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.

Chondroitin Sulfate Derivative Cross-Linking of Decellularized Heart Valve for the Improvement of Mechanical Properties, Hemocompatibility, and Endothelialization.

Tissue-engineered heart valve (TEHV) has emerged as a prospective alternative to conventional valve prostheses. The decellularized heart valve (DHV) represents a promising TEHV scaffold that preserves the natural three-dimensional structure and retains essential biological activity. However, the limited mechanical strength, fast degradation, poor hemocompatibility, and lack of endothelialization of DHV restrict its clinical use, which is necessary for ensuring its long-term durability. Herein, we used oxidized chondroitin sulfate (ChS), one of the main components of the extracellular matrix with various biological activities, to cross-link DHV to overcome the above problems. In addition, the ChS-adipic dihydrazide was used to react with residual aldehyde groups, thus preventing potential calcification. The results indicated notable enhancements in mechanical properties and resilience against elastase and collagenase degradation in vitro as well as the ability to withstand extended periods of storage without compromising the structural integrity of valve scaffolds. Additionally, the newly cross-linked valves exhibited favorable hemocompatibility in vitro and in vivo, thereby demonstrating exceptional biocompatibility. Furthermore, the scaffolds exhibited traits of gradual degradation and resistance to calcification through a rat subcutaneous implantation model. In the rat abdominal aorta implantation model, the scaffolds demonstrated favorable endothelialization, commendable patency, and a diminished pro-inflammatory response. As a result, the newly constructed DHV scaffold offers a compelling alternative to traditional valve prostheses, which potentially advances the field of TEHV.

Melt-electrowriting-enabled anisotropic scaffolds loaded with valve interstitial cells for heart valve tissue Engineering.

Tissue engineered heart valves (TEHVs) demonstrates the potential for tissue growth and remodel, offering particular benefit for pediatric patients. A significant challenge in designing functional TEHV lies in replicating the anisotropic mechanical properties of native valve leaflets. To establish a biomimetic TEHV model, we employed melt-electrowriting (MEW) technology to fabricate an anisotropic PCL scaffold. By integrating the anisotropic MEW-PCL scaffold with bioactive hydrogels (GelMA/ChsMA), we successfully crafted an elastic scaffold with tunable mechanical properties closely mirroring the structure and mechanical characteristics of natural heart valves. This scaffold not only supports the growth of valvular interstitial cells (VICs) within a 3D culture but also fosters the remodeling of extracellular matrix of VICs. The in vitro experiments demonstrated that the introduction of ChsMA improved the hemocompatibility and endothelialization of TEHV scaffold. The in vivo experiments revealed that, compared to their non-hydrogel counterparts, the PCL-GelMA/ChsMA scaffold, when implanted into SD rats, significantly suppressed immune reactions and calcification. In comparison with the PCL scaffold, the PCL-GelMA/ChsMA scaffold exhibited higher bioactivity and superior biocompatibility. The amalgamation of MEW technology and biomimetic design approaches provides a new paradigm for manufacturing scaffolds with highly controllable microstructures, biocompatibility, and anisotropic mechanical properties required for the fabrication of TEHVs.

Modulation of anti-cardiac fibrosis immune responses by changing M2 macrophages into M1 macrophages.

BACKGROUND: Macrophages play a crucial role in the development of cardiac fibrosis (CF). Although our previous studies have shown that glycogen metabolism plays an important role in macrophage inflammatory phenotype, the role and mechanism of modifying macrophage phenotype by regulating glycogen metabolism and thereby improving CF have not been reported. METHODS: Here, we took glycogen synthetase kinase 3ß (GSK3ß) as the target and used its inhibitor NaW to enhance macrophage glycogen metabolism, transform M2 phenotype into anti-fibrotic M1 phenotype, inhibit fibroblast activation into myofibroblasts, and ultimately achieve the purpose of CF treatment. RESULTS: NaW increases the pH of macrophage lysosome through transmembrane protein 175 (TMEM175) and caused the release of Ca2+ through the lysosomal Ca2+ channel mucolipin-2 (Mcoln2). At the same time, the released Ca2+ activates TFEB, which promotes glucose uptake by M2 and further enhances glycogen metabolism. NaW transforms the M2 phenotype into the anti-fibrotic M1 phenotype, inhibits fibroblasts from activating myofibroblasts, and ultimately achieves the purpose of treating CF. CONCLUSION: Our data indicate the possibility of modifying macrophage phenotype by regulating macrophage glycogen metabolism, suggesting a potential macrophage-based immunotherapy against CF.

