Bioinspired nanogels as cell-free DNA trapping and scavenging organelles for rheumatoid arthritis treatment.

Excessive cell-free DNA (cfDNA) in the serum and synovium is considered a causative factor of rheumatoid arthritis (RA). Thus, cfDNA scavenging by using cationic polymers has been an effective therapeutic avenue, while these stratagems still suffer from systemic toxicity and unstable capture of cfDNA. Here, inspired by the biological charge-trapping effects and active degradation function of enzyme-containing organelles in vivo, we proposed a cationic peptide dendrimer nanogel with deoxyribonuclease I (DNase I) conjugation for the treatment of RA. Benefitting from their naturally derived peptide components, the resultant nanogels were highly biocompatible. More attractively, by tailoring them with a larger size and higher surface charge density, these cationic nanogels could achieve the fastest targeting capability, highest accumulation amounts, longer persistence time, and superior DNA scavenging capacity in inflamed joints. Based on these features, we have demonstrated that the organelle mimicking cationic nanogels could significantly down-regulate toll-like receptor (TLR)-9 signaling pathways and attenuate RA symptoms in collagen-induced arthritis mice. These results make the bioinspired DNase I conjugated cationic nanogels an ideal candidate for treating RA and other immune dysregulation diseases.

USP38 exacerbates pressure overload-induced left ventricular electrical remodeling.

BACKGROUND: Ubiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes. Ventricular arrhythmias (VAs) following heart failure (HF) are closely linked to ventricular electrical remodeling, yet the specific mechanisms underlying VAs in HF remain inadequately explored. In this study, we examined the impact of USP38 on VAs in pressure overload-induced HF. METHODS: Cardiac-specific USP38 knockout mice, cardiac-specific USP38 transgenic mice and their matched control littermates developed HF induced by aortic banding (AB) surgery. After subjecting the mice to AB surgery for a duration of four weeks, comprehensive investigations were conducted, including pathological analysis and electrophysiological assessments, along with molecular analyses. RESULTS: We observed increased USP38 expression in the left ventricle of mice with HF. Electrocardiogram showed that the USP38 knockout shortened the QRS interval and QTc, while USP38 overexpression prolonged these parameters. USP38 knockout decreased the susceptibility of VAs by shortening action potential duration (APD) and prolonging effective refractory period (ERP). In addition, USP38 knockout increased ion channel and Cx43 expression in ventricle. On the contrary, the increased susceptibility of VAs and the decreased expression of ventricular ion channels and Cx43 were observed with USP38 overexpression. In both in vivo and in vitro experiments, USP38 knockout inhibited TBK1/AKT/CAMKII signaling, whereas USP38 overexpression activated this pathway. CONCLUSION: Our data indicates that USP38 increases susceptibility to VAs after HF through TBK1/AKT/CAMKII signaling pathway, Consequently, USP38 may emerge as a promising therapeutic target for managing VAs following HF.

Retracted: MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-κB) Signaling Pathway.

This publication has been retracted by the Editor due to the identification of non-original figure images and manuscript content that raise concerns regarding the credibility and originality of the study and the manuscript. Reference: Ying-Jun Zhang, He Huang, Yu Liu, Bin Kong, Guangji Wang. MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-kappaB) Signaling Pathway. Med Sci Monit, 2019; 25: 7898-7907. DOI: 10.12659/MSM.919861.

USP38 regulates inflammatory cardiac remodeling after myocardial infarction.

