S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages.

BACKGROUND: S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection. METHODS: Biotin-switch assay combined with liquid chromatography-tandem mass spectrometry was performed to identify the S-nitrosylated proteins in aortic tissue from both patients undergoing surgery for aortic dissection and Apoe-/- mice infused with angiotensin II. Angiotensin II-induced aortic aneurysm model and ß-aminopropionitrile-induced aortic aneurysm and dissection model were used to determine the role of SNO of Septin2 (SNO-Septin2) in aortic aneurysm and dissection development. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of SNO-Septin2 in macrophages in aortic aneurysm and dissection. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation were used to uncover the TIAM1-RAC1 (Ras-related C3 botulinum toxin substrate 1) axis as the downstream target of SNO-Septin2. Both R-Ketorolac and NSC23766 treatments were used to inhibit the TIAM1-RAC1 axis. RESULTS: Septin2 was identified S-nitrosylated at cysteine 111 (Cys111) in both aortic tissue from patients undergoing surgery for aortic dissection and Apoe-/- mice infused with Angiotensin II. SNO-Septin2 was demonstrated driving the development of aortic aneurysm and dissection. By RNA-sequencing, SNO-Septin2 in macrophages was demonstrated to exacerbate vascular inflammation and extracellular matrix degradation in aortic aneurysm. Next, TIAM1 (T lymphoma invasion and metastasis-inducing protein 1) was identified as a SNO-Septin2 target protein. Mechanistically, compared with unmodified Septin2, SNO-Septin2 reduced its interaction with TIAM1 and activated the TIAM1-RAC1 axis and consequent nuclear factor-κB signaling pathway, resulting in stronger inflammation and extracellular matrix degradation mediated by macrophages. Consistently, both R-Ketorolac and NSC23766 treatments protected against aortic aneurysm and dissection by inhibiting the TIAM1-RAC1 axis. CONCLUSIONS: SNO-Septin2 drives aortic aneurysm and dissection through coupling the TIAM1-RAC1 axis in macrophages and activating the nuclear factor-κB signaling pathway-dependent inflammation and extracellular matrix degradation. Pharmacological blockade of RAC1 by R-Ketorolac or NSC23766 may therefore represent a potential treatment against aortic aneurysm and dissection.

Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration.

BACKGROUND: Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism. METHODS: Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (H2S) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/H2S system and the findings were confirmed in transgenic mice. RESULTS: Higher plasma H2S levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of CTH, the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the H2S donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD. CONCLUSIONS: Decreased plasma H2S levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses CTH, impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.

Computed Tomography Scan of the Aorta to Predict Type B Aortic Dissection.

BACKGROUND: The purpose of this study is to find the high-risk morphological features in type B aortic dissection (TBAD) population and to establish an early detection model. METHODS: From June 2018 to February 2022, 234 patients came to our hospital because of chest pain. After examination and definite diagnosis, we excluded people with previous cardiovascular surgery history, connective tissue disease, aortic arch variation, valve malformation, and traumatic dissection. Finally, we included 49 patients in the TBAD group and 57 in the control group. The imaging data were retrospectively analyzed by Endosize (Therevna 3.1.40) software. The aortic morphological parameters mainly include diameter, length, direct distance, and tortuosity index. Multivariable logistic regression models were performed and systolic blood pressure (SBP), aortic diameter at the left common carotid artery (D3), and length of ascending aorta (L1) were chosen to build a model. The predictive capacity of the models was evaluated through the receiver operating characteristic (ROC) curve analysis. RESULTS: The diameters in the ascending aorta and aortic arch are larger in the TBAD group (33.9 ± 5.9 vs. 37.8 ± 4.9 mm, p < 0.001; 28.2 ± 3.9 vs. 31.7 ± 3.0 mm, p < 0.001). The ascending aorta was significantly longer in the TBAD group (80.3 ± 11.7 vs. 92.3 ± 10.6 mm, p < 0.001). Besides, the direct distance and tortuosity index of the ascending aorta in the TBAD group increased significantly (69.8 ± 9.0 vs. 78.7 ± 8.8 mm, p < 0.001; 1.15 ± 0.05 vs. 1.17 ± 0.06, p < 0.05). Multivariable models demonstrated that SBP, aortic diameter at the left common carotid artery (D3), and length of ascending aorta (L1) were independent predictors of TBAD occurrence. Based on the ROC analysis, area under the ROC curve of the risk prediction models was 0.831. CONCLUSION: Morphological characteristic including diameter of total aorta, length of ascending aorta, direct distance of ascending aorta, and tortuosity index of ascending aorta are valuable geometric risk factors. Our model shows a good performance in predicting the incidence of TBAD.

