Cardiovascular Drugs and Therapy最新文献

{"title":"Epicardial Versus Circulating Adiponectin: An Unresolved Distinction in Liraglutide's Anti-Arrhythmic Mechanism.","authors":"Miao Miao, Chen Zhikui","doi":"10.1007/s10557-026-07977-1","DOIUrl":"https://doi.org/10.1007/s10557-026-07977-1","url":null,"abstract":"","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR‑18a‑5p Serves as a Diagnostic and Prognostic Biomarker and Attenuates Hypoxia‑Induced Cardiac Microvascular Endothelial Injury by Targeting the HIF1A/NF‑κB Pathway in Chronic Heart Failure.","authors":"Min-Na Hou, Ying Sun, Rongwen Lin, Liqiu Yan, Jingwei Zheng","doi":"10.1007/s10557-026-07967-3","DOIUrl":"https://doi.org/10.1007/s10557-026-07967-3","url":null,"abstract":"<p><strong>Purpose: </strong>Chronic heart failure (CHF) is a severe end-stage cardiovascular syndrome with high mortality and poor prognosis. This study aimed to investigate the expression, diagnostic, and prognostic value of serum miR-18a-5p in CHF patients and to explore its molecular mechanism in regulating hypoxia-induced injury.</p><p><strong>Methods: </strong>A total of 125 CHF patients and 125 healthy controls were enrolled. The expression of miR-18a-5p was detected by RT-qPCR. The diagnostic efficacy was evaluated by the ROC curve. The prognostic value was analyzed by Kaplan-Meier survival analysis and multivariate Cox regression. Human cardiac microvascular endothelial cells (hCMECs) were used to establish a hypoxic injury model. Cell viability, apoptosis, and inflammatory cytokines were measured by CCK-8, flow cytometry, and ELISA. The targeting relationship between miR-18a-5p and HIF1A was verified by a dual-luciferase reporter assay. The expression of apoptosis, fibrosis, and NF-κB pathway proteins was detected by RT-qPCR and Western blot.</p><p><strong>Results: </strong>In patients with CHF, circulating miR‑18a‑5p was markedly downregulated, exhibiting a diagnostic AUC value of 0.874. Diminished miR‑18a‑5p expression was closely linked to decreased LVEF, increased levels of BNP and cTnI, higher NYHA classification, and a poorer long‑term prognosis. miR-18a-5p was a protective factor for CHF. In vitro, overexpression of miR-18a-5p enhanced cell viability, inhibited apoptosis, reduced the secretion of pro-inflammatory factors, and downregulated collagen I, collagen III, and α-SMA expression in hypoxic hCMECs. miR-18a-5p targeted HIF1A 3'UTR and negatively regulated HIF1A/NF-κB signaling. Overexpression of HIF1A reversed the protective effects of miR-18a-5p.</p><p><strong>Conclusion: </strong>miR-18a-5p attenuates hypoxia-induced inflammation, apoptosis, and fibrosis by targeting the HIF1A/NF-κB pathway. Circulating miR-18a-5p therefore holds promising clinical prospects as a non-invasive serum biomarker for CHF diagnosis and risk stratification. Upregulation of miR-18a-5p provides a potential molecular strategy for preventing hypoxia-mediated cardiac microvascular remodeling in chronic heart failure.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking Plaque Stabilization with Evolocumab in Diabetes: Methodological Considerations from the YELLOW III Trial.","authors":"Jianqi Qiao, Taotao Li","doi":"10.1007/s10557-026-07980-6","DOIUrl":"https://doi.org/10.1007/s10557-026-07980-6","url":null,"abstract":"","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MSCs-derived Exosomal miRNA-335-5p Alleviates Apoptosis and Inflammation in Myocardial Infarction by Inhibiting BCL2L11.","authors":"Chan Wang, Zhou Ji","doi":"10.1007/s10557-026-07969-1","DOIUrl":"https://doi.org/10.1007/s10557-026-07969-1","url":null,"abstract":"<p><strong>Background: </strong>Myocardial infarction (MI) leads to heart cell death and inflammation, resulting in permanent heart damage. Exosomes derived from mesenchymal stem cells (MSCs), which can deliver miRNAs to cells, have shown potential as therapeutic agents for MI, this study sought to elucidate the role of MSC-derived exosomal miRNA-335-5p in MI.