[Progress in the Role of Mechanical Stimulus in Cardiac Development].

Mechanical stimulus is critical to cardiovascular development during embryogenesis period.The mechanoreceptors of endocardial cells and cardiac myocytes may sense mechanical signals and initiate signal transduction that induce gene expression at a cellular level,and then translate molecular-level events into tissue-level deformations,thus guiding embryo development.This review summarizes the regulatory roles of mechanical signals in the early cardiac development including the formation of heart tube,looping,valve and septal morphogenesis,ventricular development and maturation.Further,we discuss the potential mechanical transduction mechanisms of platelet endothelial cell adhesion molecule 1-vascular endothelial-cadherin-vascular endothelial growth factor receptor 2 complex,primary cilia,ion channels,and other mechanical sensors that affect some cardiac malformations.

A simple, quick, and efficient CRISPR/Cas9 genome editing method for human induced pluripotent stem cells.

Induced pluripotent stem cells (iPSCs) have become an essential research platform to study different human diseases once being discovered by Dr. Shinya Yamanaka in 2006. Another breakthrough in biomedical research is the application of CRISPR/Cas9 system for genome editing in mammalian cells. Although numerous studies have been done to develop methods for gene editing in iPSCs, the current approaches suffer from several limitations, including time and labor consuming, low editing efficiency, and potential off-target effects. In the current study, we report an electroporation-mediated plasmid CRISPR/Cas9 delivery approach for genome editing in iPSCs. With this approach, an edited iPSC cell line could be obtained within 2 weeks. In addition, the transit introducing of CRISPR/Cas9 machinery could minimize genomic integration of Cas9 gene, which avoided potential long-term side effects of Cas9 enzyme. We showed that CRISPR/Cas9-mediated genomic editing did not affect pluripotency and differentiation ability of iPSCs. With the quickly evolving of both iPSC and CRISPR/Cas9-mediated genome editing research fields, we believe that our method can significantly facilitate the application of genome editing in iPSCs research.

Pathologic T-cell response in ischaemic failing hearts elucidated by T-cell receptor sequencing and phenotypic characterization.

AIMS: A persistent cardiac T-cell response initiated by myocardial infarction is linked to subsequent adverse ventricular remodelling and progression of heart failure. No data exist on T-cell receptor (TCR) repertoire changes in combination with phenotypic characterization of T cells in ischaemic failing human hearts. METHODS AND RESULTS: Analysis of TCR repertoire with high-throughput sequencing revealed that compared with T cells in control hearts, those in ischaemic failing hearts showed a clonally expanded TCR repertoire but similar usage patterns of TRBV-J rearrangements and V gene segments; compared with T cells in peripheral blood, those in ischaemic failing hearts exhibited a restricted and clonally expanded TCR repertoire and different usage patterns of TRBV-J rearrangements and V gene segments, suggesting the occurrence of tissue-specific T-cell expansion in ischaemic failing hearts. Consistently, TCR clonotype sharing was prominent in ischaemic failing hearts, especially in hearts of patients who shared human leucocyte antigen (HLA) alleles. Furthermore, ischaemia heart failure (IHF) heart-associated clonotypes were more frequent in peripheral blood of IHF patients than in that of controls. Heart-infiltrating T cells displayed memory- and effector-like characteristics. Th1 cells were the predominant phenotype among CD4+ T cells; CD8+ T cells were equally as abundant as CD4+ T cells and produced high levels of interferon-γ, granzyme B, and perforin. CONCLUSION: We provide novel evidence for a tissue-specific T-cell response predominated by Th1 cells and cytotoxic CD8+ T cells in ischaemic failing human hearts that may contribute to the progression of heart failure.

Right Anterolateral Minithoracotomy versus Median Sternotomy Approach for Resection of Left Atrial Myxoma.

