Journal of Cardiovascular Pharmacology最新文献

Abstract: Fine particulate matter (PM2.5) is a pervasive air pollutant strongly linked to cardiovascular morbidity, yet effective countermeasures remain elusive. Here, we report that the natural triterpenoid asiatic acid (AA) protects against PM2.5-induced cardiotoxicity in male BALB/c mice by interrupting a mitochondrial DNA (mtDNA)-driven pyroptotic cascade. Animals exposed to intranasal PM2.5 (16.2 mg·kg⁻¹, every 48 hours for 21 days) developed cardiac hypertrophy, contractile dysfunction, extensive fibrosis and ultrastructural mitochondrial damage concomitant with cytosolic release of mtDNA fragments (cytochrome c oxidase subunit I [CO1], NADH dehydrogenase subunit 1 [ND1], cytochrome b [Cytb]), down-regulation of mitochondrial transcription factor A (TFAM), and robust activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling (cGAS, STING, phosphorylated TANK-binding kinase 1 [p-TBK1], phosphorylated interferon regulatory factor 3 [p-IRF3]). Downstream, NOD-like receptor protein 3 (NLRP3) inflammasome assembly, caspase-1 cleavage, gasdermin D pore formation and maturation of interleukin-1 beta (IL-1β)/interleukin-18 (IL-18) were markedly elevated. Oral administration of AA (12.5 or 25 mg·kg⁻¹ from day 7) dose-dependently restored TFAM expression, reduced cytosolic mtDNA, blunted cGAS-STING-NLRP3 axis activation, attenuated pyroptosis and preserved cardiac architecture and function. These findings identify mtDNA-triggered cGAS-STING-NLRP3 signalling as a critical pathway underlying PM2.5-elicited cardiomyocyte pyroptosis and establish AA as a promising therapeutic agent against air-pollution-associated cardiovascular injury.

Abstract: To identify potential agents associated with the development of valvular heart diseases (VHD), we used Mendelian randomization and colocalization analyses to pinpoint genes significantly linked to VHD. A total of 324 genes were found to be positively associated with VHD, among which AGK and TLE5 demonstrated evidence of colocalization. Then, transcriptome data of aortic and mitral valve diseases were retrieved from GEO database. Based on the expression levels of AGK and TLE5, sequencing data for aortic and mitral valve diseases were stratified into 2 subtypes, respectively. Differentially expressed genes between these subtypes underwent KEGG pathway enrichment analysis. Molecular docking revealed that ergotamine and fosfomycin exhibited the highest binding affinities to AGK and TLE5, respectively. Then, FDA Adverse Event Reporting System database was used to corroborate the associations between the identified drugs and aortic and mitral valve diseases. Analysis of the FDA Adverse Event Reporting System database indicated reporting odds ratios of 13.82 [95% confidence interval (CI): 5.17-36.94] for ergotamine and 2.14 (95% CI: 0.69-6.63) for fosfomycin. For further validation, naratriptan and aztreonam were used as control drugs. The adjusted odds ratios for ergotamine and fosfomycin were 8.31 (95% CI: 1.61-38.39) and 2.96 (95% CI: 0.84-18.75), respectively, when compared with the control drugs. Finally, human aortic and mitral interstitial cells were isolated and transfected with AGK plasmid. After adding Ly294002 (inhibitor of PI3K-Akt), the Western blot results showed that AGK promoted the fibrosis of aortic and mitral interstitial cells by PI3K-Akt signaling pathway. In conclusion, ergotamine may contribute to the development of aortic and mitral valve diseases through the activation of AGK.

Abstract: Warfarin inhibits vitamin K-dependent proteins that prevent vascular calcification. We hypothesized that direct oral anticoagulants (DOACs), which do not interact with vitamin K, would slow coronary plaque progression compared with warfarin in patients with atrial fibrillation (AF). Following PRISMA guidelines and a prospectively registered protocol (PROSPERO: CRD420251026977), we systematically searched PubMed, Embase, and Cochrane databases through April 2025 for randomized controlled trials comparing DOACs with warfarin in patients with AF. Primary outcomes included changes in coronary plaque volumes (PV). Mean differences (MD) were calculated using Mantel-Haenszel method, with trial sequential analysis performed for all outcomes. Three RCTs with 272 patients (136 receiving DOACs) were included. Patients receiving DOACs showed significantly slower progression of calcified PV (MD -7.07 mm 3 ; 95% CI: -12.99 to -1.14; P = 0.02; I 2 = 0%) and fibrous PV (MD -12.52 mm 3 ; 95% CI: -24.92 to -0.12; P = 0.05; I 2 = 0%) compared with patients receiving warfarin. No significant differences were observed in total PV, noncalcified PV, fibro-fatty PV, or low attenuation PV. Trial sequential analysis indicated that 391 patients would be necessary for definitive conclusions regarding calcified PV. Risk of bias assessment indicated some concerns for all studies, with moderate certainty of evidence for most end points. DOACs significantly reduce progression of calcified and fibrous PV compared with warfarin in patients with AF. These findings suggest DOACs may promote more stable plaque composition, potentially reducing cardiovascular event risk. However, larger studies with longer follow-up are needed to confirm these results.

