Bradykinin induces acute kidney injury after hypothermic circulatory arrest through the repression of the Nrf2-xCT pathway.

Postoperative acute kidney injury (AKI) is a common complication in patients undergoing deep hypothermic circulatory arrest (HCA); however, its underlying pathogenesis is unclear. In this study, we established a rat cardiopulmonary bypass model and demonstrated that hypothermia during HCA, rather than circulatory arrest, was responsible for the occurrence of AKI. By recruiting 56 patients who underwent surgery with HCA and analyzing the blood samples, we found that post-HCA AKI was associated with an increase in bradykinin. Animal experiments confirmed this and showed that hypothermia during HCA increased bradykinin levels by increasing kallikrein expression. Mechanistically, bradykinin inhibited the Nrf2-xCT pathway through B2R and caused renal oxidative stress damage. Application of Icatibant, a B2R inhibitor, reversed changes in the Nrf2-xCT pathway and oxidative stress damage. Finally, Icatibant reversed hypothermia-induced AKI in vivo. This finding reveals the pathogenesis of AKI after HCA and helps to provide therapeutic strategy for patients with post-HCA AKI.

Scoring model based on cardiac CT and clinical factors to predict early good mitral valve repair in rheumatic mitral disease.

OBJECTIVE: We aimed to evaluate the mitral valve calcification and mitral structure detected by cardiac computed tomography (cardiac CT) and establish a scoring model based on cardiac CT and clinical factors to predict early good mitral valve repair (EGMR) and guide surgical strategy in rheumatic mitral disease (RMD). MATERIALS AND METHODS: This is a retrospective bi-center cohort study. Based on cardiac CT, mitral valve calcification and mitral structure in RMD were quantified and evaluated. The primary outcome was EGMR. A logical regression algorithm was applied to the scoring model. RESULTS: A total of 579 patients were enrolled in our study from January 1, 2019, to August 31, 2022. Of these, 443 had baseline cardiac CT scans of adequate quality. The calcification quality score, calcification and thinnest part of the anterior leaflet clean zone, and papillary muscle symmetry were the independent CT factors of EGMR. Coronary artery disease and pulmonary artery pressure were the independent clinical factors of EGMR. Based on the above six factors, a scoring model was established. Sensitivity = 95% and specificity = 95% were presented with a cutoff value of 0.85 and 0.30 respectively. The area under the receiver operating characteristic of external validation set was 0.84 (95% confidence interval [CI] 0.73-0.93). CONCLUSIONS: Mitral valve repair is recommended when the scoring model value > 0.85 and mitral valve replacement is prior when the scoring model value < 0.30. This model could assist in guiding surgical strategies for RMD. CLINICAL RELEVANCE STATEMENT: The model established in this study can serve as a reference indicator for surgical repair in rheumatic mitral valve disease. KEY POINTS: • Cardiac CT can reflect the mitral structure in detail, especially for valve calcification. • A model based on cardiac CT and clinical factors for predicting early good mitral valve repair was established. • The developed model can help cardiac surgeons formulate appropriate surgical strategies.

Prognostic Value of Left Ventricular Longitudinal Function and Myocardial Fibrosis in Patients With Ischemic and Non-Ischemic Dilated Cardiomyopathy Concomitant With Type 2 Diabetes Mellitus: A 3.0 T Cardiac MR Study.

