The Effect of Atrial Septal Defect in the Treatment of ARDS with Left Ventricular Dysfunction Simulating Severe COVID-19.

OBJECTIVE: To explore the effect of atrial septal defect (ASD) and venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the treatment of ARDS combined with left ventricular dysfunction (LVD) to find a new effective method for treating severe COVID-19 patients. MATERIALS AND METHODS: Five large animal ARDS models of sheep were established by intravenous injection of Lipopolysaccharide. ASD was made under general anesthesia and VA-ECMO was simulated by extracorporeal circulation machine. The oxygenation of peripheral blood, systemic circulation, and cardiac function were observed under conditions of closed and opened ASD, and the significance of ASD shunt in improving cardiopulmonary function was evaluated. RESULTS: With ASD closed, the atrial shunts disappeared, the peripheral artery pressure of oxygen(PaO2): 141.2±21.4mmHg, the oxygenation index (PaO2/FiO2): 353.0±53.5, the mean blood pressure (MAP): 49.3±13.5 mmHg, the heart was full; with ASD opened, the left-to-right shunt was observed, PaO2: 169.3±18.9mmHg, PaO2/FiO2: 423.3±47.3, MAP: 68.2±16.1 mmHg, the range of cardiac motion significantly increased, heart beat was powerful, and systemic circulation significantly improved. Statistical analysis showed that there were significant differences between opened and closed ASD (P < .01). CONCLUSION: ASD plus VA-ECMO is an effective method for the treatment of ARDS combined with LVD, which is the main cause of death in severe COVID-19 patients. However, further clinical validation is needed.

Long-chain noncoding RNA GAS5 mediates oxidative stress in cardiac microvascular endothelial cells injury.

This study is performed to figure out the role of long-chain noncoding RNA growth-arrest specific transcript 5 (GAS5) in homocysteine (HCY)-induced cardiac microvascular endothelial cells (CMECs) injury. CMECs were cultured and the model of CMECs injury was established by coincubation with HCY. To construct stable overexpression of GAS5 cells, the expression of GAS5, microRNA-33a-5p (miR-33a-5p) and ATP-binding cassette transporter A1 (ABCA1), and biological characteristics of cells were determined. The messenger RNA (mRNA) level and secretion of vascular endothelial growth factor (VEGF), activity of reactive oxygen species (ROS) and superoxide dismutase (SOD), and the content of malondialdehyde (MDA) were measured. The binding site between GAS5 and miR-33a-5p and between miR-33a-5p and ABCA1 was verified. CMECs were successfully cultured. Reduction of GAS5 expression and ABCA1 expression together with increased expression of miR-33a-5p was found in CMECs induced by HCY. After overexpression of GAS5, there showed increased proliferative activity, decreased cell apoptosis rate and apoptosis index, enhanced cell migration ability, increased number of lumen formation, increased mRNA expression of VEGF in cells and the secretion in the supernatant, decreased activity of ROS and SOD in cells, and decreased content of ROS in cells. miR-33a-5p could promote the enrichment of GAS5 and ABCA1 was the direct target gene of miR-33a-5p. Our study suggests that the low expression of GAS5 was observed in HCY-induced CMECs injury, and the upregulation of GAS5 could attenuate HCY-induced CMECs injury by mediating oxidative stress, and its mechanism is related to the upregulation of ABCA1 expression by competitively binding with miR-33a-5p.

Aortic Dissection Detection Risk Score and D-Dimer for Acute Aortic Syndromes in the Chinese Population: Exploration of Optimal Thresholds and Integrated Diagnostic Value.

This study aimed to assess the diagnostic performance of the aortic dissection detection risk score (ADD-RS) plus D-dimer for acute aortic syndrome (AAS) in Chinese patients. Two hundred and sixty-two and 200 patients with suspected AAS symptoms were enrolled as exploration cohort and validation cohort, respectively. In exploration cohort, ADD-RS plus D-dimer (AUC = 0.929, 95%CI: 0.887-0.971) presented a better diagnostic value for AAS than ADD-RS or D-dimer alone. Meanwhile, ADD-RS > 1 and D-dimer > 2000 ng/mL were the optimal thresholds. Then, a diagnostic model integrating ADD-RS > 1 plus D-dimer > 2000 ng/mL was established, presenting sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 92.5%, 70.3%, 34.9%, and 98.2%, respectively. In validation cohort, the established diagnostic model exhibited a sensitivity, specificity, PPV, and NPV of 93.1%, 70.2%, 34.6%, and 98.4%, respectively, for diagnosing AAS. Summarily, ADD-RS > 1 and D-dimer > 2000 ng/mL are optimal thresholds for diagnosing AAS in the Chinese population. However, confirmative MSCT results are necessary.

Meteorin-like protein elevation post-exercise improved vascular inflammation among coronary artery disease patients by downregulating NLRP3 inflammasome activity.

