Dihydroartemisinin alleviates doxorubicin-induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy.

Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.

The glycemic gap as a prognostic indicator in cardiogenic shock: a retrospective cohort study.

BACKGROUND: Stress-induced hyperglycemia (SIH) is associated with poor outcomes in cardiogenic shock (CS), and there have been inconsistent results among patients with or without diabetes mellitus (DM). The glycemic gap (GG) is derived by subtracting A1c-derived average glucose from blood glucose levels; it is a superior indicator of SIH. We aimed to explore the role of GG in the outcomes of patients with CS. METHODS: Data on patients diagnosed with CS were extracted from the MIMIC-IV v2.0 database to investigate the relationship between GG and 30-day mortality (Number of absolute GG subjects = 359; Number of relative GG subjects = 357). CS patients from the Second Affiliated Hospital of Wenzhou Medical University were enrolled to explore the correlation between GG and lactic acid (Number of absolute GG subjects = 252; Number of relative GG subjects = 251). Multivariate analysis, propensity score-matched (PSM) analysis, inverse probability treatment weighting (IPTW), and Pearson correlation analysis were applied. RESULTS: Absolute GG was associated with 30-day all-cause mortality in CS patients (HRadjusted: 1.779 95% CI: 1.137-2.783; HRPSM: 1.954 95% CI: 1.186-3.220; HRIPTW: 1.634 95% CI: 1.213-2.202). The higher the absolute GG level, the higher the lactic acid level (ßadjusted: 1.448 95% CI: 0.474-2.423). A similar trend existed in relative GG (HRadjusted: 1.562 95% CI: 1.003-2.432; HRPSM: 1.790 95% CI: 1.127-2.845; HRIPTW: 1.740 95% CI: 1.287-2.352; ßadjusted:1.294 95% CI: 0.369-2.219). Subgroup analysis showed that the relationship existed irrespective of DM. The area under the curve of GG combined with the Glasgow Coma Scale (GCS) for 30-day all-cause mortality was higher than that of GCS (absolute GG: 0.689 vs. 0.637; relative GG: 0.688 vs. 0.633). GG was positively related to the triglyceride-glucose index. Kaplan-Meier curves revealed that groups of higher GG with DM had the worst outcomes. The outcomes differed among races and GG levels (all P < 0.05). CONCLUSIONS: Among patients with CS, absolute and relative GGs were associated with increased 30-day all-cause mortality, regardless of DM. The relationship was stable after multivariate Cox regression analysis, PSM, and IPTW analysis. Furthermore, they reflect the severity of CS to some extent. Hyperlactatemia and insulin resistance may underlie the relationship between stress-induced hyperglycemia and poor outcomes in CS patients. They both improve the predictive efficacy of the GCS.

Association between fibrinogen-to-albumin ratio and prognosis of patients with heart failure.

BACKGROUND: Systemic inflammation is closely associated with the development and progression of heart failure (HF), increasing vulnerability to thromboembolic events. This retrospective cohort study assessed the potential of the fibrinogen-to-albumin ratio (FAR), a new inflammatory biomarker, as a prognostic indicator for HF risk. METHODS: One thousand one hundred and sixty six women and 826 men with a mean age of 70.70 ± 13.98 years were extracted from the Medical Information Mart for Intensive Care-IV (MIMIC-IV v2.0) database. Additionally, a second cohort was obtained, including 309 patients from the Second Affiliated Hospital of Wenzhou Medical University. The relationship between FAR and the prognosis of HF was evaluated using multivariate analysis, propensity score-matched analysis, and subgroup analysis. RESULTS: Fibrinogen-to-albumin ratio was an independent risk factor for 90-day all-cause mortality (hazard ratio: 1.19; 95% confidence interval (CI): 1.01-1.40), 1-year all-cause mortality (hazard ratio: 1.23; 95% confidence interval: 1.06-1.41), and length of hospital stay (LOS) (ß: 1.52; 95% CI: 0.67-2.37) in the MIMIC-IV dataset, even after adjusting for potential covariates. These findings were verified in the second cohort (ß: 1.82; 95% CI: 0.33-3.31) and persisted after propensity score-matching and subgroup analysis. FAR was positively correlated with C-reactive protein, NT-proBNP, and Padua score. The correlation between FAR and NT-proBNP (R = .3026) was higher than with fibrinogen (R = .2576), albumin (R = -.1822), platelet-to-albumin ratio (R = .1170), and platelet-to-lymphocyte ratio (R = .1878) (ps < .05). CONCLUSIONS: Fibrinogen-to-albumin ratio is an independent risk prognostic factor for 90-day, 1-year all-cause mortality and LOS among HF patients. Inflammation and prothrombotic state may underlie the relationship between FAR and poor prognosis in HF.

