Cardiovascular Drugs and Therapy最新文献

Background: Rapid development in coronary chronic total occlusion (CTO) interventional techniques and devices have achieved a greater success rate with favorable outcomes. Antegrade dissection re-entry (ADR) technique is an important CTO crossing strategy and a desirable approach for long CTOs with good distal landing zone. However, unsuccessful procedures in contemporary CTO-percutaneous coronary intervention (PCI) remain, especially in lesions with non-interventional collaterals.

Method: Based on a single center experience, a hybrid interventional algorithm, parallel wire-based ADR (PW-ADR) combines the advantages of parallel wire technique (PWT) and device-based ADR to target CTO lesions with failed retrograde approach. A retrospective analysis of patients who underwent PW-ADR was performed. A risk nomogram was created to identify patients at high risk for technical failure.

Results: A total of 57 patients treated with PW-ADR were ultimately included in the present study. A total of 46 (80.7%) cases achieved technical success and procedural success, with low incidence of in-hospital complications or 1-year major adverse cardiac events (MACE). The risk nomogram identified 3 predictor variables associated with technical failure of PW-ADR, including tortuous vessel, J-CTO score, and times of antegrade coronary angiography (CAG) during ADR, with promising accuracy (AUROC 0.947).

Conclusion: The novel hybrid CTO-PCI algorithm, PW-ADR, provided an alternative interventional approach for complex CTO lesions with a promising success rate. The risk nomogram served as a prompter for high-risk cases, which may warrant a change in treatment strategy.

Background: Myocardial infarction remains a disease with high morbidity and death rate among cardiovascular diseases. Macrophages are abundant immune cells in the heart. Under different stimulatory factors, macrophages can differentiate into different phenotypes and play a dual pro-inflammatory and anti-inflammatory role. Therefore, a potential strategy for the treatment of myocardial infarction is to regulate the energy metabolism of macrophages and thereby regulate the polarization of macrophages. Tan IIA is an effective liposolubility component extracted from the root of Salvia miltiorrhiza and plays an important role in the treatment of cardiovascular diseases. On this basis, this study proposed whether Tan IIA could affect phenotype changes by regulating energy metabolism of macrophages, and thus exert its potential in the treatment of MI.

Methods: Establishing a myocardial infarction model, Tan IIA was given for 3 days and 7 days for intervention. Cardiac function was detected by echocardiography, and cardiac pathological sections of each group were stained with HE and Masson to observe the inflammatory cell infiltration and fibrosis area after administration. The expression and secretion of inflammatory factors in heart tissue and serum of each group, as well as the proportion of macrophages at the myocardial infarction site, were detected using RT-PCR, ELISA, and immunofluorescence. The mitochondrial function of macrophages was evaluated using JC-1, calcium ion concentration detection, reactive oxygen species detection, and mitochondrial electron microscopic analysis. Mechanically, single-cell transcriptome data mining, cell transcriptome sequencing, and molecular docking technology were used to anchor the target of Tan IIA and enrich the pathways to explore the mechanism of Tan IIA regulating macrophage energy metabolism and phenotype. The target of Tan IIA was further determined by gene knockdown and overexpression assay.

Results: The intervention of Tan IIA can improve the cardiac function, inflammatory cell infiltration and fibrosis after MI, reduce the expression of inflammatory factors in the heart, enhance the secretion of anti-inflammatory factors, increase the proportion of M2-type macrophages, reduce the proportion of M1-type macrophages, and promote tissue repair, suggesting that Tan IIA has pharmacological effects in the treatment of MI. In terms of mechanism, RNA-seq results suggest that the phenotype of macrophages is strongly correlated with energy metabolism, and Tan IIA can regulate the PGK1-PDHK1 signaling pathway, change the energy metabolism mode of macrophages, and then affect its phenotype.

Conclusion: Tan IIA regulates the energy metabolism of macrophages and changes its phenotype through the PGK1-PDHK1 signaling pathway, thus playing a role in improving MI.

Background and purpose: The purpose of this study was to evaluate the association between different antiplatelet therapy regimens and the functional outcomes and bleeding complications among mild-to-moderate ischaemic stroke patients based on real-world data.

Methods: We used data from the SEACOAST trial (Safety and efficacy of aspirin-clopidogrel in acute noncardiogenic minor ischaemic stroke) to analyse the data of patients with mild-to-moderate stroke within 72 h after onset who were treated with aspirin or clopidogrel alone or a combination of clopidogrel and aspirin from September 2019 to November 2021. Propensity score matching (PSM) was used to balance the differences between groups. We performed an analysis to evaluate the association of different antiplatelet regimens and 90-day disability, which was defined as a modified Rankin Scale score ≥2, as well as disability ascribed to index or recurrent stroke by the local investigator. In terms of safety, we then compared the bleeding events between the two groups.