</p><p><strong>Methods: </strong>Exosomes secreted from MSCs were observed using transmission electron microscope (TEM) and nanoparticle tracking analysis (NTA). Inflammatory cytokines, cell apoptosis were evaluated. The dual luciferase gene assay was used to validate the interaction between miRNA-335-5p and BCL2-like 11 (BCL2L11). Cardiac function indicators in MI rats were detected using echocardiography. The levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and cardiac troponin (cTnI) were detected by commercial kits. To confirm fibrosis detection, Masson staining was employed.</p><p><strong>Results: </strong>MSCs-derived exosomes (MSC-exos) are abundant in miR-335-5p. MSCs-derived exosomal miR-335-5p inhibited hypoxia induced H9c2 cells apoptosis and inflammation, while reducing miRNA-335-5p in MSC-exos does not produce this effect. Mechanically, miRNA-335-5p interacted with BCL2L11 and reduced its expression. Reducing miRNA-335-5p in MSC-exos or overexpressing BCL2L11 can counteract the improvement of MSC-exos on apoptosis and inflammation in H9c2 cells under hypoxic conditions and MI rats.</p><p><strong>Conclusion: </strong>In MI, MSCs-derived exosomal miRNA-335-5p alleviated apoptosis and inflammation by targeting BCL2L11.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epac1 Functions as a Central Cardioprotective cAMP Effector During Ischemic and β-adrenergic Preconditioning.","authors":"M S Eriksen, F E Ravn, A Aspevik, J T Haugom, A Wergeland, K S Nordhus, R Kopperud, M Bakke, S O Døskeland, A K Jonassen","doi":"10.1007/s10557-026-07963-7","DOIUrl":"https://doi.org/10.1007/s10557-026-07963-7","url":null,"abstract":"<p><strong>Background: </strong>β-adrenergic receptor (β-AR) stimulated cAMP signaling may be impaired in pathophysiological conditions such as myocardial ischemia and heart failure, highlighting the need for cardioprotective strategies bypassing β-ARs, directly targeting downstream cAMP effectors. cAMP signaling has traditionally been attributed to protein kinase A (PKA), while contribution of the alternative cAMP effector Epac1 remains controversial.</p><p><strong>Objective: </strong>To examine whether Epac1 is required for cardioprotection induced by ischemic preconditioning (IPC) and β-adrenergic preconditioning (β-PC), and to identify downstream signaling pathways.</p><p><strong>Methods: </strong>Langendorff-perfused hearts from wild-type (WT) and Epac1-deficient (Epac1^-/-) mice were subjected to global ischemia and reperfusion. Complementary experiments were performed in human cardiac-derived cells exposed to simulated ischemia-reoxygenation (sIR) with pharmacological modulation of Epac1, PKA, Akt, and STAT3.</p><p><strong>Results: </strong>IPC and β-PC significantly reduced infarct size in WT hearts but failed to confer protection in Epac1^-/- hearts, demonstrating that Epac1 is essential for IPC- and β-PC mediated cardioprotection. Consistently, pharmacological inhibition of Epac1 abolished IPC- and β-PC induced protection in vitro. Direct activation of Epac1 with the selective agonist I942 markedly reduced cell death and increased phosphorylation of Akt, GSK3β, and STAT3. Inhibition of Akt or STAT3 completely eliminated Epac1-mediated protection, indicating that both RISK- and SAFE-associated signaling are required. In contrast, selective PKA activation failed to induce protection in either WT or Epac1^-/- hearts, although PKA inhibition partially attenuated IPC- and β-PC-induced protection, consistent with a permissive rather than primary effector role for PKA.</p><p><strong>Conclusion: </strong>Epac1 mediates IPC and β-PC induced cardioprotection through Akt/GSK3β- and STAT3-dependent signaling, supporting Epac1 as a promising β-AR-independent therapeutic target.