BACKGROUND: The inflammatory response and subsequent ventricular remodeling are key factors contributing to ventricular arrhythmias (VAs) after myocardial infarction (MI). Ubiquitin-specific protease 38 (USP38) is a member of the USP family, but the impact of USP38 in arrhythmia substrate generation after MI remains unclear. This study aimed to determine the role of USP38 in post-MI VAs and its underlying mechanisms. METHODS AND RESULTS: Surgical left descending coronary artery ligation was used to construct MI models. Morphological, biochemical, histological, and electrophysiological studies and molecular analyses were performed after MI on days 3 and 28. We found that the USP38 expression was remarkably increased after MI. Cardiac-conditional USP38 knockout (USP38-CKO) reduces the expression of the inflammatory marker CD68 as well as the inflammatory factors TNF-α and IL-1ß after MI, thereby alleviating advanced cardiac fibrosis, electrical remodeling, ion channel remodeling, and susceptibility to VAs. In contrast, cardiac-specific USP38 overexpression (USP38-TG) showed a significant opposite effect, exacerbating the early inflammatory response and cardiac remodeling after MI. Mechanistically, USP38 knockout inhibited activation of the TAK1/NF-κB signaling pathway after MI, whereas USP38 overexpression enhanced activation of the TAK1/NF-κB signaling pathway after MI. CONCLUSIONS: Our study confirms that USP38-CKO attenuates the inflammatory response, improves ventricular remodeling after myocardial infarction, and reduces susceptibility to malignant VA by inhibiting the activation of the TAK1/NF-κB pathway, with USP38-TG playing an opposing role. These results suggest that USP38 may be an important target for the treatment of cardiac remodeling and arrhythmias after MI.

Ubiquitin-specific protease 38 promotes inflammatory atrial fibrillation induced by pressure overload.

AIMS: Atrial structural and electrical remodelling is a major reason for the initiation and perpetuation of atrial fibrillation (AF). Ubiquitin-specific protease 38 (USP38) is a deubiquitinating enzyme, but its function in the heart remains unknown. The aim of this study was to investigate the effect of USP38 in pressure overload-induced AF. METHODS AND RESULTS: Cardiac-specific knockout USP38 and cardiac-specific transgenic USP38 mice and their corresponding control mice were used in this study. After 4 weeks with or without aortic banding (AB) surgery, atrial echocardiography, atrial histology, electrophysiological study, and molecular analysis were assessed. Ubiquitin-specific protease 38 knockout mice showed a remarkable improvement in vulnerability to AF, atrial weight and diameter, atrial fibrosis, and calcium-handling protein expression after AB surgery. Conversely, USP38 overexpression further increased susceptibility to AF by exacerbating atrial structural and electrical remodelling. Mechanistically, USP38 interacted with and deubiquitinated nuclear factor-kappa B (NF-κB), and USP38 overexpression increased the level of p-NF-κB in vivo and in vitro, accompanied by the upregulation of NOD-like receptor protein 3 (NLRP3) and inflammatory cytokines, suggesting that USP38 contributes to adverse effects by driving NF-κB/NLRP3-mediated inflammatory responses. CONCLUSION: Overall, our study indicates that USP38 promotes pressure overload-induced AF through targeting NF-κB/NLRP3-mediated inflammatory responses.

PCL scaffold combined with rat tail collagen type I to reduce keratocyte differentiation and prevent corneal stroma fibrosis after injury.

The cornea is one of the major refractive eye components and could be easily injured. An ineffective healing of corneal stromal wound may cause fibrosis and even loss of vision. Therefore, it is pivotal to prevent corneal fibrosis after injury. In this study, a poly (ε-caprolactone) (PCL) microfibrous scaffold infused with rat tail collagen type I was fabricated to obtain a 3D composite material. Physical and biological properties of PCL/collagen scaffold were evaluated, the effect of PCL/collagen scaffold on the proliferation and differentiation of limbal stromal stem cells (LSSCs) were detected in vitro, the differentiation of keratocytes as well as the expression and arrangement of extracellular matrix (ECM) influenced by PCL/collagen scaffold were investigated in vivo. RNA-sequencing on normal and injured corneas was carried out to find out the differential enriched pathways and gene expression. We discovered that the PCL/collagen scaffold simulated the stromal structure with properties that were most similar to the native cornea, the PCL/collagen scaffold exhibited good mechanical and biological properties. We also observed that the PCL/collagen scaffold reduced keratocyte differentiation. Injured corneas treated with PCL/collagen scaffold exhibited more regular collagen distribution and less fibroblasts and myofibroblasts distribution. By RNA-sequencing, we observed that in injured group, ECM-related pathway was enriched and several ECM-related genes were up-regulated. This study provides evidence that application of PCL/collagen scaffold could be a new therapeutic strategy for corneal injury.

