Directed Differentiation of Human Induced Pluripotent Stem Cells to Heart Valve Cells.

BACKGROUND: A main obstacle in current valvular heart disease research is the lack of high-quality homogeneous functional heart valve cells. Human induced pluripotent stem cells (hiPSCs)-derived heart valve cells may help with this dilemma. However, there are no well-established protocols to induce hiPSCs to differentiate into functional heart valve cells, and the networks that mediate the differentiation have not been fully elucidated. METHODS: To generate heart valve cells from hiPSCs, we sequentially activated the Wnt, BMP4, VEGF (vascular endothelial growth factor), and NFATc1 signaling pathways using CHIR-99021, BMP4, VEGF-165, and forskolin, respectively. The transcriptional and functional similarity of hiPSC-derived heart valve cells compared with primary heart valve cells were characterized. Longitudinal single-cell RNA sequencing was used to uncover the trajectory, switch genes, pathways, and transcription factors of the differentiation. RESULTS: An efficient protocol was developed to induce hiPSCs to differentiate into functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells. After 6-day differentiation and CD144 magnetic bead sorting, ≈70% CD144+ cells and 30% CD144- cells were obtained. On the basis of single-cell RNA sequencing data, the CD144+ cells and CD144- cells were found to be highly similar to primary heart valve endothelial cells and primary heart valve interstitial cells in gene expression profile. Furthermore, CD144+ cells had the typical function of primary heart valve endothelial cells, including tube formation, uptake of low-density lipoprotein, generation of endothelial nitric oxide synthase, and response to shear stress. Meanwhile, CD144- cells could secret collagen and matrix metalloproteinases, and differentiate into osteogenic or adipogenic lineages like primary heart valve interstitial cells. Therefore, we identified CD144+ cells and CD144- cells as hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells, respectively. Using single-cell RNA sequencing analysis, we demonstrated that the trajectory of heart valve cell differentiation was consistent with embryonic valve development. We identified the main switch genes (NOTCH1, HEY1, and MEF2C), signaling pathways (TGF-ß, Wnt, and NOTCH), and transcription factors (MSX1, SP5, and MECOM) that mediated the differentiation. Finally, we found that hiPSC-derived valve interstitial-like cells might derive from hiPSC-derived valve endothelial-like cells undergoing endocardial-mesenchymal transition. CONCLUSIONS: In summary, this is the first study to report an efficient strategy to generate functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells from hiPSCs, as well as to elucidate the differentiation trajectory and transcriptional dynamics of hiPSCs differentiated into heart valve cells.

Dose approach matter? A meta-analysis of outcomes following transfemoral versus transapical transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has gained increasing acceptance for patients with aortic disease. Both transfemoral (TF-TAVR) and transapical (TA-TAVR) approach were widely adopted while their performances are limited to a few studies with controversial results. This meta-analysis aimed to compare the mortality and morbidity of complications between TF- versus TA-TAVR based on the latest data. METHODS: Electronic databases were searched until April 2021. RCTs and observational studies comparing the outcomes between TF-TAVR versus TA-TAVR patients were included. Heterogeneity assumption was assessed by an I2 test. The pooled odds ratios(OR) or mean differences with corresponding 95% confidence intervals (CI) were used to evaluate the difference for each end point using a fixed-effect model or random-effect model based on I2 test. RESULTS: The meta-analysis included 1 RCT and 20 observational studies, enrolling 19,520 patients (TF-TAVR, n = 11,986 and TA-TAVR, n = 7,534). Compared with TA-TAVR, TF-TAVR patients showed significantly lower rate of postoperative in-hospital death (OR = 0.67, 95% CI 0.59-0.77, P < 0.001) and 1-year death (OR = 0.53, 95% CI 0.41-0.69, P < 0.001). Incidence of major bleeding and acute kidney injury were lower and length of hospital stay was shorter, whereas those of permanent pacemaker and major vascular complication were higher in TF-TAVR patients. There were no significant differences between TF-TAVR versus TA-TAVR for stroke and mid-term mortality. CONCLUSIONS: There were fewer early deaths in patients with transfemoral approach, whereas the number of mid-term deaths and stroke was not significantly different between two approaches. TF-TAVR was associated with lower risk of bleeding, acute kidney injury as well as shorter in-hospital stay, but higher incidence of vascular complication and permanent pacemaker implantation.