Deciphering the role of CX3CL1-CX3CR1 in aortic aneurysm pathogenesis: insights from Mendelian randomization and transcriptomic analyses.

Background: The crucial role of inflammation in aortic aneurysm (AA) is gaining prominence, while there is still a lack of key cytokines or targets for effective clinical translation. Methods: Mendelian randomization (MR) analysis was performed to identify the causal relationship between 91 circulating inflammatory proteins and AA and between 731 immune traits and AA. Bulk RNA sequencing data was utilized to demonstrate the expression profile of the paired ligand-receptor. Gene enrichment analysis, Immune infiltration, and correlation analysis were employed to deduce the potential role of CX3CR1. We used single-cell RNA sequencing data to pinpoint the localization of CX3CL1 and CX3CR1, which was further validated by multiplex immunofluorescence staining. Cellchat analysis was utilized to infer the CX3C signaling pathway. Trajectory analysis and the Cytosig database were exploited to determine the downstream effect of CX3CL1-CX3CR1. Results: We identified 4 candidates (FGF5, CX3CL1, IL20RA, and SCF) in multiple two-sample MR analyses. Subsequent analysis of the expression profile of the paired receptor revealed the significant upregulation of CX3CR1 in AA and its positive correlation with pro-inflammatory macrophages. Two sample MR between immune cell traits and AA demonstrated the potential causality between intermediate monocytes and AA. We finally deciphered in single-cell sequencing data that CX3CL1 sent by endothelial cells (ECs) acted on CX3CR1 of intermediated monocytes, leading to its recruitment and pro-inflammatory responses. Conclusion: Our study presented a genetic insight into the pathogenetic role of CX3CL1-CX3CR1 in AA, and further deciphered the CX3C signaling pathway between ECs and intermediate monocytes.

FOXO1 regulates RUNX2 ubiquitination through SMURF2 in calcific aortic valve disease.

The prevalence of calcific aortic valve disease (CAVD) remains substantial while there is currently no medical therapy available. Forkhead box O1 (FOXO1) is known to be involved in the pathogenesis of cardiovascular diseases, including vascular calcification and atherosclerosis; however, its specific role in calcific aortic valve disease remains to be elucidated. In this study, we identified FOXO1 significantly down-regulated in the aortic valve interstitial cells (VICs) of calcified aortic valves by investigating clinical specimens and GEO database analysis. FOXO1 silencing or inhibition promoted VICs osteogenic differentiation in vitro and aortic valve calcification in Apoe-/- mice, respectively. We identified that FOXO1 facilitated the ubiquitination and degradation of RUNX2, which process was mainly mediated by SMAD-specific E3 ubiquitin ligase 2 (SMURF2). Our discoveries unveil a heretofore unacknowledged mechanism involving the FOXO1/SMURF2/RUNX2 axis in CAVD, thereby proposing the potential therapeutic utility of FOXO1 or SMURF2 as viable strategies to impede the progression of CAVD.

Functional Oxidized Hyaluronic Acid Cross-Linked Decellularized Heart Valves for Improved Immunomodulation, Anti-Calcification, and Recellularization.

Tissue engineering heart valves (TEHVs) are expected to address the limitations of mechanical and bioprosthetic valves used in clinical practice. Decellularized heart valve (DHV) is an important scaffold of TEHVs due to its natural three-dimensional structure and bioactive extracellular matrix, but its mechanical properties and hemocompatibility are impaired. In this study, DHV is cross-linked with three different molecular weights of oxidized hyaluronic acid (OHA) by a Schiff base reaction and presented enhanced stability and hemocompatibility, which could be mediated by the molecular weight of OHA. Notably, DHV cross-linked with middle- and high-molecular-weight OHA could drive the macrophage polarization toward the M2 phenotype in vitro. Moreover, DHV cross-linked with middle-molecular-weight OHA scaffolds are further modified with RGD-PHSRN peptide (RPF-OHA/DHV) to block the residual aldehyde groups of the unreacted OHA. The results show that RPF-OHA/DHV not only exhibits anti-calcification properties, but also facilitates endothelial cell adhesion and proliferation in vitro. Furthermore, RPF-OHA/DHV shows excellent performance under an in vivo hemodynamic environment with favorable recellularization and immune regulation without calcification. The optimistic results demonstrate that OHA with different molecular weights has different cross-linking effects on DHV and that RPF-OHA/DHV scaffold with enhanced immune regulation, anti-calcification, and recellularization properties for clinical transformation.

