Abstract Introduction Plaque erosion (PE) is a distinct pathological cause of acute coronary syndrome (ACS), characterized by neutrophil-mediated endothelial injury. However, the specific contribution of neutrophil heterogeneity, particularly low-density neutrophils (LDNs), to PE pathogenesis remains undefined. Methods We performed single-cell RNA sequencing and quantitative proteomics on peripheral blood from patients with optical coherence tomography (OCT)-verified PE-ACS, PR-ACS, and healthy controls. Findings were validated using flow cytometry and functional assays. Mechanistic pathways were investigated in an ApoE−/− mouse model of PE and human aortic endothelial cell (HAEC) co-cultures, utilizing CXCR2 inhibitors (AZD-5069) and NET inhibitors (GSK484). Results A distinct, pro-inflammatory LDN subset was significantly expanded in PE-ACS patients, correlating strongly with endothelial microvesicles and thrombus burden. These LDNs exhibited an immature (CD10−), hyperactive phenotype with enhanced chemotaxis and neutrophil extracellular trap (NET) release. We identified that these cells are recruited to erosion sites via the CXCL1/2-CXCR2 axis; pharmacological inhibition of CXCR2 significantly ameliorated PE phenotypes in mice. Mechanistically, PE LDN-derived NETs caused endothelial apoptosis and detachment. Specifically, these NETs impaired Annexin A1 (ANXA1)-mediated plasma membrane repair by physically sequestering ANXA1. An ANXA1 mimetic peptide rescued this impairment and reduced thrombus formation in vivo. Conclusion PE LDNs constitute a pathogenic neutrophil subset that drives PE-ACS. They are recruited via the CXCL1/2-CXCR2 axis and promote endothelial denudation and thrombosis by releasing NETs that compromise ANXA1-mediated membrane repair. Targeting the PE LDN-NET-ANXA1 axis represents a potential therapeutic strategy for PE. Funding Source National Natural Science Foundation of China (Grant No. 82170346); Grant of Shanghai Municipal Health Commission (NO. 202440145); Shanghai Science and Technology Committee (NO. 22Y11901600 and 22Y11909800) Topic Categories Immune Mechanisms of Human Disease (HUM)

BACKGROUND:The multicenter, randomized, sham-controlled FAVOR III China trial (Comparison of Quantitative Flow Ratio-Guided and Angiography-Guided Percutaneous Intervention in Patients with Coronary Artery Disease) demonstrated that quantitative flow ratio (QFR)-guided percutaneous coronary intervention (PCI) resulted in better outcomes compared with angiographic guidance at 1-year and 2-year follow-up. Whether these benefits are sustained over long-term follow-up remains uncertain. OBJECTIVES:The purpose of this study was to evaluate the long-term effectiveness and safety of a QFR-guided PCI strategy compared with angiography-guided PCI at 5 years. METHODS:Patients with at least 1 angiographically intermediate coronary lesion (50%-90% diameter stenosis) in a vessel ≥2.5 mm diameter were randomized to a QFR-guided (PCI performed only if QFR ≤0.80) or angiography-guided strategy. The primary endpoint was major adverse cardiac events (a composite of all-cause death, myocardial infarction, or ischemia-driven revascularization) at 1 year; 5-year outcomes data are reported herein. RESULTS:At 5 years, major adverse cardiac events composite was lower with QFR guidance than with angiography guidance (17.5% vs 21.1%; HR: 0.80; 95% CI: 0.69-0.92; P = 0.002), driven by fewer myocardial infarctions (5.8% vs 9.0%; HR: 0.63; 95% CI: 0.49-0.80; P < 0.0001) and ischemia-driven revascularizations (9.6% vs 12.0%; HR: 0.78; 95% CI: 0.64-0.95; P = 0.02) in the QFR-guided group. All-cause death did not differ between groups. Landmark analysis showed that the benefit of QFR guidance accrued predominantly within the first 2 years (8.5% vs 12.5%; HR: 0.66; 95% CI: 0.54-0.81; P < 0.0001), with similar outcomes between 2 and 5 years (10.2% vs 11.2%; HR: 0.90; 95% CI: 0.73-1.11; P = 0.32; P for interaction = 0.001). CONCLUSIONS:Compared with angiography guidance, QFR-guided strategy improved 5-year clinical outcomes, with benefits primarily achieved within the first 2 years. (The FAVOR III China Study; NCT03656848).

