Cardiovascular Drugs and Therapy最新文献

We appreciate the thoughtful commentary by Drs. Dziewierz and Siudak regarding our study comparing tirzepatide versus semaglutide in post-CABG diabetic patients. While we acknowledge the inherent limitations of observational research, our propensity score matching achieved near-perfect balance across 40+ covariates (SMD = 0.033), including comprehensive medication proxies for diabetes control, lipid management, and blood pressure control. We observed consistent protective effects across multiple distinct outcome domains-cerebrovascular, cardiovascular, thrombotic, mortality, and healthcare utilization-with nine outcomes significant after Benjamini-Hochberg correction. The cerebrovascular benefit is particularly noteworthy given semaglutide's neutral stroke effect in SELECT trial, suggesting differential GIP receptor-mediated neurovascular protection. SURPASS-CVOT, comparing tirzepatide to dulaglutide (not semaglutide) in general ASCVD populations, addresses a different clinical question and may lack power for post-CABG subgroup analysis. Our findings provide hypothesis-generating evidence for an understudied high-risk population, warranting further investigation in dedicated trials.

Purpose: Pulmonary hypertension (PH) is a clinicopathological syndrome characterized by structural and functional alterations in the pulmonary vasculature arising from heterogeneous etiologies (including hypoxia) and diverse pathogenic mechanisms. These changes elevate pulmonary vascular resistance and increase pulmonary arterial pressure, ultimately progressing to right heart failure and potential fatality. Resistin-like molecule (RELM)-β activates multiple signaling pathways. This study aimed to explore the role of RELM-β in the development of chronic hypoxia-induced PH and its potential mechanisms.

Methods: Exogenous human RELM-β was injected into a mouse model of hypoxia for 3 weeks, followed by histological and hemodynamic analyses. The relationship between RELM-β and membrane proteins or receptors (OR1N1, GIPC1 and CLIC4) was determined by affinity purification-mass spectrometry (AP-MS) and co-immunoprecipitation. At the same time, in vitro cell culture experiments were carried out.

Results: Cell membrane proteins or receptors (OR1N1, GIPC1, and CLIC4) were identified as proteins interacting with RELM-β and potentially involving in the development of PH. Compared with the RELM-β overexpression group, siRNA-mediated silencing of OR1N1, GIPC1, or CLIC4 resulted in significant reduction of cell viability in both human pulmonary artery smooth muscle cells (PASMCs) and human pulmonary arterial endothelial cells (PAECs). Moreover, augmenting effect of exogenous RELM-ß on the hypoxia-induced PH was remarkably reduced in the mice with genetic deficiency of GIPC1 (GIPC1 CKO) or CLIC4 (CLIC4 CKO) compared to the wild type mice.

Conclusions: Findings of the current study suggested that RELM-β may play an important role in the development of hypoxia-induced PH through interacting with membrane proteins or receptors, including GIPC1, OR1N1, and CLIC4.

Purpose: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure with preserved ejection fraction (HFpEF), yet comparative effectiveness between steroidal and nonsteroidal agents remains unknown. Our aim was to compare cardiovascular and safety outcomes associated with finerenone versus spironolactone among patients with HFpEF.

Methods: This retrospective cohort study used a global federated health research network to identify adults with new-onset HFpEF between January 1, 2021, and August 1, 2025. Propensity score matching (1:1) balanced baseline characteristics, and outcomes were assessed with Cox proportional hazards models. A total of 253 patients prescribed finerenone and 32,266 prescribed spironolactone were identified; after matching, 251 patients were retained in each cohort (mean age, 73 years; 47% female). The primary outcome was acute HF events. Secondary outcomes included all-cause hospitalizations, mortality, myocardial infarction, stroke, and a composite of major adverse cardiovascular events. Safety outcomes included acute kidney injury (AKI) and hyperkalemia.

Results: Acute HF events occurred in 6.0% of patients receiving finerenone and 4.4% receiving spironolactone (HR 1.26, 95% CI 0.58-2.74). All-cause mortality was lower with finerenone (4.4% vs. 8.0%; HR 0.48, 95% CI 0.23-1.00). Other clinical and safety outcomes, including MACE (11.6% vs. 10.8%), AKI (10.4% vs. 8.0%), and hyperkalemia (5.8% vs. 6.2%), were similar between groups.

