Single-cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor-related myocarditis.

Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)-associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single-cell RNA sequencing from ICI-related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single-cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD-1 inhibitor therapy who did not develop myocarditis (PD-1 Group); (3) patients during fulminant ICI-related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI-related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single-cell trajectory and cell-cell interaction analysis were performed after scRNA-seq. Bulk-RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI-related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI-related myocarditis. With integrated analysis of scRNA-seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI-related myocarditis. Our study has created a cell atlas of PBMC during ICI-related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI-related myocarditis in continuous exploration.

Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner.

Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.

Impaired Detoxification of Trans, Trans-2,4-Decadienal, an Oxidation Product from Omega-6 Fatty Acids, Alters Insulin Signaling, Gluconeogenesis and Promotes Microvascular Disease.

Omega-6 fatty acids are the primary polyunsaturated fatty acids in most Western diets, while their role in diabetes remains controversial. Exposure of omega-6 fatty acids to an oxidative environment results in the generation of a highly reactive carbonyl species known as trans, trans-2,4-decadienal (tt-DDE). The timely and efficient detoxification of this metabolite, which has actions comparable to other reactive carbonyl species, such as 4-hydroxynonenal, acrolein, acetaldehyde, and methylglyoxal, is essential for disease prevention. However, the detoxification mechanism for tt-DDE remains elusive. In this study, the enzyme Aldh9a1b is identified as having a key role in the detoxification of tt-DDE. Loss of Aldh9a1b increased tt-DDE levels and resulted in an abnormal retinal vasculature and glucose intolerance in aldh9a1b-/- zebrafish. Transcriptomic and metabolomic analyses revealed that tt-DDE and aldh9a1b deficiency in larval and adult zebrafish induced insulin resistance and impaired glucose homeostasis. Moreover, alterations in hyaloid vasculature is induced by aldh9a1b knockout or by tt-DDE treatment can be rescued by the insulin receptor sensitizers metformin and rosiglitazone. Collectively, these results demonstrated that tt-DDE is the substrate of Aldh9a1b which causes microvascular damage and impaired glucose metabolism through insulin resistance.

Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism.

BACKGROUND: Increased circulating uric acid (UA) concentration may disrupt cardiac function in heart failure patients, but the specific mechanism remains unclear. Here, we postulate that hyperuremia induces sterol regulatory element binding protein 1 (SREBP1), which in turn activate hepatic fatty acid biosynthesis response, leading to cardiac dysfunction. METHODS AND RESULTS: Increased circulating uric acid was observed in heart failure patients and inversely correlated to cardiac function. Besides, uric acid correlated to circulating lipids profile based on metabolomics in heart failure patients. Using cultured human hepatoellular carcinomas (HepG2) and Tg(myl7:egfp) zebrafish, we demonstrated that UA regulated fatty acid synthase (FASN) via SREBP1 signaling pathway, leading to FFA accumulation and impaired energy metabolism, which could be rescued via SREBP1 knockdown. In ISO treated zebrafish, UA aggravated heart failure via increased cardiovascular cavity size, decreased heart beats, pericardial edema and long-stretched heart deformation. CONCLUSIONS: Our findings suggest that UA-SREBP1-FASN signaling exacerbates cardiac dysfunction during FFA accumulation. Identification of this mechanism may help in treatment and prevention of heart failure.