Endothelial dysfunction contributes to the pathogenesis/progression of diabetes and atherosclerotic cardiovascular diseases (ASCVDs) with Sirtuin-6 (SIRT6) downregulation in vascular endothelial cells (ECs). This study aimed to investigate the effects and underlying mechanisms of SIRT6 as a deacetylase in maintaining EC integrity against diabetes-exacerbated atherogenesis. SIRT6 downregulation was exacerbated in carotid artery ECs of STZ-induced-diabetic/HFD-fed and PCL-induced-atherosclerotic Apoe-/- mice, which had aggravated atherosclerotic plaque formation. Further study showed SIRT6 knockdown aggravated advanced glycation end-products (AGEs)-induced EC monolayer hyperpermeability, while SIRT6 overexpression exerted opposite protective effects. Moreover, exacerbated atherosclerosis progression with greater vascular hyperpermeability was observed in EC-specific Sirt6 knockout mice. Co-IP/mass-spectrometry identified SIRT6 interacting with zinc-finger E-box binding homeobox 1 (ZEB1) for deacetylation/degradation, maintaining ZEB1 at low level for normal expression of tight junction protein Claudin-1 (CLDN1) in ECs. SIRT6 deficiency reduced ZEB1 deacetylation to inhibit CLDN1 expression, which impaired EC integrity, promoted monocyte/macrophage infiltration and exacerbated atherosclerosis. Finally, Naringin, a natural ZEB1 inhibitor, was observed to reverse EC-Sirt6-knockout-mediated ZEB1 accumulation, restore CLDN1 expression and improve vascular hyperpermeability, which reduced monocyte/macrophage accumulation and attenuated atherosclerosis progression. Conclusively, SIRT6 regulation of ZEB1 deacetylation/degradation for EC-CLDN1 expression advances understanding of diabetes-exacerbated atherosclerosis; meanwhile, it provides a novel therapeutic target for intervention of diabetic ASCVDs.

Cardiovascular-kidney-metabolic (CKM) syndrome, recently defined by the American Heart Association, represents a complex interplay of cardiovascular, renal, and metabolic disorders linked by shared inflammatory pathways. This study investigates Dietary Inflammatory Index (DII) and Healthy Eating Index (HEI) influence CKM progression and mortality, while exploring the mediating role of inflammatory markers and identifying key dietary predictors. We analyzed 19,742 National Health and Nutrition Examination Survey participants (1999–2020) with complete dietary and clinical data. DII and HEI were calculated from 24-hour dietary recalls. Advanced CKM syndrome (stages 3–4) and all-cause mortality were primary outcomes. We employed (1) multivariable logistic/cox regression to assess DII/HEI-outcomes associations; (2) mediation analysis for inflammatory markers; (3) machine learning with SHAP analysis to identify critical dietary components. Higher DII was associated with advanced CKM syndrome (OR = 1.046, 95

