GPR30 Agonist G1 Mitigates Sepsis-Induced Cardiac Dysfunction by Inhibiting ACE2/c-FOS-Mediated Necroptosis in Female Mice.

Sepsis is a severe inflammatory syndrome with high mortality and morbidity. Sepsis-induced myocardial dysfunction (SIMD) is a common cause of death in sepsis. The female sex is less susceptible to sepsis-related organ dysfunction, although the underlying mechanism of this sex difference remains unclear. This study explored the role of estrogen receptor G protein-coupled estrogen receptor 30 (GPR30) in septic cardiac dysfunction. Results from the present study indicated that GPR30 activation by the G1 agonist protected female mouse hearts against SIMD exposed to lipopolysaccharides. However, this beneficial effect was absent in female ACE2-knockout mice, as demonstrated by poorer cardiac contractility, myocardial injury, and necroptosis. We also demonstrated that the Stat6 transcription factor induced ace2 transcription by enhancing its promoter activity under GPR30 activation in septic hearts. The adenovirus-mediated inhibition of ACE2 targeting c-FOS expression reversed the deterioration, restored cardiac function, and improved survival in female ACE2-knockout mice. These results demonstrate the essential role of GPR30/STAT6/ACE2/c-FOS-mediated necroptosis in G1-mediated protection and provide novel insight into the pathogenesis of sepsis-related organ damage.

ACE2 deficiency inhibits thoracic aortic dissection by enhancing SIRT3 mediated inhibition of inflammation and VSCMs phenotypic switch.

BACKGROUND: Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in ß-aminopropionitrile fumarate (BAPN)-induced TAD. METHODS: A mouse model of TAD induced by BAPN and IL-1ß -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. RESULTS: We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. CONCLUSION: ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.

Developing a calculable risk prediction model for sternal wound infection after median sternotomy: a retrospective study.

Background: Diagnosing sternal wound infection (SWI) following median sternotomy remains laborious and troublesome, resulting in high mortality rates and great harm to patients. Early intervention and prevention are critical and challenging. This study aimed to develop a simple risk prediction model to identify high-risk populations of SWI and to guide examination programs and intervention strategies. Methods: A retrospective analysis was conducted on the clinical data obtained from 6715 patients who underwent median sternotomy between January 2016 and December 2020. The least absolute shrink and selection operator (LASSO) regression method selected the optimal subset of predictors, and multivariate logistic regression helped screen the significant factors. The nomogram model was built based on all significant factors. Area under the curve (AUC), calibration curve and decision curve analysis (DCA) were used to assess the model's performance. Results: LASSO regression analysis selected an optimal subset containing nine predictors that were all statistically significant in multivariate logistic regression analysis. Independent risk factors of SWI included female [odds ratio (OR) = 3.405, 95% confidence interval (CI) = 2.535-4.573], chronic obstructive pulmonary disease (OR = 4.679, 95% CI = 2.916-7.508), drinking (OR = 2.025, 95% CI = 1.437-2.855), smoking (OR = 7.059, 95% CI = 5.034-9.898), re-operation (OR = 3.235, 95% CI = 1.087-9.623), heart failure (OR = 1.555, 95% CI = 1.200-2.016) and repeated endotracheal intubation (OR = 1.975, 95% CI = 1.405-2.774). Protective factors included bone wax (OR = 0.674, 95% CI = 0.538-0.843) and chest physiotherapy (OR = 0.446, 95% CI = 0.248-0.802). The AUC of the nomogram was 0.770 (95% CI = 0.745-0.795) with relatively good sensitivity (0.798) and accuracy (0.620), exhibiting moderately good discernment. The model also showed an excellent fitting degree on the calibration curve. Finally, the DCA presented a remarkable net benefit. Conclusions: A visual and convenient nomogram-based risk calculator built on disease-associated predictors might help clinicians with the early identification of high-risk patients of SWI and timely intervention.

GDF15 attenuates sepsis-induced myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the SOCS1/GPX4 signaling pathway.

