Activation of GPR81 by lactate inhibits oscillatory shear stress-induced endothelial inflammation by activating the expression of KLF2.

Atherosclerosis is a common and deadly cardiovascular disease with extremely high prevalence. Areas of the vasculature exposed to oscillatory shear stress (OSS) or disturbed blood flow are particularly prone to the development of atherosclerotic lesions. In part, various mechanosensitive receptors on the surface of endothelial cells play a role in regulating the ability of the vasculature to cope with variations in blood flow patterns. However, the exact mechanisms behind flow-mediated endothelial responses remain poorly understood. Along with the development of highly specific receptor agonists, the class of G coupled-protein receptors has been receiving increasing attention as potential therapeutic targets. G coupled-protein receptor 81 (GPR81), also known as hydroxycarboxylic acid receptor 1 (HCA1 ), is activated by lactate, its endogenous ligand. In the present study, we show for the first time that expression of GPR81 is significantly downregulated in response to OSS in endothelial cells and that activation of GPR81 using physiologically relevant doses of lactate can rescue OSS-induced reduced GPR81 expression. Importantly, our findings demonstrate that activation of GPR81 can exert valuable atheroprotective effects in endothelial cells exposed to OSS by reducing oxidative stress and significantly downregulating the expression of inflammatory cytokines including interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and high mobility group box 1 (HMGB1). We also show that activation of GPR81 can potentially prevent the attachment of monocytes to the endothelium by suppressing OSS-induced secretion of vascular cellular adhesion molecule (VCAM)-1 and endothelial-selectin (E-selectin). Finally, we show that activation of GPR81 can rescue OSS-induced reduced expression of the key atheroprotective transcription factor Kruppel-like factor 2 (KLF2), which is mediated through the extracellular-regulated kinase 5 (ERK5) pathway. These findings demonstrate a potential protective role of GPR81 against atherogenesis and that targeted activation of GPR81 may inhibit endothelial inflammation and dysfunction induced by OSS.

Perventricular device closure of doubly committed sub-arterial ventricular septal defects via a left infra-axillary approach.

BACKGROUND: This study sought to evaluate the feasibility, safety, and efficacy of perventricular device closure of a doubly committed sub-arterial ventricular septal defect (dcVSD) through a left infra-axillary approach. METHOD: Forty-five patients, with a dcVSD of less than 8 mm in diameter, were enrolled in this study. The pericardium was exposed and opened through a left infra-axillary mini-incision. Two parallel purse-string sutures were placed on the right ventricle outflow tract and under transesophageal echocardiography guidance, a delivery sheath loaded with the device was inserted into the right ventricle and advanced through the defect into the left ventricle. The device, connected to a delivery cable, was then deployed. RESULTS: Forty-one patients achieved successful device closure. In four patients, the device failed to occlude the VSD due to device dislodgement, device-related aortic regurgitation, and residual shunts, and open surgical repair was required. The mean dcVSD diameter was 4.5 ± 1.0 mm (range, 3.0-8.0 mm). The implanted device size was 6.0 ± 1.5 mm (range, 4-10 mm). All patients were implanted with an eccentric device. The mean intracardiac manipulation time was 20.9 ± 7.1 min (range, 9-45 min). The procedure time was 62.5 ± 19.5 min (range 34-105 min). There were no severe adverse events. CONCLUSIONS: Perventricular device closure of a dcVSD through a left infra-axillary approach is feasible, safe, and efficacious in selected patients with dcVSD.

Transjugular closure of secundum atrial septal defects.

OBJECTIVE: This study reports the results of a steerable delivery system under the guidance of transesophageal echocardiography (TEE) for the treatment of transjugular closure of secundum atrial septal defects (ASD). METHODS: From July 2015 to May 2016, 33 patients underwent transjugular closure of a secundum ASD under general anesthesia with TEE guidance. The right internal jugular vein was punctured and a FuStar™ steerable sheath was implanted into the right atrium and aligned vertically with the septum, and a closure device was deployed to close the defect. RESULTS: Thirty-two patients with an ASD were successfully occluded; one patient required ASD closure on cardiopulmonary bypass. Procedure time ranged from 5 to 15 (8.2 ± 3.8) min. The length of stay was three to five days after the operation. The follow-up time ranged from 1.1 to 11.0 (5.5 ± 1.5) months. There was no valve regurgitation, no malignant arrhythmias, no device dislocation, or other serious complications. CONCLUSIONS: A steerable delivery system under the guidance of TEE is a safe, effective, and cosmetic method for the transjugular closure of secundum ASDs.

[Study on the effect of artificial cartilage with different elastic modulus on the mechanical environment of the chondrocyte in defect cartilage repaired area].