BACKGROUND: Minimally invasive surgery has become the standard approach for several cardiac diseases. In this retrospective study, we compared right anterolateral minithoracotomy (RALT) with standard median sternotomy (SMS) for resection of left atrial myxoma (LAM). MATERIALS AND METHODS: From January 2009 to June 2015, the clinical data of patients who underwent RALT (n = 30) and SMS (n = 36) for resection of LAM in our hospital were collected. The preoperative clinical data and operative results were compared between the two groups. RESULTS: There were no significant differences in aortic cross-clamp and cardiopulmonary bypass time between the two groups. The total incision length was significantly shorter in RALT group compared with SMS group (p < 0.001). For RALT and SMS groups, respectively, the intensive care unit length of stay was 29.2 ± 6.5 versus 43.5 ± 6.9 hours (p < 0.001), and the postoperative hospital length of stay was 5 days (interquartile range [IQR]: 4-6) versus 8 days (IQR: 7-10) (p < 0.001). The total cost in RALT group was 27,000 RMB (IQR: 25,000-29,000) versus 33,000 RMB (IQR: 31,000-35,000) in SMS group (p < 0.001). There were no significant differences in mortality and postoperative complications between the two groups. CONCLUSION: RALT approach for LAM resection can be performed safely with favorable cosmetic outcome, accepted clinical results, and lower cost. It should be considered as a promising alternative to SMS and merit additional study.

Should a Mechanical or Biological Prosthesis Be Used for a Tricuspid Valve Replacement? A Meta-Analysis.

BACKGROUND AND AIM OF THE STUDY: The prosthesis of choice for a tricuspid valve replacement is still unkown. This meta-analysis was undertaken to review the results of mechanical and bioprosthetic valves in the tricuspid position. METHODS: We identified all relevant studies published in the past 20 years (from January 1, 1995 to December 31, 2014) through the Embase, Current Contents, and PubMed databases. The hazard ratio and its 95% confidence limits were utilized to evaluate time-to-event related effects of surgical procedures. The Q-statistic, Index of Inconsistency test, funnel plots, and Egger's test were used to assess the degree of heterogeneity and publication bias. Random effects models were used, and study quality was also assessed. RESULTS: In our meta-analysis, 22 studies published from 1995 to 2014 were reviewed and 2630 patients and 14,694 follow-up years were analyzed. No statistically significant difference was identified between mechanical and biological valves in terms of survival, reoperation, and prosthetic valve failure. The respective pooled hazard ratio estimates were 0.95 (0.79 to 1.16, p = 0.62, I(2) = 29%), 1.20 (0.84 to 1.71, p = 0.33, I(2) = 0%), and 0.35 (0.06 to 2.01, p = 0.24, I(2) = 0%). A higher risk of thrombosis was found in mechanical tricuspid valve prostheses (3.86, 1.38 to 10.82, p = 0.01, I(2) = 0%). CONCLUSIONS: No statistically significant difference was identified between mechanical and biological valves in terms of survival, reoperation, or prosthetic valve failure, but mechanical tricuspid valve prostheses had a higher risk of thrombosis. doi: 10.1111/jocs.12730 (J Card Surg 2016;31:294-302).

Secretion of adipocytes and macrophages under conditions of inflammation and/or insulin resistance and effect of adipocytes on preadipocytes under these conditions.

The purpose of the present study was to examine changes in preadipocytes following the coculture of preadipocytes and adipocytes and the effects on the secretion of adipocytes and macrophages following induction of inflammation and insulin resistance. Mature adipocytes and RAW264.7 macrophages were treated with lipopolysaccharide and insulin to establish models of inflammation and insulin resistance, respectively. The mRNA expression levels of IL-6, MCP-1, and TNF-α in all adipocyte treatment groups were significantly greater compared with the control, and that of adiponectin was less (P<0.05). In the RAW264.7 macrophages, the mRNA expression levels of IL-6 and TNF-α were greater than those in the control group (P<0.05). Moreover, the results of this study confirmed that adipocytes and macrophages increased the secretion of inflammatory factors under conditions of induced inflammation and insulin resistance. In addition, 3T3-L1 adipocytes inhibited the proliferation and differentiation of preadipocytes when cocultured with adipocytes under conditions of inflammation and/or insulin resistance, and the phenotype of preadipocytes did not change.

Association between frailty and acute kidney injury after cardiac surgery: unraveling the moderation effect of body fat through an international, retrospective, multi-cohort study.