Preoperative monocyte-to-HDL-cholesterol ratio predicts early recurrence after radiofrequency maze procedure of valvular atrial fibrillation.

BACKGROUND: Monocyte-to-high-density lipoprotein (M/H) ratio has emerged as a novel cardiovascular prognostic biomarker. We aimed to evaluate the prognostic values of M/H with early recurrence in persistent valvular atrial fibrillation (AF) patients after radiofrequency (RF) maze procedure. METHODS: We retrospectively analyzed 131 consecutive persistent AF patients with valvular heart diseases who were followed up 3 months after RF maze procedure. Their clinical data were recorded. Logistic regression analyses were performed for significant predictors. Receiver operating characteristic analysis was used for validation with corresponding area under the curve. RESULTS: 70 (53.4%) patients experienced early recurrence after procedure. Patients with early recurrence were older, have longer AF duration history, larger left atria diameter (LAD), higher plasma C-reactive protein (CRP), lower triglycerides (TG), lower cholesterol (TC), increased monocyte counts, lower HDL cholesterol, and increased M/H ratio. In multivariate analysis, age (OR 1.1 95% CI 1.0-1.1 P = .003), LAD (OR 2.1, 95%CI 1.2-3.5, P = .006), TG (OR 0.35, 95% CI 0.15-0.84, P = .019), M/H (OR 6.1, 95% CI 2.9-13.0, P < .001) were significantly independent predictors of AF early recurrence. M/H ratio demonstrated a significant predictive value (AUC = 0.77, sensitivity 89.0%, specificity 54%). Further, there was a positive correlation of M/H ratio with CRP and white blood cell. CONCLUSION: Preoperative M/H ratio was an independent risk factor of AF early recurrence following RF maze operation. M/H ratio should be considered in prediction of early recurrence for valvular AF patients.

Predictive Factors for In-Hospital Preoperative Rupture in Hyperacute Type A Aortic Dissection.

OBJECTIVE: This study aims to figure out risk factors of in-hospital preoperative rupture of hyperacute type A aortic dissection (haTAAD) patients and build a prediction and risk stratification model. METHODS: From January 2011 to December 2019, 830 patients diagnosed as haTAAD from Nanjing Drum Tower Hospital were enrolled. Among them, 799 patients received prompt surgery and 31 suffered aortic rupture before operation. The association between in-hospital preoperative rupture and perioperative parameters were examined. Best subset selection was used for feature selection and ROC curve was used to identify the model. RESULTS: Age, winter season, back pain, preoperative hypotension, albumin and globulin ratio, high serum phosphorus level are risk factors for in-hospital preoperative rupture of haTAAD. On the basis of six variables with AUC 0.828, a nomogram was established. According to the robustness test, actual in-hospital preoperative ruptures were fitted well. CONCLUSIONS: The in-hospital rupture prediction model was developed using logistic regression analysis. High serum phosphorus level is one of the strongest predictors. This nomogram may be useful when evaluating the risk of aortic dissection in-hospital rupture in future trials.

Transcriptome analysis of maize reveals potential key genes involved in the response to belowground herbivore Holotrichia parallela larvae feeding.

The larvae of Holotrichia parallela, a destructive belowground herbivore, causes tremendous damages to maize plants. However, little is known if there are any defense mechanisms in maize roots to defend themselves against this herbivore. In the current research, we carried out RNA-sequencing to investigate the changes in gene transcription level in maize roots after H. parallela larvae infestation. A total of 644 up-regulated genes and 474 down-regulated genes was found. In addition, Gene ontology (GO) annotation analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Weighted gene co-expression network analysis (WGCNA) indicated that peroxidase genes may be the hub genes that regulate maize defenses to H. parallela larvae attack. We also found 105 transcription factors, 44 hormone-related genes, and 62 secondary metabolism-related genes within differentially expressed genes (DEGs). Furthermore, the expression profiles of 12 DEGs from the transcriptome analysis were confirmed by quantitative real-time PCR experiments. This transcriptome analysis provides insights into the molecular mechanisms of the underground defense in maize roots to H. parallela larvae attack and will help to select target genes of maize for defense against belowground herbivory.