Sepsis is a systemic inflammatory response syndrome triggered by infection, presenting with symptoms such as fever, increased heart rate, and low blood pressure. In severe cases, it can lead to multiple organ dysfunction, posing a life-threatening risk. Sepsis-induced cardiomyopathy (SIC) is a critical factor in the poor prognosis of septic patients, leading to myocardial dysfunction characterized by cell death, inflammation, and diminished cardiac function. Ferroptosis, an iron-dependent form of programmed cell death, is a key mechanism causing cardiomyocyte damage in SIC. Growth differentiation factor 15 (GDF15), a member of the TGF-ß superfamily, is associated with various cardiovascular diseases and can inhibit oxidative stress, reduce reactive oxygen species (ROS), and suppress ferroptosis. Elevated serum GDF15 levels in sepsis are correlated with organ injuries, suggesting its potential as a therapeutic target. However, its role and mechanisms in SIC remain unclear. Glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid peroxides within cells, protects cells by reducing lipid peroxidation levels and inhibiting ferroptosis. Investigating the regulatory factors of GPX4 may provide a theoretical basis for SIC treatment. In this study, a mouse SIC model revealed that elevated GDF15 exerts a protective effect. Antagonizing GDF15 exacerbates myocardial damage. Through transcriptomic analysis and other methods, we confirmed that GDF15 inhibits the expression of SOCS1 by activating the ALK5-SMAD2/3 pathway, thereby activates the JAK2/STAT3 pathway, promotes the transcription of GPX4, inhibits ferroptosis in cardiomyocytes, and plays a myocardial protective role in SIC.

Electrical impedance tomography provides information of brain injury during total aortic arch replacement through its correlation with relative difference of neurological biomarkers.

Postoperative neurological dysfunction (PND) is one of the most common complications after a total aortic arch replacement (TAAR). Electrical impedance tomography (EIT) monitoring of cerebral hypoxia injury during TAAR is a promising technique for preventing the occurrence of PND. This study aimed to explore the feasibility of electrical impedance tomography (EIT) for warning of potential brain injury during total aortic arch replacement (TAAR) through building the correlation between EIT extracted parameters and variation of neurological biomarkers in serum. Patients with Stanford type A aortic dissection and requiring TAAR who were admitted between December 2021 to March 2022 were included. A 16-electrode EIT system was adopted to monitor each patient's cerebral impedance intraoperatively. Five parameters of EIT signals regarding to the hypothermic circulatory arrest (HCA) period were extracted. Meanwhile, concentration of four neurological biomarkers in serum were measured regarding to time before and right after surgery, 12 h, 24 h and 48 h after surgery. The correlation between EIT parameters and variation of serum biomarkers were analyzed. A total of 57 TAAR patients were recruited. The correlation between EIT parameters and variation of biomarkers were stronger for patients with postoperative neurological dysfunction (PND(+)) than those without postoperative neurological dysfunction (PND(-)) in general. Particularly, variation of S100B after surgery had significantly moderate correlation with two parameters regarding to the difference of impedance between left and right brain which were MRAIabs and TRAIabs (0.500 and 0.485 with p < 0.05, respectively). In addition, significantly strong correlations were seen between variation of S100B at 24 h and the difference of average resistivity value before and after HCA phase (ΔARVHCA), the slope of electrical impedance during HCA (kHCA) and MRAIabs (0.758, 0.758 and 0.743 with p < 0.05, respectively) for patients with abnormal S100B level before surgery. Strong correlations were seen between variation of TAU after surgery and ΔARVHCA, kHCA and the time integral of electrical impedance for half flow of perfusion (TARVHP) (0.770, 0.794 and 0.818 with p < 0.01, respectively) for patients with abnormal TAU level before surgery. Another two significantly moderate correlations were found between TRAIabs and variation of GFAP at 12 h and 24 h (0.521 and 0.521 with p < 0.05, respectively) for patients with a normal GFAP serum level before surgery. The correlations between EIT parameters and serum level of neurological biomarkers were significant in patients with PND, especially for MRAIabs and TRAIabs, indicating that EIT may become a powerful assistant for providing a real-time warning of brain injury during TAAR from physiological perspective and useful guidance for intensive care units.

Corrigendum to "Extra-anatomic revascularization and a new cannulation strategy for preoperative cerebral malperfusion due to severe stenosis or occlusion of supra-aortic branch vessels in acute type A aortic dissection" <[Heliyon Volume 9, Issue 7, July 2023, Article e18251]>.

[This corrects the article DOI: 10.1016/j.heliyon.2023.e18251.].

One-year results of the Flowdynamics Dense Mesh Stent for residual dissection after proximal repair of stanford type A or type B aortic dissection: a multicenter, prospective, and randomized study.

