Journal of Cardiovascular Pharmacology最新文献

Abstract: Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG data sets. Unsupervised clustering categorized patients with HF into LacRG-based subgroups. An LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing expression patterns. HF mouse models were constructed and verified for LacRG expression. In 200 HF versus 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunologic features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (area under the curve: 0.999, 1.000, 0.744). Single-cell RNA sequencing (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T-cell, and NK-cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External data sets (GSE46224, GSE116250) identified 6 hub genes-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. In addition, analysis of HF dataset further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and 6 hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF through immune microenvironmental mechanisms.

Abstract: Excessive surgical bleeding is a potential risk in patients taking ticagrelor who must undergo urgent cardiothoracic (CT) surgery before adequate washout of the drug can occur. The DrugSorb-Antithrombotic removal (ATR) device is a polymer sorbent-filled hemoadsorption cartridge that can remove unbound (active) fractions of ticagrelor and ticagrelor active metabolite (TAM) from blood. STAR-T was a randomized double-blind sham-controlled clinical trial investigating whether the intraoperative use of the device could reduce perioperative bleeding complications in patients undergoing CT surgery within 2 days of ticagrelor discontinuation. Blood samples were collected during the study for total drug level measurements because the ability to measure unbound ticagrelor and TAM (0.2% of total levels) requires an ultra-high sensitivity assay, which is not commercially available. A published and validated pharmacokinetic (PK) model was used to explore the effect of the device on unbound ticagrelor/TAM using the total drug concentrations from the study. The model performed well for simulations of total ticagrelor and TAM, which indicated that the unbound concentrations were also appropriate. The model demonstrated that DrugSorb-ATR significantly reduced unbound ticagrelor and TAM concentrations. Linear and logistic regression analyses of summed ticagrelor and TAM concentrations showed that the DrugSorb-ATR device reduced the probability of clinically relevant bleeding in STAR-T because of the reduction in unbound ticagrelor and TAM.

Immune checkpoint inhibitors (ICIs) have successfully revolutionized cancer therapy, but their immune-mediated adverse events include rare, often severe myocarditis. While dual ICI blockade is associated with increased cardiotoxic risk, little is known about the potential effects of triplet combinations currently under clinical investigation. We developed a co-culture model of human cardiomyocytes and human peripheral blood mononuclear cells (hPBMCs) to evaluate immune-mediated cytotoxicity induced by ICIs. HFCs were exposed for 48h to Nivolumab plus Relatlimab, Ipilimumab, or Atezolizumab, either alone or in triplet combinations. Cell lysis was quantified by LDH release. Cytokine secretion (IL-2, granzyme B, and additional inflammatory mediators including NLRP3 activation pathway) was measured by ELISA. Digital microscopy was used for morphological assessment. Triplet combinations of Nivolumab-Relatlimab with Ipilimumab or Atezolizumab induced significantly higher cardiomyocyte lysis compared to single agents or doublets (p < 0.001). This effect correlated with a robust increase in IL-2 and granzyme B secretion, as well as activation of pro-inflammatory cytokines and NLRP3 inflammasome-related mediators. Microscopic analyses confirmed immune cell activation and reduced density of HFCs exposed to triplets. Our findings demonstrate that ICI triplets elicit potent immune activation against cardiomyocytes, providing the first preclinical evidence of direct cardiotoxic potential in this setting. These results highlight the need for enhanced clinical surveillance and cardio-oncology monitoring in patients receiving triple ICI combinations, as these regimens expand in clinical practice.

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.

Abstract: Diabetic cardiomyopathy (DCM), a global cardiovascular complication of diabetes, is characterized by concurrent diastolic and systolic ventricular dysfunction that progressively leads to heart failure, arrhythmias, and cardiogenic shock. Despite advancements in modern therapeutics, DCM continues to exhibit high mortality rates, underscoring the critical need for novel preventive and therapeutic strategies. In recent years, traditional Chinese medicine (TCM) has gained prominence in DCM management due to its established safety profile and emerging evidence of clinical efficacy. Current research focuses on elucidating TCM's multitarget mechanisms, particularly its regulatory effects on metabolic homeostasis, oxidative stress, and inflammatory pathways-key pathological processes in DCM progression. This review systematically investigates the latest advancements in TCM for DCM management through 3 principal dimensions: First, it synthesizes the etiological understanding of DCM from both TCM theory and modern medical perspectives, highlighting their complementary mechanisms in disease pathogenesis. Second, it critically evaluates the therapeutic potential of clinically validated Chinese herbal agents, focusing on their bioactive compounds that target myocardial energy metabolism and oxidative stress pathways. Third, it systematically summarizes evidence-based TCM therapeutic strategies. By consolidating existing evidence, this review aims to provide a rigorous assessment of TCM's clinical value in DCM management, while proposing standardized frameworks to facilitate deeper integration of TCM principles with evidence-based cardiology practice.