BACKGROUND:Calcified coronary lesion, assessed by intravascular ultrasound (IVUS)-based maximum calcium angle, is an important predictor for stent underexpansion. AIMS:We aimed to determine whether the mean of all calcium angles measured within a specified distance from the maximum calcium site (distance-averaged) using IVUS was associated with stent underexpansion. METHODS:Patients undergoing IVUS-guided percutaneous coronary intervention (PCI) with drug-eluting stent implantation between 2016 and 2022 in a single tertiary center were retrospectively analyzed. Pre-PCI IVUS was used to assess the angles of calcified plaque every 1 mm; a total of 11 calcium angles were measured within 5 mm of the maximum calcium site. The endpoint was percent stent expansion, and stent underexpansion was defined as percent stent expansion < 70%. RESULTS:In the analysis of 87 stent underexpansions that occurred among 292 patients, distance-averaged calcium angles were significantly associated with stent underexpansion. Discrimination increased when using distance-averaged calcium angles instead of maximum calcium angle, with the area under the receiver operating characteristic curve (AUC) ranging from 0.75 (95% CI, 0.69-0.82) for 10 mm-averaged calcium angles to 0.77 (95% CI, 0.72-0.83) for 2 mm-averaged calcium angles (p < 0.05). Compared to 2 mm-averaged calcium angles, increasing measuring distance did not result in significant improvement in AUC. CONCLUSION:Distance-averaged calcium angles were associated with stent underexpansion. Compared with maximum calcium angle, distance-averaged calcium angles improved the prediction of stent underexpansion. Among these, 2 mm-averaged calcium angles may be a simpler, equally accurate approach to predicting stent underexpansion.

ARTICLE HIGHLIGHTS:SIRT6 downregulation in atherosclerotic vascular endothelial cells (ECs) is exacerbated under diabetic conditions, and EC-specific Sirt6 knockout aggravates diabetic atherosclerosis progression. EC-specific Sirt6 knockout aggravates atherosclerosis progression through vasculature hyperpermeability and monocyte/macrophage accumulation in vessels. SIRT6 directly interacts with transcription factor zinc finger E-box binding homeobox 1 (ZEB1) for deacetylation/degradation, preserving ZEB1 at a low level for normal expression of tight junction protein claudin-1 in ECs to maintain endothelial barrier function for vascular homeostasis. Naringin, a natural flavonoid ZEB1 inhibitor, reverses the diabetes-exacerbated vascular endothelial dysfunction to attenuate atherosclerosis progression, offering a promising, novel therapeutic strategy for diabetic atherosclerotic cardiovascular diseases.

Lipoprotein(a) [Lp(a)] is causally linked to cardiovascular disease, but its role in the progression of coronary artery disease (CAD) remains uncertain. We investigated the association of Lp(a) levels with both functional severity and progression of coronary atherosclerosis, as assessed by angiography-derived quantitative flow ratio (QFR). We retrospectively enrolled 290 patients who underwent serial coronary angiography and had baseline Lp(a) measurement. The global QFR, representing the total physiological burden, was calculated as the sum of the QFR values in the 3 major coronary arteries. Functional atherosclerotic progression was defined as a decline in global QFR. At baseline, patients with elevated Lp(a) (≥ 30 mg/dL) had a lower global QFR compared to those with Lp(a) < 30 mg/dL (2.46 [2.20, 2.64] vs. 2.61 [2.44, 2.73]; P < 0.001). The prevalence of functional significant multivessel disease was also higher in the elevated Lp(a) group (31.4

Background: In critically ill patients, the non-linear relationship between body mass index (BMI) and survival has persisted across studies, but whether it is affected by the triglyceride-glucose (TyG) index is unclear. Methods: We extracted critically ill patients without diabetes mellitus from the Medical Information Mart for Intensive Care (MIMIC)-IV database and categorized them into T1, T2, and T3 groups according to the TyG index tertiles, with the primary outcome of 365-day all-cause mortality. We used Kaplan-Meier (KM) survival curves, COX regression analyses, and restricted cubic spline curves (RCS) to assess the effect of TyG on the risk of BMI-related mortality. Estimation of optimal change points using segmented linear models. Results: The final analytic cohort comprised 6933 critically ill patients with a median age of 66 (54, 76) years, showing male predominance (60.9%). KM curves showed a lower protective effect of obesity in the high-TyG group. COX regression analyses showed that overweight and obesity were associated with lower 365-day all-cause mortality in the T1 and T2 groups and not in the T3 group. RCS analyses showed a U-shaped association between BMI and 365-day all-cause mortality in the T1 and T2 groups and a J-shaped association in the T3 group. The optimal BMI change points were 33 kg/m2 (T1), 32.5 kg/m2 (T2) and 29.7 kg/m2 (T3). Conclusions: Our findings demonstrate that the protective effect of obesity was significantly reduced in patients with high TyG levels. Consequently, it is necessary to consider the TyG index in the weight management of critically ill patients.

