Cardiovascular Therapeutics

Purpose. An arteriovenous fistula (AVF) is the preferred vascular access mode for maintenance hemodialysis, and access stenosis and thrombosis are the primary causes of AVF dysfunction. This study is aimed at exploring the molecular mechanisms underlying AVF development and the roles of the heme oxygenase 1/peroxisome proliferator-activated receptor gamma (HO-1/PPAR-γ) pathway in AVF. Method. AVF model mice were established, and the vascular tissues from the arteriovenous anastomosis site were sent for mRNA sequencing. Differentially expressed mRNAs (DEmRNAs) were screened and subjected to functional analysis. Thereafter, the mice with HO-1 knockdown and coprotoporphyrin IX chloride (COPP) pretreatment were used to investigate the roles of the HO-1/PPAR-γ pathway in AVF. Results. By sequencing, 2514 DEmRNAs, including 1323 upregulated and 1191 downregulated genes, were identified. These DEmRNAs were significantly enriched in the PPAR signaling pathway, AMPK signaling pathway, glucagon signaling pathway, IL-17 signaling pathway, and Toll-like receptor signaling pathway. High expression of HO-1 and PPAR-γ reduced endothelial damage and intimal hyperplasia during AVF maturation. After AVF was established, the levels of transforming growth factor-β (TGF-β), interleukin-1β (IL-1β), interleukin-18 (IL-18), and reactive oxygen species (ROS) were significantly increased (), and HO-1 normal expression and COPP pretreatment evidently decreased their levels in AVF (). Additionally, AVF significantly upregulated HO-1 and PPAR-γ and downregulated MMP9, and COPP pretreatment and HO-1 normal expression further upregulated and downregulated their expression. Conclusion. The HO-1/PPAR-γ pathway may suppress intimal hyperplasia induced by AVF and protect the intima of blood vessels by regulating MMP9 and ROS, thus mitigating AVF dysfunction.

Background. Rivaroxaban and apixaban are the most widely used nonvitamin K oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE). This meta-analysis evaluates the effectiveness and safety of both NOACs versus standard of care (SoC) in real-world practice. Methods. Real-world evidence (RWE) studies were identified through a systematic literature review conducted between January 2012 and July 2020, using Embase, MEDLINE, and the websites of cardiological, hematological, and oncological associations. Eligible RWE studies recruited adult patients with deep vein thrombosis and/or pulmonary embolism and presented a comparison between rivaroxaban and apixaban versus SoC, consisting either of vitamin K antagonists, heparins, or combinations thereof. Hazard ratios (HRs) for the comparison between NOACs and SoC were extracted from the relevant studies or estimated based on the reported binary data. The between-treatment contrasts were reported as HRs with associated 95% confidence intervals. Results. A total of 65 RWE studies were identified and considered relevant for the meta-analysis. Compared with SoC, both rivaroxaban and apixaban were associated with reduced risks of recurrent VTE and a lower rate of major bleeding events. Patients treated with rivaroxaban were at a lower risk of all-cause death compared with those receiving SoC ( [0.39-0.80]), while evidence for apixaban from the identified studies was insufficient to demonstrate a statistically significant change in mortality ( [0.30-1.47]). Conclusion. This analysis indicates that in real-world practice, rivaroxaban and apixaban are associated with a lower risk of recurrent VTE and major bleeding events compared with SoC. Survival benefit in patients treated with rivaroxaban was also observed.

Objective. The purpose of this study is to compare the effects of high-intensity interval training (HIIT) versus moderate-intensity continuous training (MICT) on exercise capacity and several prognostic markers in patients with coronary artery disease (CAD) and heart failure (HF). Methods. This systematic review is registered on the INPLASY website (number: INPLASY202080112). We conducted a comprehensive search in eight databases of literature before September 13, 2019. Trials comparing HIIT and MICT in participants with CAD or HF aged 52–78 years were included. Exercise capacity (peak oxygen consumption (peak VO₂)) and prognostic markers, such as the anaerobic threshold (AT), minute ventilation/carbon dioxide production (VE/VCO₂) slope, left ventricular ejection fraction (LVEF), and prognostic value of the predicted VO₂ max per cent (the predicted VO₂ peak (%)) were examined. Results. A total of 15 studies were included comprising 664 patients, 50% of which were male, with an average age of years. For patients with CAD, HIIT significantly improved peak VO₂ values (95% CI 0.7 to 2.11) compared with MICT, but peak VO₂ values in patients with HF did not seem to change. For training lasting less than eight weeks, HIIT significantly improved peak VO₂ values (95% CI 0.70 to 2.10), while HIIT lasting 12 weeks or longer resulted in a modestly increased peak VO₂ value (95% CI 0.31 to 5.31). High-intensity interval training significantly increased the AT when compared with MICT (95% CI 0.50 to 1.48). High-intensity interval training also caused a moderate increase in LVEF (95% CI 0.55 to 5.71) but did not have a significant effect on the VE/VCO₂ slope (95% CI −2.32 to 0.98) or the predicted VO₂ peak (95% CI −2.54 to 9.59) compared with MICT. Conclusions. High-intensity interval training is an effective therapy for improving peak VO₂ values in patients with CAD. High-intensity interval training in the early stage (eight weeks or fewer) is superior to MICT. Finally, HIIT significantly improved prognostic markers, including the AT and LVEF in patients with CAD and HF.