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication after cardiac surgery that significantly affects patient outcomes. Given the limited treatment options available, identifying modifiable risk factors is critical. Frailty and obesity, two heterogeneous physiological states, have significant implications for identifying and preventing AKI. Our study investigated the interplay among frailty, body composition, and AKI risk after cardiac surgery to inform patient management strategies. MATERIAL AND METHODS: This retrospective cohort study included three international cohorts. Primary analysis was conducted in adult patients who underwent cardiac surgery between 2014 and 2019 at Wuhan XX Hospital, China. We tested the generalizability of our findings with data from two independent international cohorts, the Medical Information Mart for Intensive Care IV (MIMIC-IV) and the eICU Collaborative Research Database. Frailty was assessed using a clinical lab-based frailty index (FI-LAB), while total body fat percentage (BF%) was calculated based on a formula accounting for BMI, sex, and age. Logistic regression models were used to analyze the associations between frailty, body fat, and AKI, adjusting for pertinent covariates. RESULTS: A total of 8785 patients across three international cohorts were included in the study. In the primary analysis of 3,569 patients from Wuhan XX Hospital, moderate and severe frailty were associated with an increased AKI risk after cardiac surgery. Moreover, a nonlinear relationship was observed between body fat percentage and AKI risk. When stratified by the degree of frailty, lower body fat correlated with a decreased incidence of AKI. Extended analyses using the MIMIC-IV and eICU cohorts (n=3,951 and n=1,265, respectively) validated these findings and demonstrated that a lower total BF% was associated with decreased AKI incidence. Moderation analysis revealed that the effect of frailty on AKI risk was moderated by the body fat percentage. Sensitivity analyses demonstrated results consistent with the main analyses. CONCLUSION: Higher degrees of frailty were associated with an elevated risk of AKI following cardiac surgery, and total BF% moderated this relationship. This research underscores the significance of integrating frailty and body fat assessments into routine cardiovascular care to identify high-risk patients for AKI and implement personalized interventions to improve patient outcomes.

Inhibitory effects of suppressor of cytokine signaling 3 on inflammatory cytokine expression and migration and proliferation of IL-6/IFN-γ-induced vascular smooth muscle cells.

The main pathogenesis of saphenous vein graft neointimal hyperplasia after coronary artery bypass grafting (CABG) is inflammation-caused migration and proliferation of vascular smooth muscle cells (VSMCs). Janus kinase 2/signal transducer and activators of transcription 3 (JAK2/STAT3) pathway is an important signaling pathway through which VSMCs phenotype conversion occurs. Suppressor of cytokine signaling 3 (SOCS3) is the classic negative feedback inhibitor of JAK2/STAT3 pathway. Growing studies show that SOCS3 plays an important anti-inflammatory role in numerous autoimmune diseases, inflammatory diseases and inflammation-related tumors. However, the effect and mechanism of SOCS3 on vein graft disease is unclear. The purpose of this study was to investigate the effects of SOCS3 on the inflammation, migration and proliferation of VSMCs in vitro and the mechanism. The small interference RNA plasmid targeting rat SOCS3 (SiRNA-rSOCS3) and the recombinant adenovirus vector carrying rat SOCS3 gene (pYrAd-rSOCS3) were constructed, and the empty plamid (SiRNA-control) and vector (pYrAd-GFP) only carrying GFP reported gene were constructed as control. The rat VSMCs were cultured. There were two large groups of A (SOCS3 up-regulated): control group, IL-6/IFN-γ group, IL-6/IFN-γ+pYrAd-rSOCS3 group, IL-6/IFN-γ(+)pYrAd-GFP group; and B (SOCS3 down-regulated): control group, IL-6/IFN-γ group, IL-6/IFN-γ+SiRNA-rSOCS3 group and IL-6/ IFN -γ+SiRNA-control group. The pYrAd-rSOCS3 and SiRNA-rSOCS3 were transfected into VSMCs induced by IL-6/IFN-γ. After 24 h, real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were used to detect the mRNA and protein expression of SOCS3, STAT3 (only by Western blotting), P-STAT3 (only by Western blotting), IL-1ß, IL-6, TNF-α, MCP-1 and ICAM-1. The MTT, Transwell assay and flow cytometry were used to examine VSMCs proliferation, migration and cell cycle progression, respectively. As compared with control group, the mRNA and protein expression of SOCS3, STAT3, P-STAT3, IL-1ß, IL-6, TNF-α, MCP-1 and ICAM-1 was significantly up-regulated in VSMCs stimulated by IL-6/IFN-γ. However, in VSMCs transfected with pYrAd-rSOCS3 before stimulation with IL-6/IFN-γ, the expression of SOCS3 mRNA and protein was further up-regulated, and that of STAT3, P-STAT3, IL-1ß, IL-6, TNF-α, MCP-1 and ICAM-1 was significantly down-regulated as compared with IL-6/IFN-γ group and IL-6/IFN-γ+pYrAd-GFP group. The expression of those related-cytokines in IL-6/IFN-γ+SiRNA-rSOCS3 group was markedly increased as compared with IL-6/IFN-γ group and IL-6/IFN-γ+SiRNA-control group. The absorbance (A) values, the number of cells migrating to the lower chamber, and percentage of cells in the G2/M+S phase were increased in VSMCs stimulated by IL-6/IFN-γ. In VSMCs incubated with pYrAd-rSOCS3 or SiRNA-rSOCS3 before IL-6/IFN-γ stimulation, the A values, the number of cells migrating to the lower chamber, and the percentage of cells in the G2/M+S phase were significantly decreased, and increased respectively. These results imply that IL-6/IFN-γ, strong inflammatory stimulators, can promote transformation of VSMCs phenotype form a quiescent contractile state to a synthetic state by activating JAK2/STAT3 pathway. Over-expresssed SOCS3 might inhibit pro-inflammatory effect, migration and growth of VSMCs by blocking STAT3 activation and phosphorylation. These data in vitro confirm that SOCS3 may play a negatively regulatory role in development and progression of vein graft failure. These conclusions can provide a novel strategy for clinical treatment of vein graft diseases and a new theoretic clue for related drug development.

