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Atherosclerosis, a chronic inflammatory disease characterized by arterial plaque formation, is one of the most prominent causes of cardiovascular diseases. However, the current treatments often do not adequately compromise the chronic inflammation-mediated plaque accumulation and the disease progression. Therefore, a new and effective strategy that blocks atherosclerosis-associated inflammation is urgently needed to further reduce the risk. Colchicine, a potent anti-inflammatory medication, has shown great potential in the treatment of atherosclerosis, but its adverse effects have hampered its clinical application. Herein, we developed a novel delivery nanosystem encapsulated with colchicine (VHPK-PLGA@COL), which exhibited improved biosafety and sustained drug release along with the gradual degradation of PLGA and PEG as confirmed both in vitro and in vivo. Surface modification of the nanoparticles with the VHPK peptide ensured its capability to specifically target inflammatory endothelial cells and alleviate atherosclerotic plaque accumulation. In the ApoE - / - atherosclerotic mouse model, both colchicine and VHPK-PLGA@COL treatment significantly decreased the plaque area and enhanced plaque stability by blocking the NF-κB/NLRP3 pathways, while VHPK-PLGA@COL exhibited enhanced therapeutic effects due to its unique ability to target inflammatory endothelial cells without obvious long-term safety concerns. In summary, VHPK-PLGA@COL has the potential to overcome the key translational barriers of colchicine and open new avenues to repurpose this drug for anti-atherosclerotic therapy.

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BACKGROUND: Inflammation and immune dysfunction with classically activated macrophages(M1) infiltration are important mechanisms in the progression of atherosclerosis (AS). Dynamin-related protein 1 (DRP1)-dependent mitochondrial fission is a novel target for alleviating inflammatory diseases. This study aimed to investigate the effects of DRP1 inhibitor Mdivi-1 on AS. METHODS: ApoE-/- mice were fed with a high-fat diet supplemented with or without Mdivi-1. RAW264.7 cells were stimulated by ox-LDL, pretreated with or without MCC950, Mito-TEMPO, or Mdivi-1. The burden of plaques and foam cell formation were determined using ORO staining. The blood lipid profles and inflammatory cytokines in serum were detected by commercial kits and ELISA, respectively. The mRNA expression of macrophage polarization markers, activation of NLRP3 and the phosphorylation state of DRP1 were detected. Mitochondrial reactive oxygen species (mito-ROS), mitochondrial staining, ATP level and mitochondrial membrane potential were detected by mito-SOX, MitoTracker, ATP determination kit and JC-1 staining, respectively. RESULTS: In vivo, Mdivi-1 reduced the plaque areas, M1 polarization, NLRP3 activation and DRP1 phosphorylation at Ser616. In vitro, oxidized low-density lipoprotein (ox-LDL) triggered M1 polarization, NLRP3 activation and abnormal accumulation of mito-ROS. MCC950 and Mito-TEMPO suppressed M1 polarization mediated foam cell formation. Mito-TEMPO significantly inhibited NLRP3 activation. In addition, Mdivi-1 reduced foam cells by inhibiting M1 polarization. The possible mechanisms responsible for the anti-atherosclerotic effects of Mdivi-1 on reducing M1 polarization were associated with suppressing mito-ROS/NLRP3 pathway by inhibiting DRP1 mediated mitochondrial fission. In vitro, similar results were observed by DRP1 knockdown. CONCLUSION: Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviated atherogenesis via suppressing mito-ROS/NLRP3-mediated M1 polarization, indicating DRP1-dependent mitochondrial fission as a potential therapeutic target for AS.

