Metabolic adaptations in pressure overload hypertrophic heart.

This review article offers a detailed examination of metabolic adaptations in pressure overload hypertrophic hearts, a condition that plays a pivotal role in the progression of heart failure with preserved ejection fraction (HFpEF) to heart failure with reduced ejection fraction (HFrEF). The paper delves into the complex interplay between various metabolic pathways, including glucose metabolism, fatty acid metabolism, branched-chain amino acid metabolism, and ketone body metabolism. In-depth insights into the shifts in substrate utilization, the role of different transporter proteins, and the potential impact of hypoxia-induced injuries are discussed. Furthermore, potential therapeutic targets and strategies that could minimize myocardial injury and promote cardiac recovery in the context of pressure overload hypertrophy (POH) are examined. This work aims to contribute to a better understanding of metabolic adaptations in POH, highlighting the need for further research on potential therapeutic applications.

GSDME-mediated keratinocyte pyroptosis participates in the pathogenesis of psoriasis by promoting skin inflammation.

OBJECTIVE: Psoriasis is a common, chronic inflammatory disease with unclear etiology. Keratinocytes in psoriasis are susceptible to exogenous triggers that induce inflammatory cell death. This study investigated whether GSDME-mediated pyroptosis in keratinocytes contributes to the pathogenesis of psoriasis. METHODS: Skin samples from patients with psoriasis and healthy controls were collected to evaluate the expression of GSDME, cleaved-caspase-3, and inflammatory factors. We then analyzed the data series, GSE41662, to further compare the expression of GSDME between lesional and non-lesional skin samples in those with psoriasis. In vivo, caspase-3 inhibitor and GSDME deficiency mice (Gsdme-/-) were applied to block caspase-3/GSDME activation in the imiquimod-induced psoriasis model. Skin inflammation, disease severity, and pyroptosis-related proteins were analyzed. In vitro, tumor necrosis factor-α (TNF-α)-induced caspase-3/GSDME-mediated pyroptosis in the HACAT cell line was explored. RESULTS: Our analysis of the GSE41662 data series found that GSDME were upregulated in psoriasis lesions, compared to normal skin. High levels of inflammatory cytokines such as IL-1ß, IL-6, and TNF-α were also found in psoriasis lesions. In mice of Gsdme-/- and caspase-3 inhibitor groups, the severity of skin inflammation was attenuated, and GSDME and C-caspase-3 levels decreased after imiquimod treatment. Similarly, IL-1ß, IL-6, and TNF-α were decreased in Gsdme-/- and caspase-3 inhibitor groups. In vitro, TNF-α induced HACAT cell pyroptosis through caspase-3/GSDME pathway activation, which was suppressed by blocking caspase-3 or silencing GSDME. CONCLUSION: Our study provides a novel explanation that TNF-α/caspase-3/GSDME-mediated keratinocyte pyroptosis is highly responsible for the initiation and acceleration of skin inflammation and progression of psoriasis.

3D Aligned Nanofiber Scaffold Fabrication with Trench-Guided Electrospinning for Cardiac Tissue Engineering.

Constructing three-dimensional (3D) aligned nanofiber scaffolds is significant for the development of cardiac tissue engineering, which is promising in the field of drug discovery and disease mechanism study. However, the current nanofiber scaffold preparation strategy, which mainly includes manual assembly and hybrid 3D printing, faces the challenge of integrated fabrication of morphology-controllable nanofibers due to its cross-scale structural feature. In this research, a trench-guided electrospinning (ES) strategy was proposed to directly fabricate 3D aligned nanofiber scaffolds with alternative ES and a direct ink writing (DIW) process. The electric field effect of DIW poly(dimethylsiloxane) (PDMS) side walls on guiding whipping ES nanofibers was investigated to construct trench design rules. It was found that the width/height ratio of trenches greatly affected the nanofiber alignment, and the trench width/height ratio of 1.5 provided the nanofiber alignment degree over 60%. As a proof of principle, 3D nanofiber scaffolds with controllable porosity (60-80%) and alignment (30-60%) were fabricated. The effect of the scaffolds was verified by culturing human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which resulted in the uniform 3D distribution of aligned hiPSC-CMs with ∼1000 µm thickness. Therefore, this printing strategy shows great potential for the efficient engineered tissue construction.

