Journal of Cardiovascular Pharmacology最新文献

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.

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.