Cardiovascular Drugs and Therapy最新文献

Background: Prolonged cold ischemia and subsequent reperfusion are major causes of primary graft dysfunction in heart transplantation. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has shown cardioprotective effects in ischemia-reperfusion injury, but its role in donor heart preservation and the underlying mechanisms remain unexplored.

Methods: We evaluated the effects of empagliflozin supplementation in University of Wisconsin (UW) preservation solution using both in vitro and in vivo models. HL-1 cardiomyocytes were subjected to cold hypoxia/reoxygenation injury to simulate donor preservation conditions. A murine heterotopic heart transplantation model with 24-hour cold storage was used to assess graft function, myocardial injury, fibrosis, and immune response. Mechanistic studies were conducted using AMPK and Drp1 inhibitors to investigate mitochondrial signaling pathways.

Results: Empagliflozin (500 nM) significantly improved cardiomyocyte viability, reduced apoptosis, and preserved mitochondrial membrane potential under cold hypoxia/reoxygenation stress. In vivo, empagliflozin-supplemented UW solution improved early graft contractility, attenuated myocardial injury, reduced serum injury markers, and alleviated histological damage and immune cell infiltration. Long-term follow-up revealed mitigation of chronic rejection, with reduced fibrosis, vasculopathy, and immune activation. Mechanistically, empagliflozin activated AMPK, inhibited Drp1 phosphorylation at Ser616, promoted mitochondrial fusion (Mfn1, OPA1), and preserved mitochondrial morphology. These protective effects were abolished by AMPK inhibition and restored by Drp1 inhibition, confirming AMPK-Drp1 pathway involvement.

Conclusions: Empagliflozin enhances donor heart preservation by mitigating cold ischemia-reperfusion injury through modulation of the AMPK-Drp1 signaling axis. This study extends the pharmacological profile of empagliflozin from metabolic regulation to donor heart preservation, highlighting its translational potential in clinical transplantation.

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality globally, accounting for nearly one-third of deaths worldwide. Intercellular communication between cardiomyocytes and non-cardiomyocytes is fundamental to maintaining cardiac homeostasis and adapting to stress or injury. Among the mediators of this communication, extracellular vesicles (EVs) have emerged as pivotal regulators of cardiac function and remodelling, transporting bioactive molecules that reflect the state and origin of their parent cells. This review provides a systems-level synthesis of EV-mediated crosstalk in the heart, integrating evidence from cardiomyocyte- and non-cardiomyocyte-derived EVs, including fibroblast, endothelial, vascular smooth muscle, and immune cell sources. We discuss how these vesicles orchestrate signalling networks that influence cardiac remodelling, injury response, and disease progression. Distinct from prior reviews, our article extends beyond mechanistic summaries to explore the translational continuum of cardiac EVs-from their potential as diagnostic and prognostic biomarkers to emerging therapeutic and bioengineering strategies. Finally, we critically evaluate current technical and regulatory barriers impeding clinical translation, including isolation, characterisation, and validation challenges, and propose a forward-looking roadmap to advance EV-based diagnostics and therapeutics in cardiovascular medicine.

Background: In the contemporary reperfusion era, the benefit of beta-blocker therapy in patients after acute myocardial infarction (AMI) and preserved left ventricular ejection fraction (LVEF ≥50%) remains unclear. Recently conducted clinical trials have demonstrated mixed results about the clinical benefit of beta-blockers after myocardial infarction in pooled populations of patients with mildly reduced (LVEF 40-49%) or preserved LVEF. However, new evidence suggests a consistent benefit of beta-blocker therapy in patients specifically with mildly reduced LVEF. We aimed to assess the efficacy of beta-blockers in patients with recent myocardial infarction and mildly reduced or preserved LVEF, as well as specifically with preserved LVEF.

