Unraveling the pharmacodynamic substances and possible mechanism of Trichosanthis Pericarpium in the treatment of coronary heart disease based on plasma pharmacochemistry, network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Coronary heart disease (CHD) is a chronic disease that seriously threatens people's health and even their lives. Currently, there is no ideal drug without side effects for the treatment of CHD. Trichosanthis Pericarpium (TP) has been used for several years in the treatment of diseases associated with CHD. However, there is still a need for systematic research to unravel the pharmacodynamic substances and possible mechanism of TP in the treatment of coronary heart. AIM OF THE STUDY: The purpose of current study was to explore the pharmacodynamic substances and potential mechanisms of TP in the treatment of CHD via integrating network pharmacology with plasma pharmacochemistry and experimental validation. MATERIALS AND METHODS: The effect of TP intervention in CHD was firstly assessed on high-fat diet combined with isoprenaline-induced CHD rats and H2O2-induced H9c2 cells, respectively. Then, the LC-MS was utilized to identify the absorbed components of TP in the plasma of CHD rats, and this was used to develop a network pharmacology prediction to obtain the possible active components and mechanisms of action. Molecular docking and immunohistochemistry were used to explore the interaction between TP and key targets. Subsequently, the efficacy of the active ingredients was investigated by in vitro cellular experiments, and their metabolic pathways in CHD rats were further analyzed. RESULTS: The effects of TP on amelioration of CHD were verified by in vivo and in vitro experiments. Plasma pharmacochemistry and network pharmacology screened six active components in plasma including apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin. The interaction of these compounds with potential key targets AKT1, IL-1ß, IL-6, TNF-α and VEGFA were preliminarily verified by molecular docking. And immunohistochemical results showed that TP reduced the expression of AKT1, IL-1ß, IL-6, TNF-α and VEGFA in CHD rat hearts. Then cellular experiments confirmed that apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin were able to reduce the ROS level in H2O2-induced HUVEC cells and promote the migration and tubule formation of HUVEC cells, indicating the pharmacodynamic effects of the active components. Meanwhile, the metabolites of TP in CHD rats suggested that the pharmacological effects of TP might be the result of the combined effects of the active ingredients and their metabolites. CONCLUSION: Our study found that TP intervention in CHD is characterized by multi-component and multi-target regulation. Apigenin, phenylalanine, linoleic acid, quercetin, luteolin, and tangeretin are the main active components of TP. TP could reduce inflammatory response and endothelial damage by regulating AKT1, IL-1ß, IL-6, TNF-α and VEGFA, reduce ROS level to alleviate the oxidative stress situation and improve heart disease by promoting angiogenesis to regulate endothelial function. This study also provides an experimental and scientific basis for the clinical application and rational development of TP.

Exploring the Mechanism of Si-miao-yong-an Decoction in the Treatment of Coronary Heart Disease based on Network Pharmacology and Experimental Verification.

BACKGROUND: To investigate the active ingredients and the mechanisms of Si-miaoyong- an Decoction (SMYA) in the treatment of coronary heart disease (CHD) by using network pharmacology, molecular docking technology, and in vitro validation. METHODS: Through the Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), Uniprot database, GeneCards database, and DAVID database, we explored the core compounds, core targets and signal pathways of the effective compounds of SMYA in the treatment of CHD. Molecular docking technology was applied to evaluate the interactions between active compounds and key targets. The hypoxia-reoxygenation H9C2 cell model was applied to carry out in vitro verification experiments. A total of 109 active ingredients and 242 potential targets were screened from SMYA. A total of 1491 CHD-related targets were retrieved through the Gene- Cards database and 155 overlapping CHD-related SMYA targets were obtained. PPI network topology analysis indicated that the core targets of SMYA in the treatment of CHD include interleukin- 6 (IL-6), tumor suppressor gene (TP53), tumor necrosis factor (TNF), vascular endothelial growth factor A (VEGFA), phosphorylated protein kinase (AKT1) and mitogen-activated protein kinase (MAPK). KEGG enrichment analysis demonstrated that SMYA could regulate Pathways in cancer, phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathway, hypoxiainducible factor-1(HIF-1) signaling pathway, VEGF signaling pathway, etc. Results: Molecular docking showed that quercetin had a significant binding activity with VEGFA and AKT1. In vitro studies verified that quercetin, the major effective component of SMYA, has a protective effect on the cell injury model of cardiomyocytes, partially by up-regulating expressions of phosphorylated AKT1 and VEGFA. CONCLUSION: SMYA has multiple components and treats CHD by acting on multiple targets. Quercetin is one of its key ingredients and may protect against CHD by regulating AKT/VEGFA pathway.

