Journal of Cardiovascular Pharmacology最新文献

Protamine is frequently used to reverse unfractionated heparin, yet contemporary data on its safety and long-term outcomes in chronic total occlusion percutaneous coronary intervention (CTO PCI)-related perforation are limited. We retrospectively analyzed all CTO PCI procedures performed at a single center between January 2019 and December 2023. Patients who experienced coronary perforation were stratified by protamine administration. Inverse probability of treatment weighting (IPTW) and doubly robust logistic regression were used to adjust for baseline and procedural differences. Clinical endpoints included protamine-related reactions, cardiac tamponade requiring pericardiocentesis, periprocedural myocardial infarction (MI), acute stent thrombosis, in-hospital all-cause death, and 1-year all-cause death. Among 1,503 CTO PCI cases, perforation occurred in 199 patients (13.2%); 108 (54.3%) received protamine, and 91 (45.7%) did not. Protamine use increased over time (p-for-trend <0.001). In-hospital outcomes were comparable between groups, including death (4.6% vs. 4.4%; p>0.999), pericardiocentesis (8.3% vs. 9.9%; p=0.806), and periprocedural MI (0.9% vs. 2.2%; p=0.594). IPTW-adjusted analyses yielded similar results. No acute stent thrombosis or protamine reactions occurred. Doubly robust analysis showed no association between protamine use and in-hospital death (aOR 0.85, 95% CI 0.05-13.86; p=0.917), pericardiocentesis (aOR 0.45, 95% CI 0.10-1.98; p=0.294), or either outcome (aOR 0.53, 95% CI 0.21-2.85; p=0.390). At 1 year, all-cause death remained similar (7.4% vs. 6.6%; p>0.999), with no association on adjusted analysis (aOR 0.63, 95% CI 0.12-3.40; p=0.591). Protamine administration for CTO PCI-related perforation appears safe, without evidence of additional clinical benefit compared with no protamine use.

Musculoskeletal adverse reactions (MAEs) caused by statins are the main reason that limits their clinical application. Bempedoic acid provides an alternative treatment option for patients who cannot tolerate statins as a novel oral lipid-lowering drug. The objective of this study was to perform data mining using the FDA Adverse Event Reporting System (FAERS) to realistically observe and systematically summarize bempedoic acid-related MAEs in the real world. The FAERS database from the first quarter of 2020 to the fourth quarter of 2024 was retrospectively queried to characterize reporting of MAEs with bempedoic acid. The association between bempedoic acid and MAEs was evaluated using the reporting odds ratio (ROR) and the Bayesian Confidence Propagation Neural Network, followed by univariate logistic regression to explore factors influencing MAEs. MAEs accounted for 19.64% of the total number of bempedoic acid reports. The median onset time of MAEs with bempedoic acid was 12.5 days. Disproportion analysis showed that myalgia had the strongest AE signal (ROR 30.1[95% CI 24.93-36.35]). Subgroup analyses of age, sex, and weight showed no significant differences in the risk of bempedoic acid-related MAEs. Notably, age >65 years and male patients were significant risk factors for reporting serious MAEs (p<0.001 and p=0.015, respectively). This real-world pharmacovigilance study suggested a significant association between the MAEs and bempedoic acid. Elderly male patients were more likely to develop serious MAEs. Enhanced monitoring is recommended when administering bempedoic acid to high-risk populations.