BMSC exosome-enriched acellular fish scale scaffolds promote bone regeneration.

Tissue engineering scaffolds are essential for repairing bone defects. The use of biomimetic scaffolds for bone tissue engineering has been investigated for decades. To date, the trend in this area has been moved toward the construction of biomimetic acellular scaffolds with effective modification to enhance the osteogenic differentiation efficiency of bone marrow mesenchymal stem cells (BMSCs). The exosomes derived from BMSCs have been shown as a potential therapeutic tool for repairing bone defects. In this study, we demonstrated the pro-osteogenic effects of exosomes derived form osteogenic differentiated BMSCs (OBMSC) and presented a novel exosmes-functionalized decellularized fish scale (DE-FS) scaffold for promoting bone regeneration in vivo. The DE-FS scaffolds were obtained through decellularization and decalcification processes, which exhibited high biocompatibility and low immunological rejection. The intrinsic anisotropic structures of DE-FS could enhance the adhesion and proliferation ability of BMSCs in vitro. In addition, we demonstrated that the porous structure of DE-FS endowed them with the capacity to load and release exosomes to BMSCs, resulting in the enhanced osteogenic differentiation of BMSCs. Concerning these pro-osteogenic effects, it was further proved that OBMSC exosome-modified DE-FS scaffolds could effectively promote bone regeneration in the mouse calvarial defect models. In conclusion, our work provided a new insight to design exosome-riched biomimetic scaffolds for bone tissue engineering and clinical applications.

PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin-II by reducing TGF-ß1/Smads pathway activation.

Fibrosis serves a critical role in driving atrial remodelling-mediated atrial fibrillation (AF). Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang-II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up-regulated in the Ang-II-induced group compared with the sham/control group in vivo and in vitro. Moreover, protein expression along the TGF-ß1/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang-II were significantly higher in the Ang-II-induced group than in the sham/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF-ß1/Smads signalling pathway) diminished these Ang-II-mediated effects, and the si-Smad3-mediated effects were, in turn, antagonized by the addition of a PU.1-overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang-II and attenuated vulnerability to AF, at least in part through the TGF-ß1/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang-II-induced atrial fibrosis and vulnerability to AF.

Incidence, risk factors, and clinical impact of peridevice leak following left atrial appendage closure with the LAmbre device-Data from a prospective multicenter clinical study.

BACKGROUND: In the present study, we sought to explore the incidence, risk factors, and clinical impact of peridevice leaks (PDLs), following LAmbre-assisted left atrial appendage closure (LAAC). METHODS: We performed transesophageal echocardiography (TEE) on patients participating in the LAmbre multicenter study, at Day 1 postimplantation, then at 3 and 12 months to assess PDL, device-related thrombus, left atrial appendage (LAA) thrombus, and left atrial thrombus. Clinical events were recorded during follow-up. RESULT: A total of 152 patients with atrial fibrillation successfully completed LAAC. At 3 months follow-up, 123 patients underwent TEE, with 21 (17%) of them presenting PDL. Among the 121 patients who underwent TEE at 12 months follow-up, 19 (15.7%) presented PDL. Patients with PDL exhibited larger LAA orifice diameters and larger device sizes compared to those in the no leak group. In addition, we found no significant differences in thromboembolic events between patients in the PDL and no leak groups. CONCLUSION: LAmbre-assisted LAA closure resulted in a relatively low PDL occurrence, and its rate decreased over time. In addition, PDL was more prominent in patients with larger LAA orifice diameter and larger device size. However, the condition was not associated with an increased risk for thromboembolic events.

Cold-inducible RNA-binding protein (CIRP) in inflammatory diseases: Molecular insights of its associated signalling pathways.