Conclusion: In this first direct comparison of MRAs in HFpEF, finerenone demonstrated broadly comparable effectiveness and safety to spironolactone. While these observations are hypothesis-generating, prospective studies are warranted to confirm these findings and inform therapeutic decision-making.

Background: Atherosclerotic stenosis is a progressive vascular disease characterized by vascular narrowing. Bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) have been reported to alleviate endothelial cell dysfunction.

Aim and methods: Here, we investigated the therapeutic potential of BMSC-EVs in a rabbit model of diabetic atherosclerotic stenosis and in a high-glucose-induced human umbilical vein endothelial cell (HUVEC) injury model.

Results: Histological analysis confirmed the successful establishment of the animal model. Treatment with BMSC-EVs effectively reduced intimal thickening and lipid accumulation, attenuated collagen deposition, reduced smooth muscle cell proliferation, and alleviated macrophage infiltration. Additionally, BMSC-EVs treatment decreased the expression of pro-inflammatory cytokines and improved serum lipid profiles. The HUVEC injury model recapitulates the key features of endothelial dysfunction, including decreased cell viability, increased apoptosis, oxidative stress, and proinflammatory cytokine expression. Treatment with BMSC-EVs alleviated these effects by enhancing cell viability, suppressing apoptosis, reducing oxidative stress, and lowering pro-inflammatory cytokine expression. Mechanistically, BMSC-EVs inhibited the expression of apoptotic markers, including Bax and Cleaved Caspase 3, while enhancing the phosphorylation of heat shock protein 27 (HSP27), a cytoprotective molecule, and its upstream activator P38. HSP27 knockdown reversed the anti-apoptotic and antioxidant effects of BMSC-EVs, highlighting the crucial role of HSP27 in mediating these effects.

Conclusion: Our findings suggest that BMSC-EVs hold promise as a therapeutic intervention for vascular endothelial injury associated with atherosclerosis and diabetes mellitus. Targeting HSP27 may be a potential strategy to enhance the therapeutic efficacy of BMSC-EVs in endothelial dysfunction.

Background: Disseminated intravascular coagulation (DIC) is a life-threatening condition characterized by uncontrolled coagulation and systemic inflammation, often triggered by sepsis. Recent studies highlight the role of N6-methyladenosine (m6A) modification in regulating endothelial dysfunction and coagulation pathways. However, the specific role of Wilms tumor 1-associated protein (WTAP)-a component of the m6A methyltransferase complex-in sepsis-induced DIC remains poorly understood.

Methods: HUVECs were stimulated with LPS to establish an in vitro inflammation model. WTAP expression was knocked down using shRNA, and its effects on intercellular adhesion molecule 1 (ICAM1) and tissue factor (TF) expression were analyzed via qPCR, Western blot, and RIP assays. The stability of ICAM1 mRNA was assessed using Actinomycin D treatment. An in vivo sepsis-induced DIC rat model was used to evaluate coagulation parameters, histopathological changes, and WTAP and ICAM1, TF expression in response to WTAP knockdown.

Results: LPS stimulation significantly increased WTAP expression and m6A modification levels in HUVECs, leading to increased ICAM1 expression and enhanced TF activity. WTAP knockdown reduced ICAM1 and TF expression, as well as TF activity. RIP and mRNA stability assays confirmed that WTAP stabilizes ICAM1 mRNA via m6A modification. In the DIC rat model, WTAP knockdown improved coagulation parameters, reduced microthrombus formation in lung and kidney tissues, and inhibited the coagulation cascade.

Conclusion: WTAP stabilizes ICAM1 mRNA via m6A modification, thereby increasing ICAM1 expression and enhancing TF activity in LPS-stimulated HUVECs. Knocking down WTAP in rats improves sepsis-induced DIC.

Purpose: this study aims to screen Protease-activated receptor 1 (PAR1) inhibitory active components with low bleeding side effects from anti-thrombin phytochemicals in Polygonum amplexicaule D. Don var. sinense Forb (PAF) to achieve multi-pathway antithrombosis without disrupting platelet hemostasis.

