Journal of Cardiovascular Pharmacology最新文献

Sacubitril/valsartan, the first angiotensin receptor neprilysin inhibitor (ARNIs), has antihypertensive and organ-protective effects. However, previous meta-analyses have mainly compared it with angiotensin receptor blockers (ARBs) and neglected other commonly used antihypertensive agents, while its effect on ambulatory blood pressure remains unclear. This meta-analysis aimed to evaluate the efficacy and safety of sacubitril/valsartan in patients with hypertension. We searched CNKI, Wanfang, VIP, PubMed, Embase, and the Cochrane Library from inception to June 2025 for randomized controlled trials comparing sacubitril/valsartan with ARBs or calcium channel blockers (CCBs). Fifteen studies involving 4,824 hypertensive patients were included. Compared with ARBs or CCBs, sacubitril/valsartan significantly reduced 24-hour systolic variability (24hSBPV) and 24-hour diastolic blood pressure variability (24hDBPV), as well as 24-hour, daytime, and nighttime ambulatory blood pressure. It also improved the dipper blood pressure proportion and blood pressure control rate. Subgroup analysis showed that both 200 mg/d and 400 mg/d dosages achieved superior antihypertensive efficacy. In terms of safety, sacubitril/valsartan had a similar adverse event profile to CCBs. Compared with ARBs, sacubitril/valsartan at 200 mg/d was associated with a lower incidence of serious adverse events (SAE), and the overall rate of liver function abnormalities was also reduced. Sensitivity analyses confirmed robust results with no significant publication bias. In conclusion, sacubitril/valsartan effectively improves multiple ambulatory blood pressure parameters with a favorable safety profile, supporting its rational use in hypertensive patients.

Anthracyclines are cornerstone chemotherapeutic agents for several cancers but carry a substantial risk of cardiotoxicity. Multiple cardioprotective drugs have been investigated to prevent cardiac dysfunction in patients receiving anthracycline-based chemotherapy. This study evaluated and ranked the cardioprotective effects of these agents using network meta-analysis. A comprehensive search of PubMed, Cochrane, Scopus, and Web of Science from inception to September 22, 2024 identified randomized clinical trials and cohort studies assessing cardioprotective agents in cancer patients treated with anthracyclines. Interventions included angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists, statins, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and metformin. The primary outcome was change in left ventricular ejection fraction (LVEF). Secondary outcomes were left ventricular end-diastolic diameter (LVEDD), chemotherapy-related cardiac dysfunction (CTRCD), heart failure (HF), HF hospitalization, and all-cause mortality. Thirty-five studies were included, comprising 31 randomized controlled trials and 4 retrospective studies. Overall, cardioprotective therapy significantly improved LVEF, reduced CTRCD, all-cause mortality, HF incidence, and LVEDD, but had no significant effect on HF hospitalization. Subgroup and network meta-analyses showed that ACEIs plus beta-blockers, beta-blockers alone, statins, and ACEIs significantly improved LVEF versus controls, with ACEIs ranking highest. For CTRCD prevention, statins and beta-blockers significantly reduced risk, whereas ACEIs plus beta-blockers had the most favorable ranking. For mortality, the available retrospective SGLT2 inhibitor studies suggested an association with lower risk; however, because no randomized anthracycline-specific SGLT2 inhibitor trials were available and follow-up duration differed from the RCT evidence for other agents, this finding should be considered hypothesis-generating rather than definitive comparative evidence. ACEIs, beta-blockers, and statins appear effective for preserving cardiac function during anthracycline therapy. Treatment rankings, particularly for outcomes supported by sparse or observational evidence, should be interpreted cautiously, and further randomized trials are needed, particularly to evaluate SGLT2 inhibitors.

Chronic alcohol consumption causes serious damage to the liver and cardiovascular system and leads to neoplastic lesions in various organs such as the esophagus, liver, and breast. In our study, we evaluated the protective effects of standard and high doses of dapagliflozin against alcohol-related cardiac damage by utilizing its anti-inflammatory, anti-fibrotic, and anti-cardiac remodeling effects with biochemical and pathological parameters. Twenty male and twenty female Sprague-Dawley rats were used in the experiments. The animals were randomly divided into 5 groups, with 4 males and 4 females in each group. The experimental groups (ALCOHOL, ALCOHOL+DAP, and ALCOHOL+hDAP groups) were given 20% ethyl alcohol intraperitoneally (i.p.) once daily for 28 days. Dapagliflozin (DAP, ALCOHOL+DAP, and ALCOHOL+hDAP groups) and saline solution (CONT and ALCOHOL groups) were administered orally via gavage (o.g.). In the hearts of animals exposed to alcohol, cardiomyocyte hypertrophy, irregular myofiber arrangement, widespread or focal infiltration of inflammatory cells such as neutrophils and lymphocytes, and marked cytoplasmic vacuolization were observed. Treatment with high-dose dapagliflozin alleviated these structural changes. Alcohol caused significant proximal tubular damage. High-dose dapagliflozin resulted in a greater reduction in alcohol-induced renal damage. Although standard dose dapagliflozin improved alcohol-induced impaired Caspas-3, Cytokeratin 18-M30, Cytokeratin 18-M65, TAS, TOS, OSI, MDA, IL-1β, TNF-α, HsCRP, Endothelin-1, IMA, total thiol, native thiol, and disulfide levels, high dose dapagliflozin provided significant improvements (p<0.001). This study suggests that high-dose dapagliflozin (3 mg/kg) may have the potential to regulate mitochondrial function and thiol/disulfide balance in alcohol-related heart damage by inhibiting fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress through various mechanisms.

Abstract: Milvexian is a selective, oral factor XIa inhibitor. Individuals receiving anticoagulation may require prompt reversal of anticoagulative effects. This study assessed reversal of milvexian's anticoagulant effects by recombinant human factor VIIa (rFVIIa) and 4-factor prothrombin complex concentrate (4F-PCC) in healthy participants. This was a 2-part, randomized, crossover study. In part A, milvexian (100 or 500 mg single doses) was followed by rFVIIa (30 μg/kg) or placebo 4 hours later. In part B, milvexian 200 mg was administered q12h for 3 consecutive days, with 4F-PCC (50IU/kg) or placebo given 4 hours after last dose in the morning of day 4. Anticoagulation was assessed through activated partial thromboplastin time (aPTT) and thrombin generation [endogenous thrombin potential (ETP), peak thrombin] using 2 activators: kaolin [intrinsic pathway (IP) effects] and tissue factor [extrinsic pathway (EP) effects]. rFVIIa partially reversed milvexian's effects on aPTT (milvexian 100 mg: ∼18%; 500 mg: ∼15%), IP-induced ETP (milvexian-induced ETP reversal; 100 mg: ∼50%; 500 mg: ∼80%) and peak thrombin, and EP-induced peak thrombin but not ETP. Milvexian 200 mg prolonged aPTT, strongly inhibited IP-induced ETP/peak thrombin, and mildly inhibited EP-induced ETP. 4F-PCC partially reversed milvexian's effect on aPTT (∼17%) and IP-induced ETP/peak thrombin; it reversed milvexian's effect on EP-initiated ETP (∼68% increase). Reversal was rapid (15 minutes) and long-lasting (≥8 hours). Milvexian pharmacokinetics were unchanged by reversal agents. Regimens were generally safe and well tolerated. In conclusion, milvexian's anticoagulant effect was partially reversed by rFVIIa and 4F-PCC. These results may offer clinicians options in situations where reversal of milvexian might be considered.

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.