BACKGROUND: Poorly controlled type 2 diabetes mellitus (T2DM) is known to result in left ventricular (LV) dysfunction, myocardial fibrosis, and ischemic/nonischemic dilated cardiomyopathy (ICM/NIDCM). However, less is known about the prognostic value of T2DM on LV longitudinal function and late gadolinium enhancement (LGE) assessed with cardiac MRI in ICM/NIDCM patients. PURPOSE: To measure LV longitudinal function and myocardial scar in ICM/NIDCM patients with T2DM and to determine their prognostic values. STUDY TYPE: Retrospective cohort. POPULATION: Two hundred thirty-five ICM/NIDCM patients (158 with T2DM and 77 without T2DM). FIELD STRENGTH/SEQUENCE: 3T; steady-state free precession cine; phase-sensitive inversion recovery segmented gradient echo LGE sequences. ASSESSMENT: Global peak longitudinal systolic strain rate (GLPSSR) was evaluated to LV longitudinal function with feature tracking. The predictive value of GLPSSR was determined with ROC curve. Glycated hemoglobin (HbA1c) was measured. The primary adverse cardiovascular endpoint was follow up every 3 months. STATISTICAL TESTS: Mann-Whitney U test or student's t-test; Intra and inter-observer variabilities; Kaplan-Meier method; Cox proportional hazards analysis (threshold = 5%). RESULTS: ICM/NIDCM patients with T2DM exhibited significantly lower absolute value of GLPSSR (0.39 ± 0.14 vs. 0.49 ± 0.18) and higher proportion of LGE positive (+) despite similar LV ejection fraction, compared to without T2DM. LV GLPSSR was able to predict primary endpoint (AUC 0.73) and optimal cutoff point was 0.4. ICM/NIDCM patients with T2DM (GLPSSR < 0.4) had more markedly impaired survival. Importantly, this group (GLPSSR < 0.4, HbA1c ≥ 7.8%, or LGE (+)) exhibited the worst survival. In multivariate analysis, GLPSSR, HbA1c, and LGE (+) significantly predicted primary adverse cardiovascular endpoint in overall ICM/NIDCM and ICM/NIDCM patients with T2DM. CONCLUSIONS: T2DM has an additive deleterious effect on LV longitudinal function and myocardial fibrosis in ICM/NIDCM patients. Combining GLPSSR, HbA1c, and LGE could be promising markers in predicting outcomes in ICM/NIDCM patients with T2DM. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: 5.

Effect of Asymptomatic Common Carotid Artery Dissection on the Prognosis of Patients With Acute Type A Aortic Dissection.

BACKGROUND: Acute type A aortic dissection can extend upwards to involve the common carotid artery. However, whether asymptomatic common carotid artery dissection (CCAD) requires surgical repair remains controversial. This study aimed to explore the effect of asymptomatic CCAD without surgical intervention on the prognosis of patients who underwent surgery for acute type A aortic dissection. METHODS AND RESULTS: Between January 2015 and December 2017, 485 patients with no neurological symptoms who underwent surgery for acute type A aortic dissection were enrolled in this retrospective cohort study. The patients were divided into 2 groups based on the exposure factor of CCAD. CCAD was detected in 111 patients (22.9%), and after adjusting baseline data (standardized mean difference <0.1), the 30-day mortality (17.1% versus 6.0%, P<0.001) and incidence of fatal stroke (7.7% versus 1.6%, P=0.001) were significantly higher in the group with CCAD. Univariable and multivariable Cox regression analyses found CCAD as an independent risk factor for 30-day mortality (hazard ratio [HR], 2.8 [95% CI, 1.5-5.2]; P=0.001). At a median follow-up of 6.2 years (interquartile range, 5.6-6.9 years), landmark analysis with a cutoff value of 1 month postoperatively showed a significant increase in mortality in the group with CCAD, especially in the first month (log-rank P=0.002) and no significant difference in survival after the first month postoperatively between the 2 groups (log-rank P=0.955). CONCLUSIONS: Asymptomatic CCAD increased the risk of early fatal stroke and death in patients with acute type A aortic dissection after surgery but did not affect midterm survival in patients who survived the early postoperative period.

A scoring model based on clinical factors to predict postoperative moderate to severe acute respiratory distress syndrome in Stanford type A aortic dissection.

BACKGROUND: Postoperative acute respiratory distress syndrome (ARDS) after type A aortic dissection is common and has high mortality. However, it is not clear which patients are at high risk of ARDS and an early prediction model is deficient. METHODS: From May 2015 to December 2017, 594 acute Stanford type A aortic dissection (ATAAD) patients who underwent aortic surgery in Anzhen Hospital were enrolled in our study. We compared the early survival of MS-ARDS within 24 h by Kaplan-Meier curves and log-rank tests. The data were divided into a training set and a test set at a ratio of 7:3. We established two prediction models and tested their efficiency. RESULTS: The oxygenation index decreased significantly immediately and 24 h after TAAD surgery. A total of 363 patients (61.1%) suffered from moderate and severe hypoxemia within 4 h, and 243 patients (40.9%) suffered from MS-ARDS within 24 h after surgery. Patients with MS-ARDS had higher 30-day mortality than others (log-rank test: p-value <0.001). There were 30 variables associated with MS-ARDS after surgery. The XGboost model consisted of 30 variables. The logistic regression model (LRM) consisted of 11 variables. The mean accuracy of the XGBoost model was 70.7%, and that of the LRM was 80.0%. The AUCs of XGBoost and LRM were 0.764 and 0.797, respectively. CONCLUSION: Postoperative MS-ARDS significantly increased early mortality after TAAD surgery. The LRM model has higher accuracy, and the XGBoost model has higher specificity.

