Feng Ding

BACKGROUND: Apo (apolipoprotein) AI glycation has been implicated in HDL (high-density lipoprotein) dysfunction, but its site-resolved landscape, clinical relevance, relationship with diabetic atherosclerosis, and underlying mechanisms remain incompletely defined. METHODS: We performed unbiased site-resolved glycation proteomics in 860 patients with type 2 diabetes and coronary atherosclerosis (CAS) and 294 controls with type 2 diabetes without CAS to define the plasma apo AI glycation landscape. Apo AI glycation signatures associated with diabetic CAS were identified using integrated unsupervised and supervised analyses. An Apo AI Glycation Index was developed using least absolute shrinkage and selection operator regression and evaluated in training, testing, and independent validation cohorts. To assess functional relevance, a glycation-resistant apo AI mutant, cross-linked apo AI (apo AI _CL ), was engineered and tested under glycation conditions using surface plasmon resonance, in vitro and in vivo reverse cholesterol transport assays, HDL remodeling analyses, and atherosclerosis models. RNA sequencing, macrophage-specific knockout models, receptor-binding assays, signaling inhibition, and cholesterol efflux rescue experiments were used to investigate the underlying macrophage pathway. RESULTS: Apo AI glycation patterns differed between patients with type 2 diabetes with and without CAS, with K96 and K106/107 emerging as prominent disease-associated glycation sites. The Apo AI Glycation Index was independently associated with CAS and coronary artery disease in patients with type 2 diabetes and was inversely associated with HDL-mediated reverse cholesterol transport and lecithin-cholesterol acyltransferase activity. Compared with native apo AI, apo AI _CL showed reduced key-site glycation, preserved structural stability, enhanced binding affinity to lecithin–cholesterol acyltransferase, and improved HDL-mediated reverse cholesterol transport under glycation conditions. In diabetic mouse models, apo AI _CL attenuated HDL dysfunction and atherosclerotic lesion formation compared with glycated apo AI. These data support a candidate mechanism in which glycated apo AI enhances RAGE (receptor for advanced glycation end products) interaction and activates ERK1/2 (extracellular signal-regulated kinase 1/2)–NF-κB (nuclear factor κB)/p65 signaling, leading to upregulation of NR2C2 (nuclear receptor subfamily 2 group C member 2). LXRα (liver X receptor α) activation and macrophage NR2C2 deficiency restored cholesterol efflux in glycated apo AI–treated macrophages. CONCLUSIONS: This study provides a comprehensive site-resolved map of apo AI glycation in patients with diabetes and identifies the Apo AI Glycation Index as a glycation signature associated with diabetic CAS and impaired HDL function. Experimental data support a mechanism in which site-specific apo AI glycation contributes to HDL dysfunction and macrophage cholesterol efflux impairment through RAGE-associated NR2C2–LXRα signaling. Glycation-resistant apo AI _CL preserves HDL function and attenuates atherosclerosis in preclinical models, supporting site-specific apo AI glycation as a mechanistically relevant feature of diabetic atherosclerosis. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05659043.

Patients who undergo percutaneous coronary intervention (PCI) remain exposed to residual lipid and inflammatory risk despite contemporary secondary prevent

The COLCOT trial showed that patients with diabetes may benefit from low-dose colchicine, suggesting a potential interplay between insulin resistance (IR)

Antithrombotic therapy in patients with nonvalvular atrial fibrillation (NVAF) undergoing percutaneous coronary intervention (PCI) is clinically challenging, with real‐world strategies often remaining inconsistent. This study analyzed 2020 annual data from the Shanghai Cardiac Intervention Quality Control Center, encompassing 23,115 patients who underwent PCI across 36 centers in Shanghai. Among these, 1306 (5.65%) patients with a confirmed diagnosis of NVAF were enrolled. Dual antiplatelet therapy (DAPT) was the most common antithrombotic regimen (584, 44.7%). Anticoagulation therapy was administered to only 478 (55.8%) of male patients with a CHA ₂ DS ₂ ‐VASc score of ≥ 2 and 207 (55.6%) of female patients with a CHA ₂ DS ₂ ‐VASc score of ≥ 3. Significant differences were observed across antithrombotic strategy groups regarding gender distribution, age, atrial fibrillation (AF) type, coronary artery disease type, and history of congestive heart failure (CHF), hypertension, stroke, or myocardial infarction (MI). Patients receiving oral anticoagulants (OACs) showed higher rates of persistent AF (53.2% vs. 33.9%, p < 0.001) and more frequent histories of CHF and stroke. Conversely, patients not receiving OAC therapy demonstrated a higher proportion of paroxysmal AF (66.1% vs. 46.8%, p < 0.001) and prior MI. A substantial gap persists between guideline recommendations and real‐world antithrombotic management in Chinese AF patients undergoing PCI. Key challenges include the underutilization of OAC therapy, a high prevalence of reduced‐dose anticoagulation, and a potential overreliance on DAPT. These findings highlight the urgent need to improve adherence to evidence‐based guidelines and conduct personalized risk–benefit assessments.