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut Microbiota and Its Metabolites in the Prognosis of Coronary Heart Disease: A Systematic Review and Mechanistic Insights.","authors":"Weiting Cheng, Guiyang Xia, Huan Xia, Xuefen Wu, Xiaohan Liu, Xiaohong Wei, Sheng Lin","doi":"10.1007/s10557-026-07972-6","DOIUrl":"https://doi.org/10.1007/s10557-026-07972-6","url":null,"abstract":"<p><strong>Purpose: </strong>Emerging evidence links gut microbiota dysbiosis and its metabolites to atherosclerosis. This systematic review aims to synthesize prospective evidence on the association of gut microbiota and its metabolites with prognosis in coronary heart disease (CHD) patients.</p><p><strong>Methods: </strong>A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted from inception to January 21, 2026. Prospective cohort studies, nested case-control studies, or prospective case-control studies reporting associations between gut microbiota features or metabolite levels and major adverse cardiovascular and cerebrovascular events (MACCE, including all-cause death, cardiovascular death, myocardial infarction, stroke, unstable angina, heart failure, and all-cause unplanned hospitalization/emergency department visits) in CHD patients were included.</p><p><strong>Results: </strong>Eighteen studies were included. Higher Lactobacillus abundance was associated with favorable prognosis, whereas a 10-species microbial risk score (MRS) predicted increased MACCE risk. For microbial metabolites, elevated trimethylamine N-oxide (TMAO) showed a consistent concentration-response association with increased MACCE risk. Phenylacetylglutamine (PAGln) and imidazole propionate (ImP) independently predicted poor outcomes in STEMI patients. Indole-3-propionic acid (IPA) was associated with reduced mortality, whereas deoxycholic acid (DCA) was associated with increased risk, while indoxyl sulfate (IS), acylcarnitines, and choline predicted worse outcomes. Mechanistically, these metabolites modulate inflammation, lipid metabolism, endothelial function, and platelet activation.</p><p><strong>Conclusions: </strong>Gut microbial features, particularly Lactobacillus abundance, are associated with favorable prognosis, whereas specific microbial risk patterns predict increased risk. Metabolites TMAO, PAGln, and ImP are linked to poor outcomes, while IPA may confer protection and DCA is associated with increased risk. These findings not only provide new insights into the pathogenesis of coronary heart disease but also identify potential therapeutic targets for microbiota-based interventions.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omega-3 Fatty Acids in the Management of Cardiovascular Disease Prevention.","authors":"Simone Finocchiaro, Luigi Cutore, Costanza Bordonaro, Carmelo Cusmano, Diego Nastasi, Francesco Nasisi, Davide Capodanno","doi":"10.1007/s10557-026-07974-4","DOIUrl":"https://doi.org/10.1007/s10557-026-07974-4","url":null,"abstract":"<p><strong>Purpose: </strong>Omega-3 polyunsaturated fatty acids lower triglycerides and modulate inflammation, thrombosis, and endothelial function, providing a rationale for their use in cardiovascular prevention. This review examines the influence of formulation, dose, and patient selection on clinical outcomes.</p><p><strong>Methods: </strong>A targeted PubMed search through 31 May 2026 informed the selection of randomized trials and relevant mechanistic and observational studies, complemented by guideline and regulatory documents and selected publications added during revision.</p><p><strong>Results: </strong>Low-dose mixed eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) formulations were generally neutral in contemporary prevention trials. JELIS reported fewer major coronary events with EPA 1.8 g/day (2.8% vs. 3.5%; hazard ratio 0.81). In REDUCE-IT, icosapent ethyl 4 g/day reduced major ischemic events (17.2% vs. 22.0%; hazard ratio 0.75), whereas STRENGTH found no benefit with 4 g/day EPA/DHA (12.0% vs. 12.2%; hazard ratio 0.99). Differences in biological exposure, placebo choice, and pharmacological properties may contribute to these findings, although their relative importance remains debated. Evidence for stroke, heart failure, and peripheral artery disease varies by population and endpoint, while higher-dose therapy requires attention to atrial fibrillation and bleeding.