T lymphocyte characteristics and immune repertoires in the epicardial adipose tissue of heart failure patients.

Background: Epicardial adipose tissue (EAT) acts as an active immune organ and plays a critical role in the pathogenesis of heart failure (HF). However, the characteristics of immune cells in EAT of HF patients have rarely been elucidated. Methods: To identify key immune cells in EAT, an integrated bioinformatics analysis was performed on public datasets. EAT samples with paired subcutaneous adipose tissue (SAT), heart, and peripheral blood samples from HF patients were collected in validation experiments. T cell receptor (TCR) repertoire was assessed by high-throughput sequencing. The phenotypic characteristics and key effector molecules of T lymphocytes in EAT were assessed by flow cytometry and histological staining. Results: Compared with SAT, EAT was enriched for immune activation-related genes and T lymphocytes. Compared with EAT from the controls, activation of T lymphocytes was more pronounced in EAT from HF patients. T lymphocytes in EAT of HF patients were enriched by highly expanded clonotypes and had greater TCR clonotype sharing with cardiac tissue relative to SAT. Experiments confirmed the abundance of IFN-γ+ effector memory T lymphocytes (TEM) in EAT of HF patients. CCL5 and GZMK were confirmed to be associated with T lymphocytes in EAT of HF patients. Conclusion: EAT of HF patients was characterized by pronounced immune activation of clonally expanded IFN-γ+ TEM and a generally higher degree of TCR clonotypes sharing with paired cardiac tissue.

Role of Neuroimmune Interactions in COVID-19-related Cardiovascular Damage.

Coronavirus disease 2019 (COVID-19) has caused a global pandemic impacting over 200 countries/regions and more than 200 million patients worldwide. Among the infected patients, there is a high prevalence of COVID-19-related cardiovascular injuries. However, the specific mechanisms linking cardiovascular damage and COVID-19 remain unclear. The COVID-19 pandemic also has exacerbated the mental health burden of humans. Considering the close association between neuroimmune interactions and cardiovascular disease, this review assessed the complex pathophysiological mechanisms connecting neuroimmune interactions and cardiovascular disease. It was revealed that the mental health burden might be a pivotal accomplice causing COVID-19-associated cardiovascular damage. Specifically, the proinflammatory status of patients with a terrible mood state is closely related to overdrive of the hypothalamus-pituitary-adrenal (HPA) axis, sympathovagal imbalance, and endothelial dysfunction, which lead to an increased risk of developing cardiovascular injury during COVID-19. Therefore, during the prevention and treatment of cardiovascular complications in COVID-19 patients, particular attention should be given to relieve the mental health burden of these patients.

