Cardiovascular Therapeutics最新文献

Background: Calcific aortic valve disease (CAVD) is a prevalent heart valve disease. The ratio of two apolipoproteins with distinct functions, Apolipoprotein B/Apolipoprotein A1 (APOB/APOA1), has been proposed as a novel assessment index for the evaluation of cardiovascular diseases. The aim of this article is to discuss the role of lipid parameters such as APOB/APOA1 in CAVD and the risk factors for CAVD, to develop a predictive model for CAVD, and to evaluate the sensitivity and specificity of this model.

Method: Patients who initially presented to the Department of Cardiology of the Second Affiliated Hospital of Dalian Medical University between 1 January 2023 and 31 December 2023 were retrospectively identified and included in the study. Patients were divided into an aortic valve calcification group (111 cases) and a control group (201 cases) based on computed tomography (CT) findings. The clinical data, laboratory examination results, and chest CT images of the patients were collected and analyzed. A variety of statistical methods were used to analyze risk factors for CAVD, to construct a CAVD prediction model, and to assess its sensitivity and specificity.

Results: Lipid parameters APOA1, APOB/APOA1, cumulative low-density lipoprotein (LDL) exposure, and non–high-density lipoprotein/high-density lipoprotein (non-HDL/HDL) were significantly associated with aortic valve calcification. Age, history of diabetes, diastolic blood pressure (DBP), APOB/APOA1, Cystatin C (Cys-c), and neutrophil-to-lymphocyte ratio (NLR) are identified as independent risk factors for CAVD, and the combined model achieved an AUC of 0.796 for CAVD prediction, corresponding to a sensitivity of 0.769 and a specificity of 0.755.

Conclusion: The lipid parameters APOA1, APOB/APOA1, cumulative LDL exposure, and non-HDL/HDL have been demonstrated to be associated with aortic valve calcification. Furthermore, APOB/APOA1 can be used for the prediction of CAVD, and the combination of APOB/APOA1 with age, history of diabetes, DBP, Cys-c, and NLR has better prediction performance for CAVD.

X. Shi, B. Zhang, Z. Chu, et al., “Wogonin Inhibits Cardiac Hypertrophy by Activating Nrf-2-Mediated Antioxidant Responses”, Cardiovascular Therapeutics 2021 (2021): 9995342, https://doi.org/10.1155/2021/9995342

In the article, there is an error in Figure 4e due to the incorrect selection of images during manuscript preparation. The correct Figure 4 is shown below:

The authors apologize for this error.

Atrial autonomic nerve system (ANS) remodeling plays an important role in atrial fibrillation (AF). Mineralocorticoid receptor antagonists (MRAs) have been proved to be effective in preventing atrial structural remodeling. However, the effects of MRA on ANS remodeling in AF and the underlying mechanisms are still unknown.

Methods: Then, 21 rabbits were randomized into sham, pacing, and pacing + eplerenone groups. To verify the effect of aldosterone on ANS remodeling, 18 SD rats were pumped with aldosterone. HL-1 cells were subjected to control treatment or rapid pacing with or without eplerenone or U0126 (an inhibitor of ERK1/2). Atrial sympathetic and parasympathetic remodeling was detected by immunohistochemical staining, Western blotting, and RT-PCR. The circulating neurohormone and atrial electrophysiology were also assessed.

Results: The ERK1/2 MAPK pathway was significantly activated in AF rabbit/HL-1 cell models, resulting in the upregulation of key downstream protein; this effect was significantly restored by eplerenone. Eplerenone prevented the alterations in circulating neurohormone, reduced the mRNA level of sympathetic and parasympathetic-related growth factors, and inhibited the inducibility and duration of AF.

Conclusions: Eplerenone inhibited atrial autonomic nerve remodeling and the occurrence of AF through modulating the ERK1/2 MAPK pathway.

Background: Sunitinib (SU) is used to treat kidney cancer. However, it can also cause cardiotoxicity. This study is performed to investigate whether rivaroxaban (RIV) attenuates SU-induced cardiotoxicity (SIC).

Methods and Materials: AC16 cells and primary cardiomyocytes of neonatal mouse were treated with different concentrations (2–10 μM) of SU for 24 h or with 6 μM SU and 10 μg/mL RIV for 24 h. The viability of cardiomyocytes was evaluated using the cell counting kit-8 (CCK-8) assay, and the apoptosis rate was evaluated using flow cytometry. The activity of caspase-3 was determined. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were also measured. The potential targets and downstream pathways of RIV in SIC treatment were investigated using network pharmacology, molecular docking, and molecular dynamics simulation. qPCR and western blotting were used to detect the regulatory effects of SU and RIV on mRNA and protein expression of MAPK pathway-related genes, respectively.