BACKGROUND: Coronary artery disease (CAD) has become the most common cause of death worldwide. However, the negative effects of CAD are able to be alleviated via exercises, possibly via increased production of meteorin-like protein (Metrnl). In this study, we aim to evaluate the connection between Metrnl production during exercise with lowered CAD risk and severity. METHODS: Two age and gender-matched groups of 60 human patients, one with CAD, and one without were randomly recruited. The CAD group were subjected to continuous training exercises. Mice were exercised by using a treadmill, establishing an animal exercise model. ELISA was used to measure plasma Metrnl and inflammatory factors. To determine the impact of Metrnl on glucose metabolism, oxygen consumption and extracellular acid rates were taken for untreated, palmitic acid (PA)-treated, and PA+Metrnl co-treated human umbilical vein endothelial cells. Western blot was used to measure expression levels for the NLR family pyrin domain containing 3 inflammasome. RESULTS: CAD patients had lower Metrnl levels compared to non-CAD controls. Furthermore, higher Metrnl levels post-exercise were inversely associated with LDL, inflammatory cytokines, and CAD severity, as well as being positively associated with HDL. Metrnl was able to counteract against PA-induced HUVEC glucose metabolic dysfunction via reducing ROS production, which in turn lowered NLRP3 inflammasome expression, thereby serving as the basis behind the inverse correlation between Metrnl and inflammatory cytokines. CONCLUSIONS: Exercise was able to increase Metrnl production from skeletal muscle among CAD patients, and subsequently improve patient atherosclerosis via counteracting against endothelial metabolic dysfunction and pro-inflammatory activities.

Transfer of lncRNA UCA1 by hUCMSCs-derived exosomes protects against hypoxia/reoxygenation injury through impairing miR-143-targeted degradation of Bcl-2.

Ischemia results in neuronal damage via alterations in gene transcription and protein expression. Long noncoding RNAs (LncRNAs) are pivotal in the regulation of target protein expression in hypoxia/reoxygenation (H/R). In this study, we observed the function of exosomes-carried lncRNA UCA1 in H/R-induced injury of cardiac microvascular endothelial cells (CMECs). In H/R cell model, CMECs were co-cultured with human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-ex). The loss-of-function experiments were conducted to assess the effect of lncRNA UCA1 on H/R injury by assessing the biological behaviors of CMECs. The relationship among lncRNA UCA1, miR-143 and Bcl-2 were verified. An ischemia-reperfusion (I/R) rat model was established. Then hUCMSC-ex was injected into I/R rats to identify its effects on apoptosis and autophagy. Functional rescue experiments were performed to verify the sponge system. In vitro and in vivo experiments showed that hUCMSC-ex protected I/R rats and H/R CMECs against injury. Silencing UCA1 in hUCMSC-ex or miR-143 overexpression aggravated H/R injury in CMECs. LncRNA UCA1 competitively bound to miR-143 to upregulate Bcl-2. And hUCMSCs-ex/si-UCA1+inhi-miR-143 treatment protected CMECs against H/R injury and inhibited hyperautophagy. Together, hUCMSC-ex-derived lncRNA UCA1 alleviates H/R injury through the miR-143/Bcl-2/Beclin-1 axis. Hence, this study highlights a stem cell-based approach against I/R injury.

Characterization of soluble N-ethylmaleimide-sensitive factor attachment protein receptor gene STX18 variations for possible roles in congenital heart diseases.

Congenital heart disease (CHD) is among the most prevalent and complex congenital anatomic malformations in newborns. Interactions of cardiac progenitor with a broad range of cellular regulatory factors play key roles in the formation of mammalian heart and pathogenesis of CHD. STX18 is a soluble N-ethylmaleimide-sensitive factor attachment protein receptor, which is involved in numeral cellular activities such as organelle assembly and the cell cycle. The aim of this work was to find evidence on whether STX18 variations might be associated with CHD in Chinese Han populations. We evaluated SNPs rs2044, rs33952588, rs61740788, rs12504020 and rs12644497, which are located within the exon or intron sequences of the STX18 gene, for 310 Chinese Han CHD patients and 400 non-CHD controls. Using SPSS software (version 19.0) and the online software OEGE, we conducted statistical analyses and Hardy-Weinberg equilibrium test, respectively. Among the five SNPs identified in the STX18 gene, rs33952588 and rs61740788 had very low genetic heterozygosity. In contrast, the genetic heterozygosity of the remaining three variations rs12504020 and rs12644497 near the 5'UTR and rs2044 within 3'UTR of the STX18 gene was considerably high. Analysis of associations of these genetic variations with the risk of CHD showed that rs12644497 (P value=0.017<0.05) was associated with the risk of CHD, specifically VSD and ASD, whereas rs12504020 (P value=0.560>0.05) and rs2044 (P value=0.972>0.05) were not. The SNP rs12644497 in the STX18 gene was associated with CHD in Chinese Han populations.