Comparison of Four Machine Learning Techniques for Prediction of Intensive Care Unit Length of Stay in Heart Transplantation Patients.

Background: Post-operative heart transplantation patients often require admission to an intensive care unit (ICU). Early prediction of the ICU length of stay (ICU-LOS) of these patients is of great significance and can guide treatment while reducing the mortality rate among patients. However, conventional linear models have tended to perform worse than non-linear models. Materials and Methods: We collected the clinical data of 365 patients from Wuhan Union Hospital who underwent heart transplantation surgery between April 2017 and August 2020. The patients were randomly divided into training data (N = 256) and test data (N = 109) groups. 84 clinical features were collected for each patient. Features were validated using the Least Absolute Shrinkage and Selection Operator (LASSO) regression's fivefold cross-validation method. We obtained Shapley Additive explanations (SHAP) values by executing package "shap" to interpret model predictions. Four machine learning models and logistic regression algorithms were developed. The area under the receiver operating characteristic curve (AUC-ROC) was used to compare the prediction performance of different models. Finally, for the convenience of clinicians, an online web-server was established and can be freely accessed via the website https://wuhanunion.shinyapps.io/PredictICUStay/. Results: In this study, 365 consecutive patients undergoing heart transplantation surgery for moderate (NYHA grade 3) or severe (NYHA grade 4) heart failure were collected in Wuhan Union Hospital from 2017 to 2020. The median age of the recipient patients was 47.2 years, while the median age of the donors was 35.58 years. 330 (90.4%) of the donor patients were men, and the average surgery duration was 260.06 min. Among this cohort, 47 (12.9%) had renal complications, 25 (6.8%) had hepatic complications, 11 (3%) had undergone chest re-exploration and 19 (5.2%) had undergone extracorporeal membrane oxygenation (ECMO). The following six important clinical features were selected using LASSO regression, and according to the result of SHAP, the rank of importance was (1) the use of extracorporeal membrane oxygenation (ECMO); (2) donor age; (3) the use of an intra-aortic balloon pump (IABP); (4) length of surgery; (5) high creatinine (Cr); and (6) the use of continuous renal replacement therapy (CRRT). The eXtreme Gradient Boosting (XGBoost) algorithm presented significantly better predictive performance (AUC-ROC = 0.88) than other models [Accuracy: 0.87; sensitivity: 0.98; specificity: 0.51; positive predictive value (PPV): 0.86; negative predictive value (NPV): 0.93]. Conclusion: Using the XGBoost classifier with heart transplantation patients can provide an accurate prediction of ICU-LOS, which will not only improve the accuracy of clinical decision-making but also contribute to the allocation and management of medical resources; it is also a real-world example of precision medicine in hospitals.

Current Status of and Opinions on Heart Transplantation in China.

The purpose of this review is to provide a comprehensive update on recent advances in heart transplantation in China. Despite advances in pharmacologic and device treatment of chronic heart failure, long-term morbidity and mortality remain high, and many patients progress to endstage heart failure. Heart transplantation has become standard treatment for selected patients with end-stage heart failure, though challenges still exist. However, multiple advances over the past few years will improve the survival and quality-of-life of heart transplant recipients. This article elaborates on the specific characteristics of heart transplantation in China, the current issues, development trends, and related experiences with heart transplantation in Wuhan Union Hospital.

Outcomes of Three Different Minimal Invasive Approaches for Secundum Atrial Septal Defect Closure: A Single Institute Experience.