Integrative metabolomics dictate distinctive signature profiles in patients with Tetralogy of Fallot.

BACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CCHD) with multifactorial etiology. We aimed to investigate the metabolic profiles of CCHD and their independent contributions to TOF. METHODS: A cohort comprising 42 individuals with TOF and atrial septal defect (ASD) was enrolled. Targeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was employed to systematically analyze metabolite levels and identify TOF-associated metabolic profiles. RESULTS: Of 370 identified metabolites in tissue and 284 in plasma, over one-third of metabolites showed an association with microbiome. Differential metabolic pathways including amino acids biosynthesis, ABC (ATP-binding cassette) transporters, carbon metabolism, and fatty acid biosynthesis, shed light on TOF biological phenotypes. Additionally, ROC curves identified potential biomarkers, such as erythronic acid with an AUC of 0.868 in plasma, and 3-ß-hydroxy-bisnor-5-cholenic acid, isocitric acid, glutaric acid, ortho-Hydroxyphenylacetic acid, picolinic acid with AUC close to 1 in tissue, whereas the discriminative performance of those substances significantly improved when combined with clinical phenotypes. CONCLUSIONS: Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing TOF from ASD patients. These metabolites may serve as biomarkers or key molecular players in the intricate metabolic pathways involved in CCHD development. IMPACT: Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing Tetralogy of Fallot from atrial septal defect patients. Similar profiling but inconsistent differential pathways between plasma and tissue. More than one-third metabolites in plasma and tissue are associated with the microbiome. The discovery of biomarkers is instrumental in facilitating early detection and diagnosis of Tetralogy of Fallot. Disturbed metabolism offers insights into interpretation of pathogenesis of Tetralogy of Fallot.

A machine learning-based prediction model for postoperative delirium in cardiac valve surgery using electronic health records.

BACKGROUND: Previous models for predicting delirium after cardiac surgery remained inadequate. This study aimed to develop and validate a machine learning-based prediction model for postoperative delirium (POD) in cardiac valve surgery patients. METHODS: The electronic medical information of the cardiac surgical intensive care unit (CSICU) was extracted from a tertiary and major referral hospital in southern China over 1 year, from June 2019 to June 2020. A total of 507 patients admitted to the CSICU after cardiac valve surgery were included in this study. Seven classical machine learning algorithms (Random Forest Classifier, Logistic Regression, Support Vector Machine Classifier, K-nearest Neighbors Classifier, Gaussian Naive Bayes, Gradient Boosting Decision Tree, and Perceptron.) were used to develop delirium prediction models under full (q = 31) and selected (q = 19) feature sets, respectively. RESULT: The Random Forest classifier performs exceptionally well in both feature datasets, with an Area Under the Curve (AUC) of 0.92 for the full feature dataset and an AUC of 0.86 for the selected feature dataset. Additionally, it achieves a relatively lower Expected Calibration Error (ECE) and the highest Average Precision (AP), with an AP of 0.80 for the full feature dataset and an AP of 0.73 for the selected feature dataset. To further evaluate the best-performing Random Forest classifier, SHAP (Shapley Additive Explanations) was used, and the importance matrix plot, scatter plots, and summary plots were generated. CONCLUSIONS: We established machine learning-based prediction models to predict POD in patients undergoing cardiac valve surgery. The random forest model has the best predictive performance in prediction and can help improve the prognosis of patients with POD.

A Randomized, Controlled Trial of Continuous Heparin Infusion to Prevent Asymptomatic Catheter-Related Thrombosis at Discharge in Infants After Cardiac Surgery: The CHIP-CRT Trial.

