BMMSC-derived Exosomes Attenuate Cardiopulmonary Bypass-related Acute Lung Injury by Reducing Inflammatory Response and Oxidative Stress.

BACKGROUND: Acute lung injury (ALI), which is characterized by inflammation and oxidative stress, is a common complication after cardiopulmonary bypass (CPB). Exosomes from bone marrow mesenchymal stem cells (BMMSC-Exo) have recently been identified as promising treatments for ALI. However, the effects of BMMSC-Exo on inflammation and oxidative stress in CPB-related ALI remain unclear. OBJECTIVE: We aim to evaluate the effects of BMMSC-Exo on post-CPB ALI and explore their potential mechanisms. METHODS: We randomly divided rats into three groups: sham, ALI, and ALI+BMMSC-Exo groups. Histological changes were evaluated by lung histo-pathology and bronchoalveolar lavage fluid (BALF). ELISA assay was used to determine inflammatory cytokine levels and oxidative stress. RESULTS AND DISCUSSION: BMMSC-Exo attenuated histological changes (including the invasion of inflammatory cells), reduced the wet/dry (W/D) weight ratio, and downregulated inflammatory cytokine levels, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1ß. BMMSC-Exo also alleviated oxidative stress. In vitro, we further administered lipopolysaccharide (LPS) to alveolar macrophages (AMs) to mimic the pathological changes of ALI and found that BMMSC-Exo suppressed reactive oxygen species (ROS) production and downregulated the levels of inflammatory cytokines. Mechanistically, BMMSC-Exo inhibited the phosphorylation of nuclear factor-κB (NF-κB), the nuclear translocation of p65, also facilitated the phosphorylation of Akt and the nuclear translocation of Nrf2, while upregulating the expression of HO-1. CONCLUSION: In summary, we indicate that BMMSC-Exo reduces CPB-related ALI by alleviating inflammation and oxidative stress. The underlying mechanism may involve the NF-κB p65 and Akt/Nrf2/HO-1 signaling pathways.

A machine learning model to predict critical care outcomes in patient with chest pain visiting the emergency department.

BACKGROUND: Currently, the risk stratification of critically ill patient with chest pain is a challenge. We aimed to use machine learning approach to predict the critical care outcomes in patients with chest pain, and simultaneously compare its performance with HEART, GRACE, and TIMI scores. METHODS: This was a retrospective, case-control study in patients with acute non-traumatic chest pain who presented to the emergency department (ED) between January 2017 and December 2019. The outcomes included cardiac arrest, transfer to ICU, and death during treatment in ED. In the randomly sampled training set (70%), a LASSO regression model was developed, and presented with nomogram. The performance was measured in both training set (70% participants) and testing set (30% participants), and findings were compared with the three widely used scores. RESULTS: We proposed a LASSO regression model incorporating mode of arrival, reperfusion therapy, Killip class, systolic BP, serum creatinine, creatine kinase-MB, and brain natriuretic peptide as independent predictors of critical care outcomes in patients with chest pain. Our model significantly outperformed the HEART, GRACE, TIMI score with AUC of 0.953 (95%CI: 0.922-0.984), 0.754 (95%CI: 0.675-0.832), 0.747 (95%CI: 0.664-0.829), 0.735 (95%CI: 0.655-0.815), respectively. Consistently, our model demonstrated better outcomes regarding the metrics of accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F1 score. Similarly, the decision curve analysis elucidated a greater net benefit of our model over the full ranges of clinical thresholds. CONCLUSION: We present an accurate model for predicting the critical care outcomes in patients with chest pain, and provide substantial support to its application as a decision-making tool in ED.

A novel HAND2 loss-of-function mutation responsible for tetralogy of Fallot.

Congenital heart disease (CHD), the most common type of developmental abnormality, is associated with substantial morbidity and mortality in humans worldwide. The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed 2 (HAND2), has been demonstrated to be crucial for normal cardiovascular development in animal models. However, whether a genetically defective HAND2 contributes to congenital heart disease (CHD) in humans remains to be explored. In this study, the entire coding region and splicing boundaries of the HAND2 gene were sequenced in a cohort of 145 unrelated patients with CHD. A total of 200 unrelated, ethnically-matched healthy individuals used as controls were also genotyped for HAND2. The functional effect of the mutant HAND2 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous HAND2 mutation, p.L47P, was identified in a patient with tetralogy of Fallot (TOF). The misense mutation, which altered the amino acid conserved evolutionarily among species, was absent in 400 control chromosomes. Functional analyses unveiled that the mutant HAND2 had a significantly decreased transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation between HAND2 and GATA4 or NKX2.5, other two cardiac key transcription factors involved in the pathogenesis of CHD. To the best of our knowledge, this study is the first to report the association of a HAND2 loss-of-function mutation with an increased vulnerability to TOF in humans, which provides novel insight into the molecular mechanism underpinning CHD, suggesting potential implications for the genetic counseling of families with CHD.