Mechanism of Lingbao Huxin Dan in the treatment of bradyarrhythmia complicated with coronary heart disease: a network pharmacology analysis.

OBJECTIVE: To investigate the mechanism of action of the Lingbao Huxin Dan in treating bradycardia arrhythmia with coronary heart disease (BA-CHD) by network pharmacology. METHODS: The active ingredients of the Lingbao Huxin Dan were screened on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Bioinformatics tools designed for the analysis of molecular mechanisms of Chinese medicine platform; target prediction was conducted with the SwissTargetPrediction database, and Cytoscape 3.8 was used to construct a drug ingredient-target network. The Genecards, Online Mendelian Inheritance in Man, and DrugBank databases were searched for disease targets. Venn plots were used to display the common targets of BA-CHD and active ingredients. The STRING platform was used to construct a protein-protein interaction network. The Metascape data platform was used for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to construct a signaling pathway network of the active ingredients of the Lingbao Huxin Dan. RESULTS: There were 121 active ingredients, 899 related targets, 39 targets important in BA-CHD and 14 targets which intersected between the active ingredients and BA-CHD. There were 27 core therapeutic ingredients, 153 biological processes, 18 cell ingredients and 20 molecular functions obtained by GO enrichment analysis. The KEGG pathway analysis yielded 19 signaling pathways. CONCLUSION: RBA-CHD may treat BA-CHD by regulating adrenergic receptor beta-1, alpha 1-α adrenergic receptor, calcium voltage-gated channel subunit alpha1 C, alpha-1ß-adrenergic receptor, nitric oxide synthase 2, beta-2 adrenergic receptor, voltage-dependent calcium channel subunit alpha-2/delta-1, an- giotensin-converting enzyme, Raf-1 proto-oncogene serine/threonine-protein kinase, and other targets, potentially by affecting adrenergic receptor binding and calcium channel opening, to regulate the activity of cardiomyocytes.

Pharmacokinetics integrated with network pharmacology to clarify effective components and mechanism of Wendan decoction for the intervention of coronary heart disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Coronary heart disease (CHD), one of the leading causes of mortality in the world among chronic non-infectious diseases, is closely associated with atherosclerosis, which ultimately leads to myocardial injury. Wendan decoction (WDD), a classical famous formula, exerted an intervention effect on CHD according to numerous reports. However, the effective components and underlying mechanisms for the treatment of CHD have not been fully elucidated. AIM OF THE STUDY: An in-depth investigation of the effective components and mechanisms of WDD for the intervention of CHD was further explored. MATERIALS AND METHODS: Firstly, based on our previous metabolic profile results, a quantification method for absorbed components was established by ultra-performance liquid chromatography triple quadrupole-mass spectrometry (UPLC-TQ-MS) and applied to the pharmacokinetics study of WDD. Then the network pharmacology analysis for considerable exposure components in rat plasma was employed to screen key components of WDD. Gene ontology and KEGG pathway enrichment analysis were further performed to obtain putative action pathways. The effective components and mechanism of WDD were confirmed by in vitro experiments. RESULTS: A rapid and sensitive quantification method was successfully applied to the pharmacokinetic study of 16 high-exposure components of WDD at three different doses. A total of 235 putative CHD targets were obtained for these 16 components. Then, 44 core targets and 10 key components with high degree values were successively screened out by the investigation of protein-protein interaction and the network of "herbal medicine-key components-core targets". Enrichment analysis suggested that the PI3K-Akt signaling pathway was closely related to this formula's therapeutic mechanism. Furthermore, pharmacological experiments demonstrated that 5 of 10 key components (liquiritigenin, narigenin, hesperetin, 3,5,6,7,8,3',4'-heptamethoxyflavone, and isoliquiritigenin) significantly enhanced DOX-induced H9c2 cell viability. The cardioprotective effects of WDD against DOX-induced cell death through the PI3K-Akt signaling pathway were verified by western blot experiments. CONCLUSION: The integration of pharmacokinetics and network pharmacology approaches successfully clarified 5 effective components and therapeutic mechanism of WDD for the intervention of CHD.