</p><p><strong>Conclusion: </strong>Current evidence supports prescription icosapent ethyl in selected statin-treated patients with persistent hypertriglyceridemia, with treatment guided by cardiovascular risk, formulation, and dose rather than considering omega-3 preparations as an interchangeable class.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision Use of Ivabradine in Contemporary HFrEF: From Heart Rate Reduction to Physiological Optimization.","authors":"Teruhiko Imamura","doi":"10.1007/s10557-026-07975-3","DOIUrl":"https://doi.org/10.1007/s10557-026-07975-3","url":null,"abstract":"<p><strong>Aims: </strong>To reassess the contemporary role of ivabradine in heart failure with reduced ejection fraction and propose a precision-oriented framework for individualized heart rate management in the era of foundational guideline-directed medical therapy.</p><p><strong>Methods and results: </strong>Ivabradine selectively reduces sinus rate without direct negative inotropic effects, with established benefits in selected patients with heart failure with reduced ejection fraction and persistent sinus tachycardia. However, recent meta-analyses differ substantially in study populations, endpoint availability, and background therapy, limiting firm conclusions regarding the incremental effect of ivabradine on major clinical outcomes in the contemporary treatment era. This review integrates established and emerging evidence, with particular emphasis on the conceptual distinction between maladaptive and compensatory tachycardia, candidate individualized and dynamic heart-rate strategies, transmitral filling patterns, atrioventricular timing, and electrophysiological effects beyond the sinoatrial node. Evidence in acute heart failure, atrial fibrillation, and acute myocardial infarction is also considered. Ivabradine should complement rather than replace foundational guideline-directed medical therapy, while physiology-guided titration remains investigational.</p><p><strong>Conclusion: </strong>The contemporary role of ivabradine may extend beyond fixed heart rate thresholds toward individualized physiological optimization. The immediate objective of such an approach is to improve filling, hemodynamic tolerance, and treatment response rather than to assume a direct survival benefit. Whether physiology-guided ivabradine therapy improves heart failure hospitalization or survival requires prospective validation before such strategies can be incorporated into routine practice.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baxdrostat in Resistant and Uncontrolled Hypertension: A Systematic Review and Meta-Analysis.","authors":"Adir Alper, Mathias Lerner, Adina Fagin, Aditya Karthikeyan, Adam Gershon, Robert Faillace","doi":"10.1007/s10557-026-07973-5","DOIUrl":"https://doi.org/10.1007/s10557-026-07973-5","url":null,"abstract":"<p><strong>Background: </strong>Aldosterone dysregulation is becoming more widely acknowledged as a key factor in resistant hypertension. Baxdrostat, a highly selective aldosterone synthase inhibitor that shows a 100:1 preference for CYP11B2 over CYP11B1, has been tested in various randomized controlled trials involving different hypertensive groups. We carried out a systematic review and meta-analysis to assess the efficacy and safety of baxdrostat for treating resistant hypertension.</p><p><strong>Methods: </strong>We included randomized, double-blind, placebo-controlled trials of baxdrostat in adults with hypertension from inception through March 2026. The primary outcome was the placebo-corrected change in seated systolic blood pressure (SBP). Secondary outcomes included the change in diastolic blood pressure (DBP), the proportion of patients achieving seated SBP < 130 mmHg, and the incidence of hyperkalemia and other adverse events.