Outcomes of Transcatheter Closure of Congenital Left Circumflex Coronary Artery Fistula.

BACKGROUND: Congenital left circumflex coronary artery fistula (LCX-CAF) is a relatively rare type of coronary artery fistula (CAF); little is known about the outcomes of transcatheter closure (TCC) of LCX-CAF.Methods and Results: All consecutive patients admitted to Fuwai Hospital and scheduled for TCC of LCX-CAF between January 2012 and December 2022 were reviewed retrospectively. Of the 25 consecutive patients (mean [±SD] age 34±20 years; 48% male) admitted and scheduled for TCC of congenital LCX-CAF, the procedure was feasible in 22 (77.3%). The mean (±SD) diameter of the fistulas was 6.99±2.04 mm; 21 (84%) patients had a large fistula (i.e., diameter >2-fold greater than non-feeding coronary artery). Occluders were deployed via a transarterial approach and arteriovenous loop in 6 (27.3%) and 16 (72.7%) patients, respectively. No procedural complications were recorded. Although the procedural success rates are similar for single LCX-CAF and left anterior descending CAF (81.25% vs. 92.86%; P=0.602), the mean time from initial angiography to first occluder deployment is significantly longer for LCX-CAF (83.06±36.07 vs. 36.00±9.49 min; P<0.001). The mean (±SD) follow-up time was 62.2±45.5 months. The incidence of myocardial infarction and recanalization of the fistula was 4.5% (1/22) and 9.1% (2/22), respectively. CONCLUSIONS: TCC of LCX-CAF is a feasible and effective alternative to surgical repair, with comparable outcomes in selected patients. Optimal medical therapy to prevent post-closure myocardial infarction requires further investigation.

Biodegradable Cardiac Occluder with Surface Modification by Gelatin-Peptide Conjugate to Promote Endogenous Tissue Regeneration.

Transcatheter intervention has been the preferred treatment for congenital structural heart diseases by implanting occluders into the heart defect site through minimally invasive access. Biodegradable polymers provide a promising alternative for cardiovascular implants by conferring therapeutic function and eliminating long-term complications, but inducing in situ cardiac tissue regeneration remains a substantial clinical challenge. PGAG (polydioxanone/poly (l-lactic acid)-gelatin-A5G81) occluders are prepared by covalently conjugating biomolecules composed of gelatin and layer adhesive protein-derived peptides (A5G81) to the surface of polydioxanone and poly (l-lactic acid) fibers. The polymer microfiber-biomacromolecule-peptide frame with biophysical and biochemical cues could orchestrate the biomaterial-host cell interactions, by recruiting endogenous endothelial cells, promoting their adhesion and proliferation, and polarizing immune cells into anti-inflammatory phenotypes and augmenting the release of reparative cytokines. In a porcine atrial septal defect (ASD) model, PGAG occluders promote in situ tissue regeneration by accelerating surface endothelialization and regulating immune response, which mitigate inflammation and fibrosis formation, and facilitate the fusion of occluder with surrounding heart tissue. Collectively, this work highlights the modulation of cell-biomaterial interactions for tissue regeneration in cardiac defect models, ensuring endothelialization and extracellular matrix remodeling on polymeric scaffolds. Bioinspired cell-material interface offers a highly efficient and generalized approach for constructing bioactive coatings on medical devices.

An anti-inflammatory chondroitin sulfate-poly(lactic-co-glycolic acid) composite electrospinning membrane for postoperative abdominal adhesion prevention.