Background: Magnesium is essential for mitochondrial function and muscle regeneration, potentially protecting against low muscle mass (LMM). We examined the association of dietary magnesium intake with LMM risk and skeletal muscle index (SMI), and whether inflammatory indicators mediate this relationship. Methods: A total of 5793 participants aged 20–59 years were included in this study from the National Health and Nutrition Examination Survey (NHANES) conducted from 2011 to 2018. To investigate the association of dietary magnesium intake with LMM and SMI, we applied weighted logistic regression model, linear regression model, restricted cubic spline analysis, subgroup analysis and sensitivity analysis. Inflammatory indicators were assessed using mediation analysis, including the C-reactive protein–albumin–lymphocyte (CALLY) index, neutrophil–platelet score (NP), platelet-to-albumin ratio (PAR) and red blood cell distribution width-to-albumin ratio (RAR) mediation. Results: In the fully adjusted model, participants in the highest magnesium quartile had a reduced risk of LMM, with OR of 0.33 (95% CI: 0.18, 0.60), and increased levels of SMI, with β values of 0.05 (95% CI: 0.04, 0.07). Mediation analysis showed that NP, PAR, and RAR mediated 18%, 13%, and 21% of the association between magnesium and LMM, respectively, and also acted as mediators of the relationship between magnesium and SMI, with mediation ratios of 32%, 24%, and 25%, respectively. Conclusion: Higher dietary magnesium intake was associated with lower LMM risk and higher SMI, partly mediated through inflammatory indicators involving NP, PAR, and RAR. This finding may provide a new perspective on the prevention and management of LMM.

Objective: To investigate the association between hypothyroidism and incident chronic kidney disease and identify potential mediators. Methods: This study included a retrospective cohort and Mendelian randomization analysis. Data were obtained from the UK Biobank and FinnGen via the Integrative Epidemiology Unit Open Genome-Wide Association Studies Project. After exclusions, 439,381 participants were included. The risk of incident chronic kidney disease was the primary outcome. Associations were assessed using Fine and Gray models as well as stratified and sensitivity analyses, and the cumulative risk was presented using Kaplan–Meier curves. For Mendelian randomization analyses, causal effects were estimated using the inverse-variance weighted method. Mendelian randomization–Egger regression, Mendelian randomization–pleiotropy residual sum and outlier test, weighted median method, and weighted mode method were used to assess the robustness of the causal estimates. Mediation analysis was conducted to explore the effects of body mass index, inflammatory factors, and senescence-associated secretory phenotype proteins. Results: Hypothyroidism was associated with a higher risk of incident chronic kidney disease (hazard ratio: 1.35, 95% confidence interval: 1.19–1.53). Mendelian randomization analysis supported a causal effect (odds ratio: 8.23, 95% confidence interval: 3.22–21.00). Absolute risk differences increased over time (5 years, 1.10; 8 years, 1.80; 10 years, 2.40; and 12 years, 3.13). Body mass index and obesity partially mediated this effect. Senescence-associated secretory phenotype proteins were also identified as important mediators, including transforming growth factor-alpha, transforming growth factor-beta, transforming growth factor-beta receptors 2 and 3, growth differentiation factor 15, C-X-C motif chemokine-10, matrix metalloproteinase 1, and matrix metalloproteinase 9. Conclusions: Hypothyroidism was associated with incident chronic kidney disease. Obesity and senescence-associated secretory phenotype proteins may mediate this relationship.

BACKGROUND: Type 2 diabetes is strongly associated with impaired collateralization, which increases the risk of cardiovascular complications, such as myocardial infarction and heart failure. This study explored the immune cell dynamics in patients with type 2 diabetes with chronic total occlusion and their impact on collateralization. METHODS: Peripheral blood mononuclear cells were extracted from patients with type 2 diabetes with chronic total occlusion, exhibiting either good or poor collateralization. Single-cell RNA sequencing was conducted to profile the quantitative and transcriptomic dynamics of immune cells in these 2 groups. Moreover, coculture experiments were executed, and ischemic models of the hindlimb and myocardium were induced in diabetic mice to corroborate the single-cell RNA sequencing findings. Additional validation was attained by conducting an analysis on a separate cohort of patients. RESULTS: Single-cell RNA sequencing of peripheral blood mononuclear cells identified elevated levels of mucosal-associated invariant T (MAIT) cells in patients with poor collateralization. In diabetic mice, inhibition of MAIT cell activation significantly improved angiogenesis under ischemic conditions. In vitro, MAIT cell–derived CCL3L1 (C-C motif chemokine ligand 3-like 1) drove macrophage polarization toward a proinflammatory phenotype through CCR5 (C-C chemokine receptor type 5) interaction. Furthermore, an independent patient cohort confirmed that elevated MAIT cell levels represent an independent risk factor for poor collateralization. CONCLUSIONS: These findings highlight the critical role of MAIT cells in regulating collateralization in type 2 diabetes chronic total occlusion patients and propose circulating MAIT cell levels as a potential biomarker for predicting and intervening in poor collateralization.