Midterm outcomes of simultaneous carotid revascularization combined with coronary artery bypass grafting.

BACKGROUND: Simultaneous carotid endarterectomy (CEA) combined with coronary artery bypass grafting (CABG) has been widely used in patients with coronary heart disease complicated with severe carotid stenosis to reduce the risk of stroke and death. Carotid artery stenting (CAS) has been proven to be an alternative to CEA in recent years. We investigated the early and mid-term outcomes of simultaneous CEA or CAS combined with CABG in these patients. METHODS: From January 2011 to January 2021, 88 patients who underwent simultaneous carotid revascularization combined with CABG under the same anesthesia in Beijing Anzhen Hospital were retrospectively analyzed, and this study included 25 patients who underwent CAS-CABG and 63 patients who underwent CEA-CABG. The main outcomes included all-cause death, stroke, myocardial infarction and combined adverse events. The main outcomes of the two groups were compared at 30 days after the operation and the mid-term follow-up. Univariate and multivariate Cox proportional hazards regression analyses were performed to determine the independent risk factors affecting mid-term mortality. RESULTS: Within 30 days after the operation, there was no significant difference in combined adverse events between the two groups (P = 0.88). During the median follow-up period of 6.69 years (IQR, 5.82-7.57 years), 9 patients (14.30%) in the combined CEA-CABG group died, while 1 patient (4.00%) in the combined CAS-CABG group died. There were no significant differences in mid-term death (P = 0.20), stroke (P = 0.78), myocardial infarction (P = 0.88), or combined adverse events (P = 0.62) between the two groups. Univariate and multivariate Cox proportional hazards regression showed that NYHA grade IV (HR 5.01, 95% CI 1.16-21.64, P = 0.03) and previous myocardial infarction (HR 5.43, 95% CI 1.01-29.29, p = 0.04) were independent risk factors for mid-term mortality. We also found that combined CEA-CABG surgery may be associated with a higher risk of death (HR, 13.15; 95% CI 1.10-157.69, p = 0.04). CONCLUSIONS: Combined CAS-CABG is a safe and effective treatment for patients with coronary heart disease complicated with severe carotid stenosis. NYHA grade IV and previous MI were independent risk factors for mid-term mortality.

Influence of Dynamic and Static Obstructive Renal Artery on Early Prognosis in Stanford Type A Aortic Dissection.

BACKGROUND: Acute kidney injury (AKI) after acute Stanford type A aortic dissection (STAAD) surgery has a high mortality rate. Clarifying what type of renal artery problem (dynamic obstructive renal artery, DORA, or static obstructive renal artery, SORA) secondary to STAAD benefits from true lumen opening is helpful in providing a reference for the indication of renal artery intervention. METHODS: From May 2018 to December 2019, 292 acute STAAD patients who underwent aortic surgery were enrolled in this study. DORA, SORA, and renal malperfusion were diagnosed according to preoperative aortic enhanced computed tomography (CTA). Renal artery problems secondary to STAAD were divided into three types: type 1, normal renal artery; type 2, DORA; and type 3, SORA. Acute kidney injury was divided into three stages: Stage 1, Stage 2, and Stage 3, according to 2012 Kidney Disease: Improving Global Outcomes (KDIGO). The primary endpoint was all-cause 30-day in-hospital death, and the secondary endpoint was postoperative dialysis requirement. Univariate and multivariate analyses were performed to assess the difference among the three types. RESULTS: Postoperative AKI occurred in 154 of 292 (52.7%) patients, and postoperative dialysis was present in 27 of 292 (9.2%) patients with STAAD. Postoperative AKI and dialysis were significantly more prevalent in the SORA group (AKI: 71% in SORA group vs 51.5% in DORA group vs 22.2% in normal group; postoperative dialysis: 22.2% in SORA group vs 5.4% in DORA group vs 6.1 in normal group). Thirty-day (30-day) mortality was also significantly higher in the SORA group (Log-rank test, p=0.012). Preoperative acute myocardial infarction and body mass index were the independent risk factors for 30-day mortality. Static obstructive renal artery, cardiopulmonary bypass time, and renal blood cell transfusion >3 units were the independent risk factors for postoperative dialysis requirement. CONCLUSION: Static obstructive renal artery led to higher 30-day in-hospital mortality and more postoperative dialysis. Open surgery reduced renal ischaemia injury caused by DORA, but it could not reduce renal ischaemia injury caused by SORA.