In-hospital initiation of PCSK9 inhibitor and short-term lipid control in patients with acute myocardial infarction.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to improve cardiovascular outcomes when added to conventional statin therapy. This study aims to investigate the efficacy and safety of in-hospital initiation of PCSK9 inhibitors among patients with acute myocardial infarction (AMI) based on real-world experience. METHODS AND RESULTS: Data were collected from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University between January 2016 and December 2020. A total of 7556 AMI patients were screened for eligibility. Propensity Score Match (PSM) was employed, and covariates were age, sex, admission blood pressure and lipid profiles. Eligible participants were (1) propensity-matched 1:2:2 of statin plus evolocumab (dual therapy) vs. statin vs. statin plus ezetimibe. Ninety-five statin plus evolocumab users achieved significantly decreased low density lipoprotein (LDL) levels (0.92 ± 0.62 mmol/L in the 1st month and 1.17 ± 0.73 in the 3rd month) and a promising attainment rate of LDL (79.5% in the 1st month and 80.0% in the 3rd month) compared to the other two groups. (2) Propensity-matched 1:2:2 of statin plus ezetimibe evolocumab (triple therapy) vs. statin vs. statin plus ezetimibe. Similarly, 75 triple medication users achieved significantly decreased LDL levels and a promising attainment rate of LDL compared to the other two groups. In-hospital mortality and readmission rates within 3 months were then analyzed, and a decreased readmission rate was observed with PCSK9i therapy. CONCLUSIONS: Based on the present single-center real-world PSM-adjusted study, PCSK9i has been effective in short-term lipid control among AMI patients. The long-term effectiveness for reducing major cardiovascular events among AMI patients based on real-world experience remains to be explored. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov, ClinicalTrials.gov ID: NCT05184530.

Association between Cystatin C and Cardiac Function in Acute Myocardial Infarction Patients: A Real-World Analysis.

Background: Acute myocardial infarction (AMI), as well as its long-term and short-term complications, is known to present with high morbidity and mortality. Cardiac function deterioration and ventricular remodelling after AMI are known to be correlated to worse long-term outcomes. However, the underlying mechanism remains elusive and there is a shortage of serum prediction markers. This study investigates the relationship between in-hospital Cystatin C (CysC) and cardiac function and subsequent prognosis among AMI patients. Research Design and Methods. We measured admission CysC and cardiac function parameters, including ejection fraction (EF) and pro-BNP value in 5956 patients diagnosed with AMI. Simple and multiregression analyses were performed to investigate the correlation between CysC and cardiac function in AMI patients. Major adverse cardiovascular events (MACE), cardiovascular, and all-cause mortality were documented, and 351 participants with high cystatin (≥1.09 mg/L) and 714 low cystatin (<1.09 mg/L) were investigated for survival analysis during a 48-month follow-up. Results: 5956 patients with AMI were enrolled in the initial observational analysis, and 1065 patients of the whole cohort were included in the follow-up survival analysis. The admission CysC level was found to be significantly positively correlated to the pro-BNP level (R square = 0.2142, 95% CI 4758 to 5265, p < 0.0001) and negatively correlated to the EF value (R square = 0.0095, 95% CI -3.503 to -1.605, p < 0.0001). Kaplan-Meier survival analysis revealed significantly increased MACE incidence (HR = 2.293, 95% CI 1.400 to 3.755, p < 0.0001), cardiovascular mortality (HR = 3.016, 95% CI 1.694 to 5.371, p = 0.0002), and all-cause mortality (HR = 3.424, 95% CI 2.010 to 5.835, p < 0.0001) in high-admission CysC cohort with AMI at the end of 4-year follow-up. Conclusions: Admission CysC is negatively correlated with cardiac function in AMI patients and acts as a novel predictor for MACE incidence in the whole population. Further studies are needed to investigate the specific mechanism of CysC in the cardiac function deterioration among AMI patients.

Accumulation of acetaldehyde in aldh2.1-/- zebrafish causes increased retinal angiogenesis and impaired glucose metabolism.

Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1-/- animals and therefore this study aimed to investigate the detoxification ability for RCS by Aldh2.1 in zebrafish independent of ethanol exposure. aldh2.1 knockout zebrafish were generated using CRISPR/Cas9 and subsequently analyzed on a histological, metabolomic and transcriptomic level. aldh2.1-/- zebrafish displayed increased endogenous acetaldehyde (AA) inducing an increased angiogenesis in retinal vasculature. Expression and pharmacological interventional studies identified an imbalance of c-Jun N-terminal kinase (JNK) and p38 MAPK induced by AA, which mediate an activation of angiogenesis. Moreover, increased AA in aldh2.1-/- zebrafish did not induce hyperglycemia, instead AA inhibited the expression of glucokinase (gck) and glucose-6-phosphatase (g6pc), which led to an impaired glucose metabolism. In conclusion, the data have identified AA as the preferred substrate for Aldh2.1's detoxification ability, which subsequently causes microvascular organ damage and impaired glucose metabolism.