Cold-inducible RNA-binding protein (CIRP) was previously identified as an intracellular stress-response protein, which can respond to a variety of stress conditions by changing its expression and regulating mRNA stability through its binding site on the 3'-UTR of its targeted mRNAs. Recently, extracellular CIRP (eCIRP) was discovered to be present in various inflammatory conditions and could act as a pro-inflammatory factor. Genetic studies have demonstrated a key role for eCIRP in inflammatory conditions that led to the importance of targeting eCIRP in these diseases. Currently, the underlying mechanism of eCIRP-induced inflammation is under intensive investigation and several signalling pathways are being explored. Here, we epitomized various signalling pathways that mediate the pro-inflammatory effects of CIRP and also recapitulated all the CIRP-derived peptides that can block the interaction between CIRP and its receptors in inflammatory setting.

LH upregulates connexin 43 expression in granulosa cells by activating the Wnt/ß-catenin signalling pathway.

Connexin (Cx) 43 is the most widely expressed gap junction protein in follicle granulosa cells and plays an important role in follicle development and growth. The aims of this study were to investigate the effects of LH on the expression of Cx43 and key proteins in the downstream Wnt-ß/catenin signalling pathway and to explore the mechanism underlying the regulation of Cx43 expression in granulosa cells. Primary culture granulosa cells were obtained from 21-day-old Sprague-Dawley rats, and were treated with different concentrations of LH (150, 300 and 600 IU L-1). Cx43 expression in granulosa cells was detected using immunofluorescence. Western blotting was used to detect the expression of Cx43, ß-catenin and Axin2 proteins (Axin2 is a protein that in humans is encoded by the AXIN2 gene, which presumably plays an important role in the regulation of the stability of ß-catenin in the Wnt signaling pathway) in granulosa cells with and without FH535 treatment (a Wnt/ß-catenin signalling pathway inhibitor). Cx43 expression was detected in the cytoplasm and cell membrane of granulosa cells. Treatment with a high concentration of LH (300 IU L-1) increased the expression of ß-catenin and Axin2, as well as that of Cx43. FH535 treatment reduced the LH-induced increases in Cx43, ß-catenin and Axin2. These results indicate that LH upregulates Cx43 expression in granular cells by activating the Wnt/ß-catenin signalling pathway.

MD1 Depletion Predisposes to Ventricular Arrhythmias in the Setting of Myocardial Infarction.

BACKGROUND: Myeloid differentiation protein 1 (MD1) is expressed in the human heart and is a negative regulator of Toll-like receptor 4 (TLR4) signalling. MD1 exerts anti-arrhythmic effects. AIM: The aim of this study was to determine the role of MD1 in myocardial infarction (MI)-related ventricular arrhythmias (VAs). METHOD: Myocardial infarction was induced by surgical ligation of the left anterior coronary artery in MD1 knockout (KO) mice and their wild-type littermates. Myocardial infarction-induced vulnerability to VAs and its underlying mechanisms were evaluated. RESULTS: Myeloid differentiation protein 1 was downregulated in the MI mice. Myeloid differentiation protein 1 deficiency decreased post-MI left ventricular (LV) function and increased the infarct size. The MI mice exhibited prolonged action potential duration (APD), enhanced APD alternans thresholds, and a higher incidence of VAs. Myocardial infarction-induced LV fibrosis and inflammation decreased the expression levels of Kv4.2, Kv4.3, Kv1.5, and Kv2.1, increased Cav1.2 expression, and disturbed Ca2+ handling protein expression. These MI-induced adverse effects were further exacerbated in KO mice. Mechanistically, MD1 deletion markedly enhanced the activation of the TLR4/calmodulin-dependent protein kinase II (CaMKII) signalling pathway in post-MI mice. CONCLUSIONS: Myeloid differentiation protein 1 deletion increases the vulnerability to VAs in post-MI mice. This is mainly caused by the aggravated maladaptive LV fibrosis and inflammation and interference with the expressions of ion channels and Ca2+ handling proteins, which is related to enhanced activation of the TLR4/CaMKII signalling pathway.