Results: A total of 2822 mild-to-moderate ischaemic stroke patients were treated with either clopidogrel plus aspirin (n = 1726, 61.2%) or aspirin/clopidogrel (n = 1096, 38.8%). Of 1726 patients in the dual antiplatelet group, 1350 (78.5%) received less than or equal to 30 days of combined therapy. At 90 days, 433 (15.3%) patients were disabled. Patients who received combined therapy had a lower overall disability rate (13.7% versus 17.9%; OR 0.78 (0.6-1.01); P = 0.064). However, investigators found that index stroke was the reason for significantly fewer patients in the dual antiplatelet group having disability (8.4% versus 12%; OR, 0.72 (0.52-0.98); P = 0.038). There was no statistically significant difference in the incidence of moderate to severe bleeding complications between the dual and mono antiplatelet drug regimens (0.4% versus 0.2%; HR 1.5 (0.25, 8.98); P = 0.657).

Conclusion: Aspirin plus clopidogrel was associated with a reduction in the incidence of disability attributed to index stroke. There was no statistically significant difference in the incidence of moderate to severe bleeding complications between the two antiplatelet drug regimens.

Trial registration number: ChiCTR1900025214.

Background: Atorvastatin and direct oral factor Xa inhibitors (for instance, rivaroxaban) are co-administrated in patients with atrial fibrillation. However, no studies have been conducted on the function of these two agents in acute pulmonary embolism (APE). Therefore, we investigated the effects of rivaroxaban + atorvastatin in rats with APE and explored the underlying mechanisms.

Methods: Patients with APE were enrolled, and rats with APE were generated for different regimens. The mean pulmonary arterial pressure (mPAP), heart rate, and PaO₂ of APE patients and rats were measured. The plasma levels of oxidative stress- and inflammation-related factors were measured, and the expression of platelet activation markers (CD63 and CD62P) was detected. The proteins targeted by rivaroxaban and atorvastatin, the targets associated with APE, and the genes aberrantly expressed in rats with APE were intersected to obtain candidate factors.

Results: Rivaroxaban + atorvastatin reduced mPAP and increased PaO₂ in patients and rats with APE. Rivaroxaban + atorvastatin repressed oxidative stress, inflammatory levels, and platelet activation during APE. NRF2 and NQO1 were increased in the lung of rats treated with rivaroxaban + atorvastatin. The therapeutic effect of the combination on APE rats was suppressed after NRF2 downregulation. NRF2 promoted the NQO1 transcription. NQO1 eliminated the inhibitory effect of sh-NRF2 on the combined therapy.

Conclusion: The alleviating effect of rivaroxaban + atorvastatin administration against APE correlates with NRF2/NQO1 expression.

Aims: Myocardial infarction (MI) is a major cause of death. Nicotinamide adenine dinucleotide (NAD⁺) is a coenzyme in oxidative phosphorylation and substrate of sirtuins and poly-ADP ribose polymerases, enzymes critical for cardiac remodeling post-MI. Decreased NAD⁺ is reported in several heart failure models with paradoxically an upregulation of nicotinamide riboside kinase 2, which uses nicotinamide riboside (NR) as substrate in an NAD⁺ biosynthetic pathway. We hypothesized that stimulating nicotinamide riboside kinase 2 pathway by NR supplementation exerts cardioprotective effects.

Methods and results: MI was induced by LAD ligation in 2-3-month-old male mice. NR was administered daily (1 µmole/g body weight) over 7 days. RT-PCR showed a 60-fold increase in nicotinamide riboside kinase 2 expression 4 days post-MI with a 60% drop in myocardial NAD⁺ and overall survival of 61%. NR restored NAD⁺ levels and improved survival to 92%. Assessment of respiration in cardiac fibers revealed mitochondrial dysfunction post-MI, and NR improved complexes II and IV activities and citrate synthase activity, a measure of mitochondrial content. Additionally, NR reduced elevated PARP1 levels and activated a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response.

Conclusion: Our data show that nicotinamide riboside could be useful for MI management.

Background: Drug-coated balloons (DCB) can be used as an alternative to drug-eluting stents (DES) in patients with de novo small vessel coronary artery disease. This study aims to assess the efficacy and safety of solely using DCB versus DES in percutaneous coronary intervention (PCI) for de novo coronary lesions in large vessels.