3,4-benzopyrene aggravates myocardial ischemia-reperfusion injury-induced pyroptosis through inhibition of autophagy-dependent NLRP3 degradation.

Polycyclic aromatic hydrocarbons (PAHs) are produced during combustion of organic matter, such as during cigarette smoking, and they exist widely in the environment. Exposure to 3,4-benzo[a]pyrene (BaP), as the most widely studied PAHs, relates to many cardiovascular diseases. However, the underlying mechanism of its involvement remains largely unclear. In this study, we developed a myocardial ischemia-reperfusion (I/R) injury mouse model and an oxygen and glucose deprivation-reoxygenation H9C2 cell model to evaluate the effect of BaP in I/R injury. After BaP exposure, the expression of autophagy-related proteins, the abundance of NLRP3 inflammasomes, and the degree of pyroptosis were measured. Our results show that BaP aggravates myocardial pyroptosis in a autophagy-dependent manner. In addition, we found that BaP activates the p53-BNIP3 pathway via the aryl hydrocarbon receptor to decrease autophagosome clearance. Our findings present new insights into the mechanisms underlying cardiotoxicity and reveal that the p53-BNIP3 pathway, which is involved in autophagy regulation, is a potential therapeutic target for BaP-induced myocardial I/R injury. Because PAHs are omnipresent in daily life, the toxic effects of these harmful substances should not be underestimated.

Inhibition of TGFß-activated protein kinase 1 ameliorates myocardial ischaemia/reperfusion injury via endoplasmic reticulum stress suppression.

Transforming growth factor ß-activated protein kinase 1 (TAK1) involves in various biological responses and is a key regulator of cell death. However, the role of TAK1 on acute myocardial ischaemia/reperfusion (MI/R) injury is unknown. We observed that TAK1 activation increased significantly after MI/R and hypoxia/reoxygenation (H/R), and we hypothesized that TAK1 has an important role in MI/R injury. Mice (TAK1 inhibiting by 5Z-7-oxozeaenol or silencing by AAV9 vector) were exposed to MI/R injury. Primary cardiomyocytes (TAK1 silencing by siRNA; and overexpressing TAK1 by adenovirus vector) were used to induce H/R injury model in vitro. Inhibition of TAK1 significantly decreased MI/R-induced myocardial infarction area, reduced cell death and improved cardiac function. Mechanistically, TAK1 silencing suppressed MI/R-induced myocardial oxidative stress and attenuated endoplasmic reticulum (ER) stress both in vitro and in vivo. In addition, the inhibition of ROS by NAC partially reversed the damage of TAK1 in vitro. Our study presents the first direct evidence that inhibition of TAK1 mitigated MI/R injury, and TAK1 mediated ROS/ER stress/apoptosis signal pathway is important for the pathogenesis of MI/R injury.

Brachial pulse pressure is associated with the presence and extent of coronary artery disease in stable angina patients: a cross-sectional study.

BACKGROUND: Previous epidemiological evidence has identified many risk factors for coronary artery disease (CAD). Pulse pressure (PP) was reported to be associated with CAD. However, more attention was paid to aortic PP than to brachial PP. This cross-sectional study aimed to investigate the direct relationship between brachial PP and the presence and extent of CAD in stable angina patients. METHODS: We recruited a total of 1118 consecutive patients with stable chest pain suspected of CAD. After screening with exclusion criteria, 654 patients were finally included in our study. Every patient underwent both blood pressure measurement and selective coronary angiography. Univariate and multivariate analysis were performed to analyze the association between PP and the presence and extent of CAD. RESULTS: This study revealed that brachial PP was an independent correlate of multivessel CAD. In multivariate generalized linear regression model, increasing brachial PP (per 1 mmHg) were associated with the increased number of diseased vessels (ß = 0.01, SE = 0.00, P < 0.0001). Binary logistic regression analysis further confirmed this association. The risk of multivessel CAD increased significantly in patients with brachial PP ≥ 60 mmHg (OR = 1.69, 95% CI = 1.14-2.48, P = 0.0084) and as per 1 mmHg increased in brachial PP (OR = 1.02, 95% CI = 1.01-1.03, P = 0.0002), independent of age, gender, body mass index (BMI), smoking, diabetes, hypercholesterolemia and creatinine (Cr). This association was still of statistical significance in subgroup analysis of hypertension and diabetes. CONCLUSION: Increasing brachial PP was significantly and independently associated with increased risk of multivessel coronary disease in stable angina patients. The association of brachial PP with CAD was more pronounced in hypertension group than in non-hypertension one.