OBJECTIVES: There are conflicting results in preventing catheter-related thrombosis (CRT). Continuing infusion of unfractionated heparin (UFH) was a potential option for CRT. This study was to determine the effect of continuous UFH infusion on asymptomatic CRT at discharge in infants after cardiac surgery. STUDY DESIGN: This study was a randomized, placebo-controlled, clinical trial at a single center. All infants with central venous catheters after cardiac surgery, below 3 months of age, were eligible. Stratified by CRT, infants were randomly assigned to the UFH group or the normal saline group. UFH was initiated at a speed of 10 to 15 units/kg/h for infants with CRT and 2 to 3 units/kg/h without CRT. The primary outcome was to determine the rate of CRT at discharge. The secondary outcomes included thrombosis 6 months after surgery, adverse events of UFH, and post-thrombotic symptoms. RESULTS: Due to slow recruitment during the COVID-19 pandemic, this trial was prematurely stopped. Only 35 infants were randomly assigned to the UFH or control groups. There was no statistically significant difference in CRT rate at discharge (P=0.429) and 6 months after surgery (P=1.000) between groups. All CRTs except one disappeared at discharge. No thrombosis or post-thrombotic symptom was reported at follow-up evaluation. There was no difference between groups in duration of thrombus (P=0.088), D dimer (P=0.412), catheter in situ days (P=0.281), and post-thrombotic syndrome (P=1.000), except for activated partial thromboplastin time (P=0.001). CONCLUSIONS: With the early stop of this trial and limited data, it is difficult to draw a definitive conclusion about the efficacy of UFH on CRT. Meanwhile, considering the data from 6 months follow-up, in this population, asymptomatic CRT might resolve with no intervention.

Non-Linear Association of Serum Sex Hormone Binding Globulin Concentration with Female Infertility.

BACKGROUND: Accumulating proofs suggested that disturbance of serum sex hormone-binding globulin (SHBG) concentration can affect the reproductive system. However, the effect of serum SHBG on female infertility remains to be clarified. METHODS: Data from 1,787 adults from the National Health and Nutrition Examination Survey (NHANES) was applied to examine the correlation between serum SHBG and female infertility. Multivariate logistic regression was used to evaluate the independent association between serum SHBG and female infertility. Furthermore, generalized additive model (GAM) and two-piecewise linear regression model were applied to assess the underlying non-linear association in our participants. RESULTS: We observed a reverse association between serum SHBG and infertility based on a fully-adjusted model (OR = 0.99, 95% CI: 0.99-1, p = 0.002), and the results were stable in several sensitive analyses. Furthermore, we detected a non-linear link by GAM and two-piecewise linear regression model. A protective association was observed at < 58.84 nmol/L serum SHGB; in contrast, no statistical link was found at > 58.84 nmol/L serum SHGB. CONCLUSIONS: Our results provide evidence for a non-linear association with serum SHBG and female infertility. This finding needs to be further confirmed in future large-scale prospective cohort studies.

Single-cell RNA sequencing reveals the role of mitochondrial dysfunction in the cardiogenic toxicity of perfluorooctane sulfonate in human embryonic stem cells.

Perfluorooctane sulfonate (PFOS), an endocrine-disrupting chemical pollutant, affects embryonic heart development; however, the mechanisms underlying its toxicity have not been fully elucidated. Here, Single-cell RNA sequencing (scRNA-seq) was used to investigate the overall effects of PFOS on myocardial differentiation from human embryonic stem cells (hESCs). Additionally, apoptosis, mitochondrial membrane potential, and ATP assays were performed. Downregulated cardiogenesis-related genes and inhibited cardiac differentiation were observed after PFOS exposure in vitro. The percentages of cardiomyocyte and cardiac progenitor cell clusters decreased significantly following exposure to PFOS, while the proportion of primitive endoderm cell was increased in PFOS group. Moreover, PFOS inhibited myocardial differentiation and blocked cellular development at the early- and middle-stage. A Gene Ontology analysis and pseudo-time trajectory illustrated that PFOS disturbed multiple processes related to cardiogenesis and oxidative phosphorylation in the mitochondria. Furthermore, PFOS decreased mitochondrial membrane potential and induced apoptosis. These results offer meaningful insights into the cardiogenic toxicity of PFOS exposure during heart formation as well as the adverse effects of PFOS on mitochondria.

