patients who had undergone redo mechanical valve replacement to treat MVD at the authors' institution. METHODS: A total of 52 consecutive patients diagnosed with MVD underwent redo mechanical valve replacement between January 2007 and December 2013. A retrospective analysis was made of the clinical data from patients with MVD, and to compare these data with that from patients who had undergone redo heart valve surgery for other reasons. RESULTS: Seven patients died in the early stage, with an overall mortality of 13.46%. All other patients were clinically cured and discharged. In total, nine patients died during this six-year review. CONCLUSIONS: The surgical management of MVD has a high mortality and involves complex surgical procedures, but remains an effective means of treating MVD. Adequate surgery time, preoperative improvements in cardiac function, effective myocardial preservation during surgery and reasonable perioperative management may all help to improve the postoperative and mid-term outcomes of the surgical management of MVD.

Multicenter Analysis of Clinical Follow-Ups in Patients with a Star GK Cardiac Valve Replacement for More than One Year.

BACKGROUND: Star GK valves were widely used in China, and we studied the clinical follow-up results of patients with Star GK valve implants for more than one year.  METHODS: Clinical data were collected from those patients who had Star GK valve implants for over one year. Patients were divided into three groups: (1) AVR group: received aortic valve replacement surgery. Based on the valve model this group was further sub-divided into two groups: 21A group, and 23A group; (2) MVR group: received mitral valve replacement surgery. Based on the valve model this group was further sub-divided into three groups: 25M group, 27M group, and 29M group; (3) DVR group: received combined replacement surgeries including AVR + MVR. According to postoperative follow-up time these patients were divided into two groups: 1-year group and 3-year group. Follow-up data were collected by telephone, outpatient visits, or correspondence. Clinical data were aggregated by professional data scientists to conduct independent analyses.  RESULTS: 959 patients were included in the study following Star GK valve implant. Follow-up after 1 year found that thrombosis occurred in 4 cases, hemorrhage in 15 cases, left heart failure in 13 cases, paravalvular leakage in 5 cases, and death due to cardiac causes in 2 cases.  CONCLUSION: The long-term efficacy of Star GK valve implants was satisfactory with low incidence of valve-related complications, and following Star GK valve implant, valve and blood were highly compatible and blood component damage was minor. Very low incidence rate of thrombosis was observed following Star GK valve implant, however, attention should be paid to adjust the anticoagulation intensity.

rs10263935 and rs6045676 identified by genome-wide association study were associated with aortic dissection in a Chinese population.

Aortic dissection (AD) is a disease characterized by a tear in the aortic intimal layer and separation of the arterial wall. Some risk factors, such as hypertension and Marfan syndrome, are well known in AD, but the role of genetic factor is largely unknown. In this study, we investigated the relation between two single nucleotide polymorphisms (SNPs) identified by genome-wide association study and AD. Approximately 177 patients diagnosed with AD through clinical evaluation and imaging techniques and 183 age- and sex-matched control subjects who were suffering from chest pain but without AD were included in the study. Genotyping of rs10263935 and rs6045676 was performed in both patients and control subjects using the TaqMan(®) method [Life Technologies (AB & Invitrogen), Carlsbad, CA]. The frequency of the AA and AG genotype in rs10263935 was significantly higher in the AD patients (0.085 and 0.435, respectively) than in the control subjects (0.033 and 0.355, respectively). The rs10263935 A allele frequency in the AD patients was higher than that in the control subjects [0.302 vs 0.210, odds ratio (OR) = 1.62, 95% confidence interval (CI): 1.26-2.28, P = 0.005]. Similarly, the frequency of the GG genotype in rs6045676 was significantly higher in the AD patients than in the control subjects (0.107 vs 0.038, P = 0.015). The rs6045676 G allele frequency in the AD patients was higher than that in the control subjects (0.282 vs 0.191, OR = 1.67, 95% CI: 1.18-2.50, P = 0.004). After adjustment of the confounding factors, such as smoking, sex, and age, the differences remain significant in several models (rs10263935: GG vs AA: OR = 3.13, 95% CI: 1.15-8.33, P = 0.025; GG vs AG: OR = 1.57, 95% CI: 1.01-2.44, P = 0.045; rs6045676: GG vs CC: OR = 3.30, 95% CI: 1.32-8.25, P = 0.011). rs10263935 on chromosome 7 and rs6045676 on chromosome 20 are associated with AD. Further studies are warranted to elucidate the functional role of these two variants.

KLF15 is an essential negative regulatory factor for the cardiac remodeling response to pressure overload.