Shear stress activates the Piezo1 channel to facilitate valvular endothelium-oriented differentiation and maturation of human induced pluripotent stem cells.

Valvular endothelial cells (VECs) derived from human induced pluripotent stem cells (hiPSCs) provide an unlimited cell source for tissue engineering heart valves (TEHVs); however, they are limited by their low differentiation efficiency and immature function. In our study, we applied unidirectional shear stress to promote hiPSCs differentiation into valvular endothelial-like cells (VELs). Compared to the static group, shear stress efficiently promoted the differentiation and functional maturation of hiPSC-VELs, as demonstrated by the efficiency of endothelial differentiation reaching 98.3% in the high shear stress group (45 dyn/cm2). Furthermore, we found that Piezo1 served as a crucial mechanosensor for the differentiation and maturation of VELs. Mechanistically, the activation of Piezo1 by shear stress resulted in the influx of calcium ions, which in turn initiated the Akt signaling pathway and promoted the differentiation of hiPSCs into mature VELs. Moreover, VELs cultured on decellularized heart valves (DHVs) exhibited a notable propensity for proliferation, robust adhesion properties, and antithrombotic characteristics, which were dependent on the activation of the Piezo1 channel. Overall, our study demonstrated that proper shear stress activated the Piezo1 channel to facilitate the differentiation and maturation of hiPSC-VELs via the Akt pathway, providing a potential cell source for regenerative medicine, drug screening, pathogenesis, and disease modeling. STATEMENT OF SIGNIFICANCE: This is the first research that systematically analyzes the effect of shear stress on valvular endothelial-like cells (VELs) derived from human induced pluripotent stem cells (hiPSCs). Mechanistically, unidirectional shear stress activates Piezo1, resulting in an elevation of calcium levels, which triggers the Akt signaling pathway and then facilitates the differentiation of functional maturation VELs. After exposure to shear stress, the VELs exhibited enhanced proliferation, robust adhesion capabilities, and antithrombotic characteristics while being cultured on decellularized heart valves. Thus, it is of interest to develop hiPSCs-VELs using shear stress and the Piezo1 channel provides insights into the functional maturation of valvular endothelial cells, thereby serving as a catalyst for potential applications in the development of therapeutic and tissue-engineered heart valves in the future.

Morusin Alleviates Aortic Valve Calcification by Inhibiting Valve Interstitial Cell Senescence Through Ccnd1/Trim25/Nrf2 Axis.

The senescence of aortic valve interstitial cells (VICs) plays a critical role in the progression of calcific aortic valve disease (CAVD). However, the precise mechanisms underlying the senescence of VICs remain unclear, demanding the identification of a novel target to mitigate this process. Previous studies have highlighted the anti-aging potential of morusin. Thus, this study aimed to explore the therapeutic potential of morusin in CAVD. Cellular experiments reveal that morusin effectively suppresses cellular senescence and cause a shift toward osteogenic differentiation of VICs in vitro. Mechanistically, morusin activate the Nrf2-mediated antiaging signaling pathway by downregulating CCND1 expression and aiding Keap1 degradation through Trim 25. This activation lead to the upregulated expression of antioxidant genes, thus reducing reactive oxygen species production and thereby preventing VIC osteogenic differentiation. In vivo experiments in ApoE-/- mice on a high-fat Western diet demonstrate the positive effect of morusin in mitigating aortic valve calcification. These findings emphasize the antiaging properties of morusin and its potential as a therapeutic agent for CAVD.

Development and validation of mortality prediction models for heart transplantation using nutrition-related indicators: a single-center study from China.