Mechanisms of Xuefu Zhuyu Decoction in the treatment of coronary heart disease based on integrated metabolomics and network pharmacology approach.

Coronary heart disease (CHD) has become the leading cause of mortality, morbidity, and disability worldwide. Though the therapeutic effect of Xuefu Zhuyu Decoction (XFZY) on CHD has been demonstrated in China, the active ingredients and molecular mechanisms of XFZY have not been elucidated. The purpose of the current study is to explore the molecular mechanisms of XFZY in the treatment of CHD via network pharmacology, metabolomics, and experimental validation. First, we established a CHD rat model by permanently ligating the left anterior descending coronary artery (LAD), and evaluated the therapeutic effect of XFZY by hemorheology and histopathology. Second, network pharmacology was employed to screen the active ingredients and potential targets of XFZY for the treatment of CHD. Metabolomic was applied to identify the molecules present in the serum after XFZY treatment. Third, the results of network pharmacology and metabolomics were further analyzed by Cytoscape to elucidate the core ingredients and pathways. Finally, the obtained key pathways were verified by transmission electron microscopy and immunofluorescence assay. The results showed that XFZY was effective in the treatment of CHD in the rat model, and the highest dose exerted the best effect. Network pharmacology analysis revealed 215 active ingredients and 129 key targets associated with XFZY treatment of CHD. These targets were enriched in pathways of cancer, lipid and atherosclerosis, fluid shear stress and atherosclerosis, proteoglycans in cancer, chemical carcinogenesis - receptor activation, HIF-1 signaling, et al. Serum metabolomic identified 1081 metabolites involved in the therapeutic effect of XFZY on CHD. These metabolites were enriched in taurine and hypotaurine metabolism, histidine metabolism, retrograde endocannabinoid signaling pathways, et al. Cytoscape analysis combining the data from serum metabolomic and network pharmacology revealed that energy metabolism as the core pathway for XFZY treatment of CHD. Electron microscope observation identified changes in the level of autophagy in the mitochondrial structure of cardiomyocytes. Immunofluorescence assay showed that the expression levels of autophagy-related proteins LC3-B and P62/SQSTM1 were consistent with the levels of autophagy observed in mitochondria. In conclusion, our findings suggest that the possible mechanisms of XFZY in the treatment of CHD are reducing the level of autophagy, improving energy metabolism, and maintaining mitochondrial homeostasis in cardiomyocytes. Our study also shows that the combined strategies of network pharmacology, metabolomics, and experimental validation may provide a powerful approach for TCM pharmacology study.

The efficacy of sodium ferulate combination therapy in coronary heart disease: A systematic review and meta-analysis.

BACKGROUND: Sodium ferulate (SF), a derivative of ferulic acid, is one of the active constituents in medicinal plants thought to be useful in fighting cardiovascular diseases. However, there still lacks a systematic review of the efficacy and safety of SF in treating coronary heart disease (CHD). It is therefore the purpose of this study to comprehensively review all clinical randomized controlled trials (RCTs) of SF in CHD to assess its efficacy and safety. METHODS: All analysis is based on 8 databases as of February 2023, which includes 35 outcomes of RCTs that investigate the effect of SF combination therapy in CHD. The present study evaluates the quality and bias of selected literature by the Jadad scale and Cochrane Collaboration's tools, and also the quality of evidence by GRADE Profiler. Furthermore, it applies sensitivity analysis to assess the high heterogeneity impact of outcomes and conducted subgroup analysis to estimate the influence factors in these studies. The study protocol was set documented, and published beforehand in PROSPERO (Registration No.CRD42022348841). RESULTS: The meta-analysis of 36 studies (with 3207 patients) shows that SF combined with conventional drugs has improved clinical effectiveness for patients with CHD [RR: 1.21 (95% CI 1.17,1.26); p < 0.00001]. Statistically significant results of meta-analyses are also seen in electrocardiography (ECG) efficacy, frequency of angina attacks, endothelium-dependent flow-mediated vasodilation (FMD), nitric oxide (NO), endothelin (ET), whole Blood low shear rate (LS), platelet aggregation test (PAgT), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL6), triglyceride (TG). Adverse events are reported in 6 RCTs. By GRADE approaches, 2 outcomes (clinical efficacy, CRP) indicate a moderate quality of evidence, 17 outcomes indicate low quality of evidence, with the other 16 very low-quality. CONCLUSION: SF combination therapy has a better curative effect than conventional therapy. However, due to items with low-quality evidence demonstrated in the study, the presence of clinical heterogeneity, and imprecision in partial outcome measures, all these led to limitations in the evidence of this study. Thus, the conclusion needs to be further verified by more in-depth research.