Prognostic Value of Neutrophil-Lymphocyte Ratio in Cardiogenic Shock: A Cohort Study.

BACKGROUND Inflammation plays an important part in the pathogenesis of cardiogenic shock (CGS). Whether the neutrophil-lymphocyte ratio (NLR), an integrated biomarker of inflammation, is associated with the outcome of CGS patients remains unknown. This retrospective cohort study was performed to identify the utility of using NLR among patients with CGS. MATERIAL AND METHODS Data were extracted from the MIMIC database. We applied smooth curve fitting to define the NLR cutoff values. The primary outcome was 30-day mortality. Cox proportional hazards models, subgroup analysis, and receiver operator characteristic (ROC) curve analysis were performed. RESULTS A total of 1470 CGS patients were extracted, among which 801 (54.5%) were men. The mean age of the population was 70.37 years. An inverse U-shaped relationship was observed between NLR and mortality in CGS patients, with the highest risk being at values ranging from 9.4 to 15. For the primary outcome of 30-day mortality, the adjusted HR (95% CI) values of the middle tertile (NLR 9.4-15) and the upper tertile (NLR >15) were 1.47 (1.14, 1.88) and 1.22 (0.94, 1.57) compared with the reference of lower tertile (NLR <9.4). ROC curve analysis showed that NLR had a more sensitive prognostic value in predicting 30-day mortality of CGS than the neutrophil or lymphocyte percentage alone (0.660 vs. 0.540, 0.549). CONCLUSIONS An inverse U-shaped curve was presented between NLR and the mortality of CGS. NLR seemed to be a readily available and independent prognostic biomarker for patients with CGS. The prognostic value of NLR was more sensitive than the neutrophil or lymphocyte percentage alone, but not as good as SOFA or SAPSII score.

Circular RNA microarray expression profile in 3,4-benzopyrene/angiotensin II-induced abdominal aortic aneurysm in mice.

Abdominal aortic aneurysm (AAA) is an unpredictable but lethal disease that poses a therapeutic dilemma. Circular RNAs (circRNAs), whose functional roles as transcriptional regulators and microRNA (miRNA) sponges have been shown in former studies, are potential biomarkers for many diseases. AAA in male C57BL/6 J mice was induced by coadministration of angiotensin II (Ang II) and 3,4-benzopyrene (BaP). The circRNA expression profiling was performed using two samples from the control group and two samples from the AAA group. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to confirm the reliability of the microarray results. Among the 14 236 detected circRNAs, 413 showed obvious expression changes (fold change ≥ 2; P < 0.05) between the BaP/Ang II-induced AAA group and control group. Of the 413 that showed significant changes, 271 were upregulated, while the other 142 were downregulated. The expression levels of 10 circRNAs were validated by qRT-PCR. The interactions of the differentially expressed circRNAs with miRNAs were predicted. Immunofluorescence showed prominent vascular smooth muscle cell apoptosis in abdominal aortic tissues in the BaP/Ang II group. Furthermore, a circRNA-miRNA coexpression network based on six apoptosis-related circRNAs was built. The genes regulated by the network mapped to several pathways, including apoptosis, the IL-17 signaling pathway, and vascular endothelial growth factor signaling pathway, all of which are related to AAA formation. This study performed circRNA expression profiling in AAA and the results specifically predicted the regulatory role of circRNAs in AAA pathogenesis.

Comparison of survival for cardiac resynchronization therapy in atrial fibrillation patients with or without atrio-ventricular junction ablation and patients in sinus rhythm: a systematic review and network meta-analysis.