Results: RIV treatment alleviated SU-induced cardiomyocyte injury by promoting viability and inhibiting apoptosis, oxidative stress, and the inflammatory response in AC16 cells and primary cardiomyocytes. Caspase 3 (CASP3), signal transducer and activator of transcription 3 (STAT3), SRC proto-oncogene, nonreceptor tyrosine kinase (SRC), ATP-binding cassette subfamily G member 2 (ABCG2), and ATP-binding cassette subfamily B member 1 (ABCB1) were candidate targets of RIV in SIC. The binding affinities between RIV and CASP3, STAT3, SRC, ABCG2, and ABCB1 were all less than −7.5 kcal/mol, indicating that RIV could bind stably to these targets. Bioinformatics analyses suggested that the mitogen-activated protein kinase (MAPK) pathway was involved in the mechanism by which RIV alleviated SIC. RIV treatment decreased the mRNA expression of CASP3 and increased the mRNA expression of STAT3, SRC, ABCG2, and ABCB1 in AC16 cells and primary cardiomyocytes. RIV also inhibited the SU-induced activation of the MAPK pathway.

Conclusion: RIV exerts a protective effect against SU-induced cardiomyocyte injury by inhibiting the MAPK signaling pathway. RIV therapy may be a promising strategy to inhibit SU’s cardiotoxicity in cancer patients.

Background: The tryptophan/kynurenic acid (KYNA) pathway plays a crucial role by modulating inflammation, oxidative stress, and immune activation. The clinical value of tryptophan metabolites in the KYNA pathway for the early diagnosis and prognosis of STEMI patients, as well as the underlying functional mechanisms, remains to be elucidated.

Objectives: This study evaluated the prognostic value of KYNA, a metabolite of the tryptophan pathway, in STEMI patients.

Methods: Untargeted metabolomics by ¹H-nuclear magnetic resonance (NMR) analysis was used to examine metabolite changes between 50 control subjects and 50 STEMI patients with an onset time of < 3 h. Furthermore, targeted metabolomic analysis was employed to investigate the association between KYNA and the prognosis of STEMI patients by LC-Q-TOF MS analysis.

Results: Fifteen differential metabolites were identified between STEMI patients and control subjects by ¹H-NMR analysis. KYNA as an important metabolite upregulated obviously in the tryptophan pathway was 337.67 nmol/L in STEMI patients (interquartile range: 241.16–500.29 nmol/L). In addition, KYNA was significantly associated with major adverse cardiovascular events (MACEs) (HR: 5.95, 95% CI: 2.03–17.44; p = 0.0012) and all-cause mortality (HR: 7.11, 95% CI: 1.52–33.29; p = 0.013) and showed moderate predictive value for 12-month MACE (area under the curve (AUC) = 0.72, 95% CI: 0.65–0.80) and all-cause mortality (AUC = 0.74, 95% CI: 0.65–0.83). KAT1 expression was upregulated in infiltrating macrophages of thrombus tissue coming from the culprit coronary artery of STEMI patients. KAT1 upregulation was also observed in macrophages located within the peri-infarct myocardium.

Conclusions: The KYNA level may correspond to the underlying status of acute myocardial infarction and is a promising biomarker for predicting STEMI progression.

Oxidative stress and mitochondrial dysfunction play critical roles in the pathology of cardiovascular diseases. However, the effects of Astragaloside IV (As-IV) on mitochondrial function remain unclear. This study is aimed at evaluating the protective effects and mechanism of As-IV against H₂O₂-induced mitochondrial dysfunction in H9c2 cells. H9c2 cells were exposed to 200 μM H₂O₂ with or without As-IV. The level of apoptosis and reactive oxygen species (ROS) was measured by flow cytometry. Confocal microscopy and transmission electron microscopy were performed to detect the changes in mitochondrial membrane potential (MMP), mitochondrial morphology, and autophagosome. Mitochondrial dynamics and mitophagy-related proteins were measured by Western blot. The results indicated that As-IV decreased H₂O₂-induced apoptosis and ROS generation. Meanwhile, As-IV significantly increased MMP, exerted regulatory effects on mitochondrial dynamics, and ameliorated the damaged mitochondrial morphology in H₂O₂-injured cardiomyocytes. Additionally, As-IV decreased the amount of autophagosome and expressions of PINK1 and Parkin, but upregulated the expressions of PI3K, p-AKT, and p-mTOR proteins. However, cotreatment with LY294002 diminished the upregulation of PI3K, p-AKT, and p-mTOR induced by As-IV. In the study, we demonstrated that As-IV protected H9c2 cells from H₂O₂-induced mitochondrial dysfunction by inhibiting mitophagy, which might be related to the PI3K/AKT/mTOR pathway.