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BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a common complication following percutaneous coronary intervention in coronary artery disease (CAD) patients with >30% incidence. Klotho is a multifunctional protein that inhibits oxidative stress and inflammation, but its role in CI-AKI is poorly understood. The present study aimed to explore the effects of klotho in CI-AKI. METHODS: Six-week-old mice and HK-2 were divided into the control, contrast medium (CM), CM + klotho, and klotho groups. H&E staining evaluated kidney injury. Scr and BUN showed renal function. DHE probe and ELISA kit detected the levels of reactive oxygen species (ROS) in kidney tissue, superoxide dismutase (SOD), and malondialdehyde (MDA) in serum. Western blot detected the expressions of NF-κB and phosphorylated NF-κB (p-NF-κB) and pyroptosis-related protein levels of NLRP3, caspase-1, GSDMD, and cleaved-GSDMD in the kidney of CI-AKI mice. CCK-8 and lactate dehydrogenase (LDH) activity assays determined cell viability and damage. Fluorescent probe dichloro-dihydro-fluorescein diacetate (DCFH-DA) and enzyme-linked immunosorbent assay (ELISA) tested oxidative stress-related indicators. These included intracellular reactive oxygen species (ROS), superoxidase dismutase (SOD), and malondialdehyde (MDA). IL-6, TNF-α, IL-1ß, and IL-18 in the cell supernatant were tested by ELISA assay and used to reflect inflammation responses. Propidium iodide (PI) staining showed the cell death of HK-2. The expressions of NF-κB, p-NF-κB and pyroptosis-related protein levels of NLRP3, caspase-1, GSDMD, and cleaved-GSDMD were detected by Western blot. RESULTS: Exogenous klotho administration reduced kidney histopathological alterations and improved renal function in vivo. The levels of reactive oxygen species (ROS) in renal tissue, superoxide dismutase (SOD), and malondialdehyde (MDA) in serum decreased after the klotho intervention. The expression levels of p-NF-κB and pyroptosis-related proteins, including NLRP3, caspase-1, GSDMD, and cleaved-GSDMD, were decreased in CI-AKI mice after the klotho intervention. In vitro, klotho significantly inhibited CM-induced oxidative stress and the production of IL-6 and TNF-α. Moreover, it was found that klotho inhibited the activation of p-NF-κB and down-regulated pyroptosis-related protein (NLRP3, caspase-1, GSDMD, and cleaved-GSDMD). CONCLUSION: Klotho has a protective effect on CI-AKI via suppressing oxidative stress, inflammation, and NF-κB/NLRP3-mediated pyroptosis that contributes to the potential therapy of CI-AKI.

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BACKGROUND: Liver dysfunction is a postulated variable for poor prognosis in dilated cardiomyopathy (DCM). OBJECTIVE: This study aimed to investigate the prognostic value of the albumin-bilirubin (ALBI) score, a relatively new model for evaluating liver function, in patients with idiopathic DCM. METHODS: A total of 1025 patients with idiopathic DCM were retrospectively included and divided into three groups based on ALBI scores: grade 1 (≤ -2.60, n = 113), grade 2 (-2.60 to -1.39, n = 835), and grade 3 (> -1.39, n = 77). The association of ALBI score with in-hospital major adverse clinical events (MACEs) and long-term mortality was analyzed. P-value less than 0.05 was considered statistically significant. RESULTS: The in-hospital MACEs rate was significantly higher in the grade 3 patients (2.7% versus 7.1% versus 24.7%, p < 0.001). Multivariate analysis showed that ALBI score was an independent predictor for in-hospital MACEs (adjusted odds ratio = 2.80, 95%CI: 1.63 - 4.80, p < 0.001). After a median 27-month follow-up, 146 (14.2%) patients died. The Kaplan-Meier curve indicated that the cumulative rate of long-term survival was significantly lower in patients with higher ALBI grade (log-rank = 45.50, p < 0.001). ALBI score was independently associated with long-term mortality (adjusted hazard ratio = 2.84, 95%CI: 1.95 - 4.13, p < 0.001). CONCLUSION: ALBI score as a simple risk model could be considered a risk-stratifying tool for patients with idiopathic DCM.