Methods: Docking simulation and platelet aggregation test were used to investigate interaction of PAR1-ligands to screen out anti-PAR1 active ingredients. FeCl₃-induced carotid artery (CA) thrombosis and inferior vena cava (IVC)-ligated thrombosis model were constructed to collect thrombi to weigh. Histopathological analysis, coagulation function, and hemorheological indicator detection of administered rats were conducted to analyze antithrombotic effectiveness and mechanism of these compounds, which were injected in tail veins of mice to evaluate bleeding side effects.

Results: Three promising ligands (epigallocatechin gallate, homoorientin, and myricetin) with strong affinity of PAR1 were selected from PAF. Epigallocatechin gallate and homoorientin showed antithrombotic effects with decreased bleeding tendency based on activity validation, suggesting that they may be prospective and effective candidate compounds of PAR1 antagonists.

Conclusion: the integrative strategy applied to these active components allowed to rapidly discover compounds with reducing bleeding side effects during thrombus treatment, providing valuable references for precisely targeted therapy and mechanism exploration of medicinal plants.

Purpose: Lipoprotein(a) [Lp(a)] is increasingly recognized as a genetically determined, independent risk factor for atherosclerotic cardiovascular disease (ASCVD). This review examines the structure, pathophysiology, and epidemiology of Lp(a), with a focus on its contribution to ASCVD and related conditions such as aortic valve stenosis and peripheral artery disease. The main research question addresses how Lp(a) influences cardiovascular risk and how emerging therapies may modify this risk.

Methods: This review synthesizes published evidence describing the biological characteristics of Lp(a), its mechanistic roles in disease, and its epidemiologic associations with cardiovascular outcomes. It also evaluates current and investigational therapeutic approaches by examining clinical trial data for agents targeting Lp(a).

Results: Lp(a) contributes to residual cardiovascular risk through proatherogenic, proinflammatory, and prothrombotic mechanisms. Current evidence highlights its involvement in ASCVD, aortic valve stenosis, and peripheral artery disease. Clinical studies of antisense oligonucleotides, small interfering RNAs, oral small molecules, and CRISPR-based gene editing, including pelacarsen, olpasiran, zerlasiran, lepodisiran, muvalaplin, and obicetrapib, demonstrate promising efficacy and safety. These agents show potential to significantly reduce Lp(a) levels and influence future cardiovascular prevention strategies.

Conclusion: As novel therapies advance and clinical guidelines evolve, Lp(a) is emerging as a central determinant in personalized cardiovascular care. The increasing emphasis on Lp(a) testing underscores its importance in risk stratification and future therapeutic decisionmaking.

Purpose: Kawasaki disease (KD) is an acute systemic vasculitis causing coronary artery lesions (CAL). Paeoniflorin (PF) exerts anti-inflammatory and antioxidant properties, but its role in KD remains unclear. This study aims to elucidate the effects of PF on CAL and the underlying regulatory mechanisms.

Methods: C57BL/6J mice were induced by Lactobacillus casei cell wall extract (LCWE) to establish a KD mouse model. Inflammatory infiltration and pathological changes of cardiac tissue in mice was evaluated by hematoxylin eosin staining. Oxidative damage of mice was evaluated by measuring protein carbonyl, 8-hydroxy-2'-deoxyguanosine, malondialdehyde and 4-hydroxynonenal (4-HNE). Superoxide dismutase, catalase, total antioxidant capacity and glutathione peroxidase 4 was measured to evaluate antioxidant levels in mice. Inflammation levels was assessed by measuring tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6. Apoptosis of cardiac tissues was detected by TUNEL assay. The underlying mechanism was determined by RNA-sequencing.

Results: Results showed that PF inhibited inflammatory infiltration and apoptosis of cardiac tissues, as well as oxidative damage and inflammation in KD mouse model, but enhanced antioxidant levels in KD mouse model. Mechanically, PF inhibited cytochrome P450 family 2 subfamily E member 1 (CYP2E1) expression but activated NRF2 pathway in KD mouse model. CYP2E1 overexpression and ML385 (a NRF2 inhibitor) reversed the therapeutic effects of PF on KD mouse model. Moreover, CYP2E1 knockdown restored the therapeutic effects of PF inhibited by ML385 on KD mouse model.

Conclusion: Collectively, our findings demonstrated that PF alleviated CAL in KD by activating NRF2 pathway and inhibiting CYP2E1 expression. These results may provide a theoretical basis for the potential use of PF as a therapeutic agent for KD associated with CAL.