Folic acid attenuates chronic visceral pain by reducing clostridiales abundance and hydrogen sulfide production.

Irritable bowel syndrome (IBS) related chronic visceral pain affects 20% of people worldwide. The treatment options are very limited. Although the scholarly reviews have appraised the potential effects of the intestinal microbiota on intestinal motility and sensation, the exact mechanism of intestinal microbiota in IBS-like chronic visceral pain remains largely unclear. The purpose of this study is to investigate whether Folic Acid (FA) attenuated visceral pain and its possible mechanisms. Chronic visceral hyperalgesia was induced in rats by neonatal colonic inflammation (NCI). 16S rDNA analysis of fecal samples from human subjects and rats was performed. Patch clamp recording was used to determine synaptic transmission of colonic-related spinal dorsal horn. Alpha diversity of intestinal flora was increased in patients with IBS, as well as the obviously increased abundance of Clostridiales order (a main bacteria producing hydrogen sulfide). The hydrogen sulfide content was positive correlation with visceral pain score in patients with IBS. Consistently, NCI increased Clostridiales frequency and hydrogen sulfide content in feces of adult rats. Notably, the concentration of FA was markedly decreased in peripheral blood of IBS patients compared with non-IBS human subjects. FA supplement alleviated chronic visceral pain and normalized the Clostridiales frequency in NCI rats. In addition, FA supplement significantly reduced the frequency of sEPSCs of neurons in the spinal dorsal horn of NCI rats. Folic Acid treatment attenuated chronic visceral pain of NCI rats through reducing hydrogen sulfide production from Clostridiales in intestine.

Novel biphasic mechanism of the canonical Wnt signalling component PYGO2 promotes cardiomyocyte differentiation from hUC-MSCs.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are used to regenerate the myocardium during cardiac repair after myocardial infarction. However, the regulatory mechanism underlying their ability to form mesodermal cells and differentiate into cardiomyocytes remains unclear. Here, we established a human-derived MSCs line isolated from healthy umbilical cords and established a cell model of the natural state to examine the differentiation of hUC-MSCs into cardiomyocytes. Quantitative RT-PCR, western blotting, immunofluorescence, flow cytometry, RNA Seq, and inhibitors of canonical Wnt signalling were used to detect the germ-layer markers T and MIXL1; the markers of cardiac progenitor cells MESP1, GATA4, and NKX2.5 and the cardiomyocyte-marker cTnT to identify the molecular mechanism associated with PYGO2, a key component of the canonical Wnt signalling pathway that regulates the formation of cardiomyocyte-like cells. We demonstrated that PYGO2 promotes the formation of mesodermal-like cells and their differentiation into cardiomyocytes through the hUC-MSC-dependent canonical Wnt signalling by promoting the early-stage entry of ß-catenin into the nucleus. Surprisingly, PYGO2 did not alter the expression of the canonical-Wnt, NOTCH, or BMP signalling pathways during the middle-late stages. In contrast, PI3K-Akt signalling promoted hUC-MSCs formation and their differentiation into cardiomyocyte-like cells. To the best of our knowledge, this is the first study to demonstrate that PYGO2 uses a biphasic mechanism to promote cardiomyocyte formation from hUC-MSCs.

Predictive performance of the perivascular fat attenuation index for interventional antegrade percutaneous coronary intervention for chronic total occlusion.