Evaluation of ß-blocker therapy for long-term outcomes in patients with low ejection fraction after cardiac surgery.

BACKGROUND: Preoperative low left ventricular ejection fraction (LVEF) has been reported as an independent risk factor for in-hospital mortality. However, there were few studies evaluating the long-term mortality in these patients. We, therefore, conducted this study to investigate long-term outcomes of surgery on patients with LVEF≤35% undergoing a broad range of cardiac procedures. METHODS: We performed a retrospective cohort study in 510 patients from January 1, 2007 to September 1, 2019. These patients were divided into survival group (n = 386) and non-survival group (n = 124). The multivariate Cox analysis was used to estimate the risk factors for survival. In Cox analysis, ß-blockers were indicated to be associated with long-term mortality. To further address bias, we derived a propensity score predicting the function of ß-blockers on survival, and matched 52 cases to 52 controls with similar risk profiles. RESULTS: Patients were followed for a median period of 24 months (interquartile range: 11-44 months). Multivariate Cox regression analysis indicated that the non-survival group had higher weight, higher EuroSCORE, more smoking patients, longer time of cardiopulmonary bypass (CPB), more intra-aortic balloon pump (IABP) use, and more patients who always used ß-blocker (HR: 2.056, 95%CI:1.236-3.420, P = 0.005) compared with survival group. After propensity matching, the group which always used ß-blocker showed higher rate of all-cause death compare with the control group (61.54% vs 80.77%, P = 0.030). CONCLUSIONS: The risk factors for long-term survival were weight, EuroSCORE, smoking, CPB, IABP, always used ß-blockers in patients with LVEF≤35%. The discharge prescription of ß-blocker should be cautiously administrated in those patients.

Diallyl trisulfide ameliorates myocardial ischemia-reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation.

Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40 mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5 mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.

A new flavonoid glycoside (APG) isolated from Clematis tangutica attenuates myocardial ischemia/reperfusion injury via activating PKCε signaling.

Clematis tangutica has been shown to be beneficial for the heart; however, the mechanism of this effectremains unknown. Apigenin-7-O-ß-D-(-6″-p-coumaroyl)-glucopyranoside (APG) is a new flavonoid glycoside isolated from Clematis tangutica. This study investigates the effects of APG on myocardial ischemia/reperfusion (IR) injury (IRI). An IRI model of primary myocardial cells and mice was used in this study. Compared with the IR group, APG preconditioning is protective against IRI in primary myocardial cells and in mice hearts in a dose-dependent manner. The cardioprotective mechanisms of APG may involve a significant PKCε translocation into the mitochondria and an activation of the Nrf2/HO-1 pathway, which respectively suppressesmitochondrial oxidative stress and inhibits apoptosis. In addition, PKCε-targeted siRNA and a PKCε specialized inhibitor (ε-V1-2) were used to inhibit PKCε expression and activity. The inhibition of PKCε reversed the cardioprotective effect of APG, with an inhibition of Nrf2/HO-1 activation and increased mitochondrial oxidative stress and cardiomyocyte apoptosis. In conclusion, PKCε activation plays an important role in the cardioprotective effects of APG. PKCε activation induced by APG preconditioning reduces mitochondrial oxidative stress and promotes Nrf2/HO-1-mediated anti-apoptosis signaling.

The diagnostic value of tenascin-C in acute aortic syndrome.

