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.

The association of glycated hemoglobin A1c with coronary artery disease, myocardial infarction, and severity of coronary lesions.

Glycated hemoglobin A1c (HbA1c) has been recognized as a predictor of cardiovascular events. However, the relationship between HbA1c and coronary artery disease (CAD) in the Chinese population has yet to be systematically explored. In addition, factors associated with HbA1c were generally analyzed linearly, thereby failing to appreciate more complex nonlinear associations. The study aimed to evaluate the relationship between the HbA1c value and the presence and severity of coronary artery stenosis. A total of 7192 consecutive patients who underwent coronary angiography were enrolled. Their biological parameters, including HbA1c, were measured. The severity of coronary stenosis was evaluated using Gensini score. After correcting for baseline confounding factors, a multivariate logistic regression analysis was used to evaluate the relationship between HbA1c and CAD severity. Restricted cubic splines were applied to explore the relation of HbA1c with the presence of CAD, myocardial infarction (MI), and the severity of coronary lesions. HbA1c was significantly associated with the presence and severity of CAD in patients without diagnosed diabetes (odds ratio: 1.306, 95% confidence interval: 1.053-1.619, p = 0.015). Spline analysis showed a U-shaped association of HbA1c with the presence of MI. Both HbA1c > 7.2% and HbA1c < 5.7% were associated with the presence of MI. In conclusion, HbA1c value was highly associated with the severity of coronary artery stenosis in the whole study population, and in CAD patients without diagnosed diabetes. Compared with patients with HbA1c levels between 6.0% and 7.0%, HbA1c < 5.7% and HbA1c > 7.2% were associated with higher presence of MI.

GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis.

Pyroptosis, a type of Gasdermin-mediated cell death, contributes to an exacerbation of inflammation. To test the hypothesis that GSDME-mediated pyroptosis aggravates the progression of atherosclerosis, we generate ApoE and GSDME dual deficiency mice. As compared with the control mice, GSDME-/-/ApoE-/- mice show a reduction of atherosclerotic lesion area and inflammatory response when induced with a high-fat diet. Human atherosclerosis single-cell transcriptome analysis demonstrates that GSDME is mainly expressed in macrophages. In vitro, oxidized low-density lipoprotein (ox-LDL) induces GSDME expression and pyroptosis in macrophages. Mechanistically, ablation of GSDME in macrophages represses ox-LDL-induced inflammation and macrophage pyroptosis. Moreover, the signal transducer and activator of transcription 3 (STAT3) directly correlates with and positively regulates GSDME expression. This study explores the transcriptional mechanisms of GSDME during atherosclerosis development and indicates that GSDME-mediated pyroptosis in the progression of atherosclerosis could be a potential therapeutic approach for atherosclerosis.

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.

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.

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.