This study evaluated the clinical efficacy and safety of repeated levosimendan administration, both as monotherapy and in combination with dapagliflozin, in outpatients with chronic heart failure (CHF) and reduced ejection fraction (<40%). We conducted a multicenter, randomized, double-blind, placebo-controlled trial across five outpatient clinics in Moscow, Russia. A total of 393 patients were randomized into three groups: levosimendan (0.1 µg/kg/min, 24-hour infusions every 3 weeks), placebo, and combination therapy (levosimendan plus dapagliflozin 10 mg/day). All patients in the combination group were SGLT2 inhibitor-naïve. The primary outcomes included changes in NT-proBNP levels and hospitalization rates, while secondary outcomes assessed quality of life using the Minnesota Living with Heart Failure Questionnaire (MLHFQ), functional parameters, and safety. Combination therapy produced the greatest clinical benefit, with significant reductions in NT-proBNP (p = 0.03) and hospitalization rates (p = 0.04), and a significantly lower risk of hospitalization or death compared with placebo (HR = 0.58, 95% CI: 0.36-0.92, p = 0.021). Improvements in quality of life were also most pronounced in the combination group, with significant MLHFQ score changes at 3 months (p = 0.02) and 6 months (p = 0.04). Levosimendan monotherapy led to moderate improvements, but effects were consistently smaller than those observed with combination therapy. Safety and tolerability were acceptable across all groups, with no clinically meaningful changes in hematologic or biochemical markers. The combination of levosimendan and dapagliflozin provides superior clinical benefits in CHF outpatients, including reduced hospitalizations and improved quality of life, while maintaining a favorable safety profile.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection that often leads to profound end organ derangement in which vascular system dysfunction plays a critical role. Septic shock is characterized by a pronounced decrease in peripheral vascular resistance, progressive hypotension and lack of response to vasoconstrictors. We have previously shown that sepsis induced cardiac hyporesponsiveness to isoproterenol by a nitric oxide (NO)-dependent mechanism, mediated by increased G protein receptor kinase 2 (GRK2) expression and receptor phosphorylation. In the present report we investigated whether this mechanism is relevant in the vascular system. The contractile response of aortic rings and the in vivo responsiveness to phenylephrine were significantly reduced in septic mice at both 12 and 24 h after cecal ligation and puncture (CLP) surgery. Higher expression of GRK2 and increased phosphorylated GRK2 were detected in the aorta of septic mice along with a reduction in the density of alpha-1 adrenergic receptors. Treatment with the selective NOS-2 inhibitor 1400W prevented vessel hyporesponsiveness, abolished GRK2 expression and activation and preserved alpha-1 adrenergic receptor density. Naïve mouse aorta rings incubated with a NO donor displayed diminished contractile response, and this effect was prevented by a GRK2 inhibitor. Our study showed that during sepsis, NOS-2-derived NO induces and activates GRK2, leading to alpha-1 adrenergic receptor internalization and hyporesponsiveness to vasoconstrictors. Therefore, our findings suggest that GRK2 inhibition is a potential new therapeutic target in sepsis-induced vascular dysfunction.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease marked by extracellular matrix deposition, oxidative stress, and profound microvascular remodeling. Endothelial dysfunction, particularly through endothelial-to-mesenchymal transition (EndMT), has been implicated in fibrotic progression but remains insufficiently characterized. In this study, human pulmonary microvascular endothelial cells were exposed to 5% serum from patients with IPF or healthy donors to model disease-associated vascular alterations. IPF serum stimulated a robust increase in reactive oxygen species (ROS) production and proliferation, concomitant with downregulation of endothelial markers (von Willebrand factor, CD31) and upregulation of mesenchymal markers (α-smooth muscle actin, collagen I), consistent with EndMT induction. Notably, pharmacological inhibition of NADPH oxidase (NOX) with diphenyleneiodonium markedly attenuated ROS generation, phenotypic switching, and junctional disruption observed under IPF serum exposure. Similarly, inhibition of protein kinase C (PKC) by chelerythrine suppressed ROS production and proliferative responses, implicating PKC-dependent pathways in ROS-mediated endothelial injury. Immunofluorescence analyses confirmed structural reorganization, revealing loss of endothelial junctional integrity and accumulation of mesenchymal proteins, both reversed by NOX inhibition. Together, these findings establish IPF serum-derived factors as potent drivers of endothelial oxidative stress and EndMT through NOX- and PKC-dependent mechanisms. Targeting these redox-sensitive pathways may represent a promising therapeutic strategy to mitigate vascular dysfunction, tissue remodeling, and disease progression in IPF.

Abstract: Triptolide (TP) is widely used clinically for multiple diseases, but its cardiotoxicity significantly limits its clinical applications. The underlying mechanisms of its cardiotoxicity are still unclear. Mitochondria are crucial for cellular survival and function. Here, we found that TP induced mitochondrial dysfunction and apoptosis of cardiomyocytes, which might be the key process underlying TP-induced cardiotoxicity. Moreover, the expression of prohibitin1 (PHB1) was significantly decreased after TP treatment in a time-dependent manner. Overexpression of PHB1 alleviated mitochondrial dysfunction and inhibited apoptosis of cardiomyocytes after TP treatment. Mechanistically, PHB1 might regulate mitochondrial dynamics, which maintain normal mitochondrial function. Based on the above results, PHB1 might be a potential therapeutic target for TP-induced cardiotoxicity.

Abstract: Fulminant myocarditis (FM) is a critical condition with high mortality. Interleukin-1 (IL-1) is a key mediator of myocardial inflammation. We describe the case of a 19-year-old man with FM, hemodynamic deterioration refractory to standard treatment, and a marked systemic inflammatory response. The introduction of anakinra, an IL-1 receptor antagonist, led to rapid clinical, hemodynamic, and laboratory improvement. A literature review identifies other cases of severe/fulminant myocarditis with hyperinflammation that benefited from IL-1 blockade, despite heterogeneous etiologies. These data suggest that anakinra could be a valuable rescue therapeutic option in selected patients with FM and hyperinflammation. Randomized trials are needed to confirm the role of IL-1 blockade in this high-risk population, focusing on the pharmacology of the immune response.

Abstract: This study investigates the cardioprotective potential of soluble guanylate cyclase (sGC) and its α1 subunit in myocardial ischemia/reperfusion (I/R) injury, along with the underlying mechanisms. We used a model involving Sprague Dawley rats undergoing left coronary artery I/R, complemented by H9c2 cell cultures in an anaerobic environment to simulate I/R conditions in vitro. Both loss- and gain-of-function approaches were applied to assess the role of sGC and its α1 subunit in myocardial I/R injury. Immunofluorescence microscopy, western blotting, and RT-PCR were employed to examine how sGC and its α1 subunit influence oxidative stress and apoptosis. Our results showed that sGC and its α1 subunit were associated with reduced I/R injury severity in both in vitro and in vivo settings. Overexpression of sGC decreased cardiomyocyte apoptosis and maintained mitochondrial function during I/R, whereas sGC silencing heightened oxidative stress and apoptosis. In addition, pharmacological modulation of sGC affected signaling in the peroxisome proliferator-activated receptor-γ coactivator-1α/uncoupling protein 2 pathway. These findings demonstrate the crucial role of sGC and its α1 subunit in protecting against cardiac injury during I/R, suggesting that sGC-targeted therapies could offer promising strategies for managing myocardial damage associated with I/R injury.