Carnosol attenuates angiotensin II-induced cardiac remodeling and inflammation via directly binding to p38 and inhibiting p38 activation.

Chronic inflammation is a significant contributor to hypertensive heart failure. Carnosol (Car), primarily derived from the sage plant (Salvia carnosa), exhibits anti-inflammatory properties in a range of systems. Nevertheless, the influence of angiotensin II (Ang II) on cardiac remodeling remains uncharted. Car was shown to protect mice's hearts against Ang II-induced heart damage at dosages of 20 and 40 mg/kg/d. This protection was evident in a concentration-related decrease in the remodeling of the heart and dysfunction. Examination of the transcriptome revealed that the pivotal roles in mediating the protective effects of Car involved inhibiting Ang II-induced inflammation and the activation of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, Car was found to inhibit p38 phosphorylation, therefore reducing the level of inflammation in cultured cardiomyocytes and mouse hearts. This effect was attributed to the direct binding to p38 and inhibition of p38 protein phosphorylation by Car both in vitro and in vivo. In addition, the effects of Car on inflammation were neutralized when p38 was blocked in cardiomyocytes.

Admission proteinuria predicts the incidence of acute kidney injury among patients with acute ST-segment elevation myocardial infarction: a retrospective cohort study.

BACKGROUND: Proteinuria indicates renal dysfunction and is associated with the development of acute kidney injury (AKI) in several conditions, but the association between proteinuria and AKI in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. This research aims to investigate the predictive value of proteinuria for the development of AKI in STEMI patients. METHODS: A total of 2735 STEMI patients were enrolled. The present study's endpoint was AKI incidence during hospitalization. AKI is defined according to the Kidney Disease: Improving Global Outcomes criteria. We defined proteinuria, measured with a dipstick, as mild (1+) or heavy (2+ to 4+). Multivariate logistic regression and subgroup analyses were used to testify to the association between proteinuria and AKI. RESULTS: Overall, proteinuria was observed in 634 (23.2%) patients. Multivariate logistic regression analyses revealed that proteinuria [odds ratio (OR), 1.58; 95% confidence interval (CI), 1.25-2.00; P  < 0.001] was the independent predictive factor for AKI. Severe proteinuria was associated with a higher adjusted risk for AKI compared with the nonproteinuria group (mild proteinuria: OR, 1.35; 95% CI, 1.04-1.75; P  = 0.025; severe proteinuria: OR, 2.50; 95% CI, 1.70-3.68; P  < 0.001). The association was highly consistent across all studied subgroups. (all P for interaction >0.05). CONCLUSION: Admission proteinuria measured using a urine dipstick is an independent risk factor for the development of AKI in STEMI patients.

Prognostic Value of Segmental Strain After ST-Elevation Myocardial Infarction: Insights From the EARLY Assessment of MYOcardial Tissue Characteristics by Cardiac Magnetic Resonance (EARLY-MYO-CMR) Study.

BACKGROUND: The prognostic value of left ventricular segmental strain (SS) in ST-elevation myocardial infarction (STEMI) remains unclear. HYPOTHESIS: To assess the prognostic value and application of SS. STUDY TYPE: Retrospective analysis of a prospective registry. POPULATION: Five hundred and forty-four patients after STEMI (500 in Cohort 1, 44 in Cohort 2). FIELD STRENGTH/SEQUENCE: 3 T, balanced steady-state free precession, gradient echo, and gradient echo contrast-enhanced images. ASSESSMENT: Participants underwent cardiac MR during the acute phase after STEMI. Infarct-related artery (IRA) strain was determined based on SS obtained from cine images. The primary endpoint was the composite of major adverse cardiovascular events (MACEs) after 8 years of follow-up. In Cohort 2, SS stability was assessed by MR twice within 8 days. Contrast and non-contrast risk models based on SS were established, leading to the development of an algorithm. STATISTICAL TEST: Student's t-test, Mann-Whitney U-test, Cox and logistic regression, Kaplan-Meier analysis, net reclassification index (NRI). P < 0.05 was considered significant. RESULTS: During a median follow-up of 5.2 years, 83 patients from Cohort 1 experienced a MACE. Among SS, IRA peak circumferential strain (IRA-CS) was an independent factor for MACEs (adjusted hazard ratio 1.099), providing incremental prognostic value (NRI 0.180, P = 0.10). Patients with worse IRA-CS (>-8.64%) demonstrated a heightened susceptibility to MACE. Additionally, IRA-CS was significantly associated with microvascular obstruction (MVO) (adjusted odds ratio 1.084) and infarct size (r = 0.395). IRA-CS showed comparable prognostic effectiveness to global peak circumferential strain (NRI 0.100, P = 0.39), also counterbalancing contrast and non-contrast risk models (NRI 0.205, P = 0.05). In Cohort 2, IRA-CS demonstrated stability between two time points (P = 0.10). Based on risk models incorporating IRA-CS, algorithm "HJKL" was preliminarily proposed for stratification. DATA CONCLUSIONS: IRA-CS is an important prognostic factor, and an algorithm based on it is proposed for stratification. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Analyzing predictors of in-hospital mortality in patients with acute ST-segment elevation myocardial infarction using an evolved machine learning approach.