Abstract: Nonobstructive hypertrophic cardiomyopathy (nHCM) is a condition that has significant therapeutic challenges due to its complicated pathophysiology. Beta-blockers and calcium channel blockers are the existing treatment modalities that offer limited symptom relief and fail to address underlying metabolic deficits. This review evaluates emerging targeted therapies, focusing on ninerafaxstat, a cardiac metabolic modulator that inhibits 3-ketoacyl-CoA thiolase to shift myocardial substrate utilization from fatty acids to glucose, thereby improving energy efficiency. Clinical trials of novel agents, including myosin inhibitors (aficamten, mavacamten) and metabolic modulators, highlight ninerafaxstat's unique potential. The phase 2 IMPROVE-HCM trial demonstrated improved ventilatory efficiency (VE/VCO 2 slope: -2.1, P = 0.005), reduced left atrial remodeling (-0.9 mm, P = 0.01), and enhanced quality of life in severe subgroups, with a favorable safety profile. Unlike myosin inhibitors, which reduce hypercontractility but not energy deficits, ninerafaxstat directly resolves metabolic dysfunction, synergizing with sarcomere-targeted therapies for dual-pathway efficacy. While myosin inhibitors (eg, REDWOOD-HCM, MAVERICK-HCM) show robust biomarker improvements, ninerafaxstat addresses the core energy mismatch driving nHCM progression. Innovative gene therapies (MyPEAK-1) and exercise programs broaden the range of available treatments. Ninerafaxstat represents a paradigm shift toward precision medicine in nHCM, offering a metabolic foundation for combination strategies. Future phase 3 trials must validate long-term benefits on functional capacity, metabolic markers, arrhythmia risk, and survival, positioning ninerafaxstat as a cornerstone therapy for restoring cardiac energetics in nHCM.

Abstract: Clopidogrel, as an antiplatelet drug, is important for the treatment of the secondary prevention of ischemic stroke according to the latest guidelines on ischemic stroke management. However, some patients still fail to achieve a drug response and experience ischemic events despite taking clopidogrel because of differences in the production of active metabolites attributable to specific factors. Although platelet function testing plays a crucial role in evaluating the efficacy of antiplatelet drugs, research on their application remains relatively limited in the ischemic stroke population; thus, it is necessary to clarify their role in guiding individualized treatment for patients with ischemic stroke. In this review, we synthesize the current state of research on clopidogrel resistance (CR) in patients with ischemic stroke, covering key aspects such as the pharmacological mechanisms and metabolism of clopidogrel, the risk factors associated with CR, and the clinical application of platelet function testing in ischemic stroke. Our study aims to explore the prevalence and predictors of CR among patients with ischemic stroke, identify its potential impact on recurrent ischemic stroke, and thereby offer insights for the development of personalized and precision treatment strategies for clopidogrel treatment in these patients.

Abstract: Left Ventricular Assist Devices (LVADs) are an established therapy for end-stage heart failure as bridge-to-transplant and destination therapy. Despite advances with fully magnetically levitated devices such as the HeartMate 3, hemocompatibility-related adverse events, most notably bleeding, remain frequent, and drive morbidity and readmissions. Bleeding risk is multifactorial, reflecting anticoagulation, comorbidities, vascular abnormalities, and acquired hematologic disorders. We conducted a narrative review of thrombotic and bleeding outcomes associated with anticoagulation strategies in continuous-flow LVAD patients. From 417 screened records, 10 studies were included, focusing on direct oral anticoagulants. The 10 studies comprised 174 LVAD-supported patients treated with direct oral anticoagulants, primarily apixaban; most were on the HeartMate 3 (n = 146). Among factor Xa inhibitor studies, thrombotic event rates ranged from 0% to 12.5% and bleeding from 6% to 20%-broadly comparable with or lower than warfarin [bleeding: 6% vs. 30% in 1 retrospective cohort ( P = 0.1); composite death or major hemocompatibility-related events: 12.5% vs. 43% at 2-year follow-up ( P = 0.087)]. Dabigatran, a direct thrombin (factor IIa) inhibitor was associated with a 50% rate of pump thrombosis in a pilot randomized trial, leading to early termination. Significant heterogeneity in patient selection, regimens, and study design limits definitive conclusions. Anticoagulation management remains a major unmet need in LVAD therapy. Factor Xa inhibitor-based anticoagulation, particularly apixaban, may be associated with comparable thrombotic outcomes and lower bleeding risk versus warfarin in selected patients. Dabigatran carries high thrombotic risk and should be avoided. Adequately powered randomized trials are required to define optimal anticoagulation strategies in this population.