Method: A database search was conducted using PubMed, EMBASE, Cochrane Library, and http://Clinicaltrials.gov for trials comparing DCB only with DES in treating de novo coronary lesions in large vessels. Efficacy outcomes included coronary angiography (CAG), follow-up minimal lumen diameter (MLD), and late luminal loss (LLL). Safety outcomes included target lesion failure [TLF: cardiac death, myocardial infarction (MI), target lesion revascularization (TLR)] and their individual components.

Results: We included seven randomized control trials (RCTs) with 816 patients, of which 422 and 394 patients were in the DCB and DES groups, respectively. MLD measured during the 6-12 months follow-up in the DCB group was statistically significantly smaller than in the DES group (MD -0.21, 95% CI -0.34 to -0.07, P = 0.003, I² = 52%). LLL measured at 6-12 months follow-up was statistically significantly lower in the DCB group than in the DES group (MD -0.13, 95% CI -0.22 to -0.05, P = 0.003, I² = 60%). TLF, cardiac death, MI, and TLR, were not statistically significantly different between the two groups.

Conclusion: Use of DCB was associated with less LLL at 6-12 months than DES and was not associated with any increase in adverse clinical events. This data suggests DCB are as effective in treating de novo coronary lesions in large vessels as DES.

Background: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by continuous constriction and occlusion of small pulmonary arteries, leading to the development of right ventricular failure and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a kind of serine protease enzyme that increases low-density lipoprotein cholesterol (LDLC) levels through degrading low-density lipoprotein cholesterol receptors (LDLr). However, whether inhibition of PCSK9 can alleviate PAH has not been reported.

Methods and results: We reported that PCSK9 expression was up-regulated in lung tissues of PAH patients. In addition, we used PCSK9 monoclonal antibody subcutaneously to inhibit PCSK9 expression in mice exposed to chronic hypoxia (10%) in combination with SU5416, a VEGF receptor inhibitor. Hypoxia plus SU5416-induced PAH was attenuated in PCSK9 monoclonal antibody-treated mice compared with wild-type mice. PCSK9 inhibited pulmonary vascular remodeling in mice. Moreover, PCSK9 knockdown significantly altered the proliferation and migration of hypoxia-induced PASMCs. We also found that PCSK9 monoclonal antibody inhibited Notch3 expression in vivo and in vitro.

Conclusion: Our results suggest that the PCSK9-Notch3 signaling pathway is critical for the proliferation and migration of PASMCs and provides a potential drug target for the treatment of PAH.

Purpose: To investigate the association between statins and muscle problems in a highly diverse sample of Brazilian civil servants.

Methods: We conducted a cross-sectional data analysis at baseline of the ELSA-Brasil MSK cohort. Pain was identified through self-reported symptoms in large muscle groups (lower back and/or hips/thighs). Muscle strength was assessed using the five-times-sit-to-stand (FTSTS) and handgrip tests, with weakness defined as the lowest and highest quintiles of age- and sex-stratified handgrip strength and FTSTS performance time, respectively. Multivariable logistic regression analyses were conducted to investigate the association between statin use and muscle pain and weakness. Secondary analyses explored the impact of different types of statins and their duration of use on the response variables.

Results: A total of 2156 participants (mean age 55.6 ± SD 8.9, 52.8% women) were included, of whom 21.1% were taking statins and 25.1% reported muscle pain. We found no significant association between statin use and muscle problems. Secondary analysis on different types of statins revealed an association between atorvastatin and muscle weakness, as measured by the five-times-sit-to-stand test (OR 1.94, 95% CI 1.12-3.37), but not by the handgrip test (OR 0.75, 95% CI 0.29-1.42). No evidence was found to support a link between the duration of statin treatment and muscle problems.

Conclusions: This study challenges previous claims of an efficacy-effectiveness gap between experimental and observational literature on statins. The findings indicate that statin use does not contribute to muscular problems.

In health, the human heart is able to match ATP supply and demand perfectly. It requires 6 kg of ATP per day to satisfy demands of external work (mechanical force generation) and internal work (ion movements and basal metabolism). The heart is able to link supply with demand via direct responses to ADP and AMP concentrations but calcium concentrations within myocytes play a key role, signalling both inotropy, chronotropy and matched increases in ATP production. Calcium/calmodulin-dependent protein kinase (CaMKII) is a key adapter to increased workload, facilitating a greater and more rapid calcium concentration change. In the failing heart, this is dysfunctional and ATP supply is impaired. This review aims to examine the mechanisms and pathologies that link increased energy demand to this disrupted situation. We examine the roles of calcium loading, oxidative stress, mitochondrial structural abnormalities and damage-associated molecular patterns.