Single-cell transcriptomic analysis reveals differential cell subpopulations and distinct phenotype transition in normal and dissected ascending aorta.

BACKGROUND: Acute thoracic aortic dissection (ATAD) is a fatal condition characterized by tear of intima, formation of false lumen and rupture of aorta. However, the subpopulations of normal and dissected aorta remain less studied. METHODS: Single-cell RNA sequencing was performed including 5 patients with ATAD and 4 healthy controls. Immunohistochemistry and immunofluorescence were used to verify the findings. RESULTS: We got 8 cell types from human ascending aorta and identified 50 subpopulations including vascular smooth muscle cells (VSMCs), endothelial cells, fibroblasts, neutrophils, monocytes and macrophages. Six transmembrane epithelial antigen of prostate 4 metalloreductase (STEAP4) was identified as a new marker of synthetic VSMCs. CytoTRACE identified subpopulations with higher differentiation potential in specified cell types including synthetic VSMCs, enolase 1+ fibroblasts and myeloid-derived neutrophils. Synthetic VSMCs-derived C-X-C motif chemokine ligand 12 (CXCL12) might interact with neutrophils and fibroblasts via C-X-C motif chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), respectively, which might recruit neutrophils and induce transdifferentitation of fibroblasts into synthetic VSMCs. CONCLUSION: We characterized signatures of different cell types in normal and dissected human ascending aorta and identified a new marker for isolation of synthetic VSMCs. Moreover, we proposed a potential mechanism that synthetic VSMCs might interact with neutrophils and fibroblasts via CXCL12-CXCR4/ACKR3 axis whereby deteriorating the progression of ATAD, which might provide new insights to better understand the development and progression of ATAD.

CircLDLR Modulates the Proliferation and Apoptosis of Vascular Smooth Muscle Cells in Coronary Artery Disease Through miR-26-5p/KDM6A Axis.

ABSTRACT: The purpose of this study was to investigate the effect of circLDLR on the proliferation and apoptosis of vascular smooth muscle cells (VSMCs) in coronary artery disease and its regulatory mechanism. The expression of KDM6A was detected by qRT-PCR or Western blot. VSMCs were transfected with miR-26-5p mimic/inhibitor or OE KDM6A. Cell proliferation and apoptosis were assessed. Luciferase reporter gene assays were used to examine interactions between miR-26-5p and KDM6A in VSMCs. Downregulation of circLDLR was associated with increased miR-26-5p in coronary artery disease tissues. In addition, circLDLR could inhibit cell proliferation and promote cell apoptosis by regulating miR-26-5p. Moreover, the overexpression of KDM6A reduced VSMCs proliferation and increased apoptosis in an miR-26-5p/circLDLR axis-dependent manner. CircLDLR modulates the proliferation and apoptosis of VSMCs through miR-26-5p/KDM6A axis.

Long-term left atrial thrombi after mitral valve replacement.

The aim of this study was to evaluate the risk factors and characteristics of long-term postoperative left atrial (LA) thrombi after mitral valve replacement. Transthoracic echocardiography (TTE) file of 3117 consecutive patients with mitral valve replacement history was reviewed (between Jan 2006 and Feb 2019). 45 LA thrombi cases (1.4%) was identified and matched to 180 thrombi-free cases by random sampling. The median detection time of LA thrombi was 58 months (IQR, 17-144) after MV replacement. Distribution of LA thrombi included roof (n = 10), posterior wall (n = 9), appendage (n = 7), lateral wall (n = 6), anterior wall (n = 2), septum (n = 1) and multiple site (n = 10). All thrombi were sessile and immobile. The independent predictors for LA thrombi development by stepwise multiple regression analysis were the larger LA size (> 55 mm), the increased of mitral valve pressure gradient (MVPG > 6 mmHg), and the reduced of left ventricular ejection fraction (LVEF < 50%). Long-term thrombi incidence after mitral valve replacement is somewhat low. In individuals with mitral prosthetic valves, larger LA size, increased MVPG and reduced LVEF were three promising independent predictors of the insistence of LA thrombi. Furthermore, LA thrombi were sessile, immobile and widespread in the long-term postoperative period after mitral valve replacement. Close monitoring should be applied in these patients with thrombi risk.