OBJECTIVE: The aims of this retrospective study were to investigate and evaluate the safety and efficacy of three approaches for closure of secundum atrial septal defect (ASD). METHODS: In this study, we reviewed clinical data for transcatheter occlusion (TCO, n=63), transthoracic occlusion (TTO, n=55), and right anterolateral minithoracotomy (RALT, n=60) techniques used for ASD closure. We compared the safety and efficacy of the three approaches. RESULTS: ASD size in the TTO group was similar to that in the RALT group (P=0.645) and significantly larger than that in the TCO group (P<0.001). The RALT group had more non-central types of ASD than the TTO and TCO groups (P=0.019 and P<0.001). The operative time in the TTO group was shorter than that in the TCO and RALT groups (P<0.001 and P<0.001). The ventilation time and intensive care unit duration were shorter in the TTO group than in the RALT group (P<0.001 and P<0.001). Hospital duration in the TCO group was shorter than that in the TTO and RALT groups (P<0.001 and P<0.001). There were no residual shunt and mortality in any group in hospital or during follow-up. There was no significant difference in the incidence of total complications among the three groups (P=0.738). CONCLUSION: TCO, TTO, and RALT can be performed with favorable cosmetic and clinical results for closing ASD. Appropriate patient selection is an important factor for successful closure. These techniques are promising alternatives to standard median sternotomy and merit additional study.

Anticalcification Potential of POSS-PEG Hybrid Hydrogel as a Scaffold Material for the Development of Synthetic Heart Valve Leaflets.

Calcification of bioprosthetics is a primary challenge in the field of artificial heart valves and a main reason for biological heart valve prostheses failure. Recent advances in nanomaterial science have promoted the development of polymers with advantageous properties that are likely suitable for artificial heart valves. In this work, we developed a nanocomposite polymeric biomaterial POSS-PEG (polyhedral oligomeric silsesquioxane-polyethylene glycol) hybrid hydrogel, which not only has improved mechanical and surface properties but also excellent biocompatibility. The results of atomic force microscopy and in vivo animal experiments indicated that the content of POSS in the PEG matrix plays an important role on the surface and contributes to its biological properties, compared to the decellularized porcine aortic valve scaffold. Additionally, this modification leads to enhanced protection of the hydrogel from thrombosis. Furthermore, the introduction of POSS nanoparticles also gives the hydrogel a better calcification resistance efficacy, which was confirmed through in vitro tests and animal experiments. These findings indicate that POSS-PEG hybrid hydrogel is a potential material for functional heart valve prosthetics, and the use of POSS nanocomposites in artificial valves may offer potential long-term performance and durability advantages.

Which is the best prosthesis in an isolated or combined tricuspid valve replacement?

OBJECTIVES: The debate concerning the optimal choice of tricuspid position continues. We compared the long-term results of mechanical and biological prostheses in patients who underwent isolated or combined tricuspid valve replacement, at 2 major cardiac surgical centres in central China. METHODS: From January 1999 to December 2018, 338 patients underwent tricuspid valve replacement. Patients were divided into an isolated group or a combined group according to whether their surgery was combined with a left heart valve surgery. Mechanical tricuspid valve replacement was performed in 142 patients (isolated group: 41 vs combined group: 101), and 196 patients underwent bioprosthetic tricuspid valve replacement (isolated group: 145 vs combined group: 51). Operative results, long-term survival and tricuspid valve-related events were compared. RESULTS: Early mortality in the combined group was higher (n = 6, 4%) than that in the isolated group (n = 3, 2%), but no significant difference was observed between the mechanical and biological subgroups. In the isolated group, there was a higher event-free rate in the biological subgroup than in the mechanical subgroup (P = 0.042) and a similar result was also observed for patients without Ebstein's anomaly (P = 0.039). In the combined group, no significant difference was observed (P = 0.98). Survival rates were similar between the mechanical and biological subgroups in both the isolated (P = 0.54) and combined (P = 0.81) groups. Mechanical valves in isolated tricuspid valve replacement were more prone to valve thrombosis and bleeding. CONCLUSIONS: Every decision regarding tricuspid valve prostheses should be individualized, but biological prostheses may be an optimal choice for patients, especially for patients without Ebstein's anomaly, in isolated tricuspid valve replacement.

Transcatheter tricuspid valve replacement in patients with severe tricuspid regurgitation.