Cardiac resynchronization therapy (CRT) has been established to improve prognosis for patients with heart failure and SR. Whether the benefit observed with CRT on survival was similar in AF patients receiving atrio-ventricular junction ablation (AVJA) or not and patients in SR remains uncertain. The primary purpose of this study was to comprehensively evaluate the impact of CRT on the outcome of survival in atrial fibrillation (AF) patients with or without AVJA and patients in sinus rhythm (SR). Medline, Embase, and the Cochrane Library were searched for inception through June 31, 2018. Two reviewers independently evaluated and extracted data from 4 studies, including a total of 7896 CRT recipients, composed of 554 AF with AVJA (CRT+AF+AVJA), 1071 AF without AVJA (CRT+AF-AVJA), and 6244 SR (CRT+SR). The benefit on survival was comparable between CRT+AF+AVJA and CRT+SR (HR = 1.00; 95% CI, 0.73-1.40). CRT+AF+AVJA and CRT+SR both were associated with significantly higher survival compared with CRT+AF-AVJA, with hazard ratio of 0.64 (95% CI, 0.46-0.91) and 0.63 (95% CI, 0.53-0.75), respectively. The survival benefit was similar for patients with CRT+AF+AVJA and CRT+SR, while it was 36-37% high as compared to CRT+AF-AVJA. Whether aggressive intervention with AVJA in AF should be routinely combined with CRT despite rate-slowing drug treatment is helpful deserves further studies.

Common and distinctive electrocardiographic characteristics and effective catheter ablation of idiopathic ventricular arrhythmias originating from different areas of ventricular septum adjacent to atrioventricular annulus.

OBJECTIVE: To investigate electrocardiographic (ECG) characteristics and radiofrequency catheter ablation (RFCA) efficacy for premature ventricular complexes (PVCs) and idiopathic ventricular tachycardias (IVTs) originating from ventricular septum areas adjacent to atrioventricular annulus (VS-AVA). METHODS: Among 1,505 consecutive PVCs/IVTs cases, 106 (7.04%) were confirmed as origin of VS-AVA guided by both fluoroscopy and three-dimensional mapping system during RFCA. Characteristics of surface 12-lead ECG were analyzed. RESULTS: The overall success rate for RFCA of PVCs/IVTs originating from VS-AVA was 82.08% (87/106), common ECG characteristics were: mainly positive R wave on lead I; dominant-positive R on aVL (91/106, 85.85%) for most, r (1/106, 0.94%) or qr (14/106, 13.21%) in few; QS or qs on aVR; and decreasing R wave amplitude and increasing S wave depth on II, III, and aVF from superior to inferior septum; and S wave on at least one inferior lead (generally III). Distinctive ECG features were: precordial transition zone before or after V2 for septum adjacent to mitral (MA, 19/19, 100.0%) or tricuspid (TA, 74/87,85.05%) annulus origin; initial r wave and rS on V1 for superior septum near TA (above His bundle) origin (9/10, 90.0%) with no initial r wave for most other origins; and QS on V1 for mid-inferior septum near TA origin (73/77, 94.81%) and QR (Qr, qR or qr) on V1 for septum near MA origin (17/19, 89.47%). CONCLUSION: Distinctive ECG characteristics of PVCs/IVTs originating from VS-AVA aid in origin localization guiding effective RFCA.

The safety of catheter ablation for premature ventricular contractions in patients without structural heart disease.

BACKGROUND: Patients with frequent premature ventricular contractions (PVCs) are often symptomatic. Catheter ablation was usually indicated to eliminate symptoms in patients with PVCs-induced cardiomyopathy. Currently, PVCs-ablation is also applied for patients with PVCs and no structural heart diseases (SHD); however, the safety and efficacy of ablation in these patients remains unclear. METHODS: In this retrospective study, data from patients who underwent ablation for PVCs from January 2010 to December 2016 at our hospital was retrieved. Predictors of complications and acute procedural success were evaluated. RESULTS: A total of 1231 patients (mean age 47.8 ± 16.8 years, 59% female) were included. The overall complication rate was 2.7%, and the most common complication was hydropericardium. Two ablation-related mortalities occurred. One patient died of coronary artery injury during the procedure and the other died from infectious endocarditis. Location (left ventricle and epicardium) was the main predictor of complications, with right ventricular outflow tract (RVOT) predicting fewer complications. The acute procedural success rate was 94.1% in all patients. The main predictor of acute procedural success was RVOT origin, while an epicardial origin was a predictor of procedural failure. CONCLUSION: Locations of left ventricle and epicardium were predictors of procedural complications for patients with PVCs. Therefore, ablation is not recommended in these patients. For other origins of PVCs, particularly RVOT origin, ablation is a safety and effective treatment.