OBJECTIVE: To investigate the mechanism of Krüppel-like factor 15 (KLF15) in cardiac remodeling and interstitial fibrosis. METHODS: A rat model was established by in vivo aortic coarctation followed by a period of pressure unloading and used to measure heart function, myocardial pathological changes, and KLF15, transforming growth factor-ß (TGF-ß), connective tissue growth factor (CTGF), and myocardin-related transcription factor A (MRTF-A) expression levels. In addition, cardiac fibroblasts were cultured in vitro and treated with KLF15-shRNA or KLF15 recombinant adenovirus to establish a TGF-ß-mediated cardiac fibroblast hypertrophy model and analyze cell morphology, collagen secretion, and changes in the expression levels of 4 cytokines. RESULTS: In vivo pressure overload impaired cardiac function and resulted in myocardial hypertrophy and fibrosis. These changes were accompanied by the downregulation of KLF15 mRNA levels and increased expression of the other factors. The response to unloading was the opposite. In in vitro cell experiments, by specifically targeting the KLF15 gene, changes in the expression levels of the 4 cytokines and the amounts of collagen I and III were observed. CONCLUSIONS: In myocardial remodeling processes induced by mechanical or metabolic factors, KLF15 regulates TGF-ß, CTGF, and MRTF-A expression and can ameliorate or even reverse myocardial fibrosis and improve cardiac function.

Early Efficacy Analysis of Biatrial Ablation versus Left and Simplified Right Atrial Ablation for Atrial Fibrillation Treatment in Patients with Rheumatic Heart Disease.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia. About 60% of patients with rheumatic heart disease have persistent AF. METHODS: A total of 197 patients underwent valve replacement concomitant bipolar radiofrequency ablation (BRFA). Patients were divided into the biatrial ablation group and the simplified right atrial ablation group. In biatrial ablation group, the patients underwent a complete left and right atrial ablation. In simplified right atrial ablation group, the patients underwent a complete left atrial ablation and a simplified right atrial ablation. RESULTS: The conversion of sinus rhythm (SR) was high in both groups during the follow-up period. In the simplified right atrial ablation group, SR conversion rate was 88.29% at discharge. At six months and 12 months after surgery, 87.39% of patients and 86.49% of patients were in SR free of antiarrhythmic drugs, respectively. While in the biatrial ablation group, SA conversion rate was 89.53% at discharge. Percentage of patients in SR free of antiarrhythmic drugs was 88.37% and 88.37% at six months and 12 months after surgery, respectively. Echocardiography showed left atrial diameter decreased significantly after the surgery in the two groups. The ejection fraction and fractional shortening were improved significantly, without significant differences between the two groups. CONCLUSIONS: The results suggest that the concomitant left atrial and simplified right atrial BRFA for AF in patients undergoing valve replacement can achieve similar early efficiency as biatrial ablation.

Erythropoietin enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia through Akt/eNOS signalling pathway.

Adaptation of cardiomyocytes to chronic hypoxia in cyanotic patients remains unclear. Mitochondrial biogenesis is enhanced in myocardium from cyanotic patients, which is possibly an adaptive response. Erythropoietin (EPO) in blood and its receptor (EPOR) on cardiomyocytes are upregulated by chronic hypoxia, suggesting that EPO-EPOR interaction is increased, which is inferred to positively regulate mitochondrial biogenesis through protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signalling pathway. H9c2 cardiomyocytes were exposed to hypoxia (1% O(2)) for 1 week and treated with different doses of recombinant human erythropoietin (rhEPO). Mitochondrial number, mitochondrial DNA (mtDNA) copy number and peroxisome proliferator activated receptor gamma coactivator alpha (PGC-1α) mRNA expression increased in a dose-dependent manner induced by rhEPO. Akt and eNOS were significantly phosphorylated by rhEPO. Both blocking Akt with Wortmannin and silencing eNOS expression with shRNA plasmid decreased the mtDNA copy number and PGC-1α mRNA expression induced by rhEPO. Blocking Akt was associated with the decreased phosphorylation of Akt and eNOS. RNA interference led to a reduction in the total and phosphorylated proteins of eNOS. Thus EPO enhances mitochondrial biogenesis in cardiomyocytes exposed to chronic hypoxia, at least partly through Akt/eNOS signalling, which might be an adaptive mechanism of cardiomyocytes associated with the increased EPO-EPOR interaction in patients with cyanotic congenital heart disease (CCHD).

Association of gestational diabetes mellitus (GDM) with subclinical atherosclerosis: a systemic review and meta-analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with an elevated risk of adverse health outcomes such as type 2 diabetes and cardiovascular diseases. Carotid intima-media thickness (cIMT) is increasingly used as a noninvasive marker for subclinical atherosclerosis. Whether there is a direct correlation between GDM and elevated cIMT is still controversial. METHODS: PubMed, Embase and reference lists of relevant papers were reviewed. Studies assessing the relationship between GDM and cIMT were included. Weighted Mean Difference (WMD) of cIMT was calculated using random-effect models. RESULTS: Fifteen studies with a total of 2247 subjects were included in our analysis, giving a pooled WMD of 0.05 (95% confidence interval [CI] 0.03 -0.07). Furthermore, meta regression and subgroup analysis found that the association between GDM and larger cIMT already existed during pregnancy, and this relation was stronger in obese GDM patients. CONCLUSIONS: GDM in and after pregnancy is associated with subclinical atherosclerosis. Weight control may be helpful to prevent cardiovascular diseases for GDM patients.