Postoperative abdominal adhesion is a very common and serious complication, resulting in pain, intestinal obstruction and heavy economic burden. Post-injury inflammation that could activate the coagulation cascade and deposition of fibrin is a major cause of adhesion. Many physical barrier membranes are used to prevent abdominal adhesion, but their efficiency is limited due to the lack of anti-inflammatory activity. Here, an electrospinning membrane composed of poly(lactic-co-glycolic acid) (PLGA) providing support and mechanical strength and chondroitin sulfate (CS) conferring anti-inflammation activity is fabricated for preventing abdominal adhesion after injury. The PLGA/CS membrane shows a highly dense fiber network structure with improved hydrophilicity and good cytocompatibility. Importantly, the PLGA/CS membrane with a mass ratio of CS at 20% provides superior anti-adhesion efficiency over a native PLGA membrane and commercial poly(D, L-lactide) (PDLLA) film in abdominal adhesion trauma rat models. The mechanism is that the PLGA/CS membrane could alleviate the local inflammatory response as indicated by the promoted percentage of anti-inflammatory M2-type macrophages and decreased expression of pro-inflammatory factors, such as IL-1ß, TNF-α and IL-6, resulting in the suppression of the coagulation system and the activation of the fibrinolytic system. Furthermore, the deposition of fibrin at the abdominal wall was inhibited, and the damaged abdominal tissue was repaired with the treatment of the PLGA/CS membrane. Collectively, the PLGA/CS electrospinning membrane is a promising drug-/cytokine-free anti-inflammatory barrier for post-surgery abdominal adhesion prevention and a bioactive composite for tissue regeneration.

Extracellular Matrix/Glycopeptide Hybrid Hydrogel as an Immunomodulatory Niche for Endogenous Cardiac Repair after Myocardial Infarction.

The treatment of myocardial infarction (MI) remains a substantial challenge due to excessive inflammation, massive cell death, and restricted regenerative potential, leading to maladaptive healing process and eventually heart failure. Current strategies of regulating inflammation or improving cardiac tissue regeneration have limited success. Herein, a hybrid hydrogel coassembled by acellular cardiac extracellular matrix (ECM) and immunomodulatory glycopeptide is developed for endogenous tissue regeneration after MI. The hydrogel constructs a niche recapitulating the architecture of native ECM for attracting host cell homing, controlling macrophage differentiation via glycopeptide unit, and promoting endotheliocyte proliferation by enhancing the macrophage-endotheliocyte crosstalk, which coordinate the innate healing mechanism for cardiac tissue regeneration. In a rodent MI model, the hybrid hydrogel successfully orchestrates a proreparative response indicated by enhanced M2 macrophage polarization, increased angiogenesis, and improved cardiomyocyte survival, which alleviates infarct size, improves wall thicknesses, and enhances cardiac contractility. Furthermore, the safety and effectiveness of the hydrogel are demonstrated in a porcine MI model, wherein proteomics verifies the regulation of immune response, proangiogenesis, and accelerated healing process. Collectively, the injectable composite hydrogel serving as an immunomodulatory niche for promoting cell homing and proliferation, inflammation modulation, tissue remodeling, and function restoration provides an effective strategy for endogenous cardiac repair.

Supramolecular Polymer-Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage-Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti-Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma.

Anti-angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro-angiogenic factors in the tumor microenvironment (TME) in response to anti-angiogenic therapy, recruiting tumor-associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti-angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX-PMI) co-assembled by anti-angiogenic nanomedicines (PCN-Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs-reprogramming polyTLR7/8a nanoregulators (p(Man-IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN-Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man-IMDQ) NRs repolarize pro-angiogenic M2-type TAMs into anti-angiogenic M1-type TAMs via mannose-binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1-6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2-subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti-angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system-based synergistic approach for tumor therapy.

A fully biodegradable polydioxanone occluder for ventricle septal defect closure.

Ventricular septal defect (VSD) is one of the commonest congenital heart diseases (CHDs). Current occluders for VSD treatment are mainly made of nitinol, which has the risk of nickel allergy, persistent myocardial abrasion and fatal arrythmia. Herein, a fully biodegradable polydioxanone (PDO) occluder equipped with a shape line and poly-l-lactic acid PLLA membranes is developed for VSD closure without the addition of metal marker. PDO occluder showed great mechanical strength, fatigue resistance, geometry fitness, biocompatibility and degradability. In a rat subcutaneous implantation model, PDO filaments significantly alleviated inflammation response, mitigated fibrosis and promoted endothelialization compared with nitinol. The safety and efficacy of PDO occluder were confirmed in a canine VSD model with 3-year follow-up, demonstrating the biodegradable PDO occluder could not only effectively repair VSD, induce cardiac remodeling but also address the complications associated with metal occluders. Furthermore, a pilot clinical trial with five VSD patients indicated that all the occluders were successfully implanted under the guidance of echocardiography and no adverse events occurred during the 3-month follow-up. Collectively, the fully bioresorbable PDO occluder is safe and effective for clinical VSD closure and holds great promise for the treatment of structural CHDs.