Atorvastatin Metabolite Pattern in Skeletal Muscle and Blood from Patients with Coronary Heart Disease and Statin-Associated Muscle Symptoms.

Self-perceived statin-associated muscle symptoms (SAMS) are prevalent, but only a minority is drug-dependent. Diagnostic biomarkers are not yet identified. The local statin exposure in skeletal muscle tissue may correlate to the adverse effects. We aimed to determine whether atorvastatin metabolites in blood reflect the corresponding metabolite levels in skeletal muscle, and whether genetic variants of statin transporters modulate this relationship. We also addressed atorvastatin metabolites as potential objective biomarkers of SAMS. Muscle symptoms were examined in patients with coronary disease and self-perceived SAMS during 7 weeks of double-blinded treatment with atorvastatin 40 mg/day and placebo in randomized order. A subset of 12 patients individually identified with more muscle symptoms on atorvastatin than placebo (confirmed SAMS) and 15 patients with no difference in muscle symptom intensity (non-SAMS) attended the present follow-up study. All received 7 weeks of treatment with atorvastatin 40 mg/day followed by 8 weeks without statins. Biopsies from the quadriceps muscle and blood plasma were collected after each treatment period. Strong correlations (rho > 0.7) between muscle and blood plasma concentrations were found for most atorvastatin metabolites. The impact of the SLCO1B1 c.521T>C (rs4149056) gene variant on atorvastatin's systemic pharmacokinetics was translated into muscle tissue. The SLCO2B1 c.395G>A (rs12422149) variant did not modulate the accumulation of atorvastatin metabolites in muscle tissue. Atorvastatin pharmacokinetics in patients with confirmed SAMS were not different from patients with non-SAMS. In conclusion, atorvastatin metabolite levels in skeletal muscle and plasma are strongly correlated, implying that plasma measurements are suitable proxies of atorvastatin exposure in muscle tissue. The relationship between atorvastatin metabolites in plasma and SAMS deserves further investigation.

Drivers of mortality in patients with chronic coronary disease in the low-dose colchicine 2 trial.

BACKGROUND: Low-dose colchicine significantly reduces the risk of cardiovascular events in patients with chronic coronary disease. An increase of non-cardiovascular death raised concerns about its safety. This study reports cause-specific mortality and baseline predictors of mortality in the Low-Dose Colchicine 2 (LoDoCo2) trial. METHODS: Patients with chronic coronary disease were randomly allocated to colchicine 0.5 mg once daily or placebo on a background of optimal medical therapy. Cause-specific mortality data were analysed, stratified by treatment status. Multivariate analyses were performed to examine the predictors of mortality as well as cardiovascular and non-cardiovascular death. RESULTS: After a median 28.6 months follow-up, 133 out of 5522 participants (2.4%) died. Forty-five deaths were cardiovascular (colchicine versus placebo: 20 [0.7%] versus 25 [0.9%], HR, 0.80; 95% CI, 0.44-1.44), while eighty-eight deaths were non-cardiovascular (53 [1.9%] versus 35 [1.3%]; HR, 1.51; 95% CI, 0.99-2.31). Forty-eight deaths were due to cancer (26 [0.9%] versus 22 [0.8%]), thirteen end-stage pulmonary disease (9 [0.3%] versus 4 [0.1%]), eight infection (4 [0.1%] versus 4 [0.1%]), five dementia (4 [0.1%] versus 1 [0.0%]) and five related multiple organ failure (3 [0.1%] versus 2 [0.1%]). Multivariable analysis demonstrated age > 65 years was the only independent baseline characteristic associated with non-cardiovascular death (HR, 3.65; 95% CI, 2.06-6.47). CONCLUSIONS: During the LoDoCo2 trial, assignment to colchicine was not associated with an adverse effect on any specific causes of death. Most deaths were related to non-cardiovascular causes, underscoring the importance of comorbidities as drivers of all-cause mortality in patients with chronic coronary disease.

Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision?

Coronary heart disease (CHD) is the leading cause of death around the world. Based on the roles of vascular endothelial growth factor (VEGF) family members to regulate blood and lymphatic vessels and metabolic functions, several therapeutic approaches have been attempted during the last decade. However proangiogenic therapies based on classical VEGF-A have been disappointing. Therefore, it has become important to focus on other VEGFs such as VEGF-B, which is a novel member of the VEGF family. Recent studies have shown the very promising potential of the VEGF-B to treat CHD and heart failure. The aim of this review article is to present the role of VEGF-B in endothelial biology and as a potential therapeutic agent for CHD and heart failure. In addition, key differences between the VEGF-A and VEGF-B effects on endothelial functions are demonstrated.

Influence of genetic polymorphisms in P2Y12 receptor signaling pathway on antiplatelet response to clopidogrel in coronary heart disease.

BACKGROUNDS: Remarkable interindividual variability in clopidogrel response is observed, genetic polymorphisms in P2RY12 and its signal pathway is supposed to affect clopidogrel response in CHD patients. METHODS: 539 CHD patients treated with clopidogrel were recruited. The platelet reaction index (PRI) indicated by VASP-P level were detected in 12-24 h after clopidogrel loading dose or within 5-7 days after initiation of maintain dose clopidogrel. A total of 13 SNPs in relevant genes were genotyped in sample A (239 CHD patients). The SNPs which have significant differences in PRI will be validated in another sample (sample B, 300 CHD patients). RESULTS: CYP2C19*2 increased the risk of clopidogrel resistance significantly. When CYP2C19*2 and CYP2C19*3 were considered, CYP2C19 loss of function (LOF) alleles were associated with more obviously increased the risk of clopidogrel resistance; P2RY12 rs6809699C > A polymorphism was also associated with increased risk of clopidogrel resistance (AA vs CC: P = 0.0398). This difference still existed after stratification by CYP2C19 genotypes. It was also validated in sample B. The association was also still significant even in the case of stratification by CYP2C19 genotypes in all patients (sample A + B). CONCLUSION: Our data suggest that P2RY12 rs6809699 is associated with clopidogrel resistance in CHD patients. Meanwhile, the rs6809699 AA genotype can increase on-treatment platelet activity independent of CYP2C19 LOF polymorphisms.

Revisiting secondary prevention in coronary heart disease.

Secondary prevention in coronary heart disease is the prevention of occurrence of recurrent coronary events after clinical diagnosis. High level of adherence to secondary prevention interventions, especially aggressive lifestyle changes and pharmacotherapy can lead to significant decline in recurrent coronary events. Both international and Indian studies have reported low adherence to such therapies. Evidence-based useful interventions include regular physical activity, yoga, intake of healthy diet, smoking and tobacco use cessation and weight management. Pharmacotherapeutic interventions useful are anti-platelet therapy, target oriented lipid lowering therapy with statins, beta blockers and angiotensin converting enzyme inhibitors in patients with impaired left ventricular function. Hypertension and diabetes management with control to targets is important. Novel strategies include use of anticoagulants, anti-inflammatory drugs, and triglyceride lowering for residual risk. Physician and patient level interventions using multifaceted educational, socioeconomic and technological innovations are important to promote life-long adherence to these strategies.