Preoperative prognostic nutritional index is an independent indicator for perioperative prognosis in coronary artery bypass grafting patients.

OBJECTIVES: The prognostic nutritional index is widely used for surgery prognosis, but the association between preoperative prognostic nutritional index and short-term prognosis for coronary artery bypass grafting surgery and the profiles of perioperative prognostic nutritional index remain unclear. METHODS: This study retrospectively enrolled a total of 879 adult patients undergoing coronary artery bypass grafting surgery in the Shanghai Chest Hospital from 2006 to 2022. The prognostic nutritional index was calculated based on serum albumin and peripheral lymphocyte count. In-hospital mortality, demographic characteristics, blood biochemistry parameters, cardiovascular medical history, and physical examination results were collected from the hospital information system. The propensity score matching method and multivariate logistic regression were used to detect the association between preoperative prognostic nutritional index and in-hospital mortality. RESULTS: Patients were divided into a high-prognostic nutritional index group (n = 500) and a low-prognostic nutritional index group (n = 379), using a cutoff value of 48.1 according to receiver operating characteristic curve analysis. The propensity score matching-adjusted mean prognostic nutritional index levels decreased from 48.35 before the operation to 34.04 an in ≤24 h after the operation and rebounded to 43.36 before discharge. High preoperative prognostic nutritional index was inversely associated with in-hospital mortality for coronary artery bypass grafting surgery (odds ratio = 0.86; 95% CI, 0.77-0.97) in propensity score matching-adjusted multivariate logistic regression. CONCLUSIONS: Preoperative prognostic nutritional index is an independent indicator for in-hospital mortality of for coronary artery bypass grafting surgery, and the variation trend of prognostic nutritional index during perioperation tends to be U-shaped.

Circular RNA hsa_circ_0008896 accelerates atherosclerosis by promoting the proliferation, migration and invasion of vascular smooth muscle cells via hsa-miR-633/CDC20B (cell division cycle 20B) axis.

Circular RNAs, a class of circularly closed non-coding RNAs, play essential roles in the formation of atherosclerosis, which is a frequent cause of cardiovascular and cerebrovascular diseases. Although many circular RNAs are found to be involved in the progression of atherosclerosis, more circular RNA regulators still need to be identified, to improve the understanding of the regulatory networks of atherosclerosis. Here, we found that hsa_circ_0008896 was significantly up-regulated in both in vitro and in vivo atherosclerosis models, indicating hsa_circ_0008896 was involved in the progression of atherosclerosis. Further functional analyses confirmed that knockdown of hsa_circ_0008896 decreased proliferation, migration, and invasion of VSMCs. In addition, we conducted bioinformatics analysis and found that hsa-miR-633 could directly bind to hsa_circ_0008896, which was confirmed by RNA immune-precipitation (RIP) assays. Results of proliferation, migration, and invasion assays showed that hsa-miR-633 inhibitor reversed the si-circ_0008896 phenotypes, indicating that hsa_circ_0008896 functionally bound to hsa-miR-633. At last, combining bioinformatics and experimental analyses, we found the protein target of hsa_circ_0008896/hsa-miR-633, CDC20B (cell division cycle 20B). The expression level of CDC20B was regulated by hsa-miR-633, and knockdown of CDC20B decreased proliferation, migration, and invasion of VSMCs. Taken together, hsa_circ_0008896 regulated the expression of CDC20B by sponging hsa-miR-633, and then enhanced proliferation, migration, and invasion of VSMCs to promote the progression of atherosclerosis.

LncRNA Nuclear-Enriched Abundant Transcript 1 Regulates Atrial Fibrosis via the miR-320/NPAS2 Axis in Atrial Fibrillation.