Background: Multimorbidity is highly prevalent among patients with atherosclerotic cardiovascular disease (ASCVD), yet the clustering patterns of chronic conditions and their prognostic implications across populations remain incompletely characterized. We aimed to identify multimorbidity patterns among individuals with ASCVD across multiple international aging cohorts and evaluate their associations with all-cause mortality. Methods: We included 19,056 participants with ASCVD from seven population-based aging cohorts: HRS (United States), ELSA (United Kingdom), SHARE (Europe), CHARLS (China), KLOSA (South Korea), MHAS (Mexico), and LASI (India). Latent class analysis (LCA) was used to identify multimorbidity patterns based on eight chronic conditions. Disease co-occurrence networks were constructed to characterize interrelationships among comorbidities. Associations between multimorbidity classes and mortality were assessed using Cox proportional hazards models. Additional analyses explored the potential role of depression within high-burden multimorbidity patterns. Results: Six distinct multimorbidity patterns were identified. Three high-burden classes characterized by a high prevalence of depression exhibited substantially increased mortality risk compared with the low-burden reference class, with hazard ratios of 1.94 (95% CI 1.81–2.08), 2.23 (95% CI 2.08–2.38), and 3.32 (95% CI 3.09–3.57), respectively. Network analysis demonstrated that depression occupied a central position within high-risk multimorbidity clusters. In inverse probability weighting analyses, depression was associated with modestly increased mortality risk (HR 1.07, 95% CI 1.01–1.14). Mediation analyses suggested that depression accounted for a limited proportion of the association between multimorbidity burden and mortality. Conclusions: Distinct multimorbidity patterns are associated with marked heterogeneity in mortality risk among patients with ASCVD. Depression is highly enriched within high-risk multimorbidity clusters and may represent an important marker of vulnerability in patients with complex comorbidity profiles. These findings support the integration of mental health assessment into multimorbidity management strategies for ASCVD populations.

BACKGROUND:The prognostic utility of residual pressure wire-based physiological assessment after percutaneous coronary intervention (PCI) has been demonstrated. OBJECTIVES:The aim of this study was to investigate the prognostic value of the residual global Murray law-based angiographic quantitative flow ratio (μQFR) in an acute coronary syndrome (ACS) population. METHODS:In this post hoc analysis from the FAVOR III China (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients With Coronary Artery Disease) trial, off-line μQFR was computed for 3 major coronary arteries. Residual global μQFR was calculated as the sum of postprocedural μQFR values for treated vessels and preprocedural values for nontreated vessels. ACS patients (including those with ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina) were categorized into high-risk (less than or equal to the cutoff value) and low-risk (greater than the cutoff value) groups according to residual global μQFR. The primary endpoint was 3-year major adverse cardiac events (MACE), the composite of all-cause death, myocardial infarction, or ischemia-driven revascularization. RESULTS:Among 2,428 ACS patients, 2,241 (92.3%) had analyzable μQFR, with a cutoff value of 2.71. High-risk patients (n = 407 [18.2%]) had a greater incidence of 3-year MACE (21.2% vs 10.4%; adjusted HR [aHR]: 1.53; 95% CI: 1.10-2.13; P = 0.01) and MACE excluding periprocedural myocardial infarction (16.2% vs 7.8%; aHR: 1.72; 95% CI: 1.17-2.53; P = 0.006) compared with the low-risk group. The prognostic effect of residual global μQFR was consistent across QFR- and angiography-guided subgroups (P for interaction = 0.35). Patients with low residual ischemia derived the best outcomes after QFR-guided PCI (MACE 8.8% vs 11.9% for angiography-guided PCI; HR: 0.73; 95% CI: 0.55-0.97). CONCLUSIONS:Residual global μQFR is a robust angiographic index for post-PCI ischemia burden and long-term risk stratification. In patients with ACS, QFR-guided PCI achieving low residual global ischemia was associated with the most favorable 3-year prognosis.