OBJECTIVES: This study aimed to investigate the association between the perivascular fat attenuation index (FAI) and the success of the antegrade percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). METHODS: This study evaluated patients with only one CTO lesion observed on conventional coronary angiography (CAG) who underwent coronary computed tomography angiography (CCTA) < 1 month before CAG, from 2018 to 2019. The clinical data, CCTA-based CTO lesion morphologic characteristics, and perivascular FAI of CTO lesions were recorded and analysed. RESULTS: In total, 156 patients with CTOs were enrolled in this study. Successful antegrade PCI (A-PCI) was achieved in 105 CTO lesions (67.3%). The perivascular FAI of the failed A-PCI group was significantly lower than the successful A-PCI group (-84.76 ± 10.44 Hounsfield unit (HU) vs. -67.54 ± 9.94 HU; p < 0.001), and the cut-off value determined by the receiver operating characteristic (ROC) curve was -77.50 HU. Multivariable analysis revealed no statistical significance in the clinical data, FAI ≤ -77.50 HU (odds ratio (OR): 33.96), negative remodeling (OR: 4.36), severe calcification degree (OR: 4.43) and occlusion length ≥ 20.25 mm (OR: 3.89) were independent predictors of A-PCI failure. The prediction performance of combining the three morphologic characteristics (severe calcification, occlusion length ≥ 20.25 mm, and negative remodeling) with FAI ≤ -77.50 HU was better than that of the three morphologic characteristics alone (0.93 versus 0.77, p < 0.001). CONCLUSIONS: As a non-invasive index for detecting coronary inflammation, FAI complements indicators based on coronary CTA well and may be helpful for choosing appropriate interventional strategies. KEY POINTS: • Perivascular FAI of CTO was significantly higher in the failed A-PCI group. • The combination of FAI with other morphological predictors showed higher predictive performance of failed A-PCI for CTOs. • FAI is a good complement to indicators based on coronary CTA.

The prophylactic effects of naringin on steroid-induced early-stage osteonecrosis in rats: a preliminary study.

The excessive steroid may cause dyslipidaemia and oxidative insult during femoral head osteonecrosis, inducing bone loss and impairment of the intraosseous blood system. In contrast, bio-flavanone naringin has shown antioxidant, antiresorptive and lipid-lowering bioactivities. The present research is an effort to explore the anti-ON potential of naringin in vivo and in vitro. After a 6-week treatment, the femora were dissected for histological examination following bone mineral density assay by X-ray absorptiometry. Blood samples were examined for coagulation, oxidative stress, lipid transportation and endothelial injury. Marrow samples were cultured and assayed for adipogenic and osteogenic alterations by ALP activity, mineralization, RT-qPCR and western blot analysis. The results showed that naringin exerted a dose-dependent effect on reducing ON incidence, with inhibition of osteoporosis, oxidative stress and dyslipidaemia. The mechanism included the suppression of PPARγ2 for adipogenesis of bone marrow stem cells (BMSCs) and the prevention of oxidative stress in endothelium injury. Naringin may restore steroid-impaired osteogenesis by enhancing the mRNA and protein expression of osteogenic markers in a dose-ascending manner and new bone formation can be found in naringin groups. Taken together, our findings showed that naringin may serve as a prophylactic agent and selective PPARγ modulator for the early-stage ON.

Light distribution technology of light-emitting-diode automotive lamps based on rippling pattern.

In this era of led-emitting-diode (LED) lighting, it is important to find a universal pattern structure for the LED automotive lamp optics. This paper starts with the secondary light distribution design method of a rippling pattern through the explanation and simulation analysis of its design principle and determines a 4 ' ' round signal lamp scheme with good performance. It then completes the proofing verification of this scheme, and the test results achieve the original design goal. Additionally, several examples of other lamp types with the rippling pattern are introduced, including a 4 ' ' round halo lamp and 7 ' ' transit lamp.

Predicting reintervention after thoracic endovascular aortic repair of Stanford type B aortic dissection using machine learning.