FUNDAMENTO: A disfunção hepática é uma variável postulada de prognóstico desfavorável na cardiomiopatia dilatada (CMD). OBJETIVO: Este estudo teve como objetivo investigar o valor prognóstico do escore albumina-bilirrubina (ALBI), um modelo relativamente novo para a avaliação da função hepática, em pacientes com CMD idiopática. MÉTODOS: Um total de 1.025 pacientes com CMD idiopática foram incluídos retrospectivamente e divididos em três grupos com base nos escores de ALBI: grau 1 (≤ −2,60, n = 113), grau 2 (−2,60 a −1,39, n = 835) e grau 3 (> −1,39, n = 77). Foi analisada a associação do escore ALBI com eventos clínicos adversos maiores (ECAM) intra-hospitalares e mortalidade a longo prazo. Valor de p inferior a 0,05 foi considerado estatisticamente significativo. RESULTADOS: A taxa de ECAM intra-hospitalares foi significativamente maior nos pacientes com grau 3 (2,7% versus 7,1% versus 24,7%, p < 0,001). A análise multivariada mostrou que o escore ALBI foi um preditor independente para ECAM intra-hospitalares (odds ratio ajustada = 2,80, IC 95%: 1,63 ­ 4,80, p < 0,001). Após seguimento mediano de 27 meses, 146 (14,2%) pacientes morreram. A curva de Kaplan-Meier indicou que a taxa cumulativa de sobrevida a longo prazo foi significativamente menor em pacientes com grau mais alto de ALBI (log-rank = 45,50, p < 0,001). O escore ALBI foi independentemente associado à mortalidade a longo prazo (hazard ratio ajustada = 2,84, IC 95%: 1,95 ­ 4,13, p < 0,001). CONCLUSÃO: O escore ALBI, como modelo de risco simples, pode ser considerado uma ferramenta de estratificação de risco para pacientes com CMD idiopática.

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Resumo Fundamento: A disfunção hepática é uma variável postulada de prognóstico desfavorável na cardiomiopatia dilatada (CMD). Objetivo: Este estudo teve como objetivo investigar o valor prognóstico do escore albumina-bilirrubina (ALBI), um modelo relativamente novo para a avaliação da função hepática, em pacientes com CMD idiopática. Métodos: Um total de 1.025 pacientes com CMD idiopática foram incluídos retrospectivamente e divididos em três grupos com base nos escores de ALBI: grau 1 (≤ −2,60, n = 113), grau 2 (−2,60 a −1,39, n = 835) e grau 3 (> −1,39, n = 77). Foi analisada a associação do escore ALBI com eventos clínicos adversos maiores (ECAM) intra-hospitalares e mortalidade a longo prazo. Valor de p inferior a 0,05 foi considerado estatisticamente significativo. Resultados: A taxa de ECAM intra-hospitalares foi significativamente maior nos pacientes com grau 3 (2,7% versus 7,1% versus 24,7%, p < 0,001). A análise multivariada mostrou que o escore ALBI foi um preditor independente para ECAM intra-hospitalares (odds ratio ajustada = 2,80, IC 95%: 1,63 - 4,80, p < 0,001). Após seguimento mediano de 27 meses, 146 (14,2%) pacientes morreram. A curva de Kaplan-Meier indicou que a taxa cumulativa de sobrevida a longo prazo foi significativamente menor em pacientes com grau mais alto de ALBI (log-rank = 45,50, p < 0,001). O escore ALBI foi independentemente associado à mortalidade a longo prazo (hazard ratio ajustada = 2,84, IC 95%: 1,95 - 4,13, p < 0,001). Conclusão: O escore ALBI, como modelo de risco simples, pode ser considerado uma ferramenta de estratificação de risco para pacientes com CMD idiopática.

Abstract Background: Liver dysfunction is a postulated variable for poor prognosis in dilated cardiomyopathy (DCM). Objective: This study aimed to investigate the prognostic value of the albumin-bilirubin (ALBI) score, a relatively new model for evaluating liver function, in patients with idiopathic DCM. Methods: A total of 1025 patients with idiopathic DCM were retrospectively included and divided into three groups based on ALBI scores: grade 1 (≤ −2.60, n = 113), grade 2 (−2.60 to −1.39, n = 835), and grade 3 (> −1.39, n = 77). The association of ALBI score with in-hospital major adverse clinical events (MACEs) and long-term mortality was analyzed. P-value less than 0.05 was considered statistically significant. Results: The in-hospital MACEs rate was significantly higher in the grade 3 patients (2.7% versus 7.1% versus 24.7%, p < 0.001). Multivariate analysis showed that ALBI score was an independent predictor for in-hospital MACEs (adjusted odds ratio = 2.80, 95%CI: 1.63 - 4.80, p < 0.001). After a median 27-month follow-up, 146 (14.2%) patients died. The Kaplan-Meier curve indicated that the cumulative rate of long-term survival was significantly lower in patients with higher ALBI grade (log-rank = 45.50, p < 0.001). ALBI score was independently associated with long-term mortality (adjusted hazard ratio = 2.84, 95%CI: 1.95 - 4.13, p < 0.001). Conclusion: ALBI score as a simple risk model could be considered a risk-stratifying tool for patients with idiopathic DCM.