Adherencia a tratamiento de prevención secundaria post síndrome coronario agudo, en pacientes adultos ingresados al Hospital Hernán Henríquez Aravena / Adherence to secondary prevention after acute coronary syndromes: experience in a chilean general hospital

Antecedentes: En prevención secundaria cardiovascular, el control de los factores de riesgo es deficiente y la falta de adherencia terapéutica parece ser uno de los factores causales. El cumplimiento terapéutico se asocia a un 20% de disminución del riesgo de enfermedad cardiovascular y un 38% de disminución de mortalidad por cualquier causa. Sin embargo, la adherencia a los fármacos preventivos ronda el 50% al año después del alta hospitalaria, lo que multiplica por 3 el riesgo de mortalidad. Objetivos: Describir la adherencia a mediano plazo a tratamiento de prevención secundaria post síndrome coronario agudo de los pacientes adultos ingresados al Hospital Hernán Henríquez Aravena durante el año 2018. Determinar las características clínicas y sociodemográficas de la población y explorar las posibles causas asociadas a la falta de adherencia terapéutica en este grupo de pacientes. Métodos y Resultados: Se evaluaron 396 pacientes con síndrome coronario agudo en el Hospital Hernán Henríquez Aravena de Temuco durante el año 2018. La adherencia a terapia farmacológica se evaluó mediante el cuestionario de Morisky-Green de ocho ítems, aplicado vía telefónica. Se evaluó la asociación de variables clínicas y sociodemográficas con el nivel de adherencia mediante regresión ordinal y análisis de correspondencias. Resultados: Un 41.9% de los pacientes mantuvieron adherencia a la terapia a 2 años de seguimiento. Variables sociodemográficas como el bajo nivel educacional, la ruralidad, y la presencia de 1 o 2 apellidos mapuche se asociaron con baja adherencia a terapia farmacológica. Conclusión: La adherencia a medidas de prevención secundaria después del tratamiento por un síndrome coronario aguda es baja. Los principales factores relacionados a la falta de adherencia fueron el bajo nivel educacional y la ruralidad.

Background: a lack of therapeutic adherence to secondary prevention measures after acute coronary events leads to a poor control of risk factors. Adherence to treatment is associated with a reduction of 20% in the risk of cardiovascular disease and 38% reduction in all-cause mortality long term. However, adherence to drug therapy is about 50% a year after hospital discharge, which leads to an approximately three fold increase in mortality. Objectives: to describe the medium-term adherence to secondary prevention treatment following an acute coronary syndrome in adult patients admitted to a general hospital during 2018. In addition, to relate clinical and sociodemographic characteristics related to poor adherence and also to explore possible causes associated with the lack of therapeutic adherence in this group of patients. Methods: 396 patients treated for an acute coronary syndrome were followed after being discharged from the Hernán Henríquez Aravena Hospital in Temuco (Chile) during 2018. Adherence to pharmacological therapy was evaluated using the eight-item Morisky-Green questionnaire applied via phone call. The association of clinical and sociodemographic variables with the level of adherence was evaluated using ordinal regression and correspondence analysis. Results: Only 41.9% of patients maintained adherence to therapy at 2 years of follow-up. Low educational level, rurality, and the presence of 1 or 2 mapuche surnames were associated to poor adherence to drug therapy.

Impacts of Omaha System-Based Continuing Care on the Medication Compliance, Quality of Life, and Prognosis of Coronary Heart Disease Patients After PCI.

INTRODUCTION: The objective of this study is to explore the impacts of Omaha System-based continuing care on medication compliance, quality of life (QOL), and prognosis of coronary heart disease (CHD) patients after percutaneous coronary intervention (PCI). METHODS: A total of 100 CHD patients who were hospitalized and received PCI were selected and divided into the control group and the observation group, 50 patients per group, according to a random number table method. The control group was given routine care, while the observation group was applied Omaha System-based continuing care on the basis of the control group. RESULTS: Follow-up demonstrated that the Morisky-Green score of the observation group was significantly higher than that of the control group (P<0.001), indicating that the medication compliance of the observation group was significantly better than that of the control group (P<0.001). The short form-36 (SF-36) scores were notably higher after nursing compared with on admission; SF-36 scores of the observation group were significantly increased than those of the control group (P<0.001). The incidence of major adverse cardiac event (MACE) in the observation group was significantly lower than in the control group (P<0.001). The nursing satisfaction of the observation group was considerably higher than that of the control group (P<0.01). CONCLUSION: Omaha System-based continuing care could improve the medication compliance and QOL, reduce the incidence of MACE, and benefit the prognosis of CHD patients after PCI.

Mechanisms of Xiong-Pi-Fang in treating coronary heart disease associated with depression: A systematic pharmacology strategy and in vivo pharmacological validation.