Predictors of Prosthetic Valve Endocarditis following Transcatheter Aortic Valve Replacement: A Meta-Analysis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has gained increasing acceptance for patients with aortic disease. A rare but fatal complication prosthetic valve endocarditis (PVE) could greatly influence the clinical outcomes of TAVR. This meta-analysis aims to pin down the predictors of PVE in TAVR patients. METHODS: We performed a systematic search for studies that reported the incidence and risk factors of PVE after TAVR. Data on studies, patients, baseline characteristics, and procedural characteristics were abstracted. Crude risk ratios (RRs) and 95% confidence intervals for each predictor were calculated by the use of random-effects models. Heterogeneity assumption was assessed by an I2 test. RESULTS: We obtained data from 8 studies that included 68,805 TAVR patients, of whom 1,256 (1.83%) were diagnosed with PVE after TAVR. 280 patients died within the 30-days of PVE diagnosis and the pooled in-hospital mortality was 22.3%. The summary estimates indicated an increased risk of PVE after TAVR for males (RR 1.53, P = .0001); for patients with orotracheal intubation (RR 1.65, P = .01), new pacemaker implantation (RR 1.46, P = .003), and residual aortic regurgitation (≥2 grade) (RR 1.62, P = .05); while older age (RR 0.97, P = .0007) and implantation of a self-expandable valve (RR 0.74, P = .02) were associated with a lower risk of PVE after TAVR. CONCLUSION: Clinical characteristics and peri- procedure factors including age, male sex, valve type, orotracheal intubation, pacemaker implantation, and residual regurgitation were proven to be associated with the occurrence of PVE-TAVR. Clinicians should pay particular attention to PVE when treating TAVR patients with these predictors.

Accelerated ovarian reserve depletion in female anti-Müllerian hormone knockout mice has no effect on lifetime fertility†.

Anti-Müllerian hormone (AMH) inhibits the activation of primordial follicles in the ovary. This causes an increased rate of ovarian reserve depletion in Amh-/- mice. The depletion of the ovarian reserve is responsible for the onset of menopause but age-related infertility occurs in advance of ovarian reserve depletion. To determine whether accelerated loss of primordial follicles leads to earlier onset infertility, Amh-/- and Amh+/+ females were paired with Amh+/+ stud males and birth rates were recorded across the females' reproductive lifespan. The number of primordial follicles remaining in the ovaries of Amh-/- and Amh+/+ females were quantified in two cohorts at 11-12 and 12-13 months of age. As expected, the ovarian reserve in the Amh-/- females became depleted approximately 1 month earlier than Amh+/+ females. However, no difference was observed in the cumulative number of births over the lifespan, nor were there any differences in mean littersize at any age. It is possible that the reproductive lifespan of mice is too short for sufficient divergence of primordial follicles numbers to cause differences in Amh-/- and Amh+/+ female fertility. An alternative explanation contradicts current thinking; the function of AMH may be unrelated to the longevity of the reproductive lifespan in female mice.

Machine learning-based analysis of risk factors for atrial fibrillation recurrence after Cox-Maze IV procedure in patients with atrial fibrillation and chronic valvular disease: A retrospective cohort study with a control group.

Objectives: To evaluate the efficacy of the Cox-Maze IV procedure (CMP-IV) in combination with valve surgery in patients with both atrial fibrillation (AF) and valvular disease and use machine learning algorithms to identify potential risk factors of AF recurrence. Methods: A total of 1,026 patients with AF and valvular disease from two hospitals were included in the study. 555 patients received the CMP-IV procedure in addition to valve surgery and left atrial appendage ligation (CMP-IV group), while 471 patients only received valve surgery and left atrial appendage ligation (Non-CMP-IV group). Kaplan-Meier analysis was used to calculate the sinus rhythm maintenance rate. 58 variables were selected as variables for each group and 10 machine learning models were developed respectively. The performance of the models was evaluated using five-fold cross-validation and metrics including F1 score, accuracy, precision, and recall. The four best-performing models for each group were selected for further analysis, including feature importance evaluation and SHAP analysis. Results: The 5-year sinus rhythm maintenance rate in the CMP-IV group was 82.13% (95% CI: 78.51%, 85.93%), while in the Non-CMP-IV group, it was 13.40% (95% CI: 10.44%, 17.20%). The eXtreme Gradient Boosting (XGBoost), LightGBM, Category Boosting (CatBoost) and Random Fores (RF) models performed the best in the CMP-IV group, with area under the curve (AUC) values of 0.768 (95% CI: 0.742, 0.786), 0.766 (95% CI: 0.744, 0.792), 0.762 (95% CI: 0.723, 0.801), and 0.732 (95% CI: 0.701, 0.763), respectively. In the Non-CMP-IV group, the LightGBM, XGBoost, CatBoost and RF models performed the best, with AUC values of 0.738 (95% CI: 0.699, 0.777), 0.732 (95% CI: 0.694, 0.770), 0.724 (95% CI: 0.668, 0.789), and 0.716 (95% CI: 0.656, 0.774), respectively. Analysis of feature importance and SHAP revealed that duration of AF, preoperative left ventricular ejection fraction, postoperative heart rhythm, preoperative neutrophil-lymphocyte ratio, preoperative left atrial diameter and heart rate were significant factors in AF recurrence. Conclusion: CMP-IV is effective in treating AF and multiple machine learning models were successfully developed, and several risk factors were identified for AF recurrence, which may aid clinical decision-making and optimize the individual surgical management of AF.

