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.

Predictive value of serum TBA for 2-year MACEs in ACS patients undergoing PCI: a prospective cohort study.

Bile acids play important roles in lipid metabolism and glucose homeostasis. Limited research exist on the association between serum total bile acid (TBA) levels and major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS), particularly those with comorbid type 2 diabetes mellitus (T2DM). This study was conducted to examine the relationship between baseline serum TBA level and T2DM status in patients with ACS after percutaneous coronary intervention (PCI) and to identify the predictive value of TBA levels for a 2-year risk of MACEs. 425 ACS patients underwent PCI were recruited and divided into three groups based on baseline serum TBA concentration. An analysis of the association between the T2DM status and baseline serum TBA levels was conducted using univariate linear regression and multivariate linear regression. The predictive relevance of serum TBA levels was evaluated using the receiver operating characteristic (ROC) curve and Cox regression. Kaplan-Meier curves were employed to analyze the differences among groups in predicting MACEs over a 2-year follow-up period. Baseline serum TBA levels were higher in ACS patients who were diagnosed with T2DM (the median 3.6 µmol/L) than those without T2DM (the median 3.0 µmol/L). T2DM status in ACS patients was positively correlated with baseline serum TBA concentrations (ß: 1.7, 95% confidence interval [CI] 0.3-3.0), particularly in the male (ß: 2.0, 95% CI 0.3-3.6) and 50-69-year-old (ß: 2.5, 95% CI 0.6-4.4) populations. The areas under the ROC curve of baseline serum TBA levels predicted MACEs in ACS and ACS-T2DM patients following PCI were 0.649 (95% CI 0.595-0.703) and 0.783 (95% CI 0.685-0.881), respectively. Furthermore, Cox regression analysis showed that baseline serum TBA level was associated with the occurrence of MACEs in patients with ACS after PCI over a 2-year follow-up period, especially in those diagnosed with T2DM, whose baseline TBA concentration was lower than 10.0 µmol/L. ACS Patients with T2DM had higher serum TBA levels. TBA level at baseline was an independent predictor of MACEs in ACS patients who underwent PCI, especially with comorbid T2DM.

The Predictive Values of White Blood Cell Indices (Lymphocyte and Eosinophilic Granulocyte) for Heart Failure in Acute Coronary Syndrome Patients Following Percutaneous Coronary Intervention: A Prospective Cohort Study.

Background: White blood cell (WBC) indices are strongly associated with cardiovascular disease, but data on the prognostic values of these parameters in patients with acute coronary syndrome (ACS) following percutaneous coronary intervention (PCI) are sparse. The current study aimed to investigate the relationship between baseline WBC indices levels and the incidence of heart failure (HF) in ACS patients after PCI and explore the predictive values over a 2-year follow-up period. Methods: A total of 416 consecutive ACS patients treated with PCI were enrolled and received a median of 27.7 months follow-up. Univariate and multivariate Cox regression analyses and the receiver operating characteristic (ROC) curves were performed. Results: Baseline lymphocyte (LYMPH) count, eosinophil (EO) count and eosinophil percentage (EO %) were higher in patients who experienced HF over a 2-year follow-up. In multivariate Cox proportional hazards analysis, LYMPH count, EO count and EO % were independently associated with the occurrence of HF (hazard ratio [HR] = 12.876, P = 0.025; HR = 16.625, P = 0.004; HR = 1.196, P = 0.031, respectively). The area under the ROC curve of baseline EO count predicting the occurrence of HF in ACS patients following PCI was 0.625 (P = 0.037). For patients aged 60 years and above, who had PCI or history of coronary artery bypass grafting, the higher EO count, the higher the risk of HF. Conclusion: Elevated baseline LYMPH count, EO count and EO % were independently associated with the incidence of HF in ACS patients following PCI, suggesting that WBC indices might be available, simple, and cost-efficient biomarkers with predictive value, especially for patients aged more than 60 years.

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.

Higher serum triglyceride can predict recurrent coronary revascularization events in patients undergoing percutaneous coronary intervention with baseline LDL-C <55 mg/dL.

Patients with low baseline low-density lipoprotein cholesterol (LDL-C) but experiencing recurrent coronary revascularization events have been rarely investigated. In this retrospective cohort study, we enrolled patients undergoing percutaneous coronary intervention (PCI) with baseline LDL-C <55 mg/dL at the First Affiliated Hospital of Xi'an Jiaotong University between January and December 2017. Subsequent ischemia-driven coronary revascularization events and all-cause death were documented during a 4-year follow-up. Cox analysis was used to evaluate the association between baseline clinical characteristics and long-term events. As a result, among 388 patients (mean age 63 years; 79.1% male) enrolled, 32 patients underwent recurrent revascularization events, and 38 patients occurred all-cause death. After adjustment for age, diabetes mellitus, multi-vessel disease, and lipoprotein(a), multivariate Cox analysis showed that baseline serum triglyceride (TG) (HR 1.691, 95% CI 1.178 to 2.428, p=0.004) was an independent predictor of recurrent coronary revascularization events. Kaplan-Meier analysis revealed that a higher TG level (≥1.17 mmol/L, determined by receiver operating characteristic curve) was associated with increased risk of recurrent revascularization events than lower TG level (<1.17 mmol/L) (p=0.021). Female (HR 2.647, 95% CI 1.350 to 5.190, p=0.005) and previous atrial fibrillation (HR 3.163, 95% CI 1.403 to 7.132, p=0.006) were associated with increased risk of all-cause death. In conclusion, for patients undergoing PCI with baseline LDL-C <55 mg/dL, higher baseline TG can predict recurrent coronary revascularization events.