Interplay Between Gut Microbiota and Amino Acid Metabolism in Heart Failure.

Heart failure (HF) is a complex clinical syndrome of which the incidence is on the rise worldwide. Cardiometabolic disorders are associated with the deterioration of cardiac function and progression of HF. Recently, there has been renewed interest in gut microbiota (GM) and its metabolites in the cardiovascular disease. HF-caused hypoperfusion could increase intestinal permeability, and a "leaky" bowel leads to bacterial translocation and make its metabolites more easily enter the circulation. Considerable evidence shows that the composition of microbiota and amino acids (AAs) has been altered in HF patients, and AAs could serve as a diagnostic and prognostic biomarker in HF. The findings indicate that the gut-amino acid-HF axis may play a key role in the progression of HF. In this paper, we focus on the interrelationship between the AA metabolism and GM alterations during the development of heart failure. We also discuss the potential prognostic and therapeutic value of the gut-amino acid-HF axis in the cortex of HF.

Targeted metabolomic analysis of plasma fatty acids in acute myocardial infarction in young adults.

BACKGROUND AND AIMS: Acute myocardial infarction (AMI) in young adults has distinct clinical features and risk profile as compared with that in elder adults. The pathophysiologic mechanism of AMI in young adults remains unclear. In this study, we used targeted metabolomics to measure metabolic profile and analyzed plasma fatty acids levels in young adults with AMI, seeking to determine whether circulating fatty acid metabolism was correlated with the occurrence of AMI in young adults. METHODS AND RESULTS: Consecutive young and elder patients admitted to hospital for AMI were enrolled. Plasma samples of all participants were obtained after overnight fast and then measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) based targeted metabolomic platform. A total of 201 plasma metabolites were measured using UPLC-MS/MS. Several plasma fatty acids were significantly altered in young AMI patients compared with control or elder AMI patients, which also showed significant prediction value for AMI in young adults. Percentage of short chain fatty acids (SCFAs) was decreased and long chain increased in AMI as compared with control. Moreover, alpha-linolenic acid and linoleic acid metabolism (ALALAM) pathway metabolites were gradually increased in control, young, and elder AMI patients. Altered fatty acid correlation network further identified fatty acid metabolism disorder in AMI in young adults. CONCLUSION: By utilizing targeted metabolomic technique, we have found several altered fatty acids and respective pathways that show diagnostic value for AMI in young adults. SCFA and long-chain fatty acid (LCFA) were differentially altered in AMI patients.

Metabolic and Transcriptional Adaptations Improve Physical Performance of Zebrafish.

Obesity is a worldwide public health problem with increasing prevalence and affects 80% of diabetes mellitus type 2 cases. Zebrafish (Danio rerio) is an established model organism for studying obesity and diabetes including diabetic microvascular complications. We aimed to determine whether physical activity is an appropriate tool to examine training effects in zebrafish and to analyse metabolic and transcriptional processes in trained zebrafish. A 2- and 8-week experimental training phase protocol with adult zebrafish in a swim tunnel system was established. We examined zebrafish basic characteristics before and after training such as body weight, body length and maximum speed and considered overfeeding as an additional parameter in the 8-weeks training protocol. Ultimately, the effects of training and overfeeding on blood glucose, muscle core metabolism and liver gene expression using RNA-Seq were investigated. Zebrafish maximum speed was correlated with body length and was significantly increased after 2 weeks of training. Maximum swim speed further increased after 8 weeks of training in both the normal-fed and the overfed groups, but training was found not to be sufficient in preventing weight gain in overfed fish. Metabolome and transcriptome profiling in trained fish exhibited increased blood glucose levels in the short-term and upregulated energy supply pathways as well as response to oxidative stress in the long-term. In conclusion, swim training is a valuable tool to study the effects of physical activity in zebrafish, which is accompanied by metabolic and transcriptional adaptations.

ARNI versus ACEI/ARB in Reducing Cardiovascular Outcomes after Myocardial Infarction.