Mid-term Patency of the Great Saphenous Bypass to Aorta vs. Non-aortic Arteries in Stanford Type A Aortic Dissection Surgery With Concomitant CABG.

Background: Stanford type A aortic dissection (STAAD) is often associated with coronary artery problems requiring coronary artery bypass grafting (CABG). However, the prognosis of different proximal graft locations remains unclear. Methods: From May 2015 to April 2020, 62 patients with acute STAAD who underwent aortic surgery concomitant with CABG were enrolled in our study. Aortic bypass was defined as connecting the proximal end of the vein bridge to the artificial aorta (SVG-AO); non-aortic bypass was defined as connecting the proximal end of the vein bridge to a non-aorta vessel, including left subclavian artery, left common carotid artery, and right brachiocephalic artery (non-SVG-AO). We compared early- and mid-term results between patients in the above two groups. Early results included death and bleeding, and mid-term results graft patency, aortic-related events, and bleeding. Grafts were evaluated by post-operative coronary computed tomography angiography. According to the Fitzgibbon classification, grade A (graft stenosis <50%) is considered a patent graft. Univariate and multivariate analyses were performed to assess differences between aortic and non-aortic bypass in STAAD. Results: SVG-AO and non-SVG-AO were performed in 15 and 47 patients, respectively. There was no significant difference in death (log-rank test, p = 0.426) or bleeding (p = 0.766) between the two groups in the short term. One year of follow-up was completed in 37 patients (eight in the SVG-AO group and 29 in the non-SVG-AO group), among which 14/15 (93.3%) grafts were patent in the SVG-AO group and 32/33 (97.0%) grafts in the non-SVG-AO at 1 week, without a significant difference (p = 0.532). At 3 months, 12/13 (92.3%) grafts were patent in the SVG-AO group and 16/32 (50.0%) grafts in the non-SVG-AO, with a significant difference (p = 0.015), and 12/13 (92.3%) grafts in the SVG-AO group and 15/32 (46.9%) grafts in the non-SVG-AO group were patents, with a significant difference. Multivariate analysis showed proximal aortic bypass and dual anticoagulation to be protective factors for the 1-year patency of grafts. Conclusion: In patients requiring aortic dissection surgery with concomitant CABG, no differencess' between SVG-AO and SVG-non-AO in early outcomes were detected, but SVG-AO may have higher mid-term patency.

Ketamine ameliorates depressive-like behaviors in mice through increasing glucose uptake regulated by the ERK/GLUT3 signaling pathway.