OBJECTIVE: Negative remodeling of the distal aorta following proximal repair for acute aortic dissection has garnered growing attention. This clinical scenario has spurred the development of techniques and devices. A multicenter, prospective, and randomized controlled study was conducted with the aim of confirming the safety and effectiveness of a newly-designed flowdynamics dense mesh stent for the treatment of residual dissection after proximal repair. METHODS: Patients with nonchronic residual dissection affecting visceral branches were prospectively enrolled at three centers and randomly allocated to either the FDMS group or the control group. Primary endpoints encompassed all-cause and aortic-related mortality, while the patency of branch arteries is indeed a key focal metric. Morphological changes (diameter, area, and volume) were analyzed to demonstrate the therapeutic effect. RESULTS: One hundred twelve patients were recruited in the clinical trial, and 103 patients completed the 12-month follow-up. The rate of freedom from all-cause and aortic-related death in the FDMS group was 94.64 and 100%, respectively. All visceral branches remained patent. The FDMS group exhibited a substantial expansion in TL and a notable shrinkage in FL at the planes below renal arteries (ΔArea TL : FDMS vs. Control, 0.74±0.46 vs. 0.34±0.66 cm 2 , P <0.001; ΔArea FL : FDMS vs. Control, -0.72±1.26 vs. -0.12±0.86 cm, P =0.01) and 5 cm below renal arteries (ΔArea TL : FDMS vs. Control, 1.06±0.75 vs. 0.16±0.63 cm 2 , P <0.001; ΔArea FL : FDMS vs. Control, -0.53±1.43 vs. -0.25±1.00 cm, P =0.27). Meanwhile, the FDMS group demonstrated an increase of 22.55±11.14 cm 3 in TL ( P <0.001) and a corresponding reduction of 21.94±11.77 cm 3 in FL ( P =0.08). CONCLUSIONS: This newly-designed FDMS for endovascular repair of residual dissection following the proximal repair is demonstrated to be safe and effective at 12 months.

Rectifying METTL4-Mediated N6-Methyladenine Excess in Mitochondrial DNA Alleviates Heart Failure.

BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N6-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury. CONCLUSIONS: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.

Nanotexture and crystal phase regulation for synergistic enhancement in re-endothelialization on medical pure titanium surface.

Re-endothelialization has been recognized as a promising strategy to address the tissue hyperplasia and subsequent restenosis which are major complications associated with vascular implant/interventional titanium devices. However, the uncontrollable over-proliferation of smooth muscle cells (SMCs) limits the clinical application of numerous modified strategies. Herein, a novel modified strategy involving with a two-step anodic oxidation and annealing treatment was proposed to achieve rapid re-endothelialization function regulated by regular honeycomb nanotexture and specific anatase phase on the titanium surface. Theoretical calculation revealed that the presence of nanotexture reduced the polar component of surface energy, while the generation of anatase significantly enhanced the polar component and total surface energy. Meanwhile, the modified surface with regular nanotexture and anatase phase produced positive effect on the expression of CD31, VE-Cadherin and down-regulated α-SMA proteins expression, indicating excellent capacity of pro-endothelial regeneration and inhibition of SMCs proliferation and migration. One-month in vivo implantation in rabbit carotid arteries further confirmed that modified tube implant surface effectively accelerated confluent endothelial monolayer formation and promoted native-like endothelium tissue regeneration. By contrast, original titanium tube implant induced a disorganized tissue proliferation in the lumen with a high risk of restenosis. Collectively, this study opens us an alternative route to achieve the function that selectively promotes endothelial cells (ECs) growth and suppresses SMCs on the medical titanium surface, which has a great potential in facilitating re-endothelialization on the surface of blood-contacting titanium implant.

Neurological prognosis in surgically treated acute aortic dissection with brain computed tomography perfusion.