Objective: We sought to develop and validate a mortality prediction model for heart transplantation (HT) using nutrition-related indicators, which clinicians could use to identify patients at high risk of death after HT. Method: The model was developed for and validated in adult participants in China who received HT between 1 January 2015 and 31 December 2020. 428 subjects were enrolled in the study and randomly divided into derivation and validation cohorts at a ratio of 7:3. The likelihood-ratio test based on Akaike information was used to select indicators and develop the prediction model. The performance of models was assessed and validated by area under the curve (AUC), C-index, calibration curves, net reclassification index, and integrated discrimination improvement. Result: The mean (SD) age was 48.67 (12.33) years and mean (SD) nutritional risk index (NRI) was 100.47 (11.89) in the derivation cohort. Mortality after HT developed in 66 of 299 patients in the derivation cohort and 28 of 129 in the validation cohort. Age, NRI, serum creatine, and triglyceride were included in the full model. The AUC of this model was 0.76 and the C statistics was 0.72 (95% CI, 0.67-0.78) in the derivation cohort and 0.71 (95% CI, 0.62-0.81) in the validation cohort. The multivariable model improved integrated discrimination compared with the reduced model that included age and NRI (6.9%; 95% CI, 1.8%-15.1%) and the model which only included variable NRI (14.7%; 95% CI, 7.4%-26.2%) in the derivation cohort. Compared with the model that only included variable NRI, the full model improved categorical net reclassification index both in the derivation cohort (41.8%; 95% CI, 9.9%-58.8%) and validation cohort (60.7%; 95% CI, 9.0%-100.5%). Conclusion: The proposed model was able to predict mortality after HT and estimate individualized risk of postoperative death. Clinicians could use this model to identify patients at high risk of postoperative death before HT surgery, which would help with targeted preventative therapy to reduce the mortality risk.

Off-pump versus on-pump coronary artery bypass grafting in elderly patients at 30 days: a propensity score matching study.

BACKGROUND: Elderly patients are at increased risk of perioperative morbidity and mortality after conventional on-pump coronary artery bypass grafting (ONCABG). This study was to determine whether such high-risk population would benefit from off-pump coronary artery bypass grafting (OPCABG). METHODS: A retrospective analysis was performed on patients aged 65 years or older who underwent isolated coronary artery bypass grafting for the first time in Wuhan Union Hospital from January 2015 to January 2021. We used propensity score matching to adjust for differences in baseline characteristics between the ONCABG and OPCABG groups. Morbidity and mortality within 30 days after surgery were compared between the two groups. All operations were performed by experienced cardiac surgeons. RESULTS: A total of 511 patients (ONCABG 202, OPCABG 309) were included. After 1:1 matching, the baseline characteristics of the two groups were comparable (ONCABG 173, OPCABG 173). The OPCABG group had higher rate of incomplete revascularization (13.9% vs. 6.9%; P = .035) than the ONCABG group. However, OPCABG reduced the risk of postoperative renal insufficiency (15.0% vs. 30.1%; P = .001) and reoperation for bleeding (0.0% vs. 3.5%; P = .030). There were no significant differences in early postoperative mortality, myocardial infarction, stroke, and other outcomes between the two groups. CONCLUSIONS: OPCABG is an alternative revascularization method for elderly patients. It reduces the risk of early postoperative renal insufficiency and reoperation for bleeding.

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.

Mitral valve leaflet blood cyst treated with minimally invasive approach: a case report and review of literature.

INTRODUCTION: Cardiac blood cyst is a very rare benign tumor of the heart in adults. Though it is very common in the first half year of life, it regresses with time and its occurrence is very rare in children older than six months and in adults. Until now less than 100 valvular blood cyst cases have been reported in adults. CASE PRESENTATION: We present a case of a 66-year-old male who presented to us with exertional chest tightness, shortness of breath, and right leg weakness for two weeks. He was diagnosed with a cardiac mass two months ago in another hospital. The physical examination was unremarkable. Abdominal ultrasound showed a cyst in the liver and left kidney. Echocardiography showed a mass-occupying lesion of a cystic nature in the mitral valve with moderate mitral regurgitation. Based on echocardiography findings and computed tomography report, the preliminary diagnosis of mitral valve cystic tumor was made. The patient underwent minimally invasive resection of the cyst. The posterior mitral cusp was repaired and a mitral annuloplasty ring was placed. The postoperative recovery was uneventful. The histopathology report confirmed the diagnosis of a cardiac blood cyst. The patient was followed up for six months without any complications. This case is presented to enrich the medical literature on the cardiac blood cyst. CONCLUSION: Although a cardiac blood cyst is a rare entity in adults, it still should be considered in the differential diagnosis of cardiac tumors. Because the natural history and hemodynamic effects are very diverse, large symptomatic cardiac blood cysts, especially in the left heart should be resected to avoid complications.