Acute ST-segment elevation myocardial infarction (STEMI) is a severe cardiac ailment characterized by the sudden complete blockage of a portion of the coronary artery, leading to the interruption of blood supply to the myocardium. This study examines the medical records of 3205 STEMI patients admitted to the coronary care unit of the First Affiliated Hospital of Wenzhou Medical University from January 2014 to December 2021. In this research, a novel predictive framework for STEMI is proposed, incorporating evolutionary computational methods and machine learning techniques. A variant algorithm, AGCOSCA, is introduced by integrating crossover operation and observation bee strategy into the original Sine Cosine Algorithm (SCA). The effectiveness of AGCOSCA is initially validated using IEEE CEC 2017 benchmark functions, demonstrating its ability to mitigate the deficiency in local mining after SCA random perturbation. Building upon this foundation, the AGCOSCA approach has been paired with Support Vector Machine (SVM) to forge the predictive framework referred to as AGCOSCA-SVM. Specifically, AGCOSCA is employed to refine the selection of predictors from a substantial feature set before SVM is utilized to forecast the occurrence of STEMI. In our analysis, we observed that SVM excels at managing nonlinear data relationships, a strength that becomes particularly prominent in smaller datasets of STEMI patients. To assess the effectiveness of AGCOSCA-SVM, diagnostic experiments were conducted based on the STEMI sample data. Results indicate that AGCOSCA-SVM outperforms traditional machine learning methods, achieving superior Accuracy, Sensitivity, and Specificity values of 97.83 %, 93.75 %, and 96.67 %, respectively. The selected features, such as acute kidney injury (AKI) stage, fibrinogen, mean platelet volume (MPV), free triiodothyronine (FT3), diuretics, and Killip class during hospitalization, are identified as crucial for predicting STEMI. In conclusion, AGCOSCA-SVM emerges as a promising model framework for supporting the diagnostic process of STEMI, showcasing potential applications in clinical settings.

Sex differences in the association between D-dimer and the incidence of acute kidney injury in patients admitted with ST-segment elevation myocardial infarction: a retrospective observational study.

Identifying the predictors of acute kidney injury (AKI) in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) remains important. We aimed to investigate the predictive value of D-dimer levels for the incidence of AKI in such a population, with particular attention paid to sex differences. A total of 2668 patients with STEMI who underwent PPCI were retrospectively included in this study and divided into quartiles according to their plasma D-dimer levels upon admission (Q1: < 0.36; Q2: 0.36-0.67; Q3: 0.68-1.17; Q4: > 1.17 mg/L). The primary endpoint was the occurrence of AKI during hospitalization. AKI was observed in 503 (18.8%) patients. The mean age of the patients was 63.0 ± 13.2 years, 2155 (80.8%) of whom were men. Multivariate analysis indicated that higher D-dimer levels were associated with a significantly increased risk of AKI (Q4 vs. Q1: OR: 1.57; 95% CI 1.11-2.23; P = 0.011). However, the prognostic effect of D-dimer was only observed in male patients (Q4 vs. Q1: OR: 2.07; 95% CI 1.37-3.13; P < 0.001), not in female patients (Q4 vs. Q1: OR: 0.72; 95% CI 0.37-1.41; P = 0.342) (P for interaction = 0.003). We demonstrated a notable sex difference in the association between D-dimer level upon admission and AKI in a large STEMI patient sample. A higher D-dimer level was associated with an increased risk of AKI in male patients but not in female patients.