AIMS: This study aimed to compare the efficacy of angiotensin receptor-neprilysin inhibitor (ARNI) therapy with angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) therapy for cardiovascular outcomes in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Data were collected from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University between January 2016 and December 2020. A total of 7556 AMI patients were screened for eligibility. Propensity score matching based on age, sex, blood pressure, kidney function, baseline left ventricular ejection fraction (LVEF), and cardiovascular medication were conducted, resulting in 291 patients with AMI being assigned to ARNI, ACEI, and ARB group, respectively. Patients receiving ARNI had significantly lower rates of the composite cardiovascular outcome than ACEI {hazard ratio [HR] 0.51, [95% confidence interval (CI), 0.27-0.95], P = 0.02}, and ARB users [HR 0.47, (95%CI, 0.24-0.90), P = 0.02]. Patients receiving ARNI showed lower rates of cardiovascular death than ACEI [HR 0.37, (95%CI, 0.18-0.79), P = 0.01] and ARB users [HR 0.41, (95%CI, 0.18-0.95), P = 0.04]. Subgroup analysis indicated that patients with LVEF no more than 40% tend to benefit more from ARNI as compared with ACEI [HR 0.30, (95%CI, 0.11-0.86), P = 0.01] or ARB [HR 0.21, (95%CI, 0.04-1.1), P = 0.05]. Patients aged no more than 60 years exhibited reduced composite endpoints [HR for ARNI vs. ARB: 0.11, (95%CI, 0.03-0.46), P = 0.002]. CONCLUSIONS: In patients with AMI, ARNI was superior to ACEI/ARB in reducing the long-term adverse cardiovascular outcomes. Subgroup analysis further indicates that ARNI is more likely to benefit patients with LVEF less than 40% and aged less than 60 years.

Impact of Age, Sex, and Renal Function on the Efficacy and Safety of Direct Oral Anticoagulants vs. Vitamin K Antagonists for the Treatment of Acute Venous Thromboembolism: A Meta-Analysis of 22,040 Patients.

Objective: In this study, we conducted a meta-analysis to assess the impact of age, sex, and renal function on the efficacy and safety of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) for the treatment of acute venous thromboembolism (VTE). Methods: Electronic databases (accessed till June 2021) were systematically searched to investigate randomized clinical trials evaluating apixaban, dabigatran, edoxaban, and rivaroxaban vs. VKAs for the treatment of acute VTE. Results were presented as odds ratio (OR) and 95% CIs. Results: Direct oral anticoagulants were associated with a borderline higher efficacy in women (OR: 0.79, 95% CI: 0.62-1.02), a significantly higher efficacy in patients with age more than 75 years (OR: 0.51, 95% CI: 0.32-0.80), and creatinine clearance <50 ml/min (OR: 0.57, 95% CI: 0.32-0.99). The primary safety endpoint of major or clinically relevant non-major bleeding was significantly reduced in DOACs as compared to VKAs in both patients with age <75 years (OR: 0.79, 95% CI: 0.70-0.89) and patients with age more than 75 years (OR: 0.75, 95% CI: 0.59-0.96). DOACs also show an advantage in terms of major or clinically relevant non-major bleeding in men (OR: 0.72, 95% CI: 0.60-0.86) and patients with creatinine clearance of more than 50 ml/min (OR: 0.75, 95% CI: 0.67-0.84). Conclusions: Direct oral anticoagulants have exhibited clinical preference among patients with acute VTE with decreased thrombosis and bleeding events, especially in patients with age more than 75 years and creatinine clearance <50 ml/min.

HDL-C/apoA-I Ratio Is Associated with the Severity of Coronary Artery Stenosis in Diabetic Patients with Acute Coronary Syndrome.