Atrial fibrosis is a key contributor to atrial fibrillation (AF). Long non-coding ribonucleic acids (lncRNAs) were demonstrated to exhibit a key role in fibrotic remodeling; however, the function of nuclear-enriched abundant transcript 1 (NEAT1) in atrial fibrosis remains unclear. In the present study, we showed that NEAT1 was upregulated in atrial tissues of AF patients and was positively related to collagen I (coll I) and collagen III (coll III) expressions. Furthermore, the deletion of NEAT1 attenuated angiotensin II (Ang II)-caused atrial fibroblast proliferation, migration, and collagen production. We further observed that NEAT1 knockdown improved Ang II caused mouse atrial fibrosis in in vivo experiments. Moreover, we demonstrated that NEAT1 could negatively regulate miR-320 expression by acting as a competitive endogenous RNA (ceRNA). miR-320 directly targeted neuronal per arnt sim domain protein 2 (NPAS2) and suppressed its expression. We observed that NEAT1 exerted its function via the miR-320-NPAS2 axis in cardiac fibroblasts. These findings indicate that NEAT1 exerts a significant effect on atrial fibrosis and that this lncRNA is a new potential molecular target for AF treatment.

Transcatheter aortic valve resection: new mechanical devices.

BACKGROUND: To improve periprocedural outcomes of transcatheter aortic valve implantation (TAVI), transcatheter mechanical resection devices were tested for prior ablation of the aortic cusps. METHODS: Three mechanical transcatheter resection devices were tested in a series of native porcine (n=30) and reassembled calcified human valves (n=54). The resection time, the resected valve area, the number of released cusps, and the degree of surrounding tissue damage were measured. Afterwards, postmortem transapical-transcatheter-resections of the aortic valve in two humans were performed. RESULTS: In the native porcine hearts, the Aesculap II device demonstrated significantly shorter resection time compared to the R&R II and the Randstad devices (6.5±2.0 vs. 28.6±24.1 vs. 23.3±14.4 sec; P=0.001). However, it created more lesions in the surrounding tissue (P=0.002). The R&R II achieved a smaller number of resected cusps than the other two devices (2.7±0.7 vs. 1.1±0.7 vs. 2.4±0.5; P<0.001, respectively). It also resected a smaller area of the aortic valve (306.5±149.2 vs. 106.7±29.6 vs. 256.8±81.3 mm2; P=0.09) but a larger mean area of the resected fragments (110.3±41.5 vs. 160.7±29.6 vs. 111.5±43.9 mm2; P=0.01). The resection of the reassembled human valves demonstrated the same results between the devices regarding resection time (P=0.001) and resected area (P=0.016), but not fragment sizes (P=0.610). Finally, transapical-transcatheter-resection of aortic valve was performed in two cadavers. CONCLUSIONS: Transcatheter aortic valve resection is feasible with variable aortic leaflet resection times and mild risk of lesions of the surrounding tissue.

Transcatheter mitral valve replacement (TMVR): annular or apical fixation?

AIMS: The aim of this study was to evaluate the impact of two different transcatheter mitral valve replacement (TMVR) fixation strategies on the neo left ventricular outflow tract (neo-LVOT) and aorto-mitral angulation (AMA) after TMVR. METHODS AND RESULTS: Two different self-expanding nitinol valved stents were developed for transapical TMVR. In one group, the stents were fixed with an annular fixation system (ANN group, n=6). These prototypes were compared with an apical tether fixation TMVR system (AP group, n=11) in another group. Echocardiographic evaluation of the AMA and the neo-LVOT was conducted before and one hour after implantation. Maximal and minimal AMA (AMAmax and AMAmin) during the cardiac cycle of the AP group were significantly narrower than those of the ANN group (AMAmax: 39±8° vs 67±15°, p<0.001, AMAmin: 33±10° vs 56±22°, p=0.009). More severe reduction of the neo-LVOT diameter was observed in the ANN group (60±11% vs 26±14%, p<0.001). The ANN group had a higher peak velocity through the neo-LVOT post implantation (200±52 cm/s vs 108±15 cm/s, p<0.001). CONCLUSIONS: The apical fixation system maintains a smaller and more stable aorto-mitral angulation and a larger neo-LVOT, thereby reducing the risk of postoperative neo-LVOT obstruction in this experimental setting.