To investigate the effects of ketamine on glucose uptake and glucose transporter (GLUT) expression in depressive-like mice. After HA1800 cells were treated with ketamine, 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) was added to the cells to test the effects of ketamine on glucose uptake, production of lactate, and expression levels of GLUT, ERK1/2, AKT, and AMPK. Adult female C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS), 27 CUMS mice were randomly divided into the depression, ketamine (i.p.10 mg/kg), and FR180204 (ERK1/2 inhibitor, i.p.100 mg/kg) + ketamine group. Three mice randomly selected from each group were injected with 18F-FDG at 6 h after treatment. The brain tissue was collected at 6 h after treatment for p-ERK1/2 and GLUTs. Treatment with ketamine significantly increased glucose uptake, extracellular lactic-acid content, expression levels of GLUT3 and p-ERK in astrocytes and glucose uptake in the prefrontal cortex (P < 0.05), and the immobility time was significantly shortened in depressive-like mice (P < 0.01). An ERK1/2 inhibitor significantly inhibited ketamine-induced increases in the glucose uptake in depressive-like mice (P < 0.05), as well as prolonged the immobility time (P < 0.01). The expression levels of p-ERK1/2 and GLUT3 in depressive-like mice were significantly lower than those in normal control mice (P < 0.01). Ketamine treatment in depressive-like mice significantly increased the expression levels of p-ERK1/2 and GLUT3 in the prefrontal cortex (P < 0.01), whereas an ERK1/2 inhibitor significantly inhibited ketamine-induced increases (P < 0.01).Our present findings demonstrate that ketamine mitigated depressive-like behaviors in female mice by activating the ERK/GLUT3 signal pathway, which further increased glucose uptake in the prefrontal cortex.

Comparison of Prognosis Between Hybrid Debranching Surgery and Total Open Arch Replacement With Frozen Elephant Trunk for Type A Acute Aortic Syndrome Patients.

Background: It is unclear whether the total arch replacement (TAR) combined with frozen elephant trunk (FET) implantation and hybrid debranching surgery have a difference in the prognosis of patients with type A acute aortic syndrome (AAS). We attempted to compare the short-term and long-term prognosis of total arch replacement (TAR) combined with frozen elephant trunk (FET) implantation and hybrid debranching surgery in patients with type A acute aortic syndrome (AAS). Methods: From January 2014 to September 2020, a total of 518 patients who underwent TAR with FET surgery and 31 patients who underwent hybrid surgery were included. We analyzed the post-operative mortality and morbidity of complications of the two surgical methods, and we determined 67 patients for subgroup analysis through a 1:2 propensity score match (PSM). We identified risk factors for patient mortality and post-operative neurological complications through multivariate regression analysis. Results: Compared with the TAR with FET group, hybrid surgery could reduce aortic cross-clamp time, reduce intraoperative blood loss and prevent some patients from cardiopulmonary bypass. There was no significant difference in 30-day mortality between the TAR with FET group and the hybrid surgery group (10.6 vs. 9.7%). However, hybrid surgery had increased the incidence of permanent neurological complications in patients (95%CI: 4.7-35.7%, P = 0.001), especially post-operative cerebral infarction (P < 0.001). During the average follow-up period of 31.6 months, there was no significant difference in the 1-year survival rate and 3-year survival rate between the TAR with FET group and the hybrid surgery group (P = 0.811), but hybrid surgery increased the incidence of long-term neurological complications (P < 0.001). In multivariate regression analysis, surgical methods were not a risk factor for post-operative deaths, but hybrid surgery was a risk factor for post-operative neurological complications (P < 0.001). Conclusions: Hybrid surgery is an acceptable treatment for AAS, and its post-operative mortality is similar to FET. But hybrid surgery may increase the risk of permanent neurological complications after surgery, and this risk must be carefully considered when choosing hybrid surgery.

Case report: a novel approach for the emergency repair of acute aortic rupture associated with congenital aortic Coarctation.

BACKGROUND: Congenital aortic coarctation (CoA) associated with aortic rupture is a rare but extremely lethal condition. In pregnant patients, the condition becomes very risky. CASE PRESENTATION: We presented a case of a pregnant (20 weeks gestation) patient with CoA associated with ruptured aortic pseudoaneurysm who was successfully rescued using a novel hybrid strategy. CONCLUSIONS: This hybrid approach may be a life-saving bridging intervention in patients with CoA associated with devastating complications, such as ruptured aneurysms, especially with extremely narrowed access.

Short Term Prognosis of Renal Artery Stenosis Secondary to Acute Type B Aortic Dissection With TEVAR.