Red yeast rice induces less muscle fatigue symptom than simvastatin in dyslipidemic patients: a single center randomized pilot trial.

BACKGROUND: About 10-15% patients who take statins experience skeletal muscle problems. Red yeast rice has a good safety profile could provide a compromise therapeutic strategy. Therefore, the aim of this study was to evaluate the effects of red yeast rice, when compared to simvastatin, on the muscle fatigue symptom and the serum lipid level in dyslipidemic patients with low to moderate cardiovascular risk. METHODS: A total of 60 dyslipidemic patients with low to moderate cardiovascular risk were recruited and randomly assigned to receive either simvastatin (n = 33) or red yeast rice (n = 27) for 4 weeks. The muscle fatigue score, the physical activity, the serum lipid profile and the safety profile were then evaluated. RESULTS: At the end of study, the fatigue score was significantly increased in patients treated with simvastatin, whereas no significant change was observed in patients receiving red yeast rice. In addition, the physical activity level was significantly decreased in patients from simvastatin group when compared to those from red yeast rice group. Similar lipid-lowering effects were observed in two groups. The safety profile was not affected after the treatments. CONCLUSIONS: Among dyslipidemic patients with low to moderate cardiovascular risk, red yeast rice induced less fatigue side effect and exerted comparable lipid-lowering effects when compared to simvastatin in this pilot primary prevention study. TRIAL REGISTRATION: NCT01686451 .

Very early recurrence predicts long-term outcome in patients after atrial fibrillation catheter ablation: a prospective study.

BACKGROUND: Long-term recurrence (LR) is a tendency that re-occurs within 3 months after catheter ablation for atrial fibrillation (AF). Whether very early recurrence (VER) within 7 days of post ablation is a prognostic factor of LR or not is unclear. For this reason, present study sought to examine the relationship between VER and LR. METHODS: In this prospective analysis 378 consecutive patients underwent an initial catheter ablation for paroxysmal or persistent AF. The association between VER and LR was analyzed by univariate and multivariate Cox regression, as well as time-dependent receiver operator characteristic (ROC) analysis. RESULTS: After a mean follow-up of 14.71 ± 8.58 months, 81 (65.90%) patients with VER experienced LR and were associated with lower event of free survival from LR (Log rank test, P < 0.001). Multivariate Cox regression analysis revealed that VER (HR = 7.02, 95% CI = 4.78-10.31; P < 0.001), left atrial enlargement (HR = 2.92, 95% CI = 1.88-4.54; P < 0.001), tendency in advanced age (HR = 1.50, 95% CI = 0.99-2.28; P = 0.054), and tendency in male (HR = 0.71, 95% CI = 0.50-1.01; P = 0.060) were independent predictors of LR. According to time-dependent ROC analysis, it was found that VER was more sensitive than common risk factors in predicting LR (0.74 vs 0.66, P < 0.001) and combination model further improved the C statistic for predicting LR (0.82 vs 0.66, P < 0.001). CONCLUSIONS: After a single procedure of catheter ablation, patients with VER were strongly associated with LR and combination of VER and common risk factors could further improve prediction of patients who were at high risk for LR.

Macrophage migration inhibitory factor promoter polymorphisms (-794 CATT5-8): Relationship with soluble MIF levels in coronary atherosclerotic disease subjects.