The interaction between hyperuricemia and low-density lipoprotein cholesterol increases the risk of 1-year post-discharge all-cause mortality in ST-segment elevation myocardial infarction patients.

BACKGROUND AND AIMS: Hyperuricemia is a known risk factor for cardiovascular diseases, but little is known on whether the association between hyperuricemia and poor outcomes in ST-segment elevation myocardial infarction (STEMI) is modified by low-density lipoprotein cholesterol (LDL-c). This study aimed to investigate the effect of the interaction between hyperuricemia and LDL-c on the risk of 1-year post-discharge all-cause mortality in STEMI patients. METHODS AND RESULTS: A total of 1396 STEMI patients were included. Cox proportional hazards models were used to determine the association between hyperuricemia and 1-year all-cause mortality in the overall population and subgroups stratified based on LDL-c levels (<3.0 mmol/L or ≥3.0 mmol/L). Multivariate analysis indicated that hyperuricemia was associated with 1-year mortality (HR: 2.66; 95% CI: 1.30-5.47; p = 0.008). However, the prognostic effect of hyperuricemia was only observed in patients with LDL-c level ≥3.0 mmol/L (HR: 12.90; 95% CI: 2.98-55.77; p < 0.001), but not in those with LDL-c level <3.0 mmol/L (HR: 0.91, 95% CI: 0.30-2.79, p = 0.875). The interaction between hyperuricemia and LDL-c levels had a significant effect on 1-year mortality. CONCLUSION: Hyperuricemia was associated with increased 1-year post-discharge mortality in patients with LDL-c level≥ 3.0 mmol/L, but not in those with LDL-c level< 3.0 mmol/L.

Clinical Outcome After Left Ventricular Thrombus Resolution: Who Needs Long-Term or Lifetime Use of Anticoagulants?

Background Patients with left ventricular thrombus (LVT) resolution can have LVT recurrence and risk for thromboembolism. However, these outcomes after LVT resolution are not well known. We aimed to assess the prevalence, risk factors, and clinical outcomes for LVT recurrence in patients with LVT resolution to inform follow-up and treatment. Methods and Results Patients with LVT resolution were identified retrospectively from a large echocardiography database between January 2009 and May 2022. Participants had echocardiograms at 3 time points, including baseline at LVT diagnosis, at LVT resolution, and a follow-up for identification of LVT recurrence. The cumulative LVT recurrence rate was estimated by the Kaplan-Meier method, and predictors of LVT recurrence were evaluated using Cox regression analysis. Among 115 patients with LVT resolution, 28 (24.3%) had LVT recurrence at a median follow-up of 1.2 (0.5-2.8) years. LV aneurysm (hazard ratio [HR], 2.59 [95% CI, 1.20-5.58], P=0.015) and anticoagulant use (HR, 0.12 [95% CI, 0.04-0.41], P=0.001) were predictors of LVT recurrence on multivariable analysis. Patients with an LV aneurysm who did not receive any anticoagulation demonstrated an LVT recurrence rate of 69.5%, whereas those without an LV aneurysm who received anticoagulation had a recurrence rate of 0%. Patients with LVT recurrence had a higher incidence of an embolic event (10.7% versus 1.1%, P=0.016). Conclusions LVT recurrence after LVT resolution is common, especially in those with an LV aneurysm, and is associated with a higher embolic risk. Continued anticoagulation is protective against LVT recurrence, although bleeding risk needs to be considered. These findings can inform follow-up and treatment of patients with documented LVT resolution.

Dectin-1 deficiency alleviates diabetic cardiomyopathy by attenuating macrophage-mediated inflammatory response.