OBJECTIVES: Misdiagnosis of acute aortic syndrome (AAS) significantly increases mortality. Tenascin-C (TN-C) is an extracellular matrix glycoprotein related to cardiovascular injury. The elevation of TN-C in AAS and whether it can discriminate sudden-onset of acute chest pain in Chinese remains unclear. METHODS: We measured the plasma concentration of TN-C by ELISA in a cohort of 376 patients with chest or back pain. Measures to discriminate AAS from acute coronary syndrome (ACS) were compared and calculated. RESULTS: From October 2016 to September 2021, 376 undiagnosed patients with chest or back pain were enrolled. 166 of them were finally diagnosed as AAS, 100 were ACS and 110 without cardiovascular diseases (NCV). TN-C was significantly elevated in AAS at 18.18 ng/mL (IQR: 13.10-27.68) compared with 7.51 ng/mL (IQR: 5.67-11.38) in ACS (P < 0.001) and 3.68 ng/mL (IQR: 2.50-5.29) in NCV (P < 0.001). There was no significant difference in TN-C level among the subtypes of AAS. Of the 166 AAS patients, the peaked level of TN-C was at acute stage (P = 0.012), then a slight of decrease was observed at subacute stage. The area under receiver operating characteristic curve for AAS patients versus NCV was 0.979 (95% CI: 0.964-0.994) for TN-C. At a cutoff level of 11.474 ng/mL, TN-C has a sensitivity of 76.0%, specificity of 85.5%, accuracy of 82.0%, positive predictive value (PPV) of 76.0%, negative predictive value (NPV) of 85.5%. Diagnostic performance of TN-C was superior to D-dimer and hs-cTnT. CONCLUSIONS: The concentration of serum TN-C in AAS patients was significantly higher than that in ACS patients and NCV. TN-C could be a new biomarker to distinguish AAS patients in the early stage after symptoms onset from other pain diseases.

Development and validation of LCMM prediction algorithms to estimate recovery pattern of postoperative AKI in type A aortic dissection: a retrospective study.

Background: Postoperative acute kidney injury (PO-AKI) is a prevalent complication among patients with acute type A aortic dissection (aTAAD) for which unrecognized trajectories of renal function recovery, and their heterogeneity, may underpin poor success in identifying effective therapies. Methods: This was a retrospective, single-center cohort study in a regional Great Vessel Center including patients undergoing aortic dissection surgery. Estimated glomerular filtration rate (eGFR) recovery trajectories of PO-AKI were defined through the unsupervised latent class mixture modeling (LCMM), with an assessment of patient and procedural characteristics, complications, and early-term survival. Internal validation was performed by resampling. Results: A total of 1,295 aTAAD patients underwent surgery and 645 (49.8%) developed PO-AKI. Among the PO-AKI cohort, the LCMM identified two distinct eGFR trajectories: early recovery (ER-AKI, 51.8% of patients) and late or no recovery (LNR-AKI, 48.2% of patients). Binary logistic regression identified five critical determinants regarding poor renal recovery, including chronic kidney disease (CKD) history, renal hypoperfusion, circulation arrest time, intraoperative urine, and myoglobin. LNR-AKI was associated with increased mortality, continuous renal replacement therapies, mechanical ventilation, ICU stay, and hospital stay. The assessment of the predictive model was good, with an area under the curve (AUC) of 0.73 (95% CI: 0.69-0.76), sensitivity of 61.74%, and specificity of 75.15%. The internal validation derived a consistent average AUC of 0.73. The nomogram was constructed for clinicians' convenience. Conclusion: Our study explored the PO-AKI recovery patterns among surgical aTAAD patients and identified critical determinants that help to predict individuals at risk of poor recovery of renal function.

A machine learning approach for predicting descending thoracic aortic diameter.

Background: To establish models for predicting descending thoracic aortic diameters and provide evidence for selecting the size of the stent graft for TBAD patients. Methods: A total of 200 candidates without severe deformation of aorta were included. CTA information was collected and 3D reconstructed. In the reconstructed CTA, a total of 12 cross-sections of peripheral vessels were made perpendicular to the axis of flow of the aorta. Parameters of the cross sections and basic clinical characteristics were used for prediction. The data was randomly split into the training set and the test set in an 8:2 ratio. To fully describe diameters of descending thoracic aorta, three predicted points were set based quadrisection, and a total of 12 models at three predicted points were established using four algorithms included linear regression (LR), support vector machine (SVM), Extra-Tree regression (ETR) and random forest regression (RFR). The performance of models was evaluated by mean square error (MSE) of the prediction value, and the ranking of feature importance was given by Shapley value. After modeling, prognosis of five TEVAR cases and stent oversizing were compared. Results: We identified a series of parameters which affect the diameter of descending thoracic aorta, including age, hypertension, the area of proximal edge of superior mesenteric artery, etc. Among four predictive models, all the MSEs of SVM models at three different predicted position were less than 2 mm2, with approximately 90% predicted diameters error less than 2 mm in the test sets. In patients with dSINE, stent oversizing was about 3 mm, while only 1 mm in patients without complications. Conclusion: The predictive models established by machine learning revealed the relationship between basic characteristics and diameters of different segment of descending aorta, which help to provide evidence for selecting the matching distal size of the stent for TBAD patients, thereby reducing the incidence of TEVAR complications.