BACKGROUND: We analyzed the relationship of -794 CATT5-8 MIF polymorphisms with soluble MIF in Coronary Atherosclerotic Disease (CAD) patients. METHODS: A total of 256 patients selected, on which 186 normal-coronary and 70 Coronary artery disease subjects, were recruited in the study (Retrospectively registered). Genotyping of -794 CATT5-8 polymorphisms were performed by PCR and DNA sequencing. Serum MIF levels were measured using an ELISA kit. Patients were classified by coronary angiogram, and CAD based on Gensini's integral degree (angiographic scoring system). RESULTS: The allele frequency and genotype frequency of -794 CATT5-8 did not show any differences in normal-coronary subjects and CAD subjects. In CAD patients, serum MIF levels was lower in CATT (5) subjects than in CATT (7) subjects, while the genotype of -794 CATT5-8 did not show differences in serum MIF levels. In addition, we found a decrease in serum MIF levels in carriers of the (5/5) genotypes the -794 CATT5-8 MIF polymorphisms, although it was not significant. There was no relationship of CAD class and the allele frequency of -794 CATT5-8. CONCLUSIONS: This study found no association between CAD class and -794 CATT5-8 MIF polymorphisms with soluble MIF levels in CAD Subjects. TRIAL REGISTRATION: NCT01750502 (November 2012, Retrospectively registered).

Exploration of the mechanisms by which 3,4-benzopyrene promotes angiotensin II-induced abdominal aortic aneurysm formation in mice.

OBJECTIVE: This study examined the influence of 3,4-benzopyrene (BaP), a compound found in cigarette smoke, on the formation of angiotensin II (Ang II)-induced abdominal aortic aneurysm (AAA) formation in mice and the underlying mechanisms. METHODS: C57/B6n mice were divided into four groups. The control group received a weekly intraperitoneal injection of medium-chain triglycerides. The Ang II group received a daily Ang II infusion (0.72 mg/kg) and a weekly intraperitoneal injection of medium-chain triglycerides. The Ang II/BaP group received a daily Ang II infusion (0.72 mg/kg) and a weekly intraperitoneal BaP injection (10 mg/kg, dissolved in medium-chain triglycerides). The BaP group received a weekly intraperitoneal BaP injection (10 mg/kg). After 5 weeks, abdominal aortic diameter was determined. Aortic tissues underwent hematoxylin and eosin, Masson, and immunochemistry staining for evaluation of vascular wall structure, collagen, macrophage infiltration, matrix metalloproteinases (MMPs), and apoptosis. RESULTS: The Ang II infusion and BaP injection induced AAAs in 41.67% of mice vs 25% in the Ang II group (P < .05). The average aortic diameter increased in the Ang II/BaP group compared with the Ang II group (1.40 ± 0.25 vs 1.2 ± 0.23 mm; P < .05). Average aortic muscular cell apoptosis was higher in the Ang II/BaP group (31% ± 12%) than in the Ang II (19% ± 5%; P < .05) or BaP groups (23% ± 4%; P < .05). Aortic macrophage infiltration and expression of MMP-2, MMP-9, MMP-12, and nuclear factor-κB increased (0.56 ± 0.12, 0.47 ± 0.13, 0.49 ± 0.14, 0.49 ± 0.11, and 0.42 ± 0.12, respectively) in the Ang II/BaP group compared with the Ang II group (0.27 ± 0.08, 0.25 ± 0.06, 0.24 ± 0.09, 0.24 ± 0.09, and 0.23 ± 0.06, respectively; P < .05 for all). CONCLUSIONS: BaP promotes Ang II-induced AAA formation in mice via elevating infiltration of macrophages, activating nuclear factor-κB, upregulating the expression of MMP-2, MMP-9, and MMP-12, and increasing the apoptosis of vascular muscle cells in its synergistic effect with Ang II in aortic wall.

Stress hyperglycemia ratio linked to worse prognosis in Cardiac Intensive Care Unit patients: A retrospective observational study.

AIMS: This study aimed to delineate correlation between stress hyperglycemia ratio (SHR) and clinical outcomes among patients in the cardiac intensive care unit (CICU). METHODS: Participants were categorized based on their SHR threshold values. Key outcomes were short-term mortality and major adverse cardiovascular events (MACEs) at 1-year follow-up. The association between SHR and outcomes was estimated using inverse probability of treatment weighting (IPTW) and Kaplan-Meier analyses. The C-statistic was used to gauge the predictive capability of SHR. RESULTS: The study included 1,133 patients from the Medical Information Mart for Intensive Care IV and 412 from the Second Affiliated Hospital of Wenzhou Medical University. Kaplan-Meier curves revealed that individuals with elevated SHR exhibited higher 90-day mortality and MACEs. When considering SHR levels and diabetes status simultaneously, those with increased SHR but non-diabetes had the highest 90-day mortality and MACEs. SHR was associated with short-term mortality and MACEs (HRadjusted 1.63 95%CI 1.15-2.30; HRIPTW 1.47 95%CI 1.05-2.05). Upon integrating SHR into the foundational model, the C-statistic was 0.821, outperforming other hyperglycemia metrics. CONCLUSION: SHR is a valuable indicator for predicting poor outcomes in CICU patients. Its utility spans potential risk stratification and offers insights for tailoring prognostic treatments to CICU patients.