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.

MED1 Regulates BMP/TGF-ß in Endothelium: Implication for Pulmonary Hypertension.

BACKGROUND: Dysregulated BMP (bone morphogenetic protein) or TGF-ß (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator complex subunit 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-ß axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive. We investigate the MED1/KLF4 co-regulation of the BMP/TGF-ß axes in endothelium by studying the epigenetic regulation of BMPR2 (BMP receptor type II), ETS-related gene (ERG), and TGFBR2 (TGF-ß receptor 2) and their involvement in the PH. METHODS: High-throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, ATAC-seq, and high-throughput chromosome conformation capture together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells (ECs) and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic PAH, animals with experimental PH, and mice with endothelial ablation of MED1 (EC-MED1-/-) were used to study the PH-protective effect of MED1. RESULTS: Levels of MED1 were decreased in lung tissue or pulmonary arterial endothelial cells from idiopathic PAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC-MED1-/- mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents. CONCLUSIONS: A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-ß signaling is implicated in the disease progression of PAH in humans and PH in rodent models.

Case Report: Acute Myocarditis Due to PD-L1 Inhibitor Durvalumab Monotherapy in a Patient With Lung Squamous Cell Carcinoma.

Background: Durvalumab, as a PD-L1 inhibitor, is commonly used for the treatment of various cancers. Adverse events associated with the therapy include hepatitis, nephritis, dermatitis, and myocarditis. Especially, myocarditis as an adverse event after PD-L1 inhibitor therapy is characterized for its low incidence and high mortality. Case Summary: Here we present a rare case of a 67-year-old male with lung squamous cell carcinoma complicated with empyema who experienced myocarditis after only PD-L1 inhibitor durvalumab monotherapy. He presented with markedly decrease left ventricular ejection fraction, elevated Natriuretic peptide BNP, Troponin T, Troponin I, ESR, CRP and interleukin-6. The electrocardiogram showed sinus tachycardia, low voltage of limb leads, T wave inversion in anterior waves and V1-V3 QS type. Myocardial injury occurred in a short period and quickly returned to normal after glucocorticoids therapy. Conclusion: This case report is of clinical value for the treatment of PD-L1 related myocarditis.

Cardiotoxicity Related to Immune Checkpoint Inhibitors: A Real-World Retrospective Analysis.

Background: Cardiotoxicity related to immune checkpoint inhibitors (ICIs) is a rare but potentially lethal. In ICI-associated adverse events, evidence of cardiotoxicity and clinical predictive factors related to ICI is lacking. Here, we aim to assess the incidence and predictive factors of cardiotoxicity related to ICIs in real-world practice. Objective: We retrospectively analyzed consecutive patients who received PD-1 or PD-L1 at the First Affiliated Hospital of Xi'an Jiaotong University. Clinical characteristics and cardiac lesion markers were collected both at baseline and during longitudinal follow-up from the Biobank database. Follow-up CKMB and NT-proBNP levels and ratios were then evaluated. Results: A total of 2,304 patients with either PD-1 or PDL-1 utilization between August 2018 and April 2021 were collected. The average age was 59.44 ± 11.45 among PD-1 inhibitor utilizer and 58.97 ± 12.16 among PDL-1 inhibitor utilizer. The baseline creatine kinase isoenzyme MB (CKMB) levels were 17 ± 19 U/L in PD-1 inhibitor users and 17 ± 23 U/L in PDL-1 inhibitor users. Majority of patients were male, with advanced stage cancer, and received ICIs as second-line therapy. The longitudinal change of cardiac enzymes and NT-pro BNP were collected. Cardiac lesion as defined by three times increase of CKMB happens in only minority of patients receiving ICIs therapy. It is also identified that increased CKMB happened in PD-1 inhibitor groups, but not PDL-1 inhibitor groups. Conclusion: We evaluated the profile of cardiotoxicities caused by ICIs based on real-world experience. The cardiac lesion markers are generally unaltered, but it appears that the increased CKMB happened in PD-1 inhibitor groups, but not PDL-1 inhibitor groups.

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.

Exosomal microRNA-16-5p from macrophage exacerbates atherosclerosis via modulating mothers against decapentaplegic homolog 7.