Clinical efficacy and safety of Cox-maze IV procedure for atrial fibrillation in patients with aortic valve calcification.

Objective: Atrial fibrillation is associated with a high incidence of heart valve disease. There are few prospective clinical research comparing aortic valve replacement with and without surgical ablation for safety and effectiveness. The purpose of this study was to compare the results of aortic valve replacement with and without the Cox-maze IV procedure in patients with calcific aortic valvular disease and atrial fibrillation. Methods: We analyzed one hundred and eight patients with calcific aortic valve disease and atrial fibrillation who underwent aortic valve replacement. Patients were divided into concomitant Cox maze surgery (Cox-maze group) and no concomitant Cox-maze operation (no Cox-maze group). After surgery, freedom from atrial fibrillation recurrence and all-cause mortality were evaluated. Results: Freedom from all-cause mortality after aortic valve replacement at 1 year was 100% in the Cox-maze group and 89%, respectively, in the no Cox-maze group. No Cox-maze group had a lower rate of freedom from atrial fibrillation recurrence and arrhythmia control than those in the Cox-maze group (P = 0.003 and P = 0.012, respectively). Pre-operatively higher systolic blood pressure (hazard ratio, 1.096; 95% CI, 1.004-1.196; P = 0.04) and post-operatively increased right atrium diameters (hazard ratio, 1.755; 95% CI, 1.182-2.604; P = 0.005) were associated with atrial fibrillation recurrence. Conclusion: The Cox-maze IV surgery combined with aortic valve replacement increased mid-term survival and decreased mid-term atrial fibrillation recurrence in patients with calcific aortic valve disease and atrial fibrillation. Pre-operatively higher systolic blood pressure and post-operatively increased right atrium diameters are associated with the prediction of recurrence of atrial fibrillation.

Donor circadian clock influences the long-term survival of heart transplantation by immunoregulation.

AIMS: Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at different timing on survival after transplantation to explore novel criteria for donor selection. METHODS AND RESULTS: In primate heart, phase set enrichment analysis (PSEA) showed rhythmic transcripts were enriched in antigen processing and presentation during activation of circadian rhythm. Digital sorting of immune cell composition and single-sample gene set enrichment analysis (ssGSEA) in unused donor transcriptomes showed the pathway, positive regulation of circadian rhythm significantly correlates with allograft rejection and antigen presentation pathways as well as with increased compositions of matured dendritic cell, CD4+ T cell, and naive B cell. Single-centre retrospective cohort of 390 adult heart transplants between 1 January 2015 and 31 December 2020 was used to generate a propensity score matching (PSM) cohort. Survival curve differed significantly showing inferior long-term survival when donor hearts were procured at activation group (12 pm to 12 am) compared to repression group (12 am to 12 pm) (6-year survival: 64.2% vs. 75.8%, P = 0.0065). Activation group was also associated with significantly higher rates of in-hospital death, cardiopulmonary resuscitation, and usage of mechanical circulatory support after heart transplantation compared to repression group. Furthermore, tendency for post-transplant free of rejection rates was higher in repression group compared to activation group (acute rejection, Gehan-Breslow P = 0.11 and 0.04; chronic rejection, Log rank P = 0.077 and 0.15, in full and PSM cohorts, respectively). Adjusted Cox regression analysis showed that activation group was associated with 2.20 times increased hazard of death (hazard ratio: 2.20; 95% confidence interval: 1.23-3.95; P = 0.008) compared to repression group. CONCLUSIONS: Circadian immunity may represent donor-related risk factors for cardiac allograft rejection through activating genes related to antigen presentation pathway and immune cells oscillation at specific time of day. Molecular circadian clock should be considered during retrieval of cardiac allografts in order to maximize graft durability.

Bioprosthetic vs mechanical mitral valve replacement for infective endocarditis in patients aged 50 to 69 years.