Cardiovascular diseases are the primary cause of mortality in patients with diabetes and obesity. Hyperglycemia and hyperlipidemia in diabetes alters cardiac function, which is associated with broader cellular processes such as aberrant inflammatory signaling. Recent studies have shown that a pattern recognition receptor called Dectin-1, expressed on macrophages, mediates pro-inflammatory responses in innate immunity. In the present study, we examined the role of Dectin-1 in the pathogenesis of diabetic cardiomyopathy. We observed increased Dectin-1 expression in heart tissues of diabetic mice and localized the source to macrophages. We then investigated the cardiac function in Dectin-1-deficient mice with STZ-induced type 1 diabetes and high-fat-diet-induced type 2 diabetes. Our results show that Dectin-1 deficient mice are protected against diabetes-induced cardiac dysfunction, cardiomyocyte hypertrophy, tissue fibrosis, and inflammation. Mechanistically, our studies show that Dectin-1 is important for cell activation and induction of inflammatory cytokines in high-concentration glucose and palmitate acid (HG + PA)-challenged macrophages. Deficiency of Dectin-1 generate fewer paracrine inflammatory factors capable of causing cardiomyocyte hypertrophy and fibrotic responses in cardiac fibroblasts. In conclusion, this study provides evidence that Dectin-1 mediates diabetes-induced cardiomyopathy through regulating inflammation. Dectin-1 may be a potential target to combat diabetic cardiomyopathy.

Sclareol attenuates angiotensin II-induced cardiac remodeling and inflammation via inhibiting MAPK signaling.

Chronic inflammation plays an important role in hypertensive heart failure. Suppressing angiotensin II (Ang II)-induced cardiac inflammation may contribute to the treatment of hypertension-associated heart failure. Sclareol, a natural product initially isolated from the leaves and flowers of Salvia sclarea, possesses antiinflammatory and immune-regulation activity in various systems. However, its effect on Ang II-induced cardiac remodeling remains unknown. In this study, we have explored the potential effects of sclareol on Ang II-induced heart failure. In vivo experiments were conducted in mice with Ang II-pump infusion for 28 days. Sclareol administration at 5 mg·kg-1 ·d-1 significantly reduced the expression of myocardial injury markers. Sclareol also exerts protective effects against Ang II-induced cardiac dysfunction in mice which is associated with alleviated cardiac inflammation and fibrosis. Transcriptome analysis revealed that inhibition of the Ang II-activated mitogen-activated protein kinase (MAPK) pathway contributed to the protective effect of sclareol. Sclareol inhibits Ang II-activated MAPKs pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Blockage of MAPKs in cardiomyocytes abolished the antiinflammatory effects of sclareol. In conclusion, we show that sclareol protects hearts against Ang II-induced injuries through inhibiting MAPK-mediated inflammation, indicating the potential use of sclareol in the prevention of hypertensive heart failure.

Hsa_circ_0007478 aggravates NLRP3 inflammasome activation and lipid metabolism imbalance in ox-LDL-stimulated macrophage via miR-765/EFNA3 axis.

Coronary heart disease can be effectively prevented by alleviating atherosclerotic plaque progression. Ox-LDL-induced inflammatory response in macrophages is a critical factor in the pathophysiology of atherosclerosis. It is well known that circular RNAs (circRNAs) are associated with the progression of several human diseases, such as coronary artery diseases, by sponging microRNAs (miRNAs), but the function and hidden mechanisms of circRNAs in macrophage inflammation and lipid metabolism remain unclear. In our study, we established an ox-LDL-stimulated macrophage model and used microarray to detect circRNA expression in macrophages. The results revealed distinct profiles of circRNA expression across the ox-LDL-stimulated macrophage group and the control group. Among them, hsa_circ_0007478 was upregulated in ox-LDL-stimulated macrophages, accompanied by reduced miR-765 and increased EFNA3 expression. Activation of NLRP3 inflammasome and IL-1ß in macrophages was decreased following silencing of hsa_circ_0007478 or transfection of miR-765 mimics. In addition, we demonstrated that as a direct target gene of miR-765, the expression of EFNA3 regulated NLRP3 inflammasome and IL-1ß levels in macrophages. Besides, hsa_circ_0007478 promoted EFNA3 expression by acting as a miR-765 sponge. We further showed that hsa_circ_0007478/miR-765/EFNA3 axis could also be involved in the inhibition of the lipid metabolism and foam cells formation in ox-LDL-macrophages. Taken together, these findings suggest that Hsa_circ_0007478 may be a potential molecular target against the inflammatory response and foam cells during atherosclerosis.

