Tomo-seq identifies NINJ1 as a potential target for anti-inflammatory strategy in thoracic aortic dissection.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening disease caused by an intimal tear in the aorta. The histological characteristics differ significantly between the tear area (TA) and the distant area. Previous studies have emphasized that certain specific genes tend to cluster at the TA. Obtaining a thorough understanding of the precise molecular signatures near the TA will assist in discovering therapeutic strategies for TAD. METHODS: We performed a paired comparison of the pathological patterns in the TA with that in the remote area (RA). We used Tomo-seq, genome-wide transcriptional profiling with spatial resolution, to obtain gene expression signatures spanning from the TA to the RA. Samples from multiple sporadic TAD patients and animal models were used to validate our findings. RESULTS: Pathological examination revealed that the TA of TAD exhibited more pronounced intimal hyperplasia, media degeneration, and inflammatory infiltration compared to the RA. The TA also had more apoptotic cells and CD31+α-SMA+ cells. Tomo-seq revealed four distinct gene expression patterns from the TA to the RA, which were inflammation, collagen catabolism, extracellular matrix remodeling, and cell stress, respectively. The spatial distribution of genes allowed us to identify genes that were potentially relevant with TAD. NINJ1 encoded the protein-mediated cytoplasmic membrane rupture, regulated tissue remodeling, showed high expression levels in the tear area, and co-expressed within the inflammatory pattern. The use of short hairpin RNA to reduce NINJ1 expression in the beta-aminopropionitrile-induced TAD model led to a significant decrease in TAD formation. Additionally, it resulted in reduced infiltration of inflammatory cells and a decrease in the number of CD31+α-SMA+ cells. The NINJ1-neutralizing antibody also demonstrated comparable therapeutic effects and can effectively impede the formation of TAD. CONCLUSIONS: Our study showed that Tomo-seq had the advantage of obtaining spatial expression information of TAD across the TA and the RA. We pointed out that NINJ1 may be involved in inflammation and tissue remodeling, which played an important role in the formation of TAD. NINJ1 may serve as a potential therapeutic target for TAD.

Deciphering mechanisms of cardiomyocytes and non-cardiomyocyte transformation in myocardial remodeling of permanent atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, and it significantly increases the risk of cardiovascular complications and morbidity, even with appropriate treatment. Tissue remodeling has been a significant topic, while its systematic transcriptional signature remains unclear in AF. OBJECTIVES: Our study aims to systematically investigate the molecular characteristics of AF at the cellular-level. METHODS: We conducted single-nuclei RNA-sequencig (snRNA-seq) analysis using nuclei isolated from the left atrial appendage (LAA) of AF patients and sinus rhythm. Pathological staining was performed to validate the key findings of snRNA-seq. RESULTS: A total of 30 cell subtypes were identified among 80, 592 nuclei. Within the LAA of AF, we observed a specific subtype of dedifferentiated cardiomyocytes (CMs) characterized by reduced expression of cardiac contractile proteins (TTN and TRDN) and heightened expression of extracellular-matrix related genes (COL1A2 and FBN1). Transcription factor prediction analysis revealed that gene expression patterns in dedifferentiated CMs were primarily regulated by CEBPG and GISLI. Additionally, we identified a distinct subtype of endothelial progenitor cells (EPCs) demonstrating elevated expression of PROM1 and KDR, a population decreased within the LAA of AF. Epicardial adipocytes disclosed a reduced release of the anti-inflammatory and anti-fibrotic factor PRG4, and an augmented secretion of VEGF signals targeting CMs. Additionally, we noted accumulation of M2-like macrophages and CD8+ T cells with high pro-inflammatory score in LAA of AF. Furthermore, the analysis of intercellular communication revealed specific pathways related to AF, such as inflammation, extracellular matrix, and vascular remodeling signals. CONCLUSIONS: This study has discovered the presence of dedifferentiated CMs, a decrease in endothelial progenitor cells, a shift in the secretion profile of adipocytes, and an amplified inflammatory response in AF. These findings could offer crucial insights for future research on AF and serve as valuable references for investigating novel therapeutic approaches for AF.

Hybrid Transthoracic Periventricular Device Closure of Ventricular Septal Defects: Single- Center Experience.