Objective Finerenone is a highly selective nonsteroidal mineralocorticoid receptor antagonist, but data on its benefits in the treatment of heart failure (HF) in real-world clinical practice remain insufficient. This study investigated the benefits and outcomes of finerenone in patients with HF using a single-center, real-world study design. Methods This single-center, retrospective observational study included consecutive patients diagnosed with HF and treated with add-on finerenone between August 2023 and May 2024 at Tongji Hospital, Shanghai, China. All patients received finerenone add-on to standard treatment. Subgroup analyses were performed in patients with HF with preserved ejection fraction (HFpEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with reduced ejection fraction (HFrEF). Adverse events were recorded, including HF readmission, outpatient visits for acute HF, and diuretic dosage escalation. Laboratory and cardiac function markers were also collected. Results Seventy-three patients were included. Left atrial diameter decreased from 50 mm to 49 mm at 6 months and further decreased to 48 mm at 12 months (P < 0.001). The E/e’ ratio decreased from a median value of 10.65 to 9.20 at 6 months and to 8.20 at 12 months (P < 0.001). The median NT-proBNP decreased from 3 months of treatment (30.41%) and continued to decline, with a 67.47% decrease at 12 months (P < 0.001). New York Heart Association (NYHA) improved from baseline (Class II: 58.9%; Class III: 41.1%) to 12 months (Class I: 5.5%; Class II: 94.5%) (P < 0.001). These changes were consistent among the HFrEF, HFmrEF, and HFpEF subgroups. LVEF improved by a median of 2% at 6 months and 3% at 12 months (P < 0.001). No patients discontinued finerenone due to adverse events, suggesting that the drug was well tolerated in real-world patients with HF. Eight (11.0%) patients were re-admitted due to HF, and seven (9.6%) required an increase in diuretic dosage during follow-up. Conclusion In real-world clinical practice, finerenone exhibited a good clinical and safety profile in patients with HF, with profiles similar across the HFrEF, HFmrEF, and HFpEF subgroups. Future larger-sample, multicenter randomized controlled trials are needed to confirm those benefits.

BACKGROUND:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, characterized by atrial fibrosis, a crucial substrate facilitating its initiation and persistence. CKAP4 (cytoskeleton-associated protein 4) has been associated with fibroblast activation; however, its involvement in atrial remodeling and AF susceptibility remains unclear. METHODS:We measured serum CKAP4 by ELISA in 189 patients with drug-refractory AF and 79 controls and then correlated these levels with left atrial scar burden assessed by 3-dimensional electroanatomic mapping. CKAP4 cell-type specificity and AF-associated regulation were evaluated in human single-cell/single-nucleus RNA-seq data sets (GSE238242 and GSE224959). CKAP4 regulation and function were examined in mice subjected to transverse aortic constriction or Ang II (angiotensin II) infusion and in neonatal rat atrial fibroblasts stimulated with Ang II using CKAP4 knockdown/overexpression. AF inducibility was tested by transesophageal burst pacing. Mechanistic studies assessed CKAP4 interactions with wingless/INT signaling pathway (WNT) 3A/WNT5A (co-immunoprecipitation and proximity ligation) and perturbed β-catenin signaling with an agonist (Wnt/β-catenin pathway agonist) or inhibitor (β-catenin/TCF pathway inhibitor) in vitro and in vivo. RESULTS:Serum CKAP4 was higher in AF than controls (P<0.001) and correlated with regional and total scar burden (r=0.16-0.29; all P<0.05). CKAP4 was enriched in fibroblasts and upregulated in AF in both human data sets. Transverse aortic constriction and Ang II increased atrial CKAP4 in vivo. In atrial fibroblasts, CKAP4 knockdown reduced α-Smooth Muscle Actin (α-SMA), collagen I/III, vimentin, and migration, whereas overexpression produced opposite effects. In mice, CKAP4 knockdown attenuated left atrial fibrosis and reduced AF inducibility. CKAP4 interacted with WNT3A and WNT5A and activated β-catenin signaling; SKL2001 rescued the antifibrotic/antiarrhythmic effects of CKAP4 knockdown, while β-catenin/TCF pathway inhibitor blunted CKAP4-overexpression-induced collagen synthesis and migration. CONCLUSIONS:CKAP4 promotes atrial fibrosis and increases AF vulnerability through the WNT/β-catenin signaling pathway, highlighting the CKAP4-WNT/β-catenin axis as a promising therapeutic target to attenuate atrial structural remodeling in AF.