Phlorizin, a novel caloric restriction mimetic, stimulates hypoxia and protects cardiomyocytes through activating autophagy via modulating the Hif-1α/Bnip3 axis in sepsis-induced myocardial dysfunction.

BACKGROUND: Sepsis is a systemic inflammatory syndrome that can lead to multiple organ dysfunction and life-threatening complications. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to be present in half of patients with septic shock, increasing their mortality rate to 70-90%. The pathogenesis of SIMD is complex, and no specific clinical treatment has yet been developed. Caloric restriction mimetics (CRM), compounds that simulate the biochemical and functional properties of CR, can improve cardiovascular injury by activating autophagy. This study investigated the effect of a new type of CRM which can induce hypoxia, the SGLT nonspecific inhibitor phlorizin on SIMD. MATERIALS AND METHODS: In vivo, phlorizin was administered at 1 mg/kg/day intragastrically for 28 days. In vitro, AC16 was treated with 120 µM phlorizin for 48 h. Echocardiography was used to assess cardiac function. Myocardial injury markers were detected in serum and cell supernatant. Western blotting was employed to detect changed proteins associated with apoptosis and autophagy. Immunofluorescence, immunohistochemistry, co-immunoprecipitation, molecular docking, and other methods were also used to illustrate cellular changes. RESULTS: In vivo, phlorizin significantly improved the survival rate and cardiac function after sepsis injury, reduced markers of myocardial injury, inhibited myocardial apoptosis and oxidative stress, and promoted autophagy. In vitro, phlorizin alleviated the apoptosis of AC16, as well as inhibited oxidative stress and apoptotic enzyme activity. Phlorizin acts on autophagy at multiple sites through low energy (activation of AMPK) and hypoxia (release of Beclin-1 by Hif-1α/Bnip3 axis), promoting the formation and degradation of autophagosomes. CONCLUSION: We indicated for the first time that phlorizin could inhibit glucose uptake via GLUT-1 and conforms to the metabolic characteristics of CRM, it can induce the hypoxic transcriptional paradigm. In addition, it inhibits apoptosis and improves SIMD by promoting autophagy generation and unobstructing autophagy flux. Moreover, it affects autophagy by releasing Beclin-1 through the Hif-1α/Bnip3 axis.

The Neutrophil Percentage-to-Albumin Ratio is Associated with All-Cause Mortality in Patients with Atrial Fibrillation: A Retrospective Study.

Objective: The present study aimed to evaluate the relationship between all-cause mortality and the neutrophil percentage-to-albumin ratio (NPAR) in patients with atrial fibrillation (AF). Methods: We obtained clinical information from patients with AF from the Medical Information Mart for Intensive Care-IV version 2.0 (MIMIC-IV) database and the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (WMU). The clinical endpoints were all-cause death measured at 30-day, 90-day, and one-year intervals. For endpoints associated with the NPAR, logistic regression models were used to calculate odds ratios (OR) with 95% confidence intervals (CI). Receiver operating characteristic (ROC) curves and area under the curve (AUC) were developed to compare the ability of different inflammatory biomarkers to predict 90-day mortality in patients with AF. Results: Higher NPAR was associated with a higher risk of 30-day (OR 2.08, 95% CI 1.58-2.75), 90-day (OR 2.07, 95% CI 1.61-2.67), and one-year mortality (OR 1.60, 95% CI 1.26-2.04) in patients with AF in 2813 patients from MIMIC-IV. The predictive performance of NPAR (AUC = 0.609) for 90-day mortality was better than that of neutrophil-to-lymphocyte ratio (NLR) (AUC = 0.565, P < 0.001), and platelet-to-lymphocyte ratio (PLR) (AUC = 0.528, P < 0.001). When NPAR and sequential organ failure assessment (SOFA) were combined, the AUC increased from 0.609 to 0.674 (P < 0.001). Higher NPAR was associated with a higher risk of 30-day mortality (OR 2.54, 95% CI 1.02-6.30) and 90-day mortality (OR 2.76, 95% CI 1.09-7.01) in 283 patients from WMU. Conclusion: An increased 30-day, 90-day, and one-year mortality risk among patients with AF were linked to a higher NPAR in MIMIC-IV. NPAR was thought to be a good predictor of 90-day all-cause mortality. Higher NPAR was associated with a higher risk of 30-day and 90-day mortality in WMU.