Bioinformatic analysis of potential biomarkers and mechanisms of immune infiltration in mitral regurgitation complicated by atrial fibrillation.

Background: Mitral regurgitation (MR) is one of the most prevalent valvular diseases. Degenerated MR-induced volume overload leads to left atrial enlargement and eventually, atrial fibrillation (AF). AF has a negative effect on patient prognosis despite recent advances in minimal invasive transcatheter devices for valve surgery. However, more effective strategies aimed at precisely treating from pathophysiology and genetic perspective are scarce. Methods: The gene expression datasets, GSE109744 and GSE79768, were obtained from the Gene Expression Omnibus database and analyzed to identify the differentially expressed genes (DEGs) in patients with mitral value prolapse (MVP) and AF. Subsequently, we predicted the extensive miRNA targets, and the protein-protein interaction (PPI) and miRNA-target gene regulatory networks were established. Functional enrichment analyses were performed for the DEGs. In addition, the co-expressed DEGs coupled with their predicted miRNAs and disease phenotypes involved in MVP and AF were assessed. Finally, the immune infiltration in both datasets was examined. Results: A total of 491 and 180 DEGs were identified in the mitral valve and left atrial specimens, respectively. From these, 11 integrated co-expressed DEGs were identified, namely, PRG4, GPR34, RELN, CA3, IL1B, EPHA3, CHGB, TCEAL2, B3GALT2, ASB11, and CRISPLD1. The enriched Gene Ontology terms and KEGG pathways associated with the DEGs were determined, and the top 10 hub genes and top 3 gene clusters were selected from the PPI network. A prediction of target miRNAs was performed based on the co-expressed DEGs. The enrichment of the co-expressed DEGs suggested that immune and inflammatory responses might be involved in the disease development through multiple immune related pathways, including the interaction of cytokines and chemokines. Notably, this result was consistent with the immune infiltration analysis since the proportions of naïve B cells and memory B cells were significantly different in MVP and AF tissues compared to normal tissues. Conclusions: MR and AF are related, and 11 co-expressed DEGs were found to be significantly associated with MVP with AF, and indeed, these may represent novel biomarkers. Several immune cells were found to contribute to the process of MVP and AF via diverse mechanisms, in particular, antigen-presenting cells.

Neuroblastoma Suppressor of Tumorigenicity 1 Mediates Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension Related to Congenital Heart Disease.

Endothelial-to-mesenchymal transition (EndMT) plays a critical role in the flow-induced vascular remodeling process, such as pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). NBL1 (neuroblastoma suppressor of tumorigenicity 1) is a secreted glycoprotein that has been implicated in CHD-PAH by aggravating the phenotypic transformation of smooth muscle cells. However, the underlying mechanisms regarding the interplay between NBL1 and endothelial cells in CHD-PAH remain to be fully elucidated. Thus, we aimed to identify the potential effect of NBL1 on EndMT using a novel flow-associated PAH model with Nbl1 knockout rats. The phenotype of EndMT was detected using RNA sequencing and further examined using western blotting and immunostaining of pulmonary arteries. Our observations demonstrated that the novel strategy of Nbl1 knockout effectively attenuated flow-associated PAH through downregulation of EndMT to some extent. Mechanistic experiments were established on human pulmonary artery endothelial cells to confirm that EndMT was induced by NBL1 in vitro. After 7 days' stimulation with NBL1, concentrations of EndMT-related biomarkers and downstream transcription factors were quantified using RNA sequencing, western blotting, and immunocytochemistry. Both in vitro and in vivo experiments supported the imbalance of increased TGF-ß (transforming growth factor-ß) and dysregulation of BMP (bone morphogenetic protein) signaling by NBL1. Blocking the canonical TGF-ß pathway efficiently preserved endothelial function upon NBL1 stimulation. These data suggested that NBL1 aggravated flow-associated PAH by inducing EndMT via the TGF-ß and BMP signaling pathway. Thus, antagonizing NBL1 and rebalancing TGF-ß and BMP signaling may be a suitable therapeutic target for CHD-PAH.