Background:The benefits of physiology-guided management in acute coronary syndrome (ACS) remain inconclusive due to limited evidence. In our FAVOR III China trial, a quantitative flow ratio (QFR)-based physiology-guided strategy versus standard angiography guidance improved the 1-year primary outcome among participants with coronary artery disease (CAD). We aimed to investigate, in a prespecified analysis, the outcomes of QFR-based physiological guidance in the FAVOR III China participants with low-risk ACS. Methods:This pre-specified secondary analysis included patients diagnosed with low-risk ACS who were enrolled in the FAVOR III China trial. The trial was a prospective, randomised study that assigned 3825 CAD patients to receive QFR-guided or angiography-guided percutaneous coronary intervention (PCI) at 26 hospitals in China between December, 2018 and January, 2020. The primary outcome of interest for this study was major adverse cardiac events (MACE), defined as a composite of all-cause death, myocardial infarction, and ischaemia-driven revascularisation, at 1-year (primary outcome of FAVOR III China) and 2-year follow-up. Secondary outcomes included PCI strategy change and the procedural characteristics. FAVOR III China is registered with ClinicalTrials.gov, NCT03656848. Findings:Of the 2371 participants with low-risk ACS (93.7% unstable angina and 6.3% non-ST elevation myocardial infarction [NSTEMI]) in the FAVOR III China trial, the QFR-guided strategy changed the original intended treatment plan in 23.6% of the low-risk ACS patients, resulting in more PCI deferrals (19.0% vs 3.8%; P < 0.001), less stenting (1.5 ± 1.1 vs 1.6 ± 1.0 per participant; P = 0.034), and shorter fluoroscopy time (13.7 ± 7.7 min vs 14.6 ± 7.1 min; P = 0.01) compared with the angiography-guided strategy. During follow-up, there was some evidence that the QFR guided strategy is superior to the angiography-guided approach at reducing the risk of MACE at 1-year follow-up (6.1% vs 8.2%; HR, 0.74; 95% CI, 0.54-1.01, P = 0.055), with a significant risk reduction at 2-year follow-up (8.3% vs 11.7%; HR, 0.70; 95% CI, 0.54-0.91, P = 0.009). The landmark analysis indicated consistent patterns both before and after 1 year (P interaction = 0.35). Interpretation:Our findings favoured the superiority of QFR-guided lesion selection strategy over standard angiography guidance in reducing long-term MACE for the low-risk ACS population. The benefits associated with QFR need to be confirmed by future studies with extended follow-up. Funding:The National High Level Hospital Clinical Research Funding, the Capital's Funds for Health Improvement and Research, the Chinese Academy of Medical Sciences, the Noncommunicable Chronic Diseases National Science and Technology Major Project, Shanghai Municipal Health Commission "Top Priority Research Centre", and Shanghai Shenkang Hospital Development Centre.

ABSTRACT Intravascular lithotripsy (IVL) is a promising therapy for calcified coronary lesions. This study evaluated the safety and effectiveness of a novel IVL system. The COronary CAlcified Lesion Lithotripsy Procedure (COCALP) study (No. ChiCTR2300073280) was a prospective, multicenter, single‐arm trial involving 266 patients with severely calcified coronary lesions. The primary endpoint was procedural success, defined as successful stent implantation with ≤30% residual stenosis and no in‐hospital major adverse cardiovascular events (MACE). In a subgroup, calcium morphology was evaluated by optical coherence tomography (OCT) assessment. A total of 266 patients were included. The procedural success rate was 97.4% (95% confidence interval [CI]: 0.947–0.989), with the lower limit of the CI exceeding the prespecified performance goal (p < 0.001). No MACE occurred intraoperatively. During hospitalization, MACE occurred in five patients (1.9%), all of which were myocardial infarctions. MACE rates at 1 and 6 months were 2.3 and 3.4%, respectively. In the OCT subgroup (n = 76), IVL induced a 76.8% rate of calcification fracture. The minimal lumen area increased from 1.77 ± 0.72 to 2.59 ± 1.11 mm2 following IVL (p < 0.001), and further expanded to 5.22 ± 1.69 mm2 poststenting (p < 0.001). The novel IVL system demonstrated high effectiveness and safety, supporting its use for treating severely calcified coronary lesions and enhancing stent implantation success.