Background: The standard oral dose of rivaroxaban for nonvalvular atrial fibrillation (NVAF) patients with a creatinine clearance rate (CrCl) ≥ 50 mL/min is 20 mg/day in Europe and 15 mg/day in Japan. In the real world, low-dosing (10 mg/day) rivaroxaban has been widely used in clinical practice in China due to bleeding concerns. However, the impact of low-dose rivaroxaban on clinical outcomes remains uncertain.

Methods: This retrospective study included NVAF patients with CrCl ≥ 50 mL/min treated at the Second Affiliated Hospital of Xi’an Jiaotong University from January 2017 to June 2022. Patients were divided into two groups: standard-dose (15 or 20 mg/day) and low-dose (10 mg/day). Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. The risk of ischemic stroke (IS)+systemic embolism (SE) and bleeding was compared between the two groups by survival analysis.

Results: A total of 1455 patients (mean age: 66.98 ± 11.16 years; 55.95% female) were included. In the low-dose group (n = 1176), 78 (6.63%) experienced IS/SE and 68 (5.78%) had bleeding. In the standard-dose group (n = 279), 13 (4.66%) experienced IS/SE and 18 (6.45%) had bleeding. Cox regression suggested that compared to the standard-dose group, patients in the low-dose group did not show a significantly different risk of IS+SE (HR = 1.01, 95% CI: 0.51–1.96, p = 0.999) or bleeding (HR = 0.90, 95% CI: 0.49–1.67, p = 0.749). Subgroup analysis revealed that for patients with BMI < 24 kg/m², low-dose rivaroxaban reduced bleeding risk (HR = 0.53, 95% CI: 0.29–0.99, p = 0.049).

Conclusion: For NVAF patients with CrCl ≥ 50 mL/min in China, low-dose rivaroxaban (10 mg/day) is a viable alternative to standard doses in preventing IS/SE. In nonoverweight patients (BMI < 24 kg/m²), it offers comparable efficacy with enhanced safety.

Aims: The aim of the present study was to investigate the inhibition of classically activated macrophages in myocardial infarction (MI) under the influence of the chemokine (C-C motif) receptor 2 (CCR2) antagonist propagermanium (PPG).

Methods and Results: Mice (C57BL/6; n = 121) were subjected to occlusion of the left anterior descending artery and were randomized to the following groups: (a) MI with daily oral administration of 0.9% sodium chloride (“MI”), (b) MI with oral administration of 8 mg/kg PPG (“MI + PPG”), and (c) sham-operated mice served as control. Mice were euthanized 2, 5, 10, or 21 days after MI for isolation of total RNA, protein, and immunofluorescence measurements. Flow cytometry was performed to investigate peripheral blood leucocytes. Scar size and cardiac function were determined by MRI on Day 7 after surgery and by trichrome staining on Day 21. PPG administration led to a significantly improved ejection fraction (MI + PPG: 38.5% ± 3.4% vs. MI: 23.8% ± 3.0%; p < 0.05) after MI. MRI also revealed improved wall thickness (34.7% ± 3.2% vs. 21.8% ± 2.9%; p < 0.05) associated with a diminished akinetic area (13.8% ± 4.0% vs. 37.3% ± 5.6%; p < 0.01). Trichrome staining confirmed less collagen scar formation in the PPG-treated group (12.7% ± 1.4% vs. 21.9% ± 3.9%; p < 0.05). Flow cytometry showed fewer peripheral blood monocytes in MI + PPG than in MI 2 days after treatment (4.0% ± 0.7% vs. 12.7% ± 1.2% of total leucocytes; p < 0.05). Immunostaining and western blotting using activation type-specific markers CCR2 and MRC1 demonstrated that the number of alternatively activated macrophages within the infarct zone increased, whereas the overall number was reduced after PPG treatment. PPG led to increased expression of VEGF-α and VEGF-β in THP-1 cells in vitro and increased capillary density in vivo 2 days after MI (MI-PPG: 1071 ± 81/mm² vs. MI: 648 ± 79/mm² (p < 0.05)).

Conclusion: Our results suggest that altering the activation type and distribution of invading macrophages in favor of alternative activation improves cardiac remodeling and function following MI.