The influence of statin-fibrate combination therapy on lipids profile and apolipoprotein A5 in patients with acute coronary syndrome.

BACKGROUND: Statin-fibrate combination therapy has been used to treat patients with acute coronary syndrome (ACS) complicated by elevated triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C). The purpose of this study was to evaluate the influence of the combination therapy on lipids profile and apolipoprotein A5 (apoA5) level in patients with ACS. METHODS: One hundred and four patients with ACS were recruited and randomly assigned into two groups: one was statin group (n = 52), given atorvastatin (20 mg QN) or other statins with equivalent dosages; the other was combination group (n = 52), given the same dose of statin plus bezafibrate (200 mg BID). Follow-up visits were scheduled at the end of 6 and 12 weeks post treatment. Serum apoA5 levels were determined using a commercial available ELISA kit. RESULTS: (1) Compared with that of statin monotherapy, statin-bezafibrate combination treatment not only resulted in a significant reduction of TG, TC and LDL-C levels, (all p < 0.05), but also led to increases in HDL-C and apoA5 levels (p < 0.05).(2) The percentage changes of TC, TG, LDL-C and apoA5 levels in both groups were even bigger at 12 weeks after treatment than that at 6 weeks (all p < 0.05). Similarly, the rates of achieving lipid-control target were higher in statin-bezafibrate combination treatment group than those in statin monotherapy group (all p < 0.05).(3) Spearman rank correlation analysis showed that the pre-treatment apoA5 level was positively correlated with TG (r = 0.359, p = 0.009). However, a negative correlation was observed between apoA5 and TG (r = -0.329, p = 0.017) after 12 weeks treatment. CONCLUSIONS: Statin and fibrate combination therapy is more effective than statin alone in achieving a comprehensive lipid control for ACS patients. Serum apoA5 elevation after statin and fibrate combination treatment could be due to the synergistic effect of both drugs on hypertriglyceridemia control.

[The lipid-regulating effect and safety of combined statin and bezafibrate therapy in acute coronary syndrome patients complicating with dyslipidemia].

OBJECTIVE: To investigate the lipid-regulating effect and safety of combined statin and bezafibrate therapy in acute coronary syndrome(ACS) patients complicating with dyslipedemia. METHODS: One hundred and four hospitalized patients with established ACS and increased serum triglycerides (TG) levels and/or low serum levels of high density lipoprotein cholesterol (HDL-C) were selected. Except for conventional therapy, the patients were randomly divided into 2 groups: control group (n = 52), treated with atorvastatin 20 mg qn or other statin equivalent to 20 mg atorvastatin; treatment group (n = 52), treated with the same dose statin plus bezafibrate 200 mg bid. The serum levels of total cholesterol (TC), TG, low-density lipoprotein cholesterol (LDL-C) and HDL-C were assessed before and after 6 and 12 weeks treatment, side effects and adverse events were recorded. RESULTS: After 6 weeks treatment, the serum levels of TC, TG and LDL-C in two groups were significantly reduced compared to baseline (all P < 0.05), which were further declined after 12 weeks treatment, and the reduction was more significant in treatment group(29.8%, 38.0% and 36.1%, respectively) than in control group(14.7%, 9.8% and 26.7%, respectively) (all P < 0.05). After treatment, the serum levels of HDL-C in the two groups were significantly higher than the baseline levels, especially after 12 weeks treatment (all P < 0.05), and the elevations of HDL-C levels in control group and in treatment group were 19.3% and 24.2%, respectively, but there were no significant difference between the two groups (P > 0.05). After 12 weeks, the rates reaching to target goals of LDL-C, TG, HDL-C, and non-HDL-C levels in the treatment group (69.2%, 88.5%, 92.3%, 46.2% and 65.4%, respectively) were significantly higher than those in the control group (34.6%, 65.4%, 46.2%, 7.7% and 42.3%, respectively, all P < 0.05). No serious side effects were observed in the two groups during the treatment period. CONCLUSION: The combined statin and bezafibrate treatment is safe and could increase the ratios of reaching target lipid levels in ACS patients complicating with increased TG and (or) decreased HDL-C.