Lactate level and lactate clearance for acute kidney injury prediction among patients admitted with ST-segment elevation myocardial infarction: A retrospective cohort study.

Background: Hyperlactatemia is a prognostic marker among patients with ST-segment elevation acute myocardial infarction (STEMI). However, the predictive value of lactate and the dynamic change associated with acute kidney injury (AKI) among patients with STEMI, remain poorly understood. We aimed to compare single lactate values at admission (Lacadm) and 12 h after admission (Lac12h) with lactate clearance (LC) 12 h after admission for AKI prediction in patients with STEMI. Methods: A total of 1,784 patients with STEMI were included. The study endpoint was AKI occurrence during hospitalization. The predictive value of lactate levels measured at admission and 12 h after admission and LC for AKI prediction was determined using multivariate logistic regression analyses and compared with receiver operator characteristic (ROC) curve analysis. Results: Overall, AKI was observed in 353 (19.8%) patients. In multivariate logistic regression analyses, Lacadm ≥ 4.3 mmol/L (OR: 1.53; 95% CI: 1.01-2.30), Lac12h ≥ 2.1 mmol/L (OR: 1.81; 95% CI: 1.36-2.42), and LC ≥ -7.5% (OR: 0.40; 95% CI: 0.30-0.53) were the independent predictive factors for AKI after adjusting for confounders. ROC curve analysis results revealed that Lac12h (0.639; 95% CI: 0.616-0.661) exhibited a significantly higher area under the curve (AUC) than those of Lacadm (0.551; 95% CI: 0.527-0.574) and LC (0.593; 95% CI: 0.570-0.616) in the prediction of AKI. LC (△AUC = 0.037, p < 0.001) and Lac12h (△AUC = 0.017, p = 0.029) enhanced the discrimination capacity of Mehran Risk Score (MRS) for AKI among patients undergoing emergency coronary angiography. Conclusion: Lac12h is more effective for AKI prediction among patients with STEMI than Lacadm and LC. Furthermore, Lac12h and LC enhance the prediction capacity of MRS for AKI among patients after emergency coronary angiography.

Interaction between Hyperuricemia and Admission Lactate Increases the Risk of Acute Kidney Injury in Patients with ST-Segment Elevation Myocardial Infarction.

BACKGROUND AND OBJECTIVE: Acute kidney injury (AKI) is a common complication associated with adverse outcomes among patients with ST-segment elevation myocardial infarction (STEMI). This is conflicting information about the relationship between hyperuricemia and AKI in STEMI. This work aimed to investigate the effect of the interaction between hyperuricemia and lactate on the risk of AKI. METHODS: We analyzed 2,008 consecutive STEMI patients between January 2014 and January 2019. Hyperuricemia was defined as a serum uric acid level >7 mg/dL for males and >6 mg/dL for females. AKI was defined based on the Kidney Disease: Improving Global Outcomes (KDIGO). Logistic regression models were applied to establish the relationship between hyperuricemia and AKI in the overall population and subgroups stratified as per lactate levels at admission (≤2.2 mmol/L or >2.2 mmol/L). RESULTS: In total, we included 1,887 STEMI patients. Multivariate analysis showed that hyperuricemia is associated with the risk of AKI (OR: 1.34; 95% CI: 1.01-1.77; p = 0.045). Nonetheless, the predictive effect of hyperuricemia was only observed in patients with lactate level >2.2 mmol/L (OR: 2.05; 95% CI: 1.36-3.10; p < 0.001), but not in those with lactate level ≤2.2 mmol/L (OR: 0.86, 95% CI: 0.56-1.32; p = 0.493). The interaction between hyperuricemia and lactate levels demonstrated a significant effect on AKI. CONCLUSIONS: In summary, hyperuricemia increases the risk of AKI in STEMI patients with lactate levels> 2.2 mmol/L, but not in those with lactate levels ≤2.2 mmol/L.

Disruption of Circadian Rhythms by Shift Work Exacerbates Reperfusion Injury in Myocardial Infarction.