3, 4-Benzopyrene (Bap) aggravated abdominal aortic aneurysm formation by targeting pyroptosis in smooth muscle cells through ET-1 mediated NLRP3-inflammasome activation.

According to epidemiological studies, smoking is one of the leading causes of the high incidence of abdominal aortic aneurysms (AAA).3,4-Benzopyrene (Bap) is a by-product of coal tar and tobacco combustion produced by the incomplete combustion of organic fuels. It is an essential component of both automobile exhaust and tobacco smoke, it is also an important member of the air pollutants. However, the exact mechanism by which Bap can worsen the condition of patients with AAA and increase the mortality of patients with AAA remains unknown. This research aims to investigate the role of Bap in inducing pyroptosis in AAA. In vitro experiments, we revealed that pyroptosis-Gasdermin D (GSDMD) increased when Bap was used. Additionally, the release of inflammatory factors, such as IL-1ß and IL-18 were also rising. An mRNA sequencing analysis revealed that macrophages expressed a high level of the endothelin gene when cells were stimulated by Bap. It seemed that smooth muscle cells pyroptosis was related to macrophages. Experiments revealed that endothelin could increase the calcium ion concentration in smooth muscle cells, resulting in a large amount of ROS and activation of NLRP3 inflammasomes. We discovered that treatment with endothelin receptor antagonist (ABT-546) in vivo and calcium ion chelator (BAPTA) in vitro decreased AAA diameter, downregulated NLRP3 inflammasomes and ROS, and significantly reduced the number of activated GSDMD. Inflammatory mediators were released at a lower level. These findings suggest that Bap-induced pyroptosis may be mediated by the ET-1-Ca2+-inflammasome pathway, providing a new way to reduce mortality in AAA patients.

3,4-benzo[a]pyrene aggravates myocardial infarction injury by activating NLRP3-related pyroptosis through PINK1/Parkin-mitophagy-mPTP opening axis.

BACKGROUND: Air pollution is an important and interventionable risk factor for cardiovascular disease. Air pollution exposure, even for a short-term exposure, is conspicuously relevant to increased risk of myocardial infarction (MI) mortality and clinical evidence has shown that air pollution particulate matter (PM) induces the aggravation of AMI. 3,4-benzo[a]pyrene (BaP), an extremely toxic polycyclic aromatic hydrocarbon (PAH) and a common component of PM, is listed as one of the main objects of environmental pollution monitoring. Both epidemiological and toxicological studies suggest that BaP exposure may be associated with cardiovascular disease. Since PM is significantly associated with the increased risk of MI mortality, and BaP is an important component of PM associated with cardiovascular disease, we intend to investigate the effect of BaP on MI models. METHODS: The MI mouse model and the oxygen and glucose deprivation (OGD) H9C2 cell model were used to investigate the effect of BaP in MI injury. The involvement of mitophagy and pyroptosis in regulating deterioration of cardiac function and aggravation of MI injury induced by BaP was comprehensively evaluated. RESULTS: Our study shows that BaP exacerbates MI injury in vivo and in vitro, a result based on BaP-induced NLRP3-related pyroptosis. In addition, BaP can inhibit PINK1/Parkin dependent mitophagy through the aryl hydrocarbon receptor (AhR), thus the mitochondrial permeability transition pore (mPTP) was induced to open. CONCLUSION: Our results suggest a role for the BaP from air pollution in MI injury aggravation and reveal that BaP aggravates MI injury by activating NLRP3-related pyroptosis via the PINK1/Parkin-mitophagy-mPTP opening axis.