Study on the Constitutive Relationship between Ordinary Concrete and Nano-Titanium Dioxide-Modified Concrete at High Temperature.

After high-temperature treatment, both nano-titanium dioxide-modified concrete and ordinary concrete exhibit typical splitting failure. High-temperature heating reduces the mechanical properties and brittleness of concrete and improves the ductility of concrete. The stress-strain relationship of the specimens was obtained through the uniaxial compression test of ordinary concrete and nano-titanium dioxide-modified concrete cube specimens under normal temperature and high-temperature conditions. In addition, the relationship between temperature and damage variables was established, and the unified constitutive model containing damage variables after room temperature and high-temperature treatment of ordinary concrete and nano-titanium dioxide-modified concrete were established. It provides a reference for future research on the mechanical properties of high-performance concrete structures after high temperatures (fire).

Evaluation of Two Online Risk Prediction Models for the Mortality Rate of Acute Type A Aortic Dissection Surgery: The German Registry of Acute Aortic Dissection Type A Score and the European System for Cardiac Operative Risk Evaluation II.

EuroSCORE II is one of the most widely utilized cardiovascular surgery risk scoring systems. Recently, a new online score calculator, namely the German Registry of Acute Aortic Dissection Type A (GERAADA), was launched to predict 30-day surgical mortality for acute type A aortic dissection (ATAAD) patients. The aim of this study is to evaluate the predictive performance of these two scores. We calculated the two scores for 1346 ATAAD patients from January 2012 to December 2021. The overall performance was evaluated using Brier scores and Hosmer-Lemeshow statistics. Receiver Operating Characteristic (ROC) curves were employed to assess diagnostic ability, and the standardized mortality ratio (SMR) was utilized to evaluate calibration. The GERAADA score and EuroSCORE II predicted 30-day mortality rates of 14.7% and 3.1%, respectively, while the observed rate was 12.5%. The predictive ability of EuroSCORE II (AUC 0.708, 95% CI: 0.664-0.792) was superior to that of the GERAADA score (0.648, 95% CI: 0.605-0.692). The GERAADA score had higher sensitivity but lower specificity than EuroSCORE II. And the GERAADA score may overestimate mortality (0.76, 95% CI: 0.65-0.89), while EuroSCORE II may underestimate the mortality rate (3.17, 95% CI: 2.92-3.44). The EuroSCORE II was superior in predicting surgical mortality among ATAAD patients. But the observed 30-day mortality rate certified a good calibration for the GERAADA score.

Atrial Fibrillation Underlies Cardiomyocyte Senescence and Contributes to Deleterious Atrial Remodeling during Disease Progression.

Accelerated senescence is triggered by key mediators of arrhythmogenic substrates and contributes to atrial fibrillation (AF). We sought to understand senescence in AF and the extent to which it aggravates the AF process. Twenty-six AF patients undergoing open-heart surgery were included, and 12 patients with sinus rhythm served as controls. Another cohort included 120 consecutive persistent AF patients with valvular heart diseases. HL-1 atrial myocytes were tachypaced (TP) to simulate experimental AF. Compared with sinus rhythm, left atrial appendages (LAAs) with AF presented a significantly increased positive area of cellular senescence, with upregulated expression of p16, p21 and p53. Next, p21 mRNA was increased in patients with AF recurrence compared with that in patients without recurrence. In multivariate analysis, p21 (OR: 2.97; 95% CI: 1.65-5.34; P<0.001) was a significant independent predictor of AF early recurrence. Interestingly, TP induced HL-1 atrial myocyte senescence in vitro, accompanied by a marked increase in the senescence-associated secretory phenotype (SASP) and altered the expression of sarcoplasmic reticulum (SR)-related proteins. Suppression of p21 by siRNA reduced TP induced cell senescence and IL-1ß, IL-6 elevation, and partly changed SR-related proteins expression. Moreover, we show that the level of γH2AX, a marker of DNA damage, was higher in AF patients than in sinus rhythm controls. Similarly, an increase in γH2AX levels was observed following TP. AF underlies cardiomyocyte senescence and contributes to deleterious atrial remodeling during disease progression. This finding may help facilitate the search for new therapeutic approaches for antiaging therapy for AF.