Abstract: Fluoropyrimidines, including 5-fluorouracil and capecitabine, are widely used antimetabolite agents and remain central to the treatment of several solid tumors, particularly gastrointestinal malignancies. However, they are a well-established cause of chemotherapy-related cardiotoxicity. Although coronary vasospasm is the best recognized manifestation, fluoropyrimidine cardiotoxicity encompasses a broad clinical spectrum, ranging from chest pain and arrhythmias to acute heart failure, and, rarely, fulminant cardiogenic shock. This review discusses severe fluoropyrimidine-associated cardiotoxicity through the illustrative presentation of a young woman without previous cardiovascular disease who developed acute biventricular dysfunction and cardiogenic shock shortly after first exposure to FOLFIRINOX, requiring temporary mechanical circulatory support. Administration of uridine triacetate within the recommended therapeutic window was associated with rapid recovery of ventricular function. Cardiac magnetic resonance imaging demonstrated diffuse myocardial edema without late gadolinium enhancement, consistent with reversible toxic-inflammatory myocardial injury. Expanded genomic analysis identified dihydropyrimidine dehydrogenase and thymidylate synthase variants not detected by standard pretreatment pharmacogenetic screening. In this study we examine the pathophysiological mechanisms of fluoropyrimidine cardiotoxicity, the rationale for uridine triacetate in severe presentations, and the potential role of expanded pharmacogenomic profiling within a precision cardio-oncology framework.

Abstract: Metabolites of arachidonic acid (AA) generated by cytochrome P450 (CYP) enzymes play significant roles in cardiac pathophysiology. Epoxyeicosatrienoic acids (EETs) exert vasodilatory, anti-inflammatory, and cardioprotective effects, but their rapid degradation limits therapeutic use. A metabolically stable analog, EET-A, was developed to mimic native 14,15-EET. The role of EET-A in cardiac hypertrophy and its interaction with CYP pathways remains unclear. This study investigated whether EET-A modulates cardiac hypertrophy, CYP enzyme expression, and AA metabolite formation in an isoproterenol (ISO)-induced model. Male Sprague-Dawley rats were administered ISO (1 mg/kg/d, i.p.) for 7 consecutive days to induce cardiac hypertrophy, with EET-A (10 mg/kg, i.p.) administered in parallel. Cardiac hypertrophy induction was confirmed, and the gene and protein levels of expression of cardiac CYP enzymes were assessed. Hydroxyeicosatetraenoic acids (HETEs) and EETs formation rates were measured using liquid chromatography-mass spectrometric analysis after incubating heart microsomes with AA. Concurrent administration of EET-A with ISO attenuated cardiac hypertrophy, as evidenced by reduced heart weight/body weight, heart weight/tibial length ratio, and the gene expression of β-myosin heavy chain compared with ISO alone. ISO significantly increased cardiac hypertrophic markers and altered CYP-mediated AA metabolism, including increased CYP1B1 expression, elevated mid-chain HETEs, and reduced EET formation rates. EET-A partially prevented these changes by suppressing CYP1B1 protein induction, decreasing 11-HETE formation, and restoring 8,9-EET levels. These findings indicate that EET-A attenuates ISO-induced cardiac hypertrophy and partially modulates CYP-dependent AA metabolism, conferring partial protection against β-adrenergic receptor agonist-induced cardiac remodeling.

In dialysis-dependent end-stage renal disease patients (ESRD), statin use remains an evidence-use dilemma: randomized controlled trials (RCTs) suggested limited benefit from statin initiation, whereas observational cohort studies reported lower mortality and cardiovascular events. This discordance creates uncertainty in prescribing, resource allocation, guideline interpretation, and shared decision-making. This analysis assessed whether this apparent conflict reflects true inconsistency, risk of bias, indirectness, or limitations in translating evidence into recommendations. Using narrative synthesis, GRADE-informed appraisal, and evidence-to-decision principles, an evidence-based, patient-centered approach is proposed based on the current available evidence.

Left ventricular thrombus (LVT) is a serious complication of anterior ST-elevation myocardial infarction (STEMI). Despite guideline endorsement of prophylactic anticoagulation in selected high-risk patients, the supporting evidence remains of low certainty. Aim of our systematic review and meta-analysis is to evaluate the efficacy and safety of triple antithrombotic treatment (TAT) versus dual antiplatelet treatment (DAPT) alone for LVT prevention in patients with anterior STEMI treated with primary percutaneous coronary intervention (pPCI). Three electronic databases (EMBASE, MEDLINE, Cochrane Library) were systematically searched from inception to February 2026, following PRISMA 2020 guidelines. Eligible studies enrolled adult patients with anterior STEMI revascularised by pPCI, compared prophylactic TAT with DAPT alone, and reported LVT outcomes. Data were pooled as risk ratios (RR) with 95% confidence intervals (CI) using random-effects models. The primary outcome was LVT formation; secondary outcomes were major bleeding and systemic embolism. Six studies including 2,021 patients were analyzed. Pooled analysis demonstrated no statistically significant reduction in LVT formation with TAT (RR 0.54, 95% CI 0.21-1.40; p=0.21; I2=61%), whereas major bleeding risk was significantly increased (RR 2.69, 95% CI 1.40-5.19; p=0.003; I2=14%). A non-significant trend toward reduced systemic embolism was observed (RR 0.44, 95% CI 0.18-1.07; p=0.07; I2=0%). The addition of prophylactic anticoagulation to DAPT in patients with anterior STEMI treated with pPCI does not show a statistically significant reduction in LVT formation while significantly increasing major bleeding risk. These findings do not support routine prophylactic TAT in unselected patients with anterior STEMI.