OBJECTIVE: To evaluate the efficacy of hybrid transthoracic periventricular device closure of ventricular septal defects (VSDs) in a single center. METHODS: All patients who underwent hybrid transthoracic periventricular device closure of VSDs between January 2018 and December 2019 were retrospectively analyzed. The preoperative, operative and postoperative findings and clinical follow-ups were reviewed. RESULTS: A total of 59 patients underwent the procedure. Transesophageal echocardiographic guidance was used in all procedures. The procedure was successful in 57 procedures (97%). The procedures of two patients were changed to openheart surgery during the same intervention due to severe aortic insufficiency (the device was not deployed) and significant residual shunt after device deployment. One major complication (1.7%) was observed after the procedure. The patient's device was dislodged within 12 hours after the procedure, and this patient underwent device extraction and VSD patch closure due to significant residual shunt. Eight (14%) minor complications were observed after the procedure, and three of them persisted during follow-up. Three of these eight complications were incomplete right bundle branch block, one of which resolved during followup; two were mild residual shunts, one of which resolved during follow-up; two were mild new-onset tricuspid valve insufficiencies; and one was mild new-onset mitral valve insufficiency; all valvular insufficiencies were resolved during follow-up. CONCLUSION: Hybrid transthoracic periventricular device closure of VSD seems to be a good alternative approach due to its procedural success and low risk rates. The best advantage of the procedure is the possibility of switching to open-heart surgery, if necessary.

House Dust Mite Specific Antibodies induce Neutrophilic Inflammation in the Heart.

Rationale: Inflammatory heart disorders are among the causes of human death. The causative factors of heart inflammation are to be further elucidated. House dust mite (HDM)-derived protein antigens are involved in the pathogenesis of many human diseases. This study aims to investigate the role of HDM-specific autoantibodies in the pathogenesis of heart inflammation. Methods: Human heart tissue samples were obtained from surgically removed hearts in heart transplantation. The interaction of the heart tissues with HDM-specific antibodies was assessed by pertinent immune analysis. The role of HDM-specific autoantibodies in the induction of heart inflammation was assessed with a murine model. Results: HDM-specific IgG (mIgG) was detected in the serum of patients with myocarditis (Mcd); the mIgG titers were positively correlated with the neutrophil counts in the heart tissues. The mIgG specifically bound to keratin-10 (KRT10) in heart vascular endothelial cells and the heart tissue protein extracts. The amounts of C3a, C5a and C5b-9 were increased in the mouse heart tissues after exposing to mIgG. In the presence of the complement-containing serum, mIgG bound cardiovascular epithelial monolayers to impair the barrier functions. Administration of mIgG or HDM induced the Mcd-like inflammation in the heart, in which neutrophils were the dominant cellular components in the infiltration of inflammatory cells. Conclusions: Mcd patients with neutrophilic inflammation in the heart had higher serum levels of mIgG. The mIgG bound heart endothelial cells to impair the endothelial barrier functions and induce neutrophilic inflammation in the heart.

Hybrid transthoracic periventricular device closure of ventricular septal defects: single-center experience

Abstract Objective: To evaluate the efficacy of hybrid transthoracic periventricular device closure of ventricular septal defects (VSDs) in a single center. Methods: All patients who underwent hybrid transthoracic periventricular device closure of VSDs between January 2018 and December 2019 were retrospectively analyzed. The preoperative, operative and postoperative findings and clinical follow-ups were reviewed. Results: A total of 59 patients underwent the procedure. Transesophageal echocardiographic guidance was used in all procedures. The procedure was successful in 57 procedures (97%). The procedures of two patients were changed to open-heart surgery during the same intervention due to severe aortic insufficiency (the device was not deployed) and significant residual shunt after device deployment. One major complication (1.7%) was observed after the procedure. The patient's device was dislodged within 12 hours after the procedure, and this patient underwent device extraction and VSD patch closure due to significant residual shunt. Eight (14%) minor complications were observed after the procedure, and three of them persisted during follow-up. Three of these eight complications were incomplete right bundle branch block, one of which resolved during follow-up; two were mild residual shunts, one of which resolved during follow-up; two were mild new-onset tricuspid valve insufficiencies; and one was mild new-onset mitral valve insufficiency; all valvular insufficiencies were resolved during follow-up. Conclusions: Hybrid transthoracic periventricular device closure of VSD seems to be a good alternative approach due to its procedural success and low risk rates. The best advantage of the procedure is the possibility of switching to open-heart surgery, if necessary.