OBJECTIVES: To construct models for predicting reintervention after thoracic endovascular aortic repair (TEVAR) of Stanford type B aortic dissection (TBAD). METHODS: A total of 192 TBAD patients who underwent TEVAR were included; 68 (35.4%) had indications for reintervention. Clinical characteristics, aorta characteristics on pre- and postoperative computed tomography angiography, and aorta characteristics on immediate postoperative aortic digital subtraction angiography were collected. The least absolute shrinkage and selection operator (LASSO) regression was applied to identify the risk factors for reintervention. Eight classifiers were used for modeling. The models were trained on 100 train-validation random splits with a ratio of 2:1. The performance was evaluated by the receiver operating characteristic curve. RESULTS: Seven predictors of reintervention were identified, including maximum false lumen diameter, aortic diameter measured at the level of approximately 15 mm distal to the left subclavian artery, aortic diameter measured at the level of the diaphragm, false lumen diameter measured at the level of the celiac artery, number of bare-metal and covered stents, number of bare-metal stents, and residual perfusion of the false lumen. Logistic regression (LR) yielded the highest performance, with an area under the curve of 0.802. A nomogram built for clinical use showed good calibration. The cutoff value for dividing patients into low- and high-risk subgroups was 0.413. Kaplan-Meier curves showed that the overall survival of high-risk patients was significantly shorter than that of low-risk patients (both p < 0.05). CONCLUSION: Our nomogram could predict the reintervention after TEVAR in patients with TBAD, which may facilitate patient selection and surveillance strategies. KEY POINTS: • Seven risk factors of reintervention after TEVAR of TBAD were identified for modeling. • Logistic regression performed best in predicting reintervention with an AUC of 0.802. • Patients with a high risk of reintervention had shorter OS than those with a low risk.

Pulmonary artery reconstruction and correction of tetralogy of Fallot combined with the absence of the mediastinal left pulmonary artery.

OBJECTIVES: Tetralogy of Fallot (TOF) is the most common deformity combined with the unilateral absence of the mediastinal pulmonary artery (UAMPA), and its treatment strategy remains controversial. In this study, we analyzed the effect of bilateral pulmonary reconstruction in patients with TOF combined with UAMPA. METHODS: This was a single-center, retrospective review of 1713 patients with TOF between January 2009 and November 2021. Overall, eight patients were diagnosed with TOF combined with UAMPA. Among them, seven underwent surgery: three underwent one-stage TOF correction with bilateral pulmonary artery reconstruction; three patients underwent bilateral pulmonary artery reconstruction, followed by two-stage TOF correction after several months; and one patient underwent two procedures of left pulmonary artery reconstruction, and the ventral septal defect remained open. The left pulmonary arteries were reconstructed with a Goretex conduit in three cases, direct anastomosis in two cases, and the modified autologous tissue extension technique in two cases. RESULTS: All seven patients survived during the postoperative follow-up and showed good cardiac function and normal oxygen saturation of >97%. During follow-up echocardiography, we noted that the left pulmonary arteries reconstructed with a Goretex conduit or direct anastomosis had thrombosis or stenosis. However, those reconstructed using the modified autologous tissue extension technique was unobstructed. CONCLUSIONS: In patients with TOF and UAMPA, if there is a pulmonary artery confluence in the affected hilum, it is feasible to implement bilateral pulmonary artery reconstruction for one-stage TOF correction. The use of the pulmonary artery extension technique and autologous tissue for bilateral pulmonary reconstruction could reduce the incidence of anastomotic stenosis.

Safety and efficacy of concomitant ablation for atrial fibrillation in rheumatic mitral valve surgery: A meta-analysis.

OBJECTIVES: This review aimed to evaluate the safety and efficacy of concomitant surgical ablation (SA) for patients with atrial fibrillation (AF) undergoing rheumatic mitral valve (MV) surgery. METHODS: A systematic search of relevant studies focusing on SA for patients with AF undergoing rheumatic MV surgery was performed. The primary outcomes included mortality, efficacy, and complications. RESULTS: Four randomized controlled trials (RCTs) and four observational studies covering 1931 patients met the inclusion criteria. In RCTs, no significant differences in reoperation for bleeding, low cardiac output syndrome, thromboembolic events, and early (risk ratio [RR], 2.07; 95% confidence intervals [CI], 0.37-11.40; p = .41) and midterm all-cause death (RR, 1.07; 95% CI, 0.40-2.88; p = .89) were noted between the SA group and the nonablation group. These results were similar to those obtained from observational studies. However, ablation was associated with a higher incidence of permanent pacemaker implantation (RR, 2.44; 95% CI, 1.15-5.18; p = .02) in observational studies but not in RCTs (RR, 2.03; 95% CI, 0.19-21.26; p = .56). Furthermore, additional SA was significantly more effective in sinus rhythm (SR) restoration than MV surgery alone at discharge and at the 12-month and 3-year follow-ups. CONCLUSIONS: Concomitant SA during rheumatic MV surgery does not increase perioperative adverse events. In addition, SA promotes considerable restoration of SR. Although some evidence exists that permanent pacemaker implantation is more common after ablation, not all studies support this notion.