Methods: We conducted a systematic review of recent randomized controlled trials that evaluated the effects of oral beta-blocker therapy in patients with AMI who had either mildly reduced LVEF or preserved LVEF and with follow-up data of at least 1 year. Using a Mantel-Haenszel random effects model, we computed risk ratios (RR) with 95% confidence intervals for the primary composite outcome along with individual outcomes of death, re-infarction, and heart failure between patients with and without beta-blocker therapy. We performed analysis of the pooled overall study population, which included patients with mildly reduced LVEF and preserved LVEF, as well as performed subgroup analysis of patients with preserved versus mildly reduced LVEF and among men versus women.

Results: 19,826 patients with mildly reduced or preserved LVEF were included in the meta-analysis. Overall, 9,892 patients were assigned to beta-blockers and 9,934 to no beta-blockers. Among the pooled population, we did not demonstrate significant differences between the beta-blocker group and the control group for the primary composite outcome (RR 0.93, 95% CI 0.83-1.04), all-cause death, reinfarction, or heart failure. We further did not detect differences in the primary outcome by sex. While there was no differences in the primary composite outcome among patients with preserved LVEF (RR 0.96, 95% CI 0.86-1.08), there was reduction in risk observed among individuals with mildly reduced LVEF (RR 0.76, 95% CI 0.61-0.94).

Conclusion: Oral beta-blocker therapy was not associated with a reduction in the primary composite outcome in patients with preserved LVEF. This contrasts with their established benefit in patients with reduced LVEF and the growing evidence of benefit in those with mildly reduced LVEF.

Background: Pulmonary hypertension (PH) is a complicated cardiovascular disorder marked by elevated pulmonary arterial pressure and vascular remodeling. The molecular interplay between Ryanodine Receptor 2 (RyR2) and FK506-binding protein 12.6 (FKBP12.6) emphasizes that their dissociation under hypoxic conditions results in intracellular calcium(Ca²⁺) dysregulation in pulmonary artery smooth muscle cells (PASMCs).

Objective: This review article highlights important discoveries about how mitochondrial ROS, particularly those mediated by the Rieske iron-sulfur protein (RISP), trigger RyR2 activation and the sub sequent release of Ca2+. Furthermore, it covers a process that establishes a connection between sarcoplasmic reticulum calcium signaling, which promotes vasoconstriction and vascular remodeling, and mitochondrial dysfunction.

Conclusion: The pathways involved inRyR2/FKBP12.6 destabilization lead to progression in PH. Moreover, targeting these pathways has been reported to be beneficial in PH management.

Purpose: Obstructive sleep apnea promotes atrial fibrillation (AF) by activating the renin-angiotensin system (RAS) and increasing angiotensin II. Alamandine(ALA), an angiotensin(1-7)-related peptide with anti-fibrotic properties, has not been thoroughly investigated for its potential effects on atrial fibrosis or its interaction with the YAP/TAZ pathway. This study investigates whether ALA attenuates hypoxia-induced atrial fibrosis and AF, and explores its underlying signaling mechanisms.

Methods: Male Sprague-Dawley rats (6-8 weeks old) were divided into four groups: negative control, chronic intermittent hypoxia (CIH), CIH + low-dose ALA (50 µg/kg/day), and CIH + high-dose ALA (250 µg/kg/day). All groups underwent CIH exposure for one month. Subsequently, ALA was administered via subcutaneous osmotic pumps for an additional month, while CIH exposure continued.

Results: Compared with the hypoxia group, ALA treatment led to a significant reduction in the transcription and expression of fibrinogen genes in atrial tissue, a decrease in left atrial area, and less atrial fibrosis-effects that were more pronounced with higher doses. ALA administration also markedly decreased the incidence and duration of AF, reduced atrial conduction heterogeneity, and increased conduction velocity. Furthermore, ALA treatment attenuated the hypoxia-induced upregulation of YAP/TAZ protein expression and nuclear translocation, as well as the elevation in plasma angiotensin II levels.

Conclusion: ALA treatment attenuated chronic intermittent hypoxia-induced atrial fibrosis and reduced AF susceptibility with more pronounced effects observed at higher doses. These results highlight the potential translational value of ALA treatment in reducing AF-related morbidity, possibly via modulation of the YAP/TAZ pathway.