BACKGROUND: Emerging evidence demonstrates that the lipid metabolism in acute coronary syndrome (ACS) patients with type 2 diabetes mellitus (T2DM) differs from nondiabetic patients. However, the distinct lipid profiles and their relationships with the severity of coronary artery stenosis and prognosis in patients with T2DM remain elusive. METHOD AND RESULT: This single-center, prospective cohort study enrolled 468 patients diagnosed with ACS undergoing coronary angiography, consisting of 314 non-DM and 154 DM patients. The HDL-C/apoA-I ratio was significantly higher in DM patients with a multivessel (≥3 affected vessels) lesion than a single-vessel (1-2 affected vessels) lesion. Regression analyses showed that the HDL-C/apoA-I ratio was positively correlated to the number of stenotic coronary arteries in DM patients but not non-DM patients. However, Kaplan-Meier survival analysis revealed no significant difference in the major adverse cardiovascular event rate regarding different HDL-C/apoA-I levels in DM or non-DM ACS patients at the end of the 2-year follow-up. CONCLUSION: A higher HDL-C/apoA-I ratio is associated with increased severity of coronary artery stenosis in DM patients with ACS but not with the rate of major adverse cardiovascular events at the end of the 2-year follow-up.

Elevated 4-hydroxynonenal induces hyperglycaemia via Aldh3a1 loss in zebrafish and associates with diabetes progression in humans.

Increased methylglyoxal (MG) formation is associated with diabetes and its complications. In zebrafish, knockout of the main MG detoxifying system Glyoxalase 1, led to limited MG elevation but significantly elevated aldehyde dehydrogenases (ALDH) activity and aldh3a1 expression, suggesting the compensatory role of Aldh3a1 in diabetes. To evaluate the function of Aldh3a1 in glucose homeostasis and diabetes, aldh3a1-/- zebrafish mutants were generated using CRISPR-Cas9. Vasculature and pancreas morphology were analysed by zebrafish transgenic reporter lines. Corresponding reactive carbonyl species (RCS), glucose, transcriptome and metabolomics screenings were performed and ALDH activity was measured for further verification. Aldh3a1-/- zebrafish larvae displayed retinal vasodilatory alterations, impaired glucose homeostasis, which can be aggravated via pdx1 silencing induced hyperglycaemia. Unexpectedly, MG was not altered, but 4-hydroxynonenal (4-HNE), another prominent lipid peroxidation RCS exhibited high affinity with Aldh3a1, was increased in aldh3a1 mutants. 4-HNE was responsible for the retinal phenotype via pancreas disruption induced hyperglycaemia and can be rescued via l-Carnosine treatment. Furthermore, in type 2 diabetic patients, serum 4-HNE was increased and correlated with disease progression. Thus, our data suggest impaired 4-HNE detoxification and elevated 4-HNE concentration as biomarkers but also the possible inducers for diabetes, from genetic susceptibility to the pathological progression.

Serum lipids profiling perturbances in patients with ischemic heart disease and ischemic cardiomyopathy.

BACKGROUND: Ischemic heart disease (IHD) is a common cardiovascular disorder associated with inadequate blood supply to the myocardium. Chronic coronary ischemia leads to ischemic cardiomyopathy (ICM). Despite their rising prevalence and morbidity, few studies have discussed the lipids alterations in these patients. METHODS: In this cross-sectional study, we analyzed serum lipids profile in IHD and ICM patients using a lipidomics approach. Consecutive consenting patients admitted to the hospital for IHD and ICM were enrolled. Serum samples were obtained after overnight fasting. Non-targeted metabolomics was applied to demonstrate lipids metabolic profile in control, IHD and ICM patients. RESULTS: A total of 63 and 62 lipids were detected in negative and positive ion mode respectively. Among them, 16:0 Lyso PI, 18:1 Lyso PI in negative ion mode, and 19:0 Lyso PC, 12:0 SM d18:1/12:0, 15:0 Lyso PC, 17:0 PC, 18:1-18:0 PC in positive ion mode were significantly altered both in IHD and ICM as compared to control. 13:0 Lyso PI, 18:0 Lyso PI, 16:0 PE, 14:0 PC DMPC, 16:0 ceramide, 18:0 ceramide in negative ion mode, and 17:0 PE, 19:0 PC, 14:0 Lyso PC, 20:0 Lyso PC, 18:0 PC DSPC, 18:0-22:6 PC in positive ion mode were significantly altered only in ICM as compared to IHD and control. CONCLUSION: Using non-targeted lipidomics profiling, we have successfully identified a group of circulating lipids that were significantly altered in IHD and ICM. The lipids metabolic signatures shed light on potential new biomarkers and therapeutics for preventing and treating ICM.