Primeval outcomes of thoracoscopic transmitral myectomy with anterior mitral leaflet extension for hypertrophic obstructive cardiomyopathy.

BACKGROUND: The transaortic Morrow procedure is the current gold standard for hypertrophic obstructive cardiomyopathy (HOCM) patients who are resistant to maximum drug therapy. It is controversial whether concomitant mitral valve intervention is necessary. Only a few centers apply for concomitant anterior mitral leaflet extension with a bovine or autologous pericardial patch to further decrease systolic anterior motion. Our aim is to assess the primeval outcomes of thoracoscopic transmitral myectomy with anterior mitral leaflet extension (TTM-AMLE) in symptomatic HOCM patients. METHODS: Between April 2019 and November 2020, 18 consecutive HOCM patients who underwent TTM-AMLE were enrolled in this study. Preoperative, postoperative, and follow-up outcomes were compared and statistically analyzed. RESULTS: The mean age was (50.17 ± 6.18) years and 10 (55.56%) were males. 18 (100%) patients had mitral regurgitation preoperatively, and they all successfully underwent TTM-AMLE with a median cardiopulmonary bypass and aortic cross-clamp time of 200.0 (150.8, 232.0), and 127.5 (116.0, 149.0) min, respectively. The median length of ICU stay was 2.7 (1.4, 5.2) days. The interventricular septum thickness was significantly reduced (from 18.03 ± 3.02 mm to 11.91 ± 1.66 mm, p < .001). There was no perioperative mortality, perforation of ventricular septum, or conversion to sternotomy observed. During a median follow-up of 18 months (IQR, 5-24 months), 1 (5.56%) patient had severe mitral regurgitation due to patch detachment and received reoperation. Moderate degree of mitral regurgitation and more than 50 mmHg in left ventricular outflow tract gradient were found in 2 (11.11%), and 1 (5.56%) patients, respectively. 1 (5.56%) patient who had second-degree atrioventricular block received permanent pacemaker implantation postoperatively. Overall, the maximum left ventricular outflow tract gradient (88.50 [59.50, 112.75] mmHg vs. 10.50 [7.00, 15.50] mmHg, p = .002), left ventricular outflow tract velocity (4.70 [3.86, 5.33] m/s vs. 1.60 [1.33, 1.95] m/s, p < .001) and the degree of mitral regurgitation (6.99 ± 4.47 cm2 vs. 2.22 ± 1.51 cm2 , p = .001) were significantly decreased, with a significant reduction in the proportion of systolic anterior motion (94.44% vs. 16.67%, p < .001). CONCLUSIONS: The TTM-AMLE is a safe and effective surgical approach for selected patients with HOCM. In our series, it provides excellent relief of left ventricular outflow tract obstruction, while significantly eliminating mitral regurgitation. The early outcomes of TTM-AMLE are satisfactory, but further studies and longer follow-ups are awaited.

Intersection of the Ubiquitin-Proteasome System with Oxidative Stress in Cardiovascular Disease.

Cardiovascular diseases (CVDs) present a major social problem worldwide due to their high incidence and mortality rate. Many pathophysiological mechanisms are involved in CVDs, and oxidative stress plays a vital mediating role in most of these mechanisms. The ubiquitin-proteasome system (UPS) is the main machinery responsible for degrading cytosolic proteins in the repair system, which interacts with the mechanisms regulating endoplasmic reticulum homeostasis. Recent evidence also points to the role of UPS dysfunction in the development of CVDs. The UPS has been associated with oxidative stress and regulates reduction-oxidation homeostasis. However, the mechanisms underlying UPS-mediated oxidative stress's contribution to CVDs are unclear, especially the role of these interactions at different disease stages. This review highlights the recent research progress on the roles of the UPS and oxidative stress, individually and in combination, in CVDs, focusing on the pathophysiology of key CVDs, including atherosclerosis, ischemia-reperfusion injury, cardiomyopathy, and heart failure. This synthesis provides new insight for continued research on the UPS-oxidative stress interaction, in turn suggesting novel targets for the treatment and prevention of CVDs.