A solid-liquid two-phase finite element model of articular cartilage and a microscopic finite element model of chondrocytes were established using the finite element software COMSOL in this study. The purpose of the study is to investigate the mechanics environment and the liquid flow field of the host cartilage chondrocytes in each layer by multi-scale method, under physiological load, with the different elastic modulus of artificial cartilage to repair cartilage defect. The simulation results showed that the uniform elastic modulus of artificial cartilage had different influences on the microenvironment of different layer chondrocytes. With the increase of the elastic modulus of artificial cartilage, the stress of the shallow surface layer and the intermediate layer chondrocytes increased and the stress of deep layer chondrocytes decreased. The flow field direction of the middle layer and the bottom layer of cartilage can also be changed by artificial cartilage implantation, as well as the ways of nourishment supply of the middle layer and underlying chondrocytes change.A barrier to underlying chondrocytes nutrition supply may be caused by this, thus resulting in the uncertainty of the repair results. With cross-scale finite element model simulation analysis of chondrocytes, we can quantitatively evaluate the mechanical environment of chondrocytes in each layer of the host cartilage. It is helpful to assess the clinical effect of cartilage defect reparation more accurately.

Peratrial device closure of perimembranous ventricular septal defects via a small right subaxillary incision: Midterm results in patients <12 months of age.

BACKGROUND: Both percutaneous and perventricular device closures of perimembranous ventricular septal defects (Pm-VSDs) are alternatives to surgical procedures，but they all present certain drawbacks. OBJECTIVE: To report our clinical experiences and midterm follow-up results of minimally invasive peratrial device closure of Pm-VSDs under the guidance of transesophageal echocardiography(TEE) in patients <12 months of age. METHODS: Between January 2015 and December 2020，268 patients <12 months of age with Pm-VSDs underwent peratrial device closure in our institute. The procedure was performed under TEE guidance via a small right subaxillary incision. The delivery pathways is established by manipulating the hollow probe, and then the device is installed. RESULTS: A total of 263 cases (98.1%) underwent successful closure, whereas five cases failed and were converted to cardiopulmonary bypass operation via the original incision during the procedure. The mean age was 9.5 ± 2.0 months and the mean body weight was 8.8 ± 1.4 kg. The mean diameter of the VSD was 4.4 ± 0.5 mm. One patient (0.4%) underwent a second thoracotomy for postoperative intercostal hemorrhage on the second day after surgery. The mean diameter of the occluder size was 5.5 ± 0.6 mm. During the follow-up (4.3 ± 1.4 y), there was no mortality, no new aortic valve regurgitation and atrioventricular block. CONCLUSION: Peratrial device closure of Pm-VSDs via the right subaxillary route under TEE guidance is safe and effective at midterm follow-up, confirming this is an valuable alternative method for patients <12 months of age.

In vitro bench testing using patient-specific 3D models for percutaneous pulmonary valve implantation with Venus P-valve.

BACKGROUND: Due to the wide variety of morphology, size, and dynamics, selecting an optimal valve size and location poses great difficulty in percutaneous pulmonary valve implantation (PPVI). This study aimed to report our experience with in vitro bench testing using patient-specific three-dimensional (3D)-printed models for planning PPVI with the Venus P-valve. METHODS: Patient-specific 3D soft models were generated using PolyJet printing with a compliant synthetic material in 15 patients scheduled to undergo PPVI between July 2018 and July 2020 in Central China Fuwai Hospital of Zhengzhou University. RESULTS: 3D model bench testing altered treatment strategy in all patients (100%). One patient was referred for surgery because testing revealed that even the largest Venus P-valve would not anchor properly. In the remaining 14 patients, valve size and/or implantation location was altered to avoid valve migration and/or compression coronary artery. In four patients, it was decided to change the point anchoring because of inverted cone-shaped right ventricular outflow tract (RVOT) (n = 2) or risk of compression coronary artery (n = 2). Concerning sizing, we found that an oversize of 2-5 mm suffices. Anchoring of the valve was dictated by the flaring of the in- and outflow portion in the pulmonary artery. PPVI was successful in all 14 patients (absence of valve migration, no coronary compression, and none-to-mild residual pulmonary regurgitation [PR]). The diameter of the Venus P-valve in the 3D simulation group was significantly smaller than that of the conventional planning group (36 [2] vs. 32 [4], Z = -3.77, P <0.001). CONCLUSIONS: In vitro testing indicated no need to oversize the Venus P-valve to the degree recommended by the balloon-sizing technique, as 2-5 mm sufficed.

Favorable mid-term performance of fully biodegradable implantable device for ventricular septal defect closure.