BACKGROUND: Shift work is associated with increased risk of acute myocardial infarction (AMI) and worsened prognosis. However, the mechanisms linking shift work and worsened prognosis in AMI remain unclear. OBJECTIVES: This study sought to investigate the impact of shift work on reperfusion injury, a major determinant of clinical outcomes in AMI. METHODS: Study patient data were obtained from the database of the EARLY-MYO-CMR (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI) registry, which was a prospective, multicenter registry of patients with ST-segment elevation myocardial infarction (STEMI) undergoing cardiac magnetic resonance (CMR) imaging after reperfusion therapy. The primary endpoint was CMR-defined post-reperfusion infarct size. A secondary clinical endpoint was the composite of major adverse cardiac events (MACE) during follow-up. Potential mechanisms were explored with the use of preclinical animal AMI models. RESULTS: Of 706 patients enrolled in the EARLY-MYO-CMR registry, 412 patients with STEMI were ultimately included. Shift work was associated with increased CMR-defined infarct size (ß = 5.94%; 95% CI: 2.94-8.94; P < 0.0001). During a median follow-up of 5.0 years, shift work was associated with increased risks of MACE (adjusted HR: 1.92; 95% CI: 1.12-3.29; P = 0.017). Consistent with clinical findings, shift work simulation in mice and sheep significantly augmented reperfusion injury in AMI. Mechanism studies identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that played a crucial role in mediating the detrimental effects of shift work on myocardial injury. CONCLUSIONS: The current study provided novel findings that shift work increases myocardial infarction reperfusion injury. It identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that might play a crucial role in mediating this process. (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI [EARLY-MYO-CMR] registry; NCT03768453).

Short-Term Postoperative Use of Rivaroxaban to Prevent Radial Artery Occlusion After Transradial Coronary Procedure: The RESTORE Randomized Trial.

BACKGROUND: Adequate procedural anticoagulation is crucial for radial artery occlusion (RAO) prevention in patients undergoing transradial access coronary catheterization, although the effect of postprocedural anticoagulation lack thorough investigation. The aim of this study was to evaluate the clinical value of short-term postoperative anticoagulation with rivaroxaban for 24 hours and 1-month RAO prevention in patients who received transradial coronary procedures. METHODS: A total of 382 patients were randomized to receive either placebo (control group) or rivaroxaban 10 mg once daily for a period of 7 days (rivaroxaban group) to evaluate the effect of the rivaroxaban in the prevention of 24 hours and 1-month RAO assessed by Doppler ultrasound. RESULTS: There was no significant difference in the incidence of 24-hour RAO (8.9% versus 11.5%; P=0.398) between the rivaroxaban group and control group (odds ratio, 0.75 [95% CI, 0.39-1.46]; P=0.399). In contrast, the 1-month RAO (3.8% versus 11.5%; P=0.011) was significantly reduced in patients who received rivaroxaban as compared with those who did placebo (odds ratio, 0.22 [95% CI, 0.08-0.65]; P=0.006). For patients with 24-hour RAO, the rivaroxaban group was associated with higher recanalization rate of the radial artery (69.2% versus 30.0%; P=0.027) compared with the control group. No significant differences can be observed between the 2 groups for access-site complications or bleeding events. CONCLUSIONS: Short-term postoperative anticoagulation with rivaroxaban did not reduce the rate of 24-hour RAO but improved 1-month RAO, because of higher recanalization of the radial artery. However, larger clinical trials are needed to prove our results. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1900026974.

Direct cardio-protection of Dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling.