Background. Inflammation is a critical factor in the development and progression of myocardial infarction and cardiac fibrosis. Thymosin β4 (Tβ4) alleviates the disease process via protective antioxidant and anti-inflammatory mechanisms. Although Tβ4 has been shown to have a protective effect in myocardial infarction, its impact on cardiac fibrosis has not been well reported. In this study, we evaluated the influence of exogenous Tβ4 on myocardial infarction and cardiac fibrosis and explored the possible underlying mechanism. Methods. Real-time quantitative reverse-transcription PCR (qRT-PCR), immunohistochemistry (IHC), and Western blot were used to analyze Tβ4 expression in acute myocardial infarction (AMI) cardiac tissues. The effects of intraperitoneal adeno-associated virus-Tβ4 (AAV-Tβ4) on ligation-induced AMI in mice were studied using cardiac function parameters, and RT-PCR, Western blot, HE staining, Masson staining, and IHC were used to assess the degree of myocardial fibrosis. The effects of Tβ4 were confirmed in vitro using mouse cardiac myocytes and myofibroblasts. Results. Tβ4 was shown to be significantly elevated in mice AMI cardiac tissues. In mice, AAV-Tβ4 induced exogenous expression of Tβ4 significantly reduced oxidative damage, inflammation, cardiac dysfunction, and fibrosis. H₂O₂ inhibited mitophagy and increased inflammation in mouse cardiac myocytes via oxidative stress, and Tβ4 substantially reduced mitophagy inhibition and inflammasome activation in myocytes caused by H₂O₂. Furthermore, Tβ4 decreased cardiac myofibroblast growth and reduced TGF-β1-induced activation. Conclusions. AAV-Tβ4 induced expression of Tβ4 reduced inflammation, heart damage, and eventual fibrosis in vivo. Tβ4 helped to reduce oxidative stress, promote mitophagy, and alleviate inflammation and fibrosis. Exogenous supplementation of Tβ4 might be a promising therapeutic agent for treating myocardial infarction as well as cardiac fibrosis.

Reperfusion therapy, the standard treatment for acute myocardial infarction (MI), can trigger necrotic death of cardiomyocytes and provoke ischemia/reperfusion (I/R) injury. However, molecular mechanisms that regulate cardiomyocyte death remain largely unknown. The abnormal expression of lncRNA MIR22HG has been found in types of diseases. The current study was aimed at exploring the function and mechanism of MIR22HG in I/R injury. In this study, mouse myocardial cells (HL-1) treated with oxygen-glucose deprivation and reoxygenation (OGD/R) were used as the in vitro models, and myocardial ischemia reperfusion injury (MIRI) animal models in vivo were established in male C57BL/6 mice. Experiments including CCK-8, flow cytometry, TUNEL, HE staining, RT-qPCR, western blotting, and luciferase reporter assays were performed to explore the function and potential mechanism of MIR22HG in MIRI in vitro and in vivo. Bioinformatics analysis was performed to predict the binding site between miR-9-3p and MIR22HG (or SH2B3). Our results indicated that the MIR22HG level was upregulated in cardiomyocytes after OGD/R treatment. The knockdown of MIR22HG promoted cell viability and inhibited apoptosis and extracellular matrix (ECM) production in OGD/R-treated HL-1 cells. In mechanism, MIR22HG binds to miR-9-3p, and miR-9-3p targets the SH2B3 3 untranslated region (UTR). Moreover, SH2B3 expression was positively regulated by MIR22HG but negatively modulated by miR-9-3p. Rescue assays suggested that the suppressive effect of MIR22HG knockdown on cell viability, apoptosis, and ECM accumulation was reversed by the overexpression of SH2B3. The in vivo experiments demonstrated that MIR22HG knockdown alleviated cardiomyocyte apoptosis and reduced myocardial infarct size in MIRI mice. In summary, MIR22HG knockdown alleviates myocardial injury through the miR-9-3p/SH2B3 axis.

Background. Multiple studies and meta-analyses examined the role of traditional risk factors for cardiovascular events in statin treatment-naive patients. Nowadays, millions receive such therapy for the primary prevention of cardiovascular events (CVE). Objective. CVEs still occur in patients on primary preventive statin therapy. Therefore, further risk stratification within these patients is urgently needed. Methods. Using the unique linkage between biomedical data and prescription data from the PharmLines Initiative, we assessed the role of several risk factors used in cardiovascular risk models, using a time-dependent Cox PH model, in the occurrence of drug treatment of CVEs after initiation of statin therapy. Results. Among 602 statin therapy starters, 11% received drug treatment for CVE within an average follow-up period of 832 days. After multivariable modelling, cholesterol levels and blood pressure at baseline were no longer associated, whereas self-reported diabetes and increasing age were highly associated with the outcome when on statin therapy (hazard ratio (HR): 3.01, 95% confidence interval (95% CI): 1.48-6.12 and 1.04; 95% CI: 1.01-1.07, respectively). Males, smokers, and nonadherent patients had increased risks (HR 1.6, 1.12, and 1.18, resp.), though not statistically significant. Conclusion. Drug treatment for CVEs after statin initiation is increased in patients with diabetes type 2, in aged patients, males, smokers, and those with poor adherence, while there was no association with baseline cholesterol levels and blood pressure. These factors should be taken into account during the monitoring of statin therapy and may lead to changes in statin treatment or risk-related lifestyle factors.