Magnesium, an essential dietary trace element, plays a crucial role in numerous physiological processes, and its deficiency has been associated with the development of hyperlipidemia. However, its potential to predict long-term outcomes and inform risk stratification in hyperlipidemic patients remains underexplored. This retrospective cohort study introduces the magnesium depletion score (MgDS), a novel index for quantifying magnesium deficiency, and investigates its association with mortality outcomes in individuals with hyperlipidemia. Data from 12,592 participants in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were analyzed. Advanced statistical methods, including weighted Cox proportional hazards models, restricted cubic spline (RCS) analysis, Kaplan–Meier survival curves, and receiver operating characteristic (ROC) analysis, were employed to assess the association between MgDS and mortality risks. The results indicate that higher MgDS is significantly associated with increased risks of both all-cause and cardiovascular mortality in individuals with hyperlipidemia, even after adjusting for confounders. Subgroup analyses identified prediabetes, smoking, and alcohol consumption as significant modifiers of this association. RCS analysis confirmed a linear relationship between MgDS and mortality, further supporting its value as a reliable predictor of long-term outcomes. ROC analysis demonstrated the potential of MgDS as an independent tool for predicting mortality at 1, 3, and 5 years. Notably, high MgDS levels in hyperlipidemic individuals with binge drinking habits were associated with significantly higher mortality risks. These results establish MgDS as a promising biomarker for mortality risk stratification in patients with hyperlipidemia. This novel index offers important insights for clinical practice and could facilitate the development of tailored management strategies, particularly for high-risk hyperlipidemia populations, to mitigate long-term health risks.

OBJECTIVES:The development of simple tools to identify individuals at high risk of coronary heart disease (CHD) would enable rapid implementation of preventive measures. This study was designed to construct predictive models and scoring systems for CHD using monocyte count and its ratio to high-density lipoprotein cholesterol (HDL-C) (MHR). DESIGN:Population-based prospective cohort study. SETTING:The Shanghai Suburban Adult Cohort and Biobank (SSACB). PARTICIPANTS AND OUTCOME MEASURES:This prospective study included 44 013 CHD-free participants of the SSACB. The Songjiang subcohort served as the training set, in which three predictive models and corresponding scoring systems were developed with monocyte count or MHR using stepwise Cox regression. The models and algorithms were tested internally using 10-fold cross-validation and externally in the Jiading subcohort. Discriminations were assessed based on area under the curve (AUC) values, while calibrations were evaluated using the Hosmer-Lemeshow goodness-of-fit test. RESULTS:During a mean follow-up period of 4.8 years, 883 CHD events occurred, with an incidence of 415.7/100 000. Monocyte count and MHR were significantly associated with the risk of CHD. The constructed model incorporating monocyte count (Model 2) achieved AUC values of 0.746 (0.726, 0.766) for 4-year CHD prediction in the training set, 0.746 (0.690, 0.796) in the cross-validation, and 0.717 (0.674, 0.761) in the external validation, comparable to the models including HDL-C (model 1) or MHR (model 3). Calibration plots demonstrated good agreement between predicted and actual probabilities. Similar results were observed for the corresponding scoring algorithms. CONCLUSIONS:The monocyte-based model is a simple, low-cost and well-calibrated risk-stratification tool for CHD. However, the declined discrimination in external validation indicates limited generalisability. Prospective multicentre validation and recalibration are therefore warranted before clinical adoption.