MD1 deletion exaggerates cardiomyocyte autophagy induced by heart failure with preserved ejection fraction through ROS/MAPK signalling pathway.

In our previous studies, we reported that myeloid differentiation protein 1 (MD1) serves as a negative regulator in several cardiovascular diseases. However, the role of MD1 in heart failure with preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain unclear. Eight-week-old MD1-knockout (MD1-KO) and wild-type (WT) mice served as models of HFpEF induced by uninephrectomy, continuous saline or d-aldosterone infusion and a 1.0% sodium chloride treatment in drinking water for 4 weeks to investigate the effect of MD1 on HFpEF in vivo. H9C2 cells were treated with aldosterone to evaluate the role of MD1 KO in vitro. MD1 expression was down-regulated in the HFpEF mice; HFpEF significantly increased the levels of intracellular reactive oxygen species (ROS) and promoted autophagy; and in the MD1-KO mice, the HFpEF-induced intracellular ROS and autophagy effects were significantly exacerbated. Moreover, MD1 loss activated the p38-MAPK pathway both in vivo and in vitro. Aldosterone-mediated cardiomyocyte autophagy was significantly inhibited in cells pre-treated with the ROS scavenger N-acetylcysteine (NAC) or p38 inhibitor SB203580. Furthermore, inhibition with the autophagy inhibitor 3-methyladenine (3-MA) offset the aggravating effect of aldosterone-induced autophagy in the MD1-KO mice and cells both in vivo and in vitro. Our results validate a critical role of MD1 in the pathogenesis of HFpEF. MD1 deletion exaggerates cardiomyocyte autophagy in HFpEF via the activation of the ROS-mediated MAPK signalling pathway.

BMP8A promotes survival and drug resistance via Nrf2/TRIM24 signaling pathway in clear cell renal cell carcinoma.

There is increasing evidence that bone morphogenetic proteins (BMP) are involved in the proliferation and drug tolerance of kidney cancer. However, the molecular mechanism of BMP8A in renal cell proliferation and drug tolerance is not clear. Here we showed that BMP8A was highly expressed in renal cell carcinoma, which suggests a poor prognosis of ccRCC. Promotion of cell proliferation and inhibition of apoptosis were detected by CCK-8 assay, Trypan Blue staining, flow cytometry and bioluminescence. BMP8A promoted resistance of As2 O3 by regulating Nrf2 and Wnt pathways in vitro and in vivo. Mechanistically, BMP8A enhanced phosphorylation of Nrf2, which, in turn, inhibited Keap1-mediated Nrf2 ubiquitination and, ultimately, promoted nuclear translocation and transcriptional activity of Nrf2. Nrf2 regulates the transcription of TRIM24 detected by ChIP-qPCR. BMP8A was highly expressed in ccRCC, which suggests a poor prognosis. BMP8A was expected to be an independent prognostic molecule for ccRCC. On the one hand, activated Nrf2 regulated reactive oxygen balance, and on the other hand, by regulating the transcription level of TRIM24, it was involved in the regulation of the Wnt pathway to promote the proliferation, invasion and metastasis of ccRCC and the resistance of As2 O3 . Taken together, our findings describe a regulatory axis where BMP8A promotes Nrf2 phosphorylation and activates TRIM24 to promote survival and drug resistance in ccRCC.

Using Artificial Intelligence to Detect COVID-19 and Community-acquired Pneumonia Based on Pulmonary CT: Evaluation of the Diagnostic Accuracy.