Serum phosphate concentration and incidence of stroke: a systemic review and meta-analysis.

Elevated serum phosphate is associated with cardiovascular and total mortality in patients with kidney diseases and healthy individuals. But whether serum phosphate is associated with stroke is controversial. We searched PubMed and Embase from January 1, 1970 to May 9, 2014 with keywords such as "serum phosphate", "serum phosphorus", and "stroke". Dose-response meta-analysis was conducted. A restricted cubic spline model was used, and then we estimated pooled RR using generalized least square regression taking into account the correlation among categories of each study. Five studies with a total of 32,608 patients were included. We identified a linear relationship between serum phosphate and risk of stroke (P for non-linearity = 0.5258). The RR of phosphate (1 mg/dL) for stroke was 1.00 (95 % CI 0.97-1.05), similar results were observed in subgroup analysis. A linear relationship between serum phosphate and risk of stroke is identified. There is no association between serum level of phosphate and stroke.

Liver X receptor activation protects against inflammation and enhances autophagy in myocardium of neonatal mouse challenged by lipopolysaccharides.

Liver X receptors (LXRs) has been emerged as negative regulators of cardiomyocytic inflammation. The cellular process of autophagy is believed to play a protective role in myocardium during the inflammatory status. In this study, we investigated the role of LXRs agonist TO901317 (TO) on lipopolysaccharides (LPS)-induced myocardial inflammation and autophagy. The results showed that TO pretreatment significantly reduced the LPS-induced infiltration of inflammatory cells, elevation of NF-κB protein, TNF-α, and IL-6 mRNA levels in the myocardium. Moreover, LPS stimulated autophagy in neonatal mice heart, and this effect was further enhanced by TO pretreatment as evidenced by increased LC3-II/GAPDH ratio increment. Furthermore, TUNEL assay revealed LPS stimulation also increased the number of apoptotic cells in the myocardium, and the increment was inhibited by TO pretreatment. Our findings suggested that attenuation of inflammation and apoptosis, and enhancement of autophagy by TO may contribute to the protection of myocardium under inflammatory condition.

Identification of differently expressed genes and small molecule drugs for Tetralogy of Fallot by bioinformatics strategy.

This study aimed to screen out differentially expressed genes (DEGs) and explore small molecule drugs for Tetralogy of Fallot (TOF). The gene expression profile of TOF GSE26125 was downloaded from the Gene Expression Omnibus database, including 16 idiopathic TOF samples and five healthy controls. The DEGs were identified by the Limma package in R language and underwent functional enrichment analysis via Database for Annotation, Visualization and Integrated Discovery tools. A protein-protein interaction (PPI) network of DEGs was then constructed and the significant clusters were selected for functional analysis. In addition, the DEGs were mapped to the connectivity map (CMap) database to identify potential small-molecule drugs. As a result, a total of 499 DEGs were selected between TOF and healthy controls. Meanwhile, the functional changes of DEGs related to TOF were mainly associated with cellular respiration and energy metabolism. Furthermore, in the PPI network, two clusters were identified via cluster 1 analysis. And only cluster 1 was significantly enriched into gene ontology terms, including respiratory chain, electron transport chain, and oxidation reduction. The hub gene of cluster 1 was NDUFAB1. Additionally, small molecules, such as harmine, solanine, and testosterone, may have the potential to repair the disordered metabolic pathways of TOF.

Bipolar radiofrequency ablation is useful for treating atrial fibrillation combined with heart valve diseases.