Background and Aims: Trimethylamine-N-oxide (TMAO) is recognized as a novel marker and mediator of atherosclerotic cardiovascular disease (ASCVD). Endothelial progenitor cells (EPCs) are crucial for maintaining vascular homeostasis. Impaired EPC numbers and function correlate with increased adverse cardiovascular events. The aim of this study was to decipher the effect of TMAO on late EPCs (LEPCs) and its underlying molecular mechanism.

Methods and Results: In vitro migration and tubulogenic capacities of LEPCs were attenuated by TMAO in a dose-dependent manner, accompanied by inhibition of manganese superoxide dismutase (MnSOD) and mitochondrial damage. TMAO-induced mitochondrial damage provoked proinflammatory responses (increased levels of IL-6, IL-1b, ICAM-1, E-sel, and TNF-α) and autophagic cell death (confirmed by western blot immunofluorescent staining and transmission electron microscopy) in LEPCs. Overexpression of MnSOD through adenovirus transfection reversed TMAO-related LEPCs dysfunction. To study the effect of TMAO on LEPC-mediated vascular repair in vivo, a hind limb ischemia model was established in nude mice, and LEPCs were injected in the ischemic hind limb. Laser Doppler imaging of mouse ischemic hindlimbs at 21 days indicated that TMAO treatment inhibited LEPCs-mediated blood flow recovery, which was restored by MnSOD overexpression. Immunohistology analyses further revealed consistent alterations in capillary density determined by CD31 staining.

Conclusions: TMAO induces mitochondrial damage in LEPCs via MnSOD suppression, which leads to cell dysfunction, proinflammatory activation, and autophagic cell death in vitro and impaired LEPCs-mediated revascularization in vivo. Overexpression of MnSOD restores TMAO-induced LEPCs dysfunction and further enhances LEPC-mediated revascularization in the ischemic hind limbs in nude mice.

Introduction: In clinical practice, patients often avoid or cease statin use due to adverse reactions or noncompliance. To elucidate statin adverse reactions, their variability across diseases, and the factors influencing them, we conducted a high-quality clinical trial–based meta-analysis.

Materials and Methods: Clinical randomized controlled trials involving statins and detailed recording of adverse reactions in the following three databases: PubMed, Embase, and Cochrane Library were included. The retrieval was completed by January 31, 2024. All studies will use the ROB2 scale for bias risk assessment.

Results: We had included a total of 41 studies, involving a collective sample size of 64,728 individuals. In patients with hyperlipidemia, there was no difference in the overall incidence of total adverse events among four types of statins (p = 0.37). Simvastatin 40 mg had fewer statin-related adverse reactions. High-dose statin users experienced no remarkable transaminase elevation 0.00201 (95% CI [0.00004, 0.00398], I² = 33%). Creatine phosphokinase (CK) elevation under three times the upper limit was rare with a rate of 0.0043 (95% CI [0.0011, 0.0075], I² = 27%). Myalgia rates were comparable between high- and moderate-dose statins (p = 0.23). Gastrointestinal symptoms were infrequent with a rate of about 0.02 (95% CI [0.00, 0.01], I² = 52%). For patients with coronary heart disease, pravastatin 40 mg resulted in fewer transaminase elevations (p < 0.01). There is no difference in myalgia rates between moderate- and high-dose statins (p = 0.78). The proportion of myopathy was higher with simvastatin 80 mg compared to other statins. The risk of rhabdomyolysis was dose-dependent (p < 0.01). For heart failure patients, elderly patients showed varying risks of CK elevation, gastrointestinal symptoms, and muscle symptoms (I² = 71%, 99%, and 99%, respectively). For patients with acute coronary syndrome or acute stroke, the rates of transaminase elevation were higher with simvastatin 40 mg and atorvastatin 80 mg compared to other statins (p < 0.01). There is no difference in myalgia rates between rosuvastatin 20 mg and atorvastatin 80 mg (p = 0.20). However, the rate of myalgia with atorvastatin 80 mg was higher than that of rosuvastatin 10 mg and atorvastatin 20 mg (p < 0.01). For diabetic patients, there was no difference in the effect on transaminases among four statin medications: rosuvastatin 10 and 40 mg, simvastatin 40 mg, and atorvastatin 80 mg (0.00058, 95% CI [0.00000, 0.00464], I² = 0%). Additionally, there was no difference in the rates of myalgia among atorvastatin 10, 40, and 80 mg and rosuvastatin 20 and 40 mg (p = 0.05).

Conclusion: Statins’ adverse reactions differ across populations. For t