OBJECTIVES: The aim of this study was to explore the prognostic value of brain computed tomography perfusion (CTP) for postoperative new stroke in acute type A aortic dissection (ATAAD) patients. METHODS: Patients with ATAAD and suspected cerebral malperfusion who underwent brain CTP and surgical repair were retrospectively analysed. Brain perfusion was quantified mainly with the averaged cerebral blood flow. Significant clinical and imaging findings were identified through univariable and multivariable regression analysis. Furthermore, the added prognostic benefit of perfusion parameters was confirmed with the receiver operating characteristic curves in the entire cohort and subgroup analysis. RESULTS: The incidence of postoperative new stroke was 30.8% (44/143). The independent adjusted predictors of postoperative new stroke included an impaired averaged cerebral blood flow (ml/100 ml/min) (odds ratio: 0.889; P < 0.001), severe stenosis (odds ratio: 5.218; P = 0.011) or occlusion (odds ratio: 14.697; P = 0.048) of the true lumen in common carotid artery (CCA), hypotension on admission (odds ratio: 9.644; P = 0.016) and a longer surgery time (odds ratio: 1.593; P = 0.021). The area under the receiver operating characteristic curves significantly improved after adding perfusion parameters to clinical and computed tomography angiography characteristics (P = 0.048). This benefit was more pronounced in patients with severe stenosis or occlusion in CCA true lumen (P = 0.004). CONCLUSIONS: Brain CTP could be a useful prognostic tool for surgically treated ATAAD patients and especially beneficial in patients with severe stenosis or occlusion of the CCA true lumen.

Integrative analysis reveals chemokines CCL2 and CXCL5 mediated shear stress-induced aortic dissection formation.

Background: Aortic dissection (AD) is a critical emergency in cardiovascular disease. AD occurs only in specific sites of the aorta, and the variation of shear stress in different aortic segments is a possible cause not reported. This study investigated the key molecules involved in shear stress-induced AD through quantitative bioinformatic analysis of a public RNA sequencing database and clinical tissue sample validation. Methods: Gene expression data from the GSE153434, GSE147026, and GSE52093 datasets were downloaded from the Gene Expression Omnibus. Next, differently expressed genes (DEGs) in each dataset were identified and integrated to identify common AD DEGs. STRING, Cytoscape, and MCODE were used to identify hub genes and crucial clustering modules, and Connectivity Map (CMap) was used to identify positive and negative agents. The same procedure was performed for the GSE160611 dataset to obtain shear stress-induced human aortic endothelial cell (HAEC) DEGs. After the integration of these two DEGs sets to identify shear stress-associated hub DEGs in AD, Gene Ontology Enrichment Analysis was performed. The common chemokine receptors and ligands in AD were identified by analyzing AD's three RNA sequencing datasets. Their origin was verified by analyzing AD single-cell sequencing data and validated by immunoblotting and immunofluorescence. Results: We identified 100 down-regulated and 50 up-regulated AD common DEGs. Enrichment results showed that common DEGs were closely related to blood vessel morphogenesis, muscle structure development, muscle tissue development, and chemotaxis. Among those DEGs, MYC, CCL2, and SPP1 are the three molecules with the highest degree. A crucial cluster of 15 genes was identified using MCODE, which contained inflammation-related genes with elevated expression and muscle cell-related genes with decreased expression, and CCL2 is central to immune-related genes. CMap confirmed MEK inhibitors and ALK inhibitors as possible therapeutic agents for AD. Moreover, 366 shear stress-associated DEGs in HAEC were identified in the GSE160611 dataset. After taking the intersection, we identified five shear stress-associated hub DEGs in AD (ANGPTL4, SNAI2, CCL2, GADD45B, and PROM1), and the enrichment analysis indicated they were related to the endothelial cell apoptotic process. Chemokine CCL2 was the molecule with a high degree in both DEG sets. Besides CCL2, CXCL5 was the only chemokine ligand differentially expressed in the three datasets. Additionally, immunoblotting confirmed the increased expression of CCL2 and CXCL5 in clinical tissue samples. Further research at the single-cell level revealed that CCL2 has multiple origins, and CXCL5 is macrophage-derived. Conclusion: Through integrative analysis, we identified core common AD DEGs and possible therapeutic agents based on these DEGs. We elucidated that the chemokine CCL2 and CXCL5-mediated "Endothelial-Monocyte-Neutrophil" axis may contribute to the development of shear stress-induced AD. These findings provide possible therapeutic targets for the prevention and treatment of AD.

Irisin improves diabetic cardiomyopathy-induced cardiac remodeling by regulating GSDMD-mediated pyroptosis through MITOL/STING signaling.