Serum metabolite profiles as potential biochemical markers in young adults with community-acquired pneumonia cured by moxifloxacin therapy.

Despite the utilization of various biochemical markers and probability calculation algorithms based on clinical studies of community-acquired pneumonia (CAP), more specific and practical biochemical markers remain to be found for improved diagnosis and prognosis. In this study, we aimed to detect the alteration of metabolite profiles, explore the correlation between serum metabolites and inflammatory markers, and seek potential biomarkers for young adults with CAP. 13 Eligible young mild CAP patients between the ages of 18 and 30 years old with CURB65 = 0 admitted to the respiratory medical department were enrolled, along with 36 healthy participants as control. Untargeted metabolomics profiling was performed and metabolites including alcohols, amino acids, carbohydrates, fatty acids, etc. were detected. A total of 227 serum metabolites were detected. L-Alanine, 2-Hydroxybutyric acid, Methylcysteine, L-Phenylalanine, Aminoadipic acid, L-Tryptophan, Rhamnose, Palmitoleic acid, Decanoylcarnitine, 2-Hydroxy-3-methylbutyric acid and Oxoglutaric acid were found to be significantly altered, which were enriched mainly in propanoate and tryptophan metabolism, as well as antibiotic-associated pathways. Aminoadipic acid was found to be significantly correlated with CRP levels and 2-Hydroxy-3-methylbutyric acid and Palmitoleic acid with PCT levels. The top 3 metabolites of diagnostic values are 2-Hydroxybutyric acid(AUC = 0.90), Methylcysteine(AUC = 0.85), and L-Alanine(AUC = 0.84). The AUC for CRP and PCT are 0.93 and 0.91 respectively. Altered metabolites were correlated with inflammation severity and were of great diagnostic value for CAP.

Altered exosomal microRNA profiles in bronchoalveolar lavage fluid can mediate metabolism in patients with Acinetobacter baumannii ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a major public health problem and is most commonly caused by Acinetobacter baumannii (Ab) infection. In our study, we investigated the profiles of exosomal microRNAs (miRNAs) extracted from the bronchoalveolar lavage fluid (BALF) and serum of patients with Acinetobacter baumannii ventilator-associated pneumonia (Ab-VAP). We also examined the serum metabolomic profiles of these patients. Our aim was to study the associations between lung tissue-derived exosomal miRNAs and changes in global metabolism in patients with Ab-VAP. METHODS: Consecutively sampled patients admitted to an intensive care unit (ICU) for pulmonary infection treatment were enrolled in this study. Demographic information and biochemical measurements were collected. Serum samples were obtained following overnight fasting on admission. Bronchoscopies were performed and BALF samples were collected from each patient. Exosomes were extracted using kits from System Biosciences (SBI) and miRNA sequencing was performed. Non-targeted metabolomics were used to express metabolic profiles. RESULTS: We found significant changes in the miRNA profiles of patients with Ab-VAP; these changes occurred in both BALF exosomal miRNA and serum exosomal miRNA. Gene Ontology analysis further identified the function of miRNA in system metabolism. Serum metabolomic profiles and ratios of biological significance were found to be differentially regulated in Ab-VAP patients. This differential regulation was correlated with the differential expression of miRNAs. CONCLUSIONS: Our data summarizes the dysregulation of serum metabolism and exosomal miRNA excretion that occurs in Ab-VAP patients. The correlation found between BALF exosomal miRNA and dysregulated metabolism, as indicated by the irregular expression of metabolites in the cellular metabolic pathway, highlights potential biomarkers for the diagnosis and treatment of Ab infection.

Clinical characteristics and protective factors in patients with acute myocardial infarction undergoing in-hospital myocardial free wall rupture: a single-center, retrospective analysis.