Transcatheter mitral valve implantation: a percutaneous transapical system.

Objectives: Despite recent achievements, implantation of a transcatheter mitral valved stent remains challenging. In this study, we present a different approach for implantation of a percutaneous mitral valved stent. Methods: Percutaneous transapical access is combined with, respectively, a left-transatrial, right-transatrial/transseptal or transfemoral/transseptal approach for mitral valve stent implantation and secure fixation. The apical fixation and occlusion are ensured with an Amplatzer occluder. This novel approach was tested in 22 porcine hearts in an in vitro setting under the guidance of fluoroscopy ( n = 11) and endoscopy ( n = 11). The in vitro setup included continuous flushing at 37 °C. We determined the feasibility, time of implantation, stent deployment and stent fixation. Results: Percutaneous mitral valved stent implantation was successful in all cases. Good handling properties and precise positioning were achieved. Time of implantation was comparable in the fluoroscopic and endoscopic groups at 10:41 ± 3:18 and 10:09 ± 2:42 min, respectively. Apical fixation with the occluder was excellent in all 22 cases. Conclusions: The feasibility of percutaneous mitral valved stent implantation has been demonstrated in preliminary in vitro experiments. Subsequent studies are warranted to determine the efficacy of this minimally invasive catheter-based mitral valved stent implantation.

Mitral valve repair with the "respect" approach in dialysis-dependent patients: a single-center experience.

BACKGROUND: Morbidity and mortality risks in patients with end-stage renal disease (ESRD) undergoing mitral valve surgery are high; however, little is known regarding the risks and results of mitral valve repair in these patients. METHODS: We retrospectively reviewed the clinical data of dialysis-dependent patients who underwent mitral valve repair with the "respect" approach between April 2012 and April 2015 in our institution. RESULTS: All five identified patients survived and their data were included in the analysis. Follow-up ranged from 3 to 48 months with a median of 24±8.9 months. Patients' cardiac function improved postoperatively with two patients in New York Heart Association class I and three patients in class II. Three patients had no or trivial mitral valve regurgitation, two patients had mild regurgitation, and none had moderate or higher regurgitation. Left ventricular end diastolic volume decreased significantly: from 166.2±32.7 mL preoperatively to 123.1±24.5 mL postoperatively (P<0.001). CONCLUSIONS: With the "respect" approach, mitral valve repair in dialysis-dependent patients with prolapse of the posterior leaflet provided good and stable results; however, appropriate perioperative management was critical in these patients.

Transapical mitral valved stent implantation: comparison between circular and D-shaped design.

AIMS: In this study two designs of a self-expanding valved stent were compared after off-pump implantation into the mitral valve to identify the superior one. METHODS AND RESULTS: Two designs of a mitral valved stent were tested. The first design is composed of a circular atrial element connected to a tube-shaped ventricular element. In the second design, the atrial element is D-shaped to achieve better anatomical alignment. Prior to in vivo testing, the area with the highest risk of PVL was identified in a hydrostatic in vitro set-up. Subsequently, eight pigs received stents (circular, n=5; D-shaped, n=3) via apical access in the beating heart. Positioning and haemodynamics were evaluated by TEE and invasive pressure measurement pre-implantation, after 1 hr, and at two and four weeks. In vitro testing showed less PVL in the anteromedial region in D-shaped design stents (p<0.001). All stents were successfully deployed in vivo and six animals maintained normal haemodynamics for two weeks or longer. Rotational reorientation of all stents with D-shaped elements was observed. Both groups indicated no clinically relevant gradients over the mitral valved stent. CONCLUSIONS: This study demonstrates that the circular design was superior to the D-shaped model after rotational reorientation of the latter occurred.