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM). However, the mechanisms underlying DCM-induced cardiac injury remain unclear. Recently, the role of cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) signaling and pyroptosis in DCM has been investigated. Based on our previous results, this study was designed to examine the impact of irisin, mitochondrial ubiquitin ligase (MITOL/MARCH5), and cGAS/STING signaling in DCM-induced cardiac dysfunction and the effect of gasdermin D (GSDMD)-dependent pyroptosis. High-fat diet-induced mice and H9c2 cells were used for cardiac geometry and function or pyroptosis-related biomarker assessment at the end of the experiments. Here, we show that DCM impairs cardiac function by increasing cardiac fibrosis and GSDMD-dependent pyroptosis, including the activation of MITOL and cGAS/STING signaling. Our results confirmed that the protective role of irisin and MITOL was partially offset by the activation of cGAS/STING signaling. We also demonstrated that GSDMD-dependent pyroptosis plays a pivotal role in the pathological process of DCM pathogenesis. Our results indicate that irisin treatment protects against DCM injury, mitochondrial homeostasis, and pyroptosis through MITOL upregulation.

Low-dose exercise protects the heart against established myocardial infarction via IGF-1-upregulated CTRP9 in male mice.

Regular exercise is recommended as an important component of therapy for cardiovascular diseases in clinical practice. However, there are still major challenges in prescribing an optimized exercise regimen to individual patients with established cardiac disease. Here, we tested the effects of different exercise doses on cardiac function in mice with established myocardial infarction (MI). Exercise was introduced to mice with MI after 4 weeks of surgery. Low-dose exercise (15 min/day for 8 weeks) improved mortality and cardiac function by increasing 44.39% of ejection fractions while inhibiting fibrosis by decreasing 37.74% of distant region. Unlike higher doses of exercise, low-dose exercise consecutively upregulated cardiac expression of C1q complement/tumor necrosis factor-associated protein 9 (CTRP9) during exercise (>1.5-fold). Cardiac-specific knockdown of CTRP9 abolished the protective effects of low-dose exercise against established MI, while cardiac-specific overexpression of CTRP9 protected the heart against established MI. Mechanistically, low-dose exercise upregulated the transcription factor nuclear receptor subfamily 2 group F member 2 by increasing circulating insulin-like growth factor 1 (IGF-1), therefore, upregulating cardiac CTRP9 expression. These results suggest that low-dose exercise protects the heart against established MI via IGF-1-upregulated CTRP9 and may contribute to the development of optimized exercise prescriptions for patients with MI.

Tetrahydrocurcumin ameliorates postinfarction cardiac dysfunction and remodeling by inhibiting oxidative stress and preserving mitochondrial function via SIRT3 signaling pathway.

BACKGROUND: Myocardial infarction (MI) often leads to sudden cardiac death. Persistent myocardial ischemia increases oxidative stress and impairs mitochondrial function, contributing significantly to postinfarction cardiac dysfunction and remodeling, and the subsequent progression to heart failure (HF). Tetrahydrocurcumin (THC), isolated from the rhizome of turmeric, has antioxidant properties and has been shown to protect against cardiovascular diseases. However, its effects on HF after MI are poorly understood. PURPOSE: The objective was the investigation of the pharmacological effects of THC and its associated mechanisms in the pathogenesis of HF after MI. METHODS: A total of 120 mice (C57BL/6, male) were used for the in vivo experiments. An MI mouse model was created by permanent ligation of the left anterior descending coronary artery. The mice received oral dose of THC at 120 mg/kg/d and the effects on MI-induced myocardial injury were evaluated by assessment of cardiac function, histopathology, myocardial oxidative levels, and mitochondrial function. Molecular mechanisms were investigated by intraperitoneal injection of 50 mg/kg of the SIRT3 selective inhibitor 3-TYP. Meanwhile, mouse neonatal cardiomyocytes were isolated and cultured in a hypoxic incubator to verify the effects of THC in vitro. Lastly, SIRT3 and Nrf2 were silenced using siRNAs to further explore the regulatory mechanism of key molecules in this process. RESULTS: The mouse hearts showed significant impairment in systolic function after MI, together with enlarged infarct size, increased myocardial fibrosis, cardiac hypertrophy, and apoptosis of cardiomyocytes. A significant reversal of these changes was seen after treatment with THC. Moreover, THC markedly reduced reactive oxygen species generation and protected mitochondrial function, thus mitigating oxidative stress in the post-MI myocardium. Mechanistically, THC counteracted reduced Nrf2 nuclear accumulation and SIRT3 signaling in the MI mice while inhibition of Nrf2 or SIRT3 reversed the effects of THC. Cell experiments showed that Nrf2 silencing markedly reduced SIRT3 levels and deacetylation activity while inhibition of SIRT3 signaling had little impact on Nrf2 expression. CONCLUSION: This is the first demonstration that THC protects against the effects of MI. THC reduced both oxidative stress and mitochondrial damage by regulating Nrf2-SIRT3 signaling. The results suggest the potential of THC in treating myocardial ischemic diseases.