Developments and Challenges in Durable Ventricular Assist Device Technology: A Comprehensive Review with a Focus on Advancements in China.

Heart transplantation is currently the most effective treatment for end-stage heart failure; however, the shortage in donor hearts constrains the undertaking of transplantation. Mechanical circulatory support (MCS) technology has made rapid progress in recent years, providing diverse therapeutic options and alleviating the dilemma of donor heart shortage. The ventricular assist device (VAD), as an important category of MCS, demonstrates promising applications in bridging heart transplantation, destination therapy, and bridge-to-decision. VADs can be categorized as durable VADs (dVADs) and temporary VADs (tVADs), according to the duration of assistance. With the technological advancement and clinical application experience accumulated, VADs have been developed in biocompatible, lightweight, bionic, and intelligent ways. In this review, we summarize the development history of VADs, focusing on the mechanism and application status of dVADs in detail, and further discuss the research progress and use of VADs in China.

Long-term survival of ischemic cardiomyopathy patients with severe left ventricular dysfunction after CABG vs heart transplantation: A single center retrospective analysis.

BACKGROUND: There are no guidelines on the surgical management for ischemic cardiomyopathy (ICM) patients with severe left ventricular dysfunction. The present study aims to assess the long-term survival of these patients treated with two different surgical techniques, coronary artery bypass grafting (CABG) and heart transplantation (HTx). METHODS: This retrospective study included 218 ICM patients with left ventricular ejection fraction (LVEF) ≤35% who underwent CABG (n = 106) and HTx (n = 112) from 2011 to 2021 in a single center. After propensity adjustment analysis each group consisted of 51 patients. Clinical characteristics were evaluated for all-cause follow-up mortality by the Cox proportional hazards regression model. A risk prediction model was generated from multivariable-adjusted Cox regression analysis and applied to stratify patients with different clinical risks. The long-term survival was estimated by Kaplan-Meier analysis for different surgery groups. RESULTS: Long-term survival was comparable between CABG and HTx groups. After being stratified into different risk subgroups according to risk predictors, the HTx group exhibited superior survival outcomes compared to the CABG group among the high-risk patients (67.8% vs 44.4%, 64.1% vs 38.9%, and 64.1% vs 33.3%, p = 0.047) at 12, 36, and 60 months respectively, while the survival was comparable between HTx and CABG groups among low-risk patients (87.0% vs 97.0%, 82.4% vs 97.0%, and 70.2% vs 91.6%, p = 0.11) at 12, 36, and 60 months respectively in the PSM cohort. CONCLUSION: Long-term survival in ICM patients with severe left ventricular dysfunction who received CABG or HTx was comparable in general. Nonetheless, a favorable outcome of HTx surgery compared to CABG was observed among high-risk patients.

MFG-E8 facilitates heart repair through M1/M2 polarization after myocardial infarction by inhibiting CaMKII.