The Protective Effects of Hydrogen Sulfide New Donor Methyl S-(4-Fluorobenzyl)-N-(3,4,5-Trimethoxybenzoyl)-l-Cysteinate on the Ischemic Stroke.

In this paper, we report the design, synthesis and biological evaluation of a novel S-allyl-l-cysteine (SAC) and gallic acid conjugate S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-l-cysteinate (MTC). We evaluate the effects on ischemia-reperfusion-induced PC12 cells, primary neurons in neonatal rats, and cerebral ischemic neuronal damage in rats, and the results showed that MTC increased SOD, CAT, GPx activity and decreased LDH release. PI3K and p-AKT protein levels were significantly increased by activating PI3K/AKT pathway. Mitochondrial pro-apoptotic proteins Bax and Bim levels were reduced while anti-apoptotic protein Bcl-2 levels were increased. The levels of cleaved caspase-9 and cleaved caspase-3 were also reduced in the plasma. The endoplasmic reticulum stress (ERS) was decreased, which in turns the survival rate of nerve cells was increased, so that the ischemic injury of neurons was protected accordingly. MTC activated the MEK-ERK signaling pathway and promoted axonal regeneration in primary neurons of the neonatal rat. The pretreatment of MEK-ERK pathway inhibitor PD98059 and PI3K/AKT pathway inhibitor LY294002 partially attenuated the protective effect of MTC. Using a MCAO rat model indicated that MTC could reduce cerebral ischemia-reperfusion injury and decrease the expression of proinflammatory factors. The neuroprotective effect of MTC may be due to inhibition of the over-activation of the TREK-1 channel and reduction of the current density of the TREK1 channel. These results suggested that MTC has a protective effect on neuronal injury induced by ischemia reperfusion, so it may have the potential to become a new type of neuro-ischemic drug candidate.

Risk of maternal exposure to mixed air pollutants during pregnancy for congenital heart diseases in offspring.

OBJECTIVE: To explore the risk of maternal exposure to mixed air pollutants of particulate matter 1 (PM 1), particulate matter 2.5 (PM 2.5), particulate matter 10 (PM 10) and NO 2 for congenital heart disease (CHD) in offspring, and to estimate the ranked weights of the above pollutants. METHODS: 6038 CHD patients and 5227 healthy controls from 40 medical institutions in 21 cities in Guangdong Registry of Congenital Heart Disease (GRCHD) from 2007 to 2016 were included. Logistic regression model was used to estimate the effect of maternal exposure to a single air pollutant on the occurrence of CHD in offspring. Spearman correlation coefficient was used to analyze the correlation between various pollutants, and Quantile g-computation was used to evaluate the joint effects of mixed exposure of air pollutants on CHD and the weights of various pollutants. RESULTS: The exposure levels of PM 1, PM 2.5, PM 10 and NO 2 in the CHD group were significantly higher than those in the control group (all P<0.01). The correlation coefficients among PM 1, PM 2.5, PM 10 and NO 2 were greater than 0.80. PM 1, PM 2.5, PM 10 and NO 2 exposure were associated with a significantly increased risk of CHD in offspring. Mixed exposure of these closely correlated pollutants presented much stronger effect on CHD than exposure of any single pollutants. There was a monotonic increasing relationship between mixed exposure and CHD risk. For each quantile increase in mixed exposure, the risk of CHD increased by 47% ( OR=1.47, 95% CI: 1.34-1.61). Mixed exposure had greater effect on CHD in the early pregnancy compared with middle and late pregnancy, but the greatest effect was the exposure in the whole pregnancy. The weight of PM 10 is the highest in the mixed exposure (81.3%). CONCLUSIONS: Maternal exposure to the mixture of air pollutants during pregnancy increases the risk of CHD in offspring, and the effect is much stronger than that of single exposure of various pollutants. PM 10 has the largest weights and the strongest effect in the mixed exposure.