BACKGROUND: The optimal choice of the valve prosthesis in mitral valve replacement (MVR) for infective endocarditis (IE) is controversial and challenging, particularly for younger patients. HYPOTHESIS: The postoperative outcomes of mechanical and biological MVR in IE patients aged 50 to 69 years are different. METHODS: All IE patients aged 50 to 69 years with primary MVR in Hubei province hospitals from 2002 to 2018 were retrospectively reviewed. The median duration of follow-up was 8.7 years (IQR, 6.8-10.9 years). Propensity score matching (1:3 ratio) was used to yield 492 patients with comparable baseline features between bioprostheses and mechanical prosthetic valve groups. Outcomes were postoperative mid- to long- term survival, mitral valve reoperation, prosthetic valve endocarditis (PVE), stroke, and major bleeding events. RESULTS: Fifteen-year survival after MVR was 80.6% in the mechanical valve group and 69.3% in the bioprostheses group (HR 0.545, P = .040). The cumulative incidence of mitral valve reoperation was 8.8% with mechanical valves and 21.4% with bioprostheses (HR 0.260, P = .002). The cumulative incidence of PVE was 5.6% with mechanical valves and 7.2% with bioprostheses (HR 0.629, P = .435). The cumulative incidence of stroke was 12.9% with mechanical valves and 10.5% with bioprostheses (HR 1.217, P = .647). The cumulative incidence of major bleeding was 12.0% with mechanical valves and 6.75% with bioprostheses (HR 1.579, P = .268). CONCLUSIONS: Mechanical valve prostheses were associated with better survival, lower rates of reoperation compared with bioprostheses within 15 years after MVR in IE patients aged 50 to 69. These findings suggest mechanical valve prostheses may be a more reasonable alternative to bioprostheses in this patient group.

Structure and Optical Properties of Co-Sputtered Amorphous Silicon Tin Alloy Films for NIR-II Region Sensor.

Near-infrared brain imaging technology has great potential as a non-invasive, real-time inspection technique. Silicon-tin (SiSn) alloy films could be a promising material for near-infrared brain detectors. This study mainly reports on the structure of amorphous silicon tin alloy thin films by Raman spectroscopy to investigate the influence of doped-Sn on an a-Si network. The variations in TO peak caused by the increase in Sn concentration indicate a decrease in the short-range order of the a-Si network. A model has been proposed to successfully explain the non-linear variation in Raman parameters of ITA/ITO and ILA+LO/ITO. The variations of Raman parameters of the films with a higher deposition temperature indicate the presence of SiSn nanocrystals, though the SiSn nanocrystals present no Raman peaks in Raman spectra. XRD and TEM analysis further illustrate the existence of nanocrystals. The ratio of photo/dark conductivity and optical bandgap results demonstrate that the films can be selected as a sensitive layer material for NIR-II region sensors.

New Half-Metallic Materials: FeRuCrP and FeRhCrP Quaternary Heusler Compounds.

The electronic structures and magnetic properties of FeRuCrP and FeRhCrP quaternary Heusler compounds with LiMgPbSb-type structures have been investigated via first-principles calculations. The calculational results show that both FeRuCrP and FeRhCrP compounds present perfect half-metallic properties: Showing large half-metallic band gaps of 0.39 eV and 0.38 eV, respectively. The total magnetic moments of FeRuCrP and FeRhCrP are 3 µB and 4 µB per formula unit, respectively. The magnetism of them mainly comes from the 3d electrons of Cr atoms and follows the Slater-Paulig behavior of Heusler compounds: Mt = Zt - 24. Furthermore, the half-metallic properties of FeRuCrP and FeRhCrP compounds can be kept in a quite large range of lattice constants (about 5.44-5.82 Å and 5.26-5.86 Å, respectively) and are quite robust against tetragonal deformation (c/a ratio in the range of 0.94-1.1 and 0.97-1.1, respectively). Moreover, the large negative cohesion energy and formation energy of FeRuCrP and FeRhCrP compounds indicate that they can be synthesized experimentally.

Structural, electronic, magnetic, half-metallic, mechanical, and thermodynamic properties of the quaternary Heusler compound FeCrRuSi: A first-principles study.

In this paper, we have investigated the structural, electronic, magnetic, half-metallic, mechanical, and thermodynamic properties of the equiatomic quaternary Heusler (EQH) compound FeCrRuSi using the density functional theory (DFT) and the quasi-harmonic Debye model. Our results reveal that FeCrRuSi is a half-metallic material (HMM) with a total magnetic moment of 2.0 µB in agreement with the well-known Slater-Pauling rule Mt = Zt - 24. Furthermore, the origin of the half-metallic band gap in FeCrRuSi is well studied through a schematic diagram of the possible d-d hybridization between Fe, Cr and Ru elements. The half-metallic behavior of FeCrRuSi can be maintained in a relatively wide range of variations of the lattice constant (5.5-5.8 Å) under uniform strain and the c/a ratio (0.96-1.05) under tetragonal distortion. The calculated phonon dispersion, cohesive and formation energies, and mechanical properties reveal that FeCrRuSi is stable with an EQH structure. Importantly, the compound of interest has been prepared and is found to exist in an EQH type structure with the presence of some B2 disorder. Moreover, the thermodynamic properties, such as the thermal expansion coefficient α, the heat capacity CV, the Grüneisen constant γ, and the Debye temperature ΘD are calculated.