The role of peripheral blood eosinophil counts in acute Stanford type A aortic dissection patients.

Background: Acute Stanford-A aortic dissection (AAAD) is a devastating cardiovascular condition with high mortality, therefore identifying risk prognosis factors is vital for the risk stratification of patients with AAAD. Here, we investigated peripheral blood eosinophil (EOS) counts in patients with AAAD and their possible biological implications. Methods: We performed a single center retrospective cohort study. From 2011 to 2021, a total of 1,190 patients underwent AAAD surgery. Patients were categorized first by death and then admission EOS counts (0.00 × 109/L or >0.00 × 109/L). Demographics, laboratory data, and outcomes were analyzed using standard statistical analyses. Ascending aorta specimens were used for western blotting and histological assessments. Results: Death group patients had lower EOS counts than the non-death group (P = 0.008). When patients were stratified using mean blood EOS counts: 681 patients had low (0.00 × 109/L) and 499 had high (>0.00 × 109/L) counts. Patients with low EOS counts at admission were more likely to have a higher mortality risk (P = 0.017) and longer treatment in the intensive care unit (ICU) days (P = 0.033) than patients with normal EOS counts. Also, the five blood coagulation items between both groups showed significantly different (P < 0.001). Hematoxylin & eosin-stained cross-sections of the ascending aorta false lumen showed that EOSs were readily observed in thrombi in the false lumen of the aorta. Conclusions: Peripheral blood EOS counts may be involved in thrombosis and could be an effective and efficient indicator for the diagnosis, evaluation, and prognosis monitoring of patients with AAAD.

Serum Oxylipin Profiles Identify Potential Biomarkers in Patients with Acute Aortic Dissection.

Aortic dissection (AD) is a life-threatening cardiovascular disease with a dismal prognosis. Inflammation plays an important role in AD. Oxylipins are bioactive lipids involved in the modulation of inflammation and may be involved in the pathogenesis and progression of AD. This study aims to identify possible metabolites related to AD. A total of 10 type A Aortic dissection (TAAD) patients, 10 type B Aortic dissection (TBAD) patients and 10 healthy controls were included in this study. Over 100 oxylipin species were identified and quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis. Our investigation demonstrated substantial alterations in 91 oxylipins between AD and healthy individuals. Patients with TAAD had 89 entries accessible compared to healthy controls. According to orthogonal partial least squares discriminant analysis (OPLS-DA), fitness (R2X = 0.362 and R2Y = 0.807, p = 0.03) and predictability (Q2 = 0.517, p = 0.005) are the validation parameters between the two groups. Using multivariate logistic regression, 13-HOTrE and 16(17)-EpDPE were the risk factors in the aortic patients group compared to healthy people (OR = 2.467, 95%CI:1.256-7.245, p = 0.035; OR = 0.015, 95%CI:0.0002-0.3240, p = 0.016, respectively). In KEGG enrichment of differential metabolites, the arachidonic acid metabolism pathway has the most metabolites involved. We established a diagnostic model in distinguishing between AD and healthy people. The AUC was 0.905. Oxylipins were significantly altered in AD patients, suggesting oxylipin profile is expected to exploit a novel, non-invasive, objective diagnosis for AD.

Hsp90 S-nitrosylation at Cys521, as a conformational switch, modulates cycling of Hsp90-AHA1-CDC37 chaperone machine to aggravate atherosclerosis.