Assessment of Use and Fit of Face Masks Among Individuals in Public During the COVID-19 Pandemic in China.

Importance: Face masks are recommended to prevent transmission of coronavirus disease 2019 (COVID-19); however, there is scarce evidence on their protection efficacy and ways to improve it. Objective: To determine the proportion of improper face mask use, the factors associated with face mask protection efficacy, and ways to improve efficacy. Design, Setting, and Participants: This population-based cross-sectional study was conducted in China from July to August 2020 in 5 kinds of public places. Participants included convenience samples of individuals wearing face masks and able to taste the check solution. Exposures: Demographic and socioeconomic characteristics, including sex, age, and education level; information on face mask model and the worn duration was recorded. Main Outcomes and Measures: The main outcome as airtightness, assessed by detecting face-to-face mask gaps, movement of cotton fiber placed at the face mask edges, and using a qualitative fit test with a bitter solution spray. Masks were further assessed for whether sealing the upper face mask edge with an adhesive tape strip was associated with improved face mask airtightness. Results: Among 6003 face mask wearers enrolled, the mean (SD) age of participants was 31.1 (13.7) years, and 3047 participants (50.8%) were female. The first qualitative fit test found air leakage in 2754 participants (45.9%; 95% CI, 44.6%-47.1%), which was mostly attributable to gaps at the upper face mask edge. After sealing the upper face mask edge with an adhesive tape strip, 69.7% (95% CI, 68.0%-71.5%) of masks that had exhibited leakage became airtight in the second qualitative fit test, and the rate of airtightness reached 96.2% (95% CI, 95.4%-96.8%) in a third qualitative fit test after new surgical face masks with tape on the upper edge were provided to those who had not converted initially. The tape was well tolerated; overall, 6 participants (1.2%) reported a rash and 24 participants (5.8%) reported significant discomfort. Conclusions and Relevance: In this study of face mask fit among participants in China, although most people used face masks in public places, compromised protection due to suboptimal airtightness was common. The simple approach of sealing the upper edge of the face mask with an adhesive tape strip was associated with substantially improved its airtightness.

Novel Panna Guide Wire Facilitates Percutaneous and Nonfluoroscopic Procedure for Atrial Septal Defect Closure: A Randomized Controlled Trial.

BACKGROUND: Echo-guided percutaneous procedures have been reported reliable and advantageous. However, the learning curve is difficult for junior doctors. We aimed to evaluate the safety and efficacy of a novel guidewire (Panna wire) in percutaneous atrial septal defect closure under transthoracic echocardiography guidance only. METHODS: The Panna wire is designed for echo-guide procedure with a retractable spindle-shaped tip. A multicenter, randomized, controlled trial was conducted to evaluate the safety and efficacy of the Panna wire versus the conventional guidewire for junior doctors with <100 cases experience. The primary outcome was operative success rate. The secondary outcomes were incidence of major adverse events, operation time, time needed to enter the left atrium, number of arrhythmia episodes, number of misguidance to tricuspid valve, and incidence of peripheral vascular complications. RESULTS: Between July 2018 and September 2019, 100 patients with atrial septal defect were randomized to either the Panna wire group (n=52) or the conventional wire group (n=48) at 3 centers. The baseline clinical characteristics were similarly distributed. The operative success rate (primary outcome) was 100% in the Panna wire group versus 68.75% in the conventional wire group (P<0.001). No major adverse events occurred in either group. Significant differences in favor of the Panna wire group were found in operation time (P=0.004), time needed to enter the left atrium (P<0.001), number of arrhythmia episodes (P<0.001), and number of misguidance to tricuspid valve (P=0.005). CONCLUSIONS: The Panna wire is safe and effective and reduces the learning curve in percutaneous atrial septal defect closure under transthoracic echocardiography guidance only. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT04096924.