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PURPOSES: The effects of preoperative statin treatment on acute kidney injury (AKI) remain controversial, and current clinical evidence regarding statin use in the elderly undergoing valve replacement surgery (VRS) is insufficient. The present study aimed to investigate the association between preoperative statin treatment and AKI after VRS in the elderly. METHODS: Three thousand seven hundred ninety-one elderly patients (≥ 60 years) undergoing VRS were included in this study and divided into 2 groups, according to the receipt of statin treatment before the operation: statin users (n = 894) and non-users (n = 2897). We determined the associations between statin use, AKI, and other adverse events using a multivariate model and propensity score-matched analysis. RESULTS: After propensity score-matched analysis, there was no difference between statin users and non-users in regard to postoperative AKI (72.5% vs. 72.4%, p = 0.954), in-hospital death (5.7% vs. 5.1%, p = 0.650) and 1-year mortality (log-rank = 0, p = 0.986). The multivariate analysis showed that statin use was not an independent risk factor for postoperative AKI (OR = 0.97, 95% CI: 0.90-1.17, p = 0.733), in-hospital mortality (OR = 1.12, 95% CI: 0.75-1.68, p = 0.568), or 1-year mortality (HR = 0.95, 95% CI: 0.70-1.28, p = 0.715). CONCLUSION: Preoperative statin treatment did not significantly affect the risk of AKI among elderly patients undergoing VRS.

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BACKGROUND: Coronary heart disease (CHD) is the most prevalent disease with an unelucidated pathogenetic mechanism and is mediated by complex molecular interactions of exosomes. Here, we aimed to identify differentially expressed exosome genes for the disease development and prognosis of CHD. METHOD: Six CHD samples and 32 normal samples were downloaded from the exoRbase database to identify the candidate genes in the CHD. The differentially expressed genes (DEGs) were identified. And then, weighted gene correlation network analysis (WGCNA) was used to investigate the modules in coexpressed genes between CHD samples and normal samples. DEGs and the module of the WGCNA were intersected to obtain the most relevant exosome genes. After that, the function enrichment analyses and protein-protein interaction network (PPI) were performed for the particular module using STRING and Cytoscape software. Finally, the CIBERSORT algorithm was used to analyze the immune infiltration of exosome genes between CHD samples and normal samples. RESULT: We obtain a total of 715 overlapping exosome genes located at the intersection of the DEGs and key modules. The Gene Ontology enrichment of DEGs in the blue module included inflammatory response, neutrophil degranulation, and activation of CHD. In addition, protein-protein networks were constructed, and hub genes were identified, such as LYZ, CAMP, HP, ORM1, and LTF. The immune infiltration profiles varied significantly between normal controls and CHD. Finally, we found that mast cells activated and eosinophils had a positive correlation. B cell memory had a significant negative correlation with B cell naive. Besides, neutrophils and mast cells were significantly increased in CHD patients. CONCLUSION: The underlying mechanism may be related to neutrophil degranulation and the immune response. The hub genes and the difference in immune infiltration identified in the present study may provide new insights into the diagnostic and provide candidate targets for CHD.