Background Coronavirus disease 2019 (COVID-19) has widely spread all over the world since the beginning of 2020. It is desirable to develop automatic and accurate detection of COVID-19 using chest CT. Purpose To develop a fully automatic framework to detect COVID-19 using chest CT and evaluate its performance. Materials and Methods In this retrospective and multicenter study, a deep learning model, the COVID-19 detection neural network (COVNet), was developed to extract visual features from volumetric chest CT scans for the detection of COVID-19. CT scans of community-acquired pneumonia (CAP) and other non-pneumonia abnormalities were included to test the robustness of the model. The datasets were collected from six hospitals between August 2016 and February 2020. Diagnostic performance was assessed with the area under the receiver operating characteristic curve, sensitivity, and specificity. Results The collected dataset consisted of 4352 chest CT scans from 3322 patients. The average patient age (±standard deviation) was 49 years ± 15, and there were slightly more men than women (1838 vs 1484, respectively; P = .29). The per-scan sensitivity and specificity for detecting COVID-19 in the independent test set was 90% (95% confidence interval [CI]: 83%, 94%; 114 of 127 scans) and 96% (95% CI: 93%, 98%; 294 of 307 scans), respectively, with an area under the receiver operating characteristic curve of 0.96 (P < .001). The per-scan sensitivity and specificity for detecting CAP in the independent test set was 87% (152 of 175 scans) and 92% (239 of 259 scans), respectively, with an area under the receiver operating characteristic curve of 0.95 (95% CI: 0.93, 0.97). Conclusion A deep learning model can accurately detect coronavirus 2019 and differentiate it from community-acquired pneumonia and other lung conditions. © RSNA, 2020 Online supplemental material is available for this article.

Percutaneous retrieval of a dislocated LAmbre left atrial appendage occluder in a canine model.

BACKGROUND: Dislocated left atrial appendage (LAA) occluders can be retrieved by percutaneous intervention when performing device embolization into the left atrium (LA), aorta (AO), or left ventricle (LV). However, few reports exist regarding LAmbre LAA occluder dislocation. OBJECTIVE: The study was aimed to explore the outcome of retrieving dislocated LAmbre LAA occluder. METHODS: Sixteen healthy dogs received LAmbre implants. After implantation of an occlusion device (not released), the occlusion device was completely retrieved. Subsequently, the device was released in the LA, resulting in the dislocation of the device. Angiography and transesophageal echocardiography (TEE) were performed to check the occluders position. Disposable grasping rat-tooth forceps were used to percutaneously retrieve the LAA occluder. RESULTS: All the 16 dogs were successfully implanted with the LAmbre LAA occluder and the success rate was 100%. After the occluder was released, TEE and angiography confirmed that the device was located in the LA in eight cases (50%), in the AO in five cases (31%), and in the LV in three cases (19%). One subject died due to cardiogenic shock before the retrieval procedure was complete as the device fell into the LV. Two cases of device-related aortic valve injury occurred during the retrieval procedure when the device was located in the LV. No complications were observed when the device was located in the LA or AO. CONCLUSIONS: Device retrieval is feasible in most cases. However, potentially lethal complications may occur once the device is dislocated into the LV/AO.

Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation.

NEW FINDINGS: What is the central question of this study? In this study, we investigated whether MD1 interacted with the sympathetic nerves in ventricular arrhythmia (VA) during heart failure with preserved ejection fraction (HFpEF). What is the main finding and its importance? Mice with HFpEF showed increased susceptibility to VA, adverse electrical remodelling, impaired heart rate variability, enhanced sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin-1ß release. These changes induced by HFpEF were exacerbated by MD1 deficiency. ABSTRACT: Sympathetic hyperactivity can promote malignant ventricular arrhythmia (VA), and myeloid differentiation 1 (MD1) has been reported to play an important role in obesity-induced VA. However, it is not known whether an interaction of MD1 with sympathetic hyperactivity contributes to the VA induced by heart failure with preserved ejection fraction (HFpEF). The aim of this study was to investigate the potential interaction between MD1 and sympathetic hyperactivity in HFpEF-induced VA and the underlying mechanism. Eight-week-old MD1-knockout (MD1-KO) and wild-type (WT) mice were subjected to a model of HFpEF induced by uninephrectomy, a continuous saline or d-aldosterone infusion and provision of drinking water containing 1.0% sodium chloride for 4 weeks. Echocardiography and haemodynamics were used to verify the model of HFpEF. An isolated electrophysiological study was performed to assess the susceptibility to VA. Four weeks later, the mice with HFpEF showed an increased heart weight to tibia length ratio, decreased left ventricular minimum rates of pressure rise (dP/dtmin ), increased τ, lung weight to tibia length ratio and preserved left ventricular ejection fraction compared with WT mice. The mice with HFpEF exhibited increased susceptibility to VA, as shown by the shortened effective refractory period, prolonged action potential duration (APD), increased APD alternans threshold and higher incidence of VA. Moreover, we also found that mice with HFpEF showed impaired heart rate variability, sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin-1ß release. These changes induced by HFpEF were exacerbated by MD1 deficiency. We conclude that MD1-KO contributes to sympathetic hyperactivity and facilitates VA in HFpEF via activation of the NLRP3 inflammasome. Treatment targeting MD1 and NLRP3 might decrease the risk of HFpEF-induced VA.