Forkhead box O6 (FoxO6) promotes cardiac pathological remodeling and dysfunction by activating Kif15-TGF-ß1 under aggravated afterload.

Pathological cardiac hypertrophy exhibits complex and abnormal gene expression patterns and progresses to heart failure. Forkhead box protein O6 (FoxO6) is a key transcription factor involved in many biological processes. This study aimed to explore the role of FoxO6 in cardiac hypertrophy. Three groups of mice were established: wild-type, FoxO6 knockout, and FoxO6-overexpressing. The mice received daily administration of angiotensin-II (Ang-II) or saline for 4 weeks, after which they were examined for cardiac hypertrophy, fibrosis, and function. Elevated cardiac expression of FoxO6 was observed in Ang-II-treated mice. FoxO6 deficiency attenuated contractile dysfunction and cardiac remodeling, including cardiomyocyte hypertrophy and fibroblast proliferation and differentiation. Conversely, FoxO6 overexpression aggravated the cardiomyopathy and heart dysfunction. Further studies identified kinesin family member 15 (Kif15) as downstream molecule of FoxO6. Kif15 inhibition attenuated the aggravating effect of FoxO6 overexpression. In vitro, FoxO6 overexpression increased Kif15 expression in cardiomyocytes and elevated the concentration of transforming growth factor-ß1 (TGF-ß1) in the medium where fibroblasts were grown, exhibiting increased proliferation and differentiation, while FoxO6 knockdown attenuated this effect. Cardiac-derived FoxO6 promoted pathological cardiac remodeling induced by aggravated afterload largely by activating the Kif15/TGF-ß1 axis. This result further complements the mechanisms of communication among different cells in the heart, providing novel therapeutic targets for heart failure.

Extra-anatomic revascularization and a new cannulation strategy for preoperative cerebral malperfusion due to severe stenosis or occlusion of supra-aortic branch vessels in acute type A aortic dissection.

Objectives: Acute type A aortic dissection (ATAAD) with severe stenosis or occlusion of the true lumen of aortic arch branch vessels often leads to an increased incidence of severe postsurgical neurological complications and mortality rate. In this study, we aimed to introduce our institutional extra-anatomic revascularization and cannulation strategy with improved postoperative outcomes for better management of patients with cerebral malperfusion in the setting of ATAAD. Methods: Twenty-eight patients with ATAAD complicated by severe stenosis or occlusion of the aortic arch branch vessels, as noted on combined computed tomography angiography of the aorta and craniocervical artery, between January 2021 and June 2022 were included in this study. Basic patient characteristics, surgical procedures, hospitalization stays, and early follow-up results were analyzed. Results: The median follow-up duration was 16.5 months (interquartile range: 11.5-20.5), with a 100% completion rate. The 30-day mortality rates was 7.1% (2/28 patients); two patients had multiple cerebral infarctions on preoperative computed tomography and persistent coma. Postoperative transient neurological dysfunction occurred in 10.7% (3/28) of the patients, and no new permanent neurological dysfunction occurred. Of all the patients, 3.6% (1/28) had novel acute renal failure. No other deaths, secondary surgeries, or serious complications occurred during the early follow-up period. Conclusions: Use of extra-anatomic revascularization and a new cannulation strategy before cardiopulmonary bypass is safe and feasible and may reduce the high incidence of postoperative neurological complications in patients with ATAAD and cerebral malperfusion.

Risk prediction of preoperative acute ischemic stroke in acute type A aortic dissection.