OBJECTIVE: Tricuspid regurgitation (TR) is a common valvular heart disease with unsatisfactory medical therapeutics and high surgical mortality. The present study aims to evaluate the safety and effectiveness of transcatheter tricuspid valve replacement (TTVR) in high-risk patients with severe TR. METHODS: This was a compassionate multicentre study. Between September 2018 and November 2019, 46 patients with TR who were not suitable for surgery received compassionate TTVR under general anaesthesia and the guidance of trans-oesophageal echocardiography and fluoroscopy in four institutions. Access to the tricuspid valve was obtained via a minimally invasive thoracotomy and transatrial approach. Patients' data at baseline, before discharge, 30 days and 6 months after the procedure were collected. RESULTS: All patients had severe TR with vena contracta width of 12.6 (11.0, 14.5) mm. Procedural success (97.8%) was achieved in all but one case with right ventricle perforation. The procedural time was 150.0 (118.8, 180.0) min. Intensive care unit time was 2.0 (1.0, 4.0) days. 6-month mortality was 17.4%. Device migration occurred in one patient (2.4%) during follow-up. Transthoracic echocardiography at 6 months after operation showed TR was significantly reduced (none/trivial in 33, mild in 4 and moderate in 1) and the primary safety end point was achieved in 38 cases (82.6%). Patients suffered from peripheral oedema and ascites decreased from 100.0% and 47.8% at baseline to 2.6% and 0.0% at 6 months. CONCLUSIONS: The present study showed TTVR was feasible, safe and with low complication rates in patients with severe TR.

Aß40 Promotes the Osteoblastic Differentiation of Aortic Valve Interstitial Cells through the RAGE Pathway.

Amyloid beta (Aß) peptide 40 enhances the activation of receptor for advanced glycation end products (RAGE) in immune-inflammatory diseases. RAGE exhibits several effects in the setting of numerous cardiovascular events. We hypothesized that the Aß40/RAGE pathway is involved in the osteoblastic differentiation of the valvular interstitial cell (VIC) phenotype, and RAGE knockout intervention could reduce the calcification of aortic valve interstitial cells (AVICs) by inhibiting the extracellular-regulated kinase1/2 (ERK1/2)/nuclear factor kappa-B (NF-κB) signaling pathway. To test this hypothesis, the activation of Aß40/RAGE pathway in human calcific AVs was evaluated with immunohistochemical staining. Cultured calcific VIC models were used in vitro. The VICs were stimulated using Aß40, with or without RAGE small interfering ribonucleic acid (siRNA), and ERK1/2 and NF-κB inhibitors for analysis. Our data revealed that Aß40 induced the ERK1/2/NF-κB signaling pathway and osteoblastic differentiation of AVICs via the RAGE pathway in vitro.

Role of Interleukin 17A in Aortic Valve Inflammation in Apolipoprotein E-deficient Mice.

Interleukin 17A (IL17A) is reported to be involved in many inflammatory processes, but its role in aortic valve diseases remains unknown. We examined the role of IL17A based on an ApoE-/- mouse model with strategies as fed with high-fat diet or treated with IL17A monoclonal antibody (mAb). 12 weeks of high-fat diet feeding can elevate cytokines secretion, inflammatory cells infiltration and myofibroblastic transition of valvular interstitial cells (VICs) in aortic valve. Moreover, diet-induction accelerated interleukin 17 receptor A (IL17RA) activation in VICs. In an IL17A inhibition model, the treatment group was intra-peritoneally injected with anti-IL17A mAb while controls received irrelevant antibody. Functional blockade of IL17A markedly reduced cellular infiltration and transition in aortic valve. To investigate potential mechanisms, NF-κB was co-stained in IL17RA+ VICs and IL17RA+ macrophages, and further confirmed by Western blotting in VICs. High-fat diet could activate NF-κB nuclear translocation in IL17RA+ VICs and IL17RA+ macrophages and this process was depressed after IL17A mAb-treatment. In conclusion, high-fat diet can lead to IL17A upregulation, VICs myofibroblastic transition and inflammatory cells infiltration in the aortic value of ApoE-/- mice. Blocking IL17A with IL17A mAb can alleviate aortic valve inflammatory states.