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BACKGROUND: Increased D-dimer levels have been shown to correlate with adverse outcomes in various clinical conditions. However, few studies with a large sample size have been performed thus far to evaluate the prognostic value of D-dimer in patients with infective endocarditis (IE). METHODS: 613 patients with IE were included in the study and categorized into two groups according to the cut-off of D-dimer determined by receiver operating characteristic (ROC) curve analysis for in-hospital death: > 3.5 mg/L (n = 89) and ≤ 3.5 mg/L (n = 524). Multivariable regression analysis was used to determine the association of D-dimer with in-hospital adverse events and six-month death. RESULTS: In-hospital death (22.5% vs. 7.3%), embolism (33.7% vs 18.2%), and stroke (29.2% vs 15.8%) were significantly higher in patients with D-dimer > 3.5 mg/L than in those with D-dimer ≤ 3.5 mg/L. Multivariable analysis showed that D-dimer was an independent risk factor for in-hospital adverse events (odds ratio = 1.11, 95% CI 1.03-1.19, P = 0.005). In addition, the Kaplan-Meier curve showed that the cumulative 6-month mortality was significantly higher in patients with D-dimer > 3.5 mg/L than in those with D-dimer ≤ 3.5 mg/L (log-rank test = 39.19, P < 0.0001). Multivariable Cox regression analysis showed that D-dimer remained a significant predictor for six-month death (HR 1.11, 95% CI 1.05-1.18, P < 0.001). CONCLUSIONS: D-dimer is a reliable prognostic biomarker that independently associated with in-hospital adverse events and six-month mortality in patients with IE.

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Trichinella spiralis represents an effective treatment for autoimmune and inflammatory diseases. The effects of recombinant T. spiralis (TS) 53-kDa protein (rTsP53) on acute lung injury (ALI) remain unclear. Here, mice were divided randomly into a control group, LPS group, and rTsP53 + LPS group. ALI was induced in BALB/c mice by LPS (10 mg/kg) injected via the tail vein. rTsP53 (200 µl; 0.4 µg/µl) was injected subcutaneously three times at an interval of 5 d before inducing ALI in the rTsP53+LPS group. Lung pathological score, the ratio and markers of classic activated macrophages (M1) and alternatively activated macrophages (M2), cytokine profiles in alveolar lavage fluid, and pyroptosis protein expression in lung tissue were investigated. RTsP53 decreased lung pathological score. Furthermore, rTsP53 suppressed inflammation by increasing IL-4, IL-10, and IL-13. There was an increase in alveolar M2 macrophage numbers, with an increase in CD206 and arginase-1-positive cells and a decrease in alveolar M1 markers such as CD197 and iNOS. In addition, the polarization of M2 macrophages induced by rTsP53 treatment could alleviate ALI by suppressing lung pyroptosis. RTsP53 was identified as a potential agent for treating LPS-induced ALI via alleviating lung pyroptosis by promoting M2 macrophage polarization.

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BACKGROUND: Melatonin (MT) has been shown to protect against various cardiovascular diseases. However, the effect of MT on lipopolysaccharide (LPS)-induced myocardial injury is poorly understood. This study aims to evaluate the effects of MT on LPS-induced myocardial injury in vitro. METHODS: H9C2 cells were divided into a control group, MT group, LPS group, and MT + LPS group. The control group was treated with sterile saline solution, the LPS group received 8 µg/mL LPS for 24 h, MT + LPS cells were pretreated with 200 µmol/L MT for 2 h then with 8 µg/mL LPS for 24 h, and the MT group received only 200 µmol/L MT for 2 h. The CCK-8 assay and lactate dehydrogenase (LDH) activity assay were used to analyze cell viability and LDH release, respectively. Intracellular reactive oxygen species (ROS) and the rate of pyroptosis were measured using the fluorescent probe dichloro-dihydro-fluorescein diacetate (DCFH-DA) and propidium iodide (PI) staining, respectively. The cell supernatants were used to measure the levels of inflammatory cytokines, including IL-6, TNF-α, and IL-1ß by enzyme-linked immunosorbent assay (ELISA). The protein levels of iNOS, COX-2, NF-κB, p-NF-κB, NLRP3, caspase-1, and GSDMD were detected by western blot. RESULTS: MT pretreatment significantly improved LPS-induced myocardial injury by inhibiting inflammation and pyroptosis in H9C2 cells. Moreover, MT inhibited the activation of the NF-κB pathway, and reduced the expression of inflammation-related proteins (iNOS and COX-2), and pyroptosis-related proteins (NLRP3, caspase-1, and GSDMD). CONCLUSIONS: Our data suggests that MT can alleviate LPS-induced myocardial injury, providing novel insights into the treatment of sepsis-induced myocardial dysfunction.