OBJECTIVES: To predict preoperative acute ischemic stroke (AIS) in acute type A aortic dissection (ATAAD). METHODS: In this multi-center retrospective study, 508 consecutive patients diagnosed as ATAAD between April 2020 and March 2021 were considered for inclusion. The patients were divided into a development cohort and two validation cohorts based on time periods and centers. Clinical data and imaging findings obtained were analyzed. Univariable and multivariable logistic regression analyses were performed to identify predictors associated with preoperative AIS. The performance of resulting nomogram was evaluated in discrimination and calibration on all cohorts. RESULTS: A total of 224 patients were in the development cohort, 94 in the temporal validation cohort, and 118 in the geographical validation cohort. Six predictors were identified: age, syncope, D-dimer, moderate to severe aortic valve insufficiency, diameter ratio of true lumen in ascending aorta < 0.33, and common carotid artery dissection. The nomogram established showed good discrimination (area under the receiver operating characteristic curve [AUC], 0.803; 95% CI: 0.742, 0.864) and calibration (Hosmer-Lemeshow test p = 0.300) in the development cohort. External validation showed good discrimination and calibration abilities in both temporal (AUC, 0.778; 95% CI: 0.671, 0.885; Hosmer-Lemeshow test p = 0.161) and geographical cohort (AUC, 0.806; 95% CI: 0.717, 0.895; Hosmer-Lemeshow test p = 0.100). CONCLUSIONS: A nomogram, based on simple imaging and clinical variables collected on admission, showed good discrimination and calibration abilities in predicting preoperative AIS for ATAAD patients. KEY POINTS: • A nomogram based on simple imaging and clinical findings may predict preoperative acute ischemic stroke in patients with acute type A aortic dissection in emergencies. • The nomogram showed good discrimination and calibration abilities in validation cohorts.

Identification of the pyroptosis-related gene signature and risk score model for esophageal squamous cell carcinoma.

Advanced esophageal squamous cell carcinoma (ESCC) still has a dismal prognostic outcome. However, the current approaches are unable to evaluate patient survival. Pyroptosis represents a novel programmed cell death type which widely investigated in various disorders and can influence tumor growth, migration, and invasion. Furthermore, few existing studies have used pyroptosis-related genes (PRGs) to construct a model for predicting ESCC survival. Therefore, the present study utilized bioinformatics approaches for analyzing ESCC patient data obtained from the TCGA database to construct the prognostic risk model and applied it to the GSE53625 dataset for validation. There were 12 differentially expressed PRGs in healthy and ESCC tissue samples, among which eight were selected through univariate and LASSO cox regression for constructing the prognostic risk model. According to K-M and ROC curve analyses, our eight-gene model might be useful in predicting ESCC prognostic outcomes. Based on the cell validation analysis, C2, CD14, RTP4, FCER3A, and SLC7A7 were expressed higher in KYSE410 and KYSE510 than in normal cells (HET-1A). Hence, ESCC patient prognostic outcomes can be assessed by our PRGs-based risk model. Further, these PRGs may also serve as therapeutic targets.

Biomarkers for prediction of neurological complications after acute Stanford type A aortic dissection: A systematic review and meta-analysis.

BACKGROUND: The predictive value of biomarkers such as neuron specific enolase (NSE), S100B, neurofilament (NFL), interleukin-6 (IL-6), coagulation factor R, and D-Dimer (DD) after acute Stanford A type aortic dissection (AAAD) with neurological complications has recently gained much attention from the research community. However, results from these studies are conflicting. This meta-analysis is conducted to assess the relationship between the biomarkers and the risk of neurological complications after AAAD. METHODS: Two reviewers performed a systematic literature search across eight databases (CNKI, Wan Fang, VIP, CBM, PubMed, Web of Science, Cochrane Library, and EMBASE). The studies regarding biomarkers in AAAD patients published up to February 2022 were included. These studies were subjected to rigorous scrutiny and data extraction to determine the weighted mean difference (WMD) and the 95% confidence interval (CI), which were analyzed using the RevMan 5.4 and Stata software 14.0. RESULTS: A total of 12 studies including 360 cases with neurological complications and 766 controls were incorporated into our meta-analysis. WMD analysis showed that there was a higher NSE levels in AAAD patients with postoperative neurological complications compared with controls (WMD = 0.640, 95% CI: 0.205 ~ 1.075, P = 0.004 < 0.005), and the level of S100B was related to the 6 h and 24 h postoperative neurological complications (6 h: WMD = 0.64, 95% CI: 0.27 ~ 1.02, P = 0.0007 < 0.001; 24 h: WMD = 0.281, 95% CI: 0.211 ~ 0.351, P < 0.001). Moreover, S100B levels at 6 hours after operation were significantly higher than that at 24 hours (WMD = 0.260, 95% CI: 0.166 ~ 0.354, P < 0.001). CONCLUSION: NSE and S100B are both candidate biomarkers to predict postoperative neurological complications in patients with AAAD. Other markers are also valuable when used in conjunction with clinical judgement. The findings accentuate the necessity of further research to establish standardized values for these biomarkers in predicting neurological complications.