Ultra-flexible Piezoelectric Devices Integrated with Heart to Harvest the Biomechanical Energy.

Power supply for medical implantable devices (i.e. pacemaker) always challenges not only the surgery but also the battery technology. Here, we report a strategy for energy harvesting from the heart motion by using ultra-flexible piezoelectric device based on lead zirconate titanate (PZT) ceramics that has most excellent piezoelectricity in commercial materials, without any burden or damage to hearts. Experimental swine are selected for in vivo test with different settings, i.e. opened chest, close chest and awake from anesthesia, to simulate the scenario of application in body due to their hearts similar to human. The results show the peak-to-peak voltage can reach as high as 3 V when the ultra-flexible piezoelectric device is fixed from left ventricular apex to right ventricle. This demonstrates the possibility and feasibility of fully using the biomechanical energy from heart motion in human body for sustainably driving implantable devices.

Application of piezoelectric nanogenerator in medicine: bio-experiment and theoretical exploration.

BACKGROUND: A large number of wearable and implantable electronic medical devices are widely used in clinic and playing an increasingly important role in diagnosis and treatment, but the limited battery capacity restricts their service life and function expansion. Piezoelectric nanogenerators can convert mechanical energy into electrical energy. Our experiment tries to find out if the piezoelectric nanogenerator fixed to the surface of the heart can convert the natural contractions and relaxations of the heart into stable electric energy for electronic medical devices such as pacemakers. METHODS: We used Chinese miniature pig and prepared with standard open chest procedure. Then we fixed two opposite edges of the rectangular nanogenerator at the following three positions of the heart respectively to detect the electric voltage output: Position A, right ventricular surface, near the atrioventricular groove, parallel to the long axis of the heart; Position B, right ventricular surface, parallel to the atrioventricular groove; and Position C, left ventricular surface, near cardiac apex, parallel to the left anterior descending branch. Then we selected the place which has the highest voltage output to fix both ends of the nanogenerator and closed the chest of pig. We recorded the voltage output of nanogenerator under closed chest condition (natural condition) and compared the result with open chest condition. Finally we used Dopamine (positive inotropic agents) and Esmolol (negative inotropic agents) respectively to detect the relation between voltage output of nanogenerator and myocardial contractility. RESULTS: With its both ends fixed on the surface of the heart, the piezoelectric nanogenerator produced stable voltage output from the mechanical contractions of the heart. Piezoelectric nanogenerator which was fixed at Position A produced the highest voltage output (3.1 V), compared with those fixed at Position B or Position C. The voltage is enough for the pacemaker's operation. The voltage output of piezoelectric nanogenerator at the natural condition (closed chest) was the same as the open chest condition and made a light emitting diode (LED) light continue to shine, which further confirmed its clinical application value. The voltage output of piezoelectric nanogenerator is positively correlated with the myocardial contractile force. The voltage output increased after we used positive inotropic agents and decreased after we used negative inotropic agents. CONCLUSIONS: Piezoelectric nanogenerators can convert the kinetic energy of the heart during the contractions and relaxations of the muscles to electric energy. The output voltage was stable in three positions on the surface of the heart. The highest voltage appeared on the surface of right ventricle, near atrioventricular groove, parallel to the long axis direction of the heart, which can be the potential new energy source for pacemakers. Piezoelectric nanogenerator can be used as cardiac function monitor in the future for its voltage output is positively correlated with myocardial contractile force.

Heat shock protein 70 induced by heat stress protects heterotopically transplanted hearts in rats.

Heat shock protein 70 (HSP70) protects cardiac function against ischemia-reperfusion injury through gene transfection, although it is not a clinically practical and economical method. This study investigated whether heat stress-induced HSP70 protects heterotopically transplanted donor hearts. A total of 60 donor rats were randomly divided into 6 groups. Five of those received heat stress and one was a control group. Donor hearts were heterotopically transplanted into recipient rats at five time points, following the heat stress (0, 24, 48, 96 and 192 h). The levels of HSP70 expression in donor hearts and the variation of myocardial enzymes in receptor blood or donor hearts were measured 24 h after transplantation. The donated hearts were also examined under a microscope for pathological changes. HSP70 expression was the highest in the 24-h group (p≤0.01) and decreased gradually in the 48- and 96-h groups. No statistically significant difference was found in the HSP70 expression in the control, the 0- and 192-h groups (p≥0.05). Of all the groups, the 24-h group had the lowest lactate dehydrogenase and creatine kinase muscle band concentrations in receptor blood. Moreover, this group showed the lowest malondialdehyde concentration and the highest atriphosphate concentration (p≤0.01), demonstrated by the mildest inflammatory injury in the transplanted hearts. We found a time-dose-effect relationship among heat stress, HSP70 and the protection of donor hearts. Heat stress is a practical method that can be clinically applied to protect donor hearts against ischemia-reperfusion injury by inducing endogenous HSP70, which indicates the future direction of clinical practice.