OBJECTIVE: Studies have probed the function of microRNA (miR)-16-5p in the progression of atherosclerosis (AS), while the regulatory function of exosomal miR-16-5p from macrophage on AS remains largely unknown. This study commits to exploring the efficiency of exosomal miR-16-5p from macrophage on AS via modulating mothers against decapentaplegic homolog 7 (SMAD7). METHODS: Macrophages were cultured and transfected with miR-16-5p antagomir, then, the exosomes from macrophages were extracted. The AS mouse model was established, and miR-16-5p or SMAD7 expression in AS mice was detected. Thereafter, the effects of macrophage-derived exosomes, miR-16-5p or SMAD7 on serum inflammatory response, oxidative stress response, pathological changes and apoptosis in AS mice were observed by immunohistochemical and biochemical analysis. Finally, the binding relation between miR-16-5p and SMAD7 was examined. RESULTS: MiR-16-5p was elevated while SMAD7 was depleted in AS mice. Macrophage-derived exosomes aggravated AS progression via facilitating inflammatory response and oxidative stress, exacerbating pathological changes and increasing cell apoptosis in AS mice; while downregulation of miR-16-5p reversed the exacerbation of AS progression by macrophage-derived exosomes in AS mice. MiR-16-5p targeted SMAD7, and the down-regulated SMAD7 reversed the impacts of depleted miR-16-5p on AS progression. CONCLUSION: Exosomal miR-16-5p from macrophages aggravates AS progression via downregulating SMAD7 expression. This study provides novel therapeutic targets for AS treatment from the animal level.

Dysregulated Arginine Metabolism in Young Patients with Chronic Persistent Asthma and in Human Bronchial Epithelial Cells.

BACKGROUND: Recent metabolomics studies have found circulatory metabolism alterations in patients with asthma, indicating that altered metabolites played a significant role in asthma. However, the regulatory mechanisms in asthma, especially in young chronic persistent asthma remain underexplored. METHODS: In this study, a prospective cohort of 162 patients diagnosed of asthma admitted to the First Affiliated Hospital of Xi'an Jiaotong University from January 2018 to December 2019 was used to perform a nested case-control study. Among them, we included 30 patients with chronic persistent asthma between 20 to 35 years old; 30 health control with evenly distributed age and sex were then recruited. Nontargeted metabolomics was applied to identify serum metabolic profiles and altered metabolic pathways. RESULTS: In vitro, human bronchial epithelial cells (HBECs) line BEAS-2B with the addition of L-citrulline and/or asymmetric dimethylarginine (ADMA) model was utilized and the concentrations of nitric oxide (NO) metabolites were tested to evaluate the therapeutic potential of L-citrulline. The young patients with chronic persistent asthma displayed dysregulated serum metabolic profiles, especially enriched in arginine metabolism. The ratio of L-citrulline to ornithine is associated with blood eosinophil count. In vitro, adding L-citrulline could reverse ADMA-mediated reduction of NOx at lower L-arginine concentration (25 µM), but was ineffective in the higher L-arginine concentration (100 µM) media. CONCLUSIONS: The arginine metabolism balance is of vital importance during the pathogenesis and progression of chronic asthma. L-citrulline could be a powerful approach to restore airway NO production, potentially exhibiting therapeutic benefits among young patients with chronic asthma.

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.

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.

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.

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.

Glycoursodeoxycholic acid ameliorates diet-induced metabolic disorders with inhibiting endoplasmic reticulum stress.

Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed, and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, was decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared with vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.

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.

Circulating lipid and lipoprotein profiles and their correlation to cardiac function and cardiovascular outcomes in patients with acute myocardial infarction.

Recent studies showed that lipoproteins represent major risk factors, both positive and negative, for atherosclerotic cardiovascular disease. The aim of the present study was to describe the relationship between plasma lipid profile and cardiac function and cardiovascular outcomes in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Two independent groups of subjects including a total of 797 patients diagnosed of AMI undergoing PCI admitted to the First Affiliated Hospital of Xi'an Jiaotong University were included in the present study. We performed a cross-sectional study for the correlation between plasma lipid profile and cardiac function based on the first group, including 503 patients with AMI. We further validated the correlation and did the follow-up of 2.4 years of major cardiovascular outcomes on the second group, including 294 patients with AMI. Our results showed that apolipoprotein A-I (ApoA-I) level was significantly reduced, and the high-density lipoprotein cholesterol (HDL-C):ApoA-I ratio was increased in the patients with lower LVEF or higher N-terminal pro-B-type natriuretic peptide levels compared with the control; there was a positive correlation between cardiac function and ApoA-I, and a negative correlation between cardiac function and the HDL-C:ApoA-I ratio. Meanwhile, multivariate Cox analysis showed that ApoA-I was independent predictors of major adverse cardiovascular events (MACEs). Kaplan-Meier survival analysis showed the ApoA-I levels exhibited a significant effect on predicting the incidence of MACEs. In sum, plasma ApoA-I level is positively associated with the cardiac function of patients with AMI after PCI, and ApoA-I is an independent indicator to predict the incidence of MACEs.