Purpose: Natriuretic peptides (NPs) ANP, BNP, and CNP extend beyond biomarkers of wall stress to regulators of cardiovascular, renal, metabolic, and immune pathways via cGMP-PKG signaling. We synthesize mechanistic and translational evidence, highlight NP "resistance," and appraise therapeutic strategies that augment NP signaling.

Methods: Narrative review integrating human physiology, preclinical studies, and key trials (e.g., PARADIGM-HF, PARAGON-HF, EMPEROR-Preserved), plus emerging agents (ARNIs, designer peptides, NPR-C modulation, receptor sensitizers).

Results: NPs exert natriuretic, vasodilatory, antifibrotic, and immunomodulatory effects. Resistance via neprilysin degradation, NPR-C-mediated clearance, and receptor desensitization blunts efficacy in advanced disease. ARNIs improve outcomes in HFrEF; benefits in HFpEF are subgroup-dependent. NP biology intersects with metabolic and inflammatory circuits, suggesting potential synergy with SGLT2 inhibitors and other modulators.

Conclusions: NPs are promising therapeutic targets across cardio-renal-metabolic spectra, but for many strategies, the evidence remains preclinical or early-phase. We propose a translational roadmap emphasizing mechanistic validation, responder phenotyping, and rigorously powered trials to test NP augmentation (and combinations) in HFrEF, obesity-related HFpEF, pulmonary vascular disease, and immune-cardiometabolic syndromes.

Background: In recent years, studies have increasingly focused on the role of magnesium ions in cardiovascular disease; however, its clinical significance in patients with acute myocardial infarction remains controversial. This study aimed to evaluate the association of intravenous magnesium sulfate administration on 28-day all-cause mortality among patients with acute myocardial infarction across different time windows of treatment initiation.

Methods: This retrospective observational cohort study analyzed data from patients diagnosed with acute type 1 myocardial infarction using the Medical Information Marketplace in Intensive Care (MIMIC)-IV database. Patients were categorized into five groups based on the timing of magnesium sulfate initiation: Q1 (not received), Q2 (≤ 2 h), Q3 (2-6 h), Q4 (6-12 h), and Q5 (≥ 12 h). The primary outcome was 28-day all-cause mortality, while the secondary outcome was one-year all-cause mortality. Adjusted Kaplan-Meier survival curve analysis and log-rank test were used to evaluate the association between intravenous magnesium sulfate administration and long-term mortality risk. Landmark analysis was performed to assess both short-term and long-term connections. Restricted mean survival time (RMST) was calculated as part of the sensitivity analysis to further investigate treatment correlations.

Results: A total of 4610 patients were included in this retrospective observational cohort study, with an overall 28-day all-cause mortality rate of 18.5%. Adjusted Kaplan-Meier survival analysis revealed that magnesium sulfate administration was significantly associated with reduced one-year all-cause mortality Lower mortality risks were observed across all treatment time groups. Landmark analysis showed a significantly higher association before the 28-day mark (P < 0.001). RMST analysis confirmed the consistency and robustness of these findings.

Conclusions: This single-center observational study in the PCI era demonstrates an association between intravenous magnesium sulfate and reduced mortality in patients with acute myocardial infarction, but it cannot establish causality because of potential residual and unmeasured confounding and other inherent biases. Future, well-designed randomized controlled trials are needed to determine whether magnesium sulfate truly improves outcomes in this population.

Mesenchymal stem-cell-derived exosomes (MSC-sEVs) represent a promising cell-free strategy for myocardial repair. Building upon the recent work by Bashir et al., we propose a complementary metabolic-lipid framework in which specific phospholipid cargoes allosterically regulate glucose-6-phosphate dehydrogenase (G6PD) to enhance pentose-phosphate-pathway (PPP) activity and sustain NADPH-dependent redox balance. Observations from LVAD-supported myocardium reveal coordinated up-regulation of G6PD-PPP enzymes during reverse remodeling, linking metabolic reprogramming to structural recovery. Lipid-mediated modulation of G6PD may therefore provide a pharmacologic bridge between exosome-based paracrine signaling and redox-driven myocardial regeneration, advancing metabolism-guided therapeutic design in heart failure.