Myocardial free wall rupture (MFWR) refers to laceration of the heart ventricle or atria, which is a rare but fatal complication of acute myocardial infarction (AMI). In this study, we aim to identify the clinical characteristics and protective factors of free wall rupture after myocardial infarction. This is a single-center, retrospective observational analysis. The study screened all patients admitted to the cardiology department of the First Affiliated Hospital of Xi'an Jiaotong University between January 2013 and April 2018. The biochemical, clinical, angiographic and echocardiographic features of these patients were then collected and analyzed. Among the 5946 screened patients with AMI, 23 patients with a diagnosis of MFWR after AMI were enrolled in the present study. 18 (78.3%) patients were diagnosed with acute ST segment elevated myocardial infarction and the remaining 5 (21.7%) have acute non-ST segment elevated myocardial infarction. Early-phase MFWR happened in 12 (52.2%) and late-phase accounted for 8 (34.8%) in total. Late-phase MFWR had lower left ventricle ejection fraction value (45.8%±5.6% vs 63.0±3.8%, p<0.001) as compared with early-phase. Patients who survived from MFWR has higher ACE inhibitor/angiotensin II receptor blocker (ACEI/ARB) and ß-blocker coverage in the in-hospital treatment of AMI (ACEI/ARB: 100.0% vs 35.3%, p=0.014; ß-blocker: 100.0% vs 47.1%, p=0.048). The present study provides evidence for better understanding of the clinical characteristics and protective functions in MFWR after AMI. Reduced cardiac function is correlated with higher incidence of later phase free wall rupture. Higher ACEI/ARB and ß-blocker coverage in the AMI treatment strategy is associated with lower MFWR incidence.

Genetic compensation by epob in pronephros development in epoa mutant zebrafish.

Zebrafish erythropoietin a (epoa) is a well characterized regulator of red blood cell formation. Recent morpholino mediated knockdown data have also identified epoa being essential for physiological pronephros development in zebrafish, which is driven by blocking apoptosis in developing kidneys. Yet, zebrafish mutants for epoa have not been described so far. In order to compare a transient knockdown vs. permanent knockout for epoa in zebrafish on pronephros development, we used CRISPR/Cas9 technology to generate epoa knockout zebrafish mutants and we performed structural and functional studies on pronephros development. In contrast to epoa morphants, epoa-/- zebrafish mutants showed normal pronephros structure; however, a previously uncharacterized gene in zebrafish, named epob, was identified and upregulated in epoa-/- mutants. epob knockdown altered pronephros development, which was further aggravated in epoa-/- mutants. Likewise, epoa and epob morphants regulated similar and differential gene signatures related to kidney development in zebrafish. In conclusion, stable loss of epoa during embryonic development can be compensated by epob leading to phenotypical discrepancies in epoa knockdown and knockout zebrafish embryos.

Combination of the CYP2C19 metabolizer and the GRACE risk score better predicts the long-term major adverse cardiac events in acute coronary syndrome undergoing percutaneous coronary intervention.

INTRODUCTION: Both Global Registry of Acute Coronary Events (GRACE) risk score and CYP2C19 metabolizer status can independently predict major adverse cardiac events (MACEs) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We investigated whether their combination could better predict MACE occurrence in patients with ACS undergoing PCI. MATERIALS AND METHODS: This retrospective cohort study included 548 consecutive patients with ACS undergoing PCI. A cumulative MACE curve was calculated using the Kaplan-Meier method. Multivariate Cox regression was used to identify MACE predictors. The predictive value of GRACE risk score alone and CYP2C19 metabolizer status was estimated by the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: In a median of 28.58 months, 17 patients (3%) were lost to follow-up, and 62 (11.3%) experienced MACEs. Multivariate Cox regression analysis showed that both GRACE score and CYP2C19 metabolizer status were independent MACE predictors (hazard ratio 1.019, 95% CI 1.011-1.027, p < 0.001; hazard ratio 2.383, 95% CI 1.601-3.547, p < 0.001, respectively). Kaplan-Meier analysis showed that CYP2C19 PM increased the MACE risk (log rank test = 10.848, p = 0.004). The GRACE score adjustment by CYP2C19 metabolizer status enhanced the predictive value (AUC increased from 0.682 for GRACE score alone to 0.731 for GRACE score plus CYP2C19 metabolizer). This result was further verified by IDI and NRI. CONCLUSIONS: CYP2C19 metabolizer status and GRACE score are readily available predictive approaches for MACEs, and their combination derives a more accurate long-term MACE prediction in clopidogrel-treated patients with ACS undergoing PCI.