Long-Term Safety and Efficacy of Percutaneous Left Atrial Appendage Closure with the LAmbre Device.

BACKGROUND: Left atrial appendage closure (LAAC) using the LAmbre device has been associated with prevention of stroke in patients with nonvalvular atrial fibrillation (AF). Here, we interrogated the long-term safety and efficacy of using the LAmbre device in percutaneous LAAC. METHODS: We analyzed 56 records of patients with nonvalvular AF undergoing LAAC procedures with the LAmbre device. We collected and analyzed the data to define the safety and efficacy of the LAmbre device implantation. RESULT: The LAAC was successfully occluded in the 56 patients. Our data showed no serious residual leak or pericardial effusion occurred during the perioperative period. At a mean follow-up of 37.8 ± 23.5 months, there were 7.1%, 3.6%, and 3.6% rates of death, stroke, and device-related thrombus, respectively. There were no cases of severe residual leak or systemic embolism. CONCLUSION: Taken together, we demonstrate that execution of LAAC with the LAmbre device has high procedural success and prevents AF-related stroke. However, further large-scale trials might be required to confirm our findings.

Myeloid differentiation protein 1 protected myocardial function against high-fat stimulation induced pathological remodelling.

Myeloid differentiation 1 (MD-1) is a secreted protein that regulates the immune response of B cell through interacting with radioprotective 105 (RP105). Disrupted immune response may contribute to the development of cardiac diseases, while the roles of MD-1 remain elusive. Our studies aimed to explore the functions and molecular mechanisms of MD-1 in obesity-induced cardiomyopathy. H9C2 myocardial cells were treated with free fatty acid (FFA) containing palmitic acid and oleic acid to challenge high-fat stimulation and adenoviruses harbouring human MD-1 coding sequences or shRNA for MD-1 overexpression or knockdown in vitro. MD-1 overexpression or knockdown transgenic mice were generated to assess the effects of MD-1 on high-fat diet (HD) induced cardiomyopathy in vivo. Our results showed that MD-1 was down-regulated in H9C2 cells exposed to FFA stimulation for 48 hours and in obesity mice induced by HD for 20 weeks. Both in vivo and in vitro, silencing of MD-1 accelerated myocardial function injury induced by HD stimulation through increased cardiac hypertrophy and fibrosis, while overexpression of MD-1 alleviated the effects of HD by inhibiting the process of cardiac remodelling. Moreover, the MAPK and NF-κB pathways were overactivated in MD-1 deficient mice and H9C2 cells after high-fat treatment. Inhibition of MAPK and NF-κB pathways played a cardioprotective role against the adverse effects of MD-1 silencing on high-fat stimulation induced pathological remodelling. In conclusion, MD-1 protected myocardial function against high-fat stimulation induced cardiac pathological remodelling through negative regulation for MAPK/NF-κB signalling pathways, providing feasible strategies for obesity cardiomyopathy.