Objective: To determine the effect of renal artery stenosis (RAS) resulting from acute type B aortic dissection (ATBAD) with thoracic endovascular aortic repair (TEVAR) on early prognosis in patients with ATBAD. Methods: A total of 129 ATBAD patients in the National Acute Aortic Syndrome Database (AASCN) who underwent TEVAR between 2019 and 2020 were enrolled in our study. Patients were divided into two groups: the RAS group and the non-RAS group. Results: There were 21 RAS patients (16.3%) and 108 non-RAS patients (83.7%) in our cohort. No patient in our cohort died during the 1-month follow-up. There was no significant difference in preoperative creatinine clearance rate (CCr) between the two groups (90.6 ± 46.1 µmol/L in the RAS group vs. 78.7 ± 39.2 µmol/L in the non-RAS group, P = 0.303) but the RAS group had a significantly lower estimated glomerular filtration rate (eGFR) than the non-RAS group (83.3 ± 25.0 vs. 101.9 ± 26.9 ml/min, respectively; P = 0.028).One month after TEVAR, CCr was significantly higher (99.0 ± 68.1 vs. 78.5 ± 25.8 ml/min, P = 0.043) and eGFR (81.7 ± 23.8 vs. 96.0 ± 20.0 ml/min, P = 0.017) was significantly lower in the RAS group than in the non-RAS group. Conclusions: In ATBAD, RAS could result in acute kidney injury (AKI) in the early stage after TEVAR. The RAS group had a high incidence of hypertension. These results suggest that patients with RAS may need further treatment.

Short-term outcomes of acute coronary involvement in type A aortic dissection without myocardial ischemia: a multiple center retrospective cohort study.

BACKGROUND: To evaluate the early prognosis and management of acute coronary involvement (ACI) in type A aortic dissection (ATAAD) patients without myocardial ischemia (MI). METHODS: We conducted a retrospective cohort study on a multicenter database. A total of 931 ATAAD patients without MI underwent thoracic aortic surgery between 2018 and 2019 in the Acute Aortic Syndrome Cooperation Network (AASCN) and were enrolled in our study. Patients were divided into two groups: ACI group and non-ACI group. RESULTS: There were 139 ACI patients (14.9%) and 792 non-ACI patients (85.1%) in our cohort. ACI group had higher 30-day mortality after surgery than non-ACI group (log-rank test: P = 0.028,Cox regression: hazard ratio [HR], 2.3; 95% confidence interval [95% CI], 1.1-5.39; P = 0.047), especially in sub-group of advanced age (53-80 years; HR, 4.0; 95% CI, 1.3-12.8; P = 0.017), low diastolic blood pressure (29-69 mmHg, HR, 3.8; 95% CI, 1.3-11.2; P = 0.018), low systolic blood pressure (51-119 mmHg, HR, 3.6; 95% CI, 1.1-12.4; P = 0.040), high body mass index (BMI;27.25-47.52 kg/m2; HR, 3.7; 95% CI, 1.3-10.7; P = 0.015) and high hemoglobin (>145 g/L; HR, 4.3; 95% CI, 1.2-16.0; P = 0.030). Acute renal failure was significant more in ACI group than non-ACI group (24.5% vs. 15.9%; P = 0.014). CONCLUSIONS: ACI increases the short-term postoperative mortality and acute renal failure in ATAAD patients without MI. ATAAD patients with ACI may need a narrower control range of blood pressure even if without myocardial ischemia. TRIAL REGISTRATION: ChiCTR1900022637 . Retrospectively registered 19 April 2019.

Correlation Between Plasma CircRNA-089763 and Postoperative Cognitive Dysfunction in Elderly Patients Undergoing Non-cardiac Surgery.