BACKGROUND: M1/M2 macrophage polarization affects patient outcomes after myocardial infarction (MI). The relationship between milk fat globule-epidermal growth factor 8 (MFG-E8) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) on macrophage polarization after MI is unknown. To investigate the functional role of MFG-E8 in modulating cardiac M1/M2 macrophage polarization after MI, especially its influence on CaMKII signaling. METHODS: Human ventricular tissue and blood were obtained from patients with MI and controls. MFG-E8-KO mice were constructed (C57BL/6). The mice were randomized to WT-sham, sham-MFG-E8-KO, WT-PBS, rmMFG-E8 (WT injected with rmMFG-E8 10 min after MI), and MFG-E8-KO. The mouse macrophage cell line RAW264.7 was obtained. CaMKII, p-CaMKII, Akt, and NF-κB p65 were determined by qRT-PCR, western blot, and immunofluorescence. RESULTS: The MFG-E8 levels were significantly enhanced after MI in the hearts and plasma of patients with MI compared with controls. The MFG-E8 levels were significantly increased in the hearts and plasma of mice after MI. MFG-E8 was derived from cardiac fibroblasts. The administration of rmMFG-E8 improved ventricular remodeling and cardiac function after MI. rmMFG-E8 did not suppress infiltrating monocyte/macrophages into the peri-infarct area. rmMFG-E8 suppressed the polarization of macrophages to the M1 phenotype and promoted the polarization of macrophages to the M2 phenotype. rmMFG-E8 suppressed CaMKII-dependent signaling in macrophages. CONCLUSIONS: MFG-E8 and CaMKII appear to collaboratively regulate myocardial remodeling and M1/M2 macrophage polarization after MI. These observations suggest new roles for MFG-E8 in inhibiting M1 but promoting M2 macrophage polarization.

Early left ventricular systolic function is a more sensitive predictor of adverse events after heart transplant.

BACKGROUND: First-phase ejection fraction (EF1) is a novel measure of early changes in left ventricular systolic function. This study was to investigate the prognostic value of EF1 in heart transplant recipients. METHODS: Heart transplant recipients were prospectively recruited at the Union Hospital, Wuhan, China between January 2015 and December 2019. All patients underwent clinical examination, biochemistry measures [brain natriuretic peptide (BNP) and creatinine] and transthoracic echocardiography. The primary endpoint was a combined event of all-cause mortality and graft rejection. RESULTS: In 277 patients (aged 48.6 ± 12.5 years) followed for a median of 38.7 [26.8-45.0] months, there were 35 (12.6%) patients had adverse events including 20 deaths and 15 rejections. EF1 was negatively associated with BNP (ß = -0.220, p < 0.001) and was significantly lower in patients with events compared to those without. EF1 had the largest area under the curve in ROC analysis compared to other measures. An optimal cut-off value of 25.8% for EF1 had a sensitivity of 96.3% and a specificity of 97.1% for prediction of events. EF1 was the most powerful predictor of events with hazard ratio per 1% change in EF1: 0.628 (95%CI: 0.555-0.710, p < 0.001) after adjustment for left ventricular ejection fraction and global longitudinal strain. CONCLUSIONS: Early left ventricular systolic function as measured by EF1 is a powerful predictor of adverse outcomes after heart transplant. EF1 may be useful in risk stratification and management of heart transplant recipients.

Pro-osteogenic role of interleukin-22 in calcific aortic valve disease.

BACKGROUND AND AIMS: Although calcific aortic valve disease (CAVD) is a common valvular disease among elderly populations and its incidence has markedly increased in recent decades, the pathogenesis of CAVD remains unclear. In this study, we explored the potential role of interleukin (IL)-22 and the underlying molecular mechanism in CAVD. METHODS AND RESULTS: Our results showed that IL-22 was upregulated in calcific aortic valves from CAVD patients, and its main sources were CD3+ T cells and CD68+ macrophages. Human aortic valve interstitial cells (VICs) expressed the IL-22-specific receptor IL-22R1, and IL-22R1 expression also was elevated in calcified valves. Treatment of cultured human VICs with recombinant human IL-22 resulted in markedly increased expression of osteogenic proteins Runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP), as well as increased matrix calcium deposition. Moreover, siRNA silencing of IL-22R1 blocked the pro-osteogenic effect of IL-22 in VICs. In IL-22-treated VICs, we also observed increased phosphorylation of JAK3 and STAT3 and nuclear translocation of STAT3. Pretreatment with a specific JAK3 inhibitor, WHIP-154, or siRNA knockout of STAT3 effectively mitigated the IL-22-induced osteoblastic trans-differentiation of human VICs. CONCLUSIONS: Together, these data indicate that IL-22 promotes osteogenic differentiation of VICs by activating JAK3/STAT3 signaling. Based on our results demonstrating a pro-osteogenic role of IL-22 in human aortic valves, pharmacological inhibition of IL-22 signaling may represent a potential strategy for alleviating CAVD.