Endothelial dysfunction is the initial process of atherosclerosis. Heat shock protein 90 (Hsp90), as a molecular chaperone, plays a crucial role in various cardiovascular diseases. Hsp90 function is regulated by S-nitrosylation (SNO). However, the precise role of SNO-Hsp90 in endothelial dysfunction during atherosclerosis remains unclear. We here identified Hsp90 as a highly S-nitrosylated target in endothelial cells (ECs) by biotin switch assay combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The elevation of SNO-Hsp90 was observed in atherosclerotic human and rodent aortas as well as in oxidized LDL (oxLDL)-treated ECs. Inhibition of inducible nitric oxide synthase (iNOS) or transfection with Hsp90 cysteine 521 (Cys521) mutation plasmid decreased the level of SNO-Hsp90 in oxLDL-cultured ECs. Coimmunoprecipitation and proximity ligation assay demonstrated that SNO-Hsp90 at Cys521 suppressed the interaction between Hsp90 and activator of Hsp90 ATPase activity 1 (AHA1), but promoted the association of Hsp90 and cell division cycle 37 (CDC37). Hsp90 Cys521 mutation increased endothelial nitric oxide synthase (eNOS) activity and inhibited nuclear factor kappa-B (NF-κB) signaling, thereby increasing nitric oxide (NO) bioavailability and alleviating endothelial adhesion, inflammation and oxidative stress in oxLDL-treated ECs. Also, administration of endothelial-specific adeno-associated viruses of Cys521-mutated Hsp90 significantly mitigated vascular oxidative stress, macrophage infiltration and atherosclerosis lesion areas in high fat diet-fed ApoE-/- mice. In conclusion, SNO-Hsp90 at Cys521, that serves as a conformational switch, disrupts Hsp90/AHA1 interaction but promotes recruitment of CDC37 to exacerbate atherosclerosis.

Prompt surgery is effective for acute type A aortic dissection with cerebral ischemia.

BACKGROUND: Acute type A aortic dissection (aTAAD) with preoperative cerebral ischemia (CI) is common and lethal, but the timing and treatment method remain uncertain. We retrospectively reviewed our aTAAD patients with CI and analyzed the outcomes and related risk factors. METHODS: From January 2011 to December 2019, 1,173 patients diagnosed with aTAAD from Nanjing Drum Tower Hospital were enrolled. Among them, 131 patients had CI preoperatively (CI group), and 1,042 patients were in the non-CI group. One hundred eight in the CI group and 984 in the non-CI group received central repair surgery. Fifteen patients had postoperative cerebral complications (CC) and 93 had non-CCs. ROC curves were used to identify the safe duration of preoperative CI. RESULTS: The CI group was older (56.3 vs. 53.2 years, P=0.013) and had lower rates of pain, chest pain and back pain (77.9% vs. 94.4%, 75.4% vs. 87.5% and 30.8% vs. 42.3%, respectively) than the non-CI group. The CI group had a higher rate of preoperative hypotension and tamponade (13.7% vs. 6.0%, 26.9% vs. 10.4%, respectively; P=0.000). More patients in the CI group did not receive central repair surgery, and the CI had higher mortality (28.2% vs. 15.9%). CI without central repair surgery was a strong risk factor for mortality. CI patients with CC after central repair had a higher mortality, and preoperative coma was the strongest risk factor for postoperative CC.A duration between CI symptoms and central repair surgery of less than 12.75 hours is recommended. CONCLUSIONS: Prompt surgery is effective for aTAAD with CI, and preoperative coma and a safe duration longer than 12.75 hours would predict worse outcomes.

S-nitrosylation-mediated coupling of G-protein alpha-2 with CXCR5 induces Hippo/YAP-dependent diabetes-accelerated atherosclerosis.

Atherosclerosis-associated cardiovascular disease is one of the main causes of death and disability among patients with diabetes mellitus. However, little is known about the impact of S-nitrosylation in diabetes-accelerated atherosclerosis. Here, we show increased levels of S-nitrosylation of guanine nucleotide-binding protein G(i) subunit alpha-2 (SNO-GNAI2) at Cysteine 66 in coronary artery samples from diabetic patients with atherosclerosis, consistently with results from mice. Mechanistically, SNO-GNAI2 acted by coupling with CXCR5 to dephosphorylate the Hippo pathway kinase LATS1, thereby leading to nuclear translocation of YAP and promoting an inflammatory response in endothelial cells. Furthermore, Cys-mutant GNAI2 refractory to S-nitrosylation abrogated GNAI2-CXCR5 coupling, alleviated atherosclerosis in diabetic mice, restored Hippo activity, and reduced endothelial inflammation. In addition, we showed that melatonin treatment restored endothelial function and protected against diabetes-accelerated atherosclerosis by preventing GNAI2 S-nitrosylation. In conclusion, SNO-GNAI2 drives diabetes-accelerated atherosclerosis by coupling with CXCR5 and activating YAP-dependent endothelial inflammation, and reducing SNO-GNAI2 is an efficient strategy for alleviating diabetes-accelerated atherosclerosis.