In our previous experiment, we found that there were abnormal levels of circRNA-089763 in the plasma exosomes of patients with postoperative cognitive dysfunction (POCD) after cardiac surgery. Therefore, the aim of this study was to further investigate the relationship between plasma circRNA-089763 level and POCD in elderly patients after non-cardiac surgery. A prospective cohort study was conducted to select elderly patients undergoing elective non-cardiac surgery. A total of 72 patients were enrolled in this study, and cognitive functions were assessed 1 day before and 3 days after surgery by a series of neuropsychological measurements. Next, patients were divided into POCD and non-POCD (NPOCD) groups according to the Z score method. Blood was collected the day before and 3 days after surgery, and the plasma circRNA-089763 level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the difference and correlation in plasma circRNA-089763 levels between the POCD and NPOCD groups were analyzed. On the third day after surgery, the incidence of POCD was 30.56%. The relative level of circRNA-089763 in the POCD group was 2.41 times higher than that in the NPOCD group (t = 4.711, p < 0.001), patients in POCD group had higher age (t = 5.971, p < 0.001), higher American Society of Anesthesiologists classification (χ2 = 14.726, p < 0.001), less years of education (t = 2.449, p = 0.017), more intraoperative blood loss (t = 3.196, p = 0.002), and higher visual analog scale (VAS) scores (t = 10.45, p < 0.001). The binary logistic regression analysis showed that the circRNA-089763 level, age, and intraoperative blood loss were independently associated with POCD (OR: 2.75, 95% CI: 1.261-5.999, p = 0.011; OR: 1.32, 95% CI: 1.114-1.565, p = 0.001; OR: 1.017, 95% CI: 1.004-1.03, p = 0.011). These results demonstrated that the circRNA-089763 plasma level was related to POCD after non-cardiac surgery in elderly patients.

Abnormal expression of circRNA_089763 in the plasma exosomes of patients with post­operative cognitive dysfunction after coronary artery bypass grafting.

Post­operative cognitive dysfunction (POCD) is a complication of the central nervous system characterized by mental disorders, anxiety, personality changes and impaired memory. POCD occurs frequently after coronary artery bypass grafting (CABG) and can severely affect quality of life for patients. To date, the development of POCD biomarkers remains a challenge. Alterations in the expression of non­coding RNAs from brain tissue and peripheral blood have been linked to POCD. The present study aimed to detect the differential circular RNAs (circRNAs) in plasma exosomes of patients with POCD after CABG. The relative expression levels of circRNAs were analyzed using circRNA microarray analysis in the plasma exosomes of patients with POCD. Differentially altered circRNAs (P<0.05, fold change >1.5) were validated by reverse transcription­quantitative PCR in the plasma exosomes of patients with POCD. The target genes of the microRNAs were predicted using bioinformatics analysis. The functions and signaling pathways of these target genes were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses. The microarray results indicated that the levels of nine circRNAs in patients with POCD were higher than those in the control subjects; and six circRNAs were at a lower level than those in control subjects. The RT­qPCR results from patients with POCD showed that only circRNA_089763 of the 15 circRNAs identified was significantly increased compared with control subjects. circRNA target gene prediction and functional annotation analysis showed significant enrichment in several GO terms and pathways associated with POCD. The present study provides evidence for the abnormal expression of POCD­induced circRNA_089763 in human plasma exosomes, as well as the involvement of POCD.

Serum miR-221-3p as a new potential biomarker for depressed mood in perioperative patients.

MicroRNAs (miRNAs) modulate various genes associated with brain disorders and circulating miRNAs may therefore serve as biomarkers for these neurological diseases. We previously found that the miRNA miR-221-3p was highly expressed in cerebrospinal fluid and the serum of major depressive disorder (MDD) patients. Here, we examined whether miR-221-3p could be used as a biomarker for depressed mood in perioperative patients. We first examined the relative expression of serum miR-221-3p by real-time quantitative PCR in perioperative patients with different degrees of depressive mood assessed by the Patient Health Questionnaire-9 (PHQ-9) diagnostic form. We found that miR-221-3p expression in the mild depressive mood group (PHQ-9 scores 5-9) was 2.21 fold that of the normal group (PHQ-9 scores 0-4) and the moderate＆severe depressive mood group (PHQ-9 scores ≥ 10) showed miR-221-3p expression levels 3.66 fold that of the normal group. Then the absolute quantification of serum miR-221-3p was obtained using an miRNA standard curve. We found that the amount of serum miR-221-3p was positively correlated with depressed mood; when serum miR-221-3p > 1.7 × 107 copies/µg RNA, all indicated PHQ-9 scores were higher than 6. Subsequently, we found that miR-221-3p could indirectly increase the expression of IFN-α (Interferon alpha) in astrocytes by targeting IRF2 (Interferon Regulatory Factor 2) and that miR-221-3p participated in the anti-neuroinflammatory signaling cascades induced by ketamine and paroxetine via the IRF2/IFN-α pathway. Our results indicate that elevated serum miR-221-3p can be used as a biomarker for depressed mood in perioperative patients and that IFN-α-induced NF-κB activation in astrocytes mediated by miR-221-3p targeting of IRF2 may be one of the potential mechanisms.

miRNA-PDGFRB/HIF1A-lncRNA CTEPHA1 Network Plays Important Roles in the Mechanism of Chronic Thromboembolic Pulmonary Hypertension.