Obesity is an important independent risk factor for cardiovascular diseases, remaining an important health concern worldwide. Evidence shows that saturated fatty acid-induced inflammation in cardiomyocytes contributes to obesity-related cardiomyopathy. Dapagliflozin (Dapa), a selective SGLT2 inhibitor, exerts a favorable preventive activity in heart failure. In this study, we investigated the protective effect of Dapa against cardiomyopathy caused by high fat diet-induced obesity in vitro and in vivo. Cultured rat cardiomyocyte H9c2 cells were pretreated with Dapa (1, 2.5 µM) for 1.5 h, followed by treatment with palmitic acid (PA, 200 µM) for 24 h. We showed that Dapa pretreatment concentration-dependently attenuated PA-induced cell hypertrophy, fibrosis and apoptosis. Transcriptome analysis revealed that inhibition of PA-activated MAPK/AP-1 pathway contributed to the protective effect of Dapa in H9c2 cells, and this was confirmed by anti-p-cJUN fluorescence staining assay. Using surface plasmon resonance analysis we found the direct binding of Dapa with NHE1. Gain and loss of function experiments further demonstrated the role of NHE1 in the protection of Dapa. In vivo experiments were conducted in mice fed a high fat diet for 5 months. The mice were administered Dapa (1 mg·kg-1·d-1, i.g.) in the last 2 months. Dapa administration significantly reduced the body weight and improved the serum lipid profiles. Dapa administration also alleviated HFD-induced cardiac dysfunction and cardiac aberrant remodeling via inhibiting MAPK/AP-1 pathway and ameliorating cardiac inflammation. In conclusion, Dapa exerts a direct protective effect against saturated fatty acid-induced cardiomyocyte injury in addition to the lowering effect on serum lipids. The protective effect results from negative regulating MAPK/AP-1 pathway in a NHE1-dependent way. The current study highlights the potential of clinical use of Dapa in the prevention of obesity-related cardiac dysfunction.

Trimetazidine affects pyroptosis by targeting GSDMD in myocardial ischemia/reperfusion injury.

OBJECTIVE: Trimetazidine (TMZ) exerts a strong inhibitory effect on ischemia/reperfusion (I/R) injury. Inflammation plays a key role in I/R injury. We hypothesized that TMZ may protect cardiomyocytes from I/R injury by inhibiting inflammation. METHODS: The left anterior descending coronary artery was ligated for 30 min followed by 6 h of reperfusion to establish a model of I/R injury. H9c2 cardiomyocytes were subjected to 2 h of hypoxia and 3 h of normoxic conditions to establish a model of hypoxia/reoxygenation (H/R) injury. We monitored the change in pyroptosis by performing Western blot analysis, microscopy and ELISA. RESULTS: I/R and H/R treatment stimulated gasdermin D-N domain (GSDMD-N) expression in cardiomyocytes (sham onefold vs. I/R 2.5-fold; control onefold vs. H/R 2.0-fold). Moreover, TMZ increased the viability of H9c2 cardiomyocytes subjected to H/R treatment (H/R 65.0% vs. H/R + TMZ 85.3%) and reduced the infarct size in vivo (I/R 47.0% vs. I/R + TMZ 28.3%). H/R and I/R treatment increased the levels of TLR4, MyD88, phospho-NF-κB p65 and the NLRP3 inflammasome; however, TMZ reduced the expression of these proteins. Additionally, TMZ inhibited noncanonical inflammasome signaling induced by I/R injury. CONCLUSIONS: In summary, TMZ alleviated pyroptosis induced by myocardial I/R injury through the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, TMZ represents an alternative treatment for myocardial I/R injury.

Impact of Pre-Revascularization and Post-Revascularization Cardiac Arrest on Survival Prognosis in Patients With Acute Myocardial Infarction and Following Emergency Percutaneous Coronary Intervention.

Objectives: To evaluate the effects of occurrence and timing of sudden cardiac arrest (SCA) on survival in patients with acute myocardial infarction (AMI) who underwent emergency percutaneous coronary intervention (PCI). Methods: We analyzed 1,956 consecutive patients with AMI with emergency PCI from 2014 to 2018. Patients with cardiac arrest events were identified, and their medical records were reviewed. Results: Patients were divided into non-cardiac arrest group (NCA group, n = 1,724), pre-revascularization cardiac arrest (PRCA group, n = 175), and post-revascularization SCA (POCA group, n = 57) according to SCA timing. Compared to NCA group, PRCA group and POCA group presented with higher brain natriuretic polypeptide (BNP), more often Killip class 3/4, atrial fibrillation, and less often completed recovery of coronary artery perfusion (all p < 0.05). Both patients with PRCA and POCA showed increased 30-day all-cause mortality when compared to patients with NCA (8.0 and 70.2% vs. 2.9%, both p < 0.001). However, when compared to patients with NCA, patients with PRCA did not lead to higher mortality during long-term follow-up (median time 917 days) (16.3 vs. 18.6%, p = 0.441), whereas patients with POCA were associated with increased all-cause mortality (36.3 vs. 18.6%, p < 0.001). Multivariate analysis identified Killip class 3/4, atrial fibrillation, high maximum MB isoenzyme of creatine kianse, and high creatinine as predictive factors for POCA. In Cox regression analysis, POCA was found as a strong mortality-increase predictor (HR, 8.87; 95% CI, 2.26-34.72; p = 0.002) for long-term all-cause death. Conclusions: POCA appeared to be a strong life-threatening factor for 30-day and long-term all-cause mortality among patients with AMI who admitted alive and underwent emergency PCI. However, PRCA experience did not lead to a poorer long-term survival in patients with AMI surviving the first 30 days.

LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation.

BACKGROUND AND PURPOSE: The profibrotic and proinflammatory effects induced by doxorubicin (DOX) are key processes in the development of serious heart damage. Lack of effective drugs and the unclear mechanisms of its side effects limit the clinical treatment of DOX-induced cardiac injury. This study aimed to explore the protective role of LCZ696 and the potential mechanism of Toll-like receptor 2 (TLR2) in doxorubicin-induced cardiac failure. EXPERIMENTAL APPROACH: DOX (5 mg/kg/week, three times) was used to establish a chronic cardiomyopathy mouse model. Heart function tests, pathology examinations and molecular biology analyses were used to explore the effects of LCZ696 and TLR2 deficiency in vivo and in vitro. Computational docking was applied to predict the key residues for protein-ligand interaction. KEY RESULTS: The EF% declined, and the LVIDd, pro-fibrosis marker levels and NF-κB related inflammatory response increased in the chronic cardiomyopathy group induced by DOX. LCZ696 treatment and TLR2 deficiency reversed these heart damage in vivo. In H9C2 cells, pre-treatment with LCZ696 and TLR2 knockdown suppressed the DOX-induced high expression of profibrotic and proinflammatory markers. Moreover, DOX notably increased the TLR2-MyD88 interaction in vivo and in vitro, which was inhibited by LCZ696. Finally, we demonstrated the direct interaction between DOX and TLR2 via hydrogen bonds on Pro-681 and Glu-727 and Pro-681 and Ser-704 may be the key residues by which LCZ696 affects the interaction between DOX and TLR2. CONCLUSION AND IMPLICATIONS: LCZ696 prevents DOX-induced cardiac dilation failure, fibrosis and inflammation by reducing the formation of TLR2-MyD88 complexes. LZC696 may be a potential effective drug to treat DOX-induced heart failure.

Toll-like receptor 2 signaling deficiency in cardiac cells ameliorates Ang II-induced cardiac inflammation and remodeling.

Activation of the innate immune system represents a vital step in inflammation during cardiac remodeling induced by the angiotensin II (Ang II). This study aimed to explore the role of Toll-like receptors 2 (TLR2) in Ang II-induced cardiac remodeling. We investigated the effect of TLR2 deficiency on Ang II-induced cardiac remodeling by utilizing TLR2 knockout mice, bone marrow transplantation models, and H9C2 cells. Though TLR2 deficiency had no effect on body weight change, cardiac Ang II content and blood pressure, it significantly ameliorated cardiac hypertrophy, fibrosis and inflammation, as well as improved heart function. Further bone marrow transplantation studies showed that TLR2-deficiency in cardiac cells but not bone marrow-derived cells prevented Ang II-induced cardiac remodeling and cardiac dysfunction. The underlying mechanism may involve increased TLR2-MyD88 interaction. Further in vitro studies in Ang II-treated H9C2 cells showed that TLR2 knockdown by siRNA significantly decreased Ang II-induced cell hypertrophy, fibrosis and inflammation. Moreover, Ang II significantly increased TLR2-MyD88 interaction in H9C2 cells in a TLR4-independent manner. TLR2 deficiency in cardiac cells prevents Ang II-induced cardiac remodeling, inflammation and dysfunction through reducing the formation of TLR2-MyD88 complexes. Inhibition of TLR2 pathway may be a therapeutic strategy of hypertensive heart failure.