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BACKGROUND Accurate risk assessment and prospective stratification are of great importance for treatment of acute coronary syndrome (ACS). However, the optimal risk evaluation systems for predicting different type of ACS adverse events in Chinese population have not been established. MATERIAL AND METHODS Our data were derived from the Improving Care for Cardiovascular Disease in China-ACS (CCC-ACS) Project, a multicenter registry program. We incorporated data on 44 750 patients in the study. We compared the performance of the following 4 different risk score systems with regard to prediction of in-hospital adverse events: the Global Registry for Acute Coronary Events (GRACE) risk score system; the age, creatinine and ejection fraction (ACEF) risk score system, and its modified version (AGEF), and the Canada Acute Coronary Syndrome (C-ACS) risk assessment system. RESULTS Admission AGEF risk score was a better prognosis index of potential for in-hospital mortality for patients with ST segment elevation myocardial infarction (STEMI) than GRACE risk score (AUC: 0.845 vs 0.819, P=0.012), ACEF (AUC: 0.845 vs 0.827, P=0.014), C-ACS (AUC: 0.845 vs 0.767, P<0.001). In patients with non-ST segment-elevation acute coronary syndrome (NSTE-ACS), there was no statistically significant difference between the GRACE risk scale and AGEF (AUC: 0.853 vs 0.832, P=0.140) for in-hospital death. CONCLUSIONS AGEF risk score showed a non-inferior utility compared with the other 3 scoring systems in estimating in-hospital mortality in ACS patients.

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BACKGROUND: Older age, renal and cardiac dysfunction are predictors of poor outcome in aortic dissection. The aim of this study was to evaluate the association of the age, creatinine and ejection fraction (ACEF) score with adverse events in patients with type B aortic dissection (TBAD) undergoing thoracic endovascular aortic repair (TEVAR). METHODS: The study enrolled 605 patients from January 2010 to July 2015, who were classified into three groups according to the tertiles of ACEF score: Tertile 1 (≤0.77, n = 204), Tertile 2 (0.77-0.96, n = 205) and Tertile 3 (>0.96, n = 196). The association between ACEF, AGEF (age, glomerular filtration rate and ejection fraction) and the updated version of the ACEF (ACEF II) score with adverse events was analyzed. RESULTS: After a median 3.4 years follow-up, 63 (10.4%) patients died. Multivariable analysis revealed that ACEF score was independently associated with long-term mortality (adjusted hazard ratio = 3.54; 95% confidence interval, 2.09-6.01; p < 0.001). ACEF, AGEF and ACEF II score had similar predictive ability for both in-hospital and long-term death. The in-hospital mortality (1.5% vs. 1.0% vs. 6.6%, p = 0.001) were significantly higher in Tertile 3. In addition, cumulative long-term mortality in Tertile 3 was significantly higher than that in Tertile 1 and 2 (Log-Rank = 23.74; p < 0.001). CONCLUSION: ACEF score could be served as an useful and relatively simple tool for pre-TEVAR risk stratification in TBAD patients.

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BACKGROUND: Few studies with a large sample size have been performed to evaluate the incidence, risk factors and prognostic value of new-onset atrial fibrillation (AF) in patients with infective endocarditis (IE).Methods and Results:A total of 1,063 IE patients were included and 83 developed new AF. Compared with no-AF, the incidence of in-hospital death (6.0% vs. 22.9%, P<0.001) was higher in patients with new-onset AF. New-onset AF was independently associated with increased risk of in-hospital (adjusted odds ratio [OR]=3.92, P=0.001) and 1-year death (adjusted hazard ratio=2.91, P=0.001), while prior AF was not an independent factor. Kaplan-Meier curve analysis demonstrated new-onset AF mainly affected short-term death (180 days). Age (OR=1.04, P<0.001), rheumatic heart disease (OR=1.88, P=0.022), NYHA Class III or IV (OR=2.09, P=0.003), and left atrial diameter (LAD; OR=1.05, P=0.006) were independent risk factors for development of new AF. CONCLUSIONS: New-onset AF, not prior AF, was a prognostic factor in IE patients, which was mainly associated with increased risk of short-term death. Patients with concomitant rheumatic heart disease, poor cardiac function, and larger LAD had higher risk of developing new AF.

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