Objectives: To assess the mid-term safety and efficacy of transthoracic perimembranous ventricular septal defect (Pm-VSD) closure using a new biodegradable device. Implantation entailed right subaxillary minithoracotomy under transesophageal echocardiography guidance. Methods: Between October 2019 and January 2020, 13 patients (males, 5; mean age, 3.6 ± 2.5 years) with Pm-VSDs underwent transthoracic device closures at Zhengzhou University Central China Fuwai Hospital as described previously. Delivery pathways were established by manipulating a hollow probe from right atrium through tricuspid valve to right ventricle and then through VSDs to left ventricle, whereupon installation took place. Results: All occluder implantations were successfully executed. Mean defect size was 4.1 ± 1.0 mm, and mean device waist size was 5.2 ± 1.1 mm. One patient (7.7%) with 1.5-mm residual shunt showed complete closure at discharge. There was 1 instance of postoperative incomplete right bundle branch block, which converted to complete right bundle branch block at month 1. During patient follow-up (mean, 24.6 ± 0.8 months), no device dislocations, new residual shunts, new valvular regurgitation, or detectable atrioventricular block ensued. Conclusions: Closure of Pm-VSDs using a novel, fully biodegradable occluder in the manner described has proven safe and effective at mid-term follow-up. Long-term safety and efficacy of this device must be further corroborated in a large patient cohort going forward.

First hybrid implantations of novel Salus-Valves in patients with severe pulmonary regurgitation: A case series.

With the increasing age of patients after right ventricular outflow tract (RVOT) reconstruction, progressive pulmonary valve (PV) dysfunction can result in different degrees of right heart insufficiency, and PV replacement is frequently needed during follow-up. The traditional redo thoracotomy is difficult and associated with higher risks when compared to transcatheter implantations. Herein, we report the advantages and describe the outcomes of the first hybrid implantations of the novel Salus-Valves (Balance Medical, Beijing, China) from the sub-xiphoid approach in five patients (mean age of 22.6 years) with severe pulmonary regurgitation (PR) after RVOT reconstruction.

Metabolic Variation Dictates Cardiac Pathogenesis in Patients With Tetralogy of Fallot.

BACKGROUND: Herein, we aimed to analyze cardiac metabolic reprogramming in patients with tetralogy of Fallot (ToF). METHODS: Cardiac metabolic reprogramming was analyzed through comprehensive bioinformatics analysis, which included gene set enrichment, gene set variation, and consensus clustering analyses, so as to assess changes in metabolic pathways. In addition, full-spectrum metabolomics analysis was performed using right atrial biopsy samples obtained from patients with ToF and atrial septal defect (ASD) before cardiopulmonary bypass; ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to construct a metabolic map of cardiac metabolic reprogramming in cyanotic congenital heart disease. RESULTS: The metabolic maps of carbohydrate metabolic process and heme metabolism were significantly activated, while bile acid metabolism, lipid droplet, and lipid binding were primarily restrained in ToF samples as compared with that in ASD samples. The reprogramming of butanoate metabolism was identified basing on the UPLC-MS/MS detection and analysis in myocardial hypoxia damage in cyanotic heart disease. Finally, the butanoate metabolism-related hub regulators ALDH5A1 and EHHADH were identified and they were significantly downregulated in ToF samples. CONCLUSIONS: The metabolic network of butanoate metabolism involved ALDH5A1 and EHHADH, which could contribute to myocardial tissue damage in cyanotic congenital heart of ToF. Our results provide further insights into the mechanisms underlying metabolic reprogramming in cyanotic congenital heart disease and could lead to the identification of potential therapeutic targets.

Minimally Invasive Peratrial Device Closure of Perimembranous Ventricular Septal Defect Through a Right Infraaxillary Route: Clinical Experience and Preliminary Results.

BACKGROUND: Both percutaneous and perventricular device closures of perimembranous ventricular septal defects (PmVSD) present certain drawbacks. We report our experiences with a new, minimally invasive surgery using a peratrial device closure of PmVSD through a right infraaxillary route. METHODS: Between January 2014 and October 2015, 145 patients (71 male, 74 female) with PmVSD, aged 0.5 to 9.7 years (mean 2.8 ± 2.2) and weighing between 6.1 kg and 43 kg (mean 14.0 ± 6.6 kg) were included in this study. In patients with left lateral position, a 2- to 3-cm incision was made along the right midaxillary line. The thoracic cavity was entered through the fourth intercostal space. With the help of transesophageal echocardiography guidance, a specially designed hollow probe was inserted into the right atrium. The probe was passed through the tricuspid valve into the right ventricle. The tip of the probe was adjusted to point to or cross the defect. A flexible guidewire was inserted into the left ventricle through the channel of the probe to establish a delivery pathway. Then, the device was deployed to close the defect. RESULTS: A total of 142 cases (97.9%) were successfully occluded, whereas 3 cases failed and were converted to cardiopulmonary bypass operation through the original incision. The device size ranged from 4.0 to 10.0 mm (mean 5.1 ± 1.4 mm), and all devices were concentric. Follow-up in all patients ranged from 1.0 to 22.8 months (mean 9.9 ± 5.6) and revealed no evident valve regurgitation, no complete atrioventricular block, and no device dislocation. CONCLUSIONS: This new minimally invasive technique of peratrial device closure through a right infraaxillary route under transesophageal echocardiography guidance was shown to be a safe, effective, feasible, and cosmetically superior treatment for PmVSD.