BACKGROUND: Atrial fibrillation (AF) is a common arrhymia, and it results in increased risk of thromboembolism and decreased cardiac function. In patients undergoing cardiac surgery, concomitant radiofrequency ablation to treat AF is effective in restoring sinus rhythm (SR). This study is an observational cohort study aimed to investigate the safety and efficacy of bipolar radiofrequency ablation (BRFA) for treating AF combined with heart valve diseases. METHODS: Clinical data were analyzed retrospectively from 324 cases of rheumatic heart disease combined with persistent AF patients who underwent valve replacement concomitant BRFA. The modified left atrial and the simplified right atrial ablation were used for AF treatments. Of the 324 patients, 248 patients underwent mitral valve replacement and 76 patients underwent double valve replacement. Meanwhile, 54 patients underwent concomitant thrombectomy and 97 underwent tricuspid valvuloplasty. And all of them received temporary pacemaker implantation. The 24 hours holter electrocardiogram (ECG) monitoring and echocardiography was performed before the operation, on the first day after operation, on discharge day, and at 6 and 12 months after operation. RESULTS: There were 299 patients with SR on the first day after operation (92.30%), 12 patients with junctional rhythm (3.70%), 11 patients with AF (3.39%), and 2 patients with atrial flutter (0.62%). The temporary pacemaker was used in 213 patients (65.74%) with heart rates less than 70 beat/minute in the ICU. Two patients died early and the mortality rate was 0.62%. Two patients had left ventricular rupture and the occurrence rate was 0.62%. They both recovered. There was no degree III atrioventricular blockage and no permanent pacemaker implantation. Overall survival rate was 99.38% (322 cases) with SR conversion rate of 89.13% (287 cases) at discharge. The SR conversion rate was 87.54% and 87.01% at 6 and 12 months after operation. Sinus bradycardia occurred in 3.42% of patients at 6 months after operation and in 3.03% of patients at 12 months after operation. Echocardiography showed that the left atrial diameter was significantly decreased, and ejection fraction and fractional shortening were significantly improved. CONCLUSIONS: BRFA for treating AF in concomitant valve replacement is safe and with good efficacy.

Silencing suppressor of cytokine signaling 3 induces apoptosis and activates the p-STAT3/NF-κB pathway in hypoxic cultivated H9c2 cells.

Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia.

Transcriptional profile of human thymus reveals IGFBP5 is correlated with age-related thymic involution.

Thymus is the main immune organ which is responsible for the production of self-tolerant and functional T cells, but it shrinks rapidly with age after birth. Although studies have researched thymus development and involution in mouse, the critical regulators that arise with age in human thymus remain unclear. We collected public human single-cell transcriptomic sequencing (scRNA-seq) datasets containing 350,678 cells from 36 samples, integrated them as a cell atlas of human thymus. Clinical samples were collected and experiments were performed for validation. We found early thymocyte-specific signaling and regulons which played roles in thymocyte migration, proliferation, apoptosis and differentiation. Nevertheless, signaling patterns including number, strength and path completely changed during aging, Transcription factors (FOXC1, MXI1, KLF9, NFIL3) and their target gene, IGFBP5, were resolved and up-regulated in aging thymus and involved in promoting epithelial-mesenchymal transition (EMT), responding to steroid and adipogenesis process of thymic epithelial cell (TECs). Furthermore, we validated that IGFBP5 protein increased at TECs and Hassall's corpuscle in both human and mouse aging thymus and knockdown of IGFBP5 significantly increased the expression of proliferation-related genes in thymocytes. Collectively, we systematically explored cell-cell communications and regulons of early thymocytes as well as age-related differences in human thymus by using both bioinformatic and experimental verification, indicating IGFBP5 as a functional marker of thymic involution and providing new insights into the mechanisms of thymus involution.

miR-138 protects cardiomyocytes from hypoxia-induced apoptosis via MLK3/JNK/c-jun pathway.

Cardiomyocytes experience a series of complex endogenous regulatory mechanisms against apoptosis induced by chronic hypoxia. MicroRNAs are a class of endogenous small non-coding RNAs that regulate cellular pathophysiological processes. Recently, microRNA-138 (miR-138) has been found related to hypoxia, and beneficial for cell proliferation. Therefore, we intend to study the role of miR-138 in hypoxic cardiomyocytes and the main mechanism. Myocardial samples of patients with congenital heart disease (CHD) were collected to test miR-138 expression. Agomir or antagomir of miR-138 was transfected into H9C2 cells to investigate its effect on cell apoptosis. Higher miR-138 expression was observed in patients with cyanotic CHD, and its expression gradually increased with prolonged hypoxia time in H9C2 cells. Using MTT and LDH assays, cell growth was significantly greater in the agomir group than in the negative control (NC) group, while antagomir decreased cell survival. Dual luciferase reporter gene and Western-blot results confirmed MLK3 was a direct target of miR-138. It was found that miR-138 attenuated hypoxia-induced apoptosis using TUNEL, Hoechst staining and Annexin V-PE/7-AAD flow cytometry analysis. We further detected expression of apoptosis-related proteins. In the agomir group, the level of pro-apoptotic proteins such as cleaved-caspase-3, cleaved-PARP and Bad significantly reduced, while Bcl-2 and Bcl-2/Bax ratio increased. Opposite changes were observed in the antagomir group. Downstream targets of MLK3, JNK and c-jun, were also suppressed by miR-138. Our study demonstrates that up-regulation of miR-138 plays a protective role in myocardial adaptation to chronic hypoxia, which is mediated mainly by MLK3/JNK/c-jun signaling pathway.