</p><p><strong>Results: </strong>Five trials (N = 1,730) were included: BrigHTN, HALO, BaxHTN, FigHTN, and Bax24. Baxdrostat significantly reduced seated SBP vs. placebo (MD -6.90 mmHg; 95% CI, -10.25 to -3.55; P < 0.0001), with high heterogeneity (I² = 74%). Numerically larger reductions were observed at higher doses: the 2 mg dose yielded the largest reduction (MD -8.16 mmHg; P < 0.00001; I² = 45%), followed by 1 mg (MD -6.06 mmHg; P = 0.010), while 0.5 mg was non-significant (P = 0.14). Baxdrostat increased the odds of achieving SBP < 130 mmHg (OR 2.70; P = 0.01), although the magnitude of this effect varied substantially across trials (I² = 89%). DBP reduction was significant at the 2 mg dose (MD -3.51 mmHg; P < 0.0001) and the 1 mg dose (MD -2.55 mmHg; P = 0.03). Safety analysis showed higher odds of hyperkalemia (8.9% vs. 1.2%; OR 5.98; P = 0.008), with potassium > 6.0 mmol/L in 3.8% of baxdrostat-treated patients versus 0.2% with placebo. Serious adverse events were not significantly increased (OR 1.35; P = 0.37). No deaths were attributable to baxdrostat.</p><p><strong>Conclusions: </strong>Baxdrostat produces statistically significant reductions in systolic blood pressure among various hypertensive populations, increasing the likelihood of achieving blood pressure targets (SBP < 130 mmHg), although the magnitude of this effect varied substantially across trials (I² = 89%). Hyperkalemia was the principal safety concern but was not associated with serious clinical sequelae in the included trials. These findings support further investigation of aldosterone synthase inhibition as a therapeutic strategy for resistant and uncontrolled hypertension, with definitive clinical positioning awaiting results from ongoing cardiovascular and renal outcomes trials.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Prognostic Value of Triglyceride-Glucose Index and Bilirubin in Drug-Eluting Stent Restenosis: From Clinical Risk Stratification to Exploratory Vascular-Cell Findings.","authors":"Yingle Wu, Xiaopeng Qu, Yanhui Han, Mengnan Fan, Xuming Yang, Pingshuan Dong, Ke Wang, Laijing Du","doi":"10.1007/s10557-026-07968-2","DOIUrl":"https://doi.org/10.1007/s10557-026-07968-2","url":null,"abstract":"<p><strong>Background: </strong>Drug-eluting stent in-stent restenosis (DES-ISR) remains a clinically relevant complication after percutaneous coronary intervention for acute coronary syndrome (ACS). We assessed the combined predictive value of the triglyceride-glucose (TyG) index and total bilirubin (TB), alongside exploratory vascular-cell findings.</p><p><strong>Methods: </strong>This retrospective cohort included 1,160 ACS patients undergoing drug-eluting stent implantation and angiographic follow-up. Associations with DES-ISR, discrimination, calibration, and incremental prediction were evaluated using multivariable models and split-sample internal validation. HUVECs and VSMCs were exposed to high-glucose/high-triglyceride or bilirubin-related conditions; network pharmacology, reverse docking, and selected pathway experiments were used to generate and evaluate hypotheses.</p><p><strong>Results: </strong>Higher TyG was associated with increased DES-ISR risk (adjusted OR = 1.487, 95% CI 1.067-2.073), whereas higher TB was associated with lower risk (OR = 0.875, 95% CI 0.838-0.914). The TyG-TB model had AUCs of 0.702 (training) and 0.676 (validation), with Brier score 0.134, calibration slope 0.858, and Hosmer-Lemeshow P = 0.868. Adding TyG and TB improved prediction (ΔAUC = 0.078; continuous NRI = 0.714; IDI = 0.060; all P < 0.001). High-glucose/high-triglyceride exposure was associated with proliferative, oxidative, RAGE/NF-κB/MAPK-related, and insulin-response changes; FPS-ZM1 attenuated selected responses.</p><p><strong>Conclusion: </strong>TyG and TB showed opposite associations with DES-ISR and jointly provided moderate incremental predictive information. The cell findings support RAGE-related vascular responses under the tested conditions but require external and mechanistic validation before clinical application.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}