Our previous studies have revealed that long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and genes were abnormally expressed in the pulmonary artery tissues of the chronic thromboembolic pulmonary hypertension (CTEPH) patients. We aim to establish the CTEPH-related miRNA-gene-lncRNA network for finding the core genes and associated miRNA and lncRNA in CTEPH patients.Firstly, the target genes of differential miRNAs were predicted by searching TargetScan databases, and the predicted target genes were intersected with the mRNAs from the gene chip. Secondly, the intersective genes were analyzed by the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway software for obtaining differential intersective genes and then establish the miRNA-gene networks. Thirdly, the possible genes regulated by the differential lncRNAs from the gene chip were intersected with the above-screened mRNA to build the lncRNA-mRNA networks. Subsequently, the miRNA-gene-lncRNA networks were constructed according to the two networks above (miRNA-gene networks and lncRNA-mRNA networks). Finally, the core genes of the networks in the experimental group were screened according to Diffk > 0.6 and used to construct the miRNA-core gene-lncRNA networks of CTEPH.The pathway network, miRNA-mRNA network, lncRNA-mRNA networks, and miRNA-gene-lncRNA networks were successfully constructed. The core genes of the miRNA-gene-lncRNA networks (Diffk > 0.6) were the human Beta-type platelet-derived growth factor receptor (PDGFRB) and hypoxia-inducible factor-1a (HIF-1A), the miRNAs-PDGFRB-lncRNAs and miRNAs-HIF1A-lncRNAs networks were constructed. Finally, miRNA-149-5p-PDGFRB-TCONS_l2_00020587-XLOC_l2_010723 and miRNA-338-5p/miRNA-199b-5p-HIF1A- TCONS_l2_00020587-XLOC_l2_010723 were found in the analysis of the network.miRNA-149-5p-PDGFRB-lncRNA CTEPH-associated 1 (CTEPHA1) (TCONS_l2_00020587-XLOC_l2_010723) and miRNA-338-5p/miRNA-199b-5p-HIF1A-lncRNA CTEPHA1 are related to the development of CTEPH.

Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats.

Ketamine has a rapid, obvious, and persistent antidepressant effect, but its underlying molecular mechanisms remain unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of ketamine's antidepressant effect. We investigated the alteration in miR-29b-3p in the brain of rats subjected to ketamine administration and chronic unpredictable mild stress (CUMS), and a sucrose preference test and forced swimming test were used to evaluate the rats' depressive-like state. We used recombination adeno-associated virus (rAAV) or lentivirus-expressing miR-29b-3p to observe the change in metabotropic glutamate receptor 4 (GRM4). Cell culture and electrophysiological recordings were used to evaluate the function of miR-29b-3p. Ketamine dramatically increased miR-29b-3p expression in the prefrontal cortex of the normal rats. The dual luciferase reporter test confirmed that GRM4 was the target of miR-29b-3p. The miR-29b-3p levels were downregulated, while the GRM4 levels were upregulated in the prefrontal cortex of the depressive-like rats. The ketamine treatment increased miR-29b-3p expression and decreased GRM4 expression in the prefrontal cortex of the depressive-like rats and primary neurons. By overexpressing and silencing miR-29b-3p, we further validated that miR-29b-3p could negatively regulate GRM4. The silencing of miR-29b-3p suppressed the Ca2+ influx in the prefrontal cortex neurons. The miR-29b-3p overexpression contributed to cell survival, cytodendrite growth, increases in extracellular glutamate concentration, and cell apoptosis inhibition. The overexpression of miR-29b-3p by rAAV resulted in a noticeable relief of the depressive behaviors of the CUMS rats and a lower expression of GRM4. The miR-29b-3p/GRM4 pathway acts as a critical mediator of ketamine's antidepressant effect in depressive-like rats and could be considered a potential therapeutic target for treating major depression disorder.