BACKGROUND: Coronary heart disease (CHD) and depression are very common and often co-existing disorders. Xiong-Pi-Fang (XPF), a therapeutic classical traditional Chinese medicine (TCM) formula, has shown satisfactory efficacy in treating CHD associated with depression. However, its mechanism of action is still unknown. PURPOSE: To employ a systematic pharmacology approach for identifying the action mechanisms of XPF in treating CHD associated with depression. METHODS: We used a systematic pharmacology approach to identify the potential active mechanisms of XPF in treating CHD with depression. Potential active compounds in XPF and the diseases targets were screened using relevant databases to build corresponding pathways, following the experiments that were conducted to confirm whether the presumptive results of systemic pharmacology were correct. RESULTS: Network pharmacology predicted 42 key targets and 20 signaling pathways involved in XPF-mediated treatment, with IL-6/JAK2/STAT3/HIF-1α/VEGF-A pathway significantly affected. The common influences were hypothalamic-pituitary-adrenal axis (HPA axis) and glucocorticoid signaling, validated through chronic unexpected mild stress (CUMS) with isoprenaline (ISO) for inducing CHD within the depression model in rats. In addition, XPF intake reduced depressive-like behaviors and improved ECG ischemic changes. Furthermore, XPF exerted some anti-inflammatory effects by inhibiting the interleukin-6 (IL-6) induced phosphorylation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), ultimately downregulating hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) activation. The dysfunctional HPA axis feedback loop was also regulated, which enhanced the glucocorticoid receptor (GR) expression. In contrast, it improved glucocorticoid resistance by reducing the mineralocorticoid receptor expression. CONCLUSIONS: Suppressing IL-6 release and maintaining the HPA feedback loop balance could be the primary mechanism of XPF against CHD with depression. The significance of the IL-6 and HPA axis identified indicates their potential as essential targets for CHD therapy with depression.

Antioxidation Function of EGCG by Activating Nrf2/HO-1 Pathway in Mice with Coronary Heart Disease.

Objective: To explore the effect and mechanism of epigallocatechin gallate (EGCG) in mice with coronary heart disease (CHD). Methods: Firstly, a CHD model of mouse was established by feeding mice high-fat diet and randomly divided into four groups, including Model group (0.5% sodium cholate) and 10 mg/kg EGCG, 20 mg/kg EGCG, and 40 mg/kg EGCG groups. After oral administration of sodium cholate or EGCG, HE staining was conducted to assess the pathological changes of mouse cardiac tissues in each group of mice, biochemical kits to measure the levels of blood lipid and oxidative stress substance activity, and western blot to detect matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGFA), as well as expression levels of protein related to Nrf2/HO-1/NQO1 pathway in cardiac tissues. Results: The mice in the CHD model appeared to have myocardial pathological damage with elevated serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C). Of note, administration of EGCG significantly attenuated myocardial injuries and improved blood lipid levels in mice in a concentration-dependent manner. The advent of EGCG significantly decreased the expression of VEGFA and MMP-2 and increased the activity of superoxide dismutase (SOD), when reducing the content of reactive oxygen species (ROS) in the myocardial tissue and upregulating the expression of HO-1, NQO1, and Nrf2. Conclusion: EGCG may reduce atherosclerotic plaque and alleviate pathological damage in the cardiac tissue of CHD mice as well as improve blood lipid levels with antioxidative effect. The mechanism of its effect may be related to the activation of the Nrf2/HO-1/NQO1 antioxidant pathway in vivo of the CHD mice.

Study on the mechanism of Gualou Xiebai Guizhi decoction (GLXBGZD) in the treatment of coronary heart disease based on network pharmacology.

BACKGROUND: This study aims to analyze the mechanism of Gualou Xiebai Guizhi decoction (GLXBGZD) in treating coronary heart disease (CHD) utilizing network pharmacology. METHODS: The GLXBGZD effective components were searched on the pharmacological database platform of the Traditional Chinese Medicine Systems Pharmacol, and its potential target was predicted. The Online Mendelian Inheritance obtained CHD disease target in Man and GeneCards database. The Venn map of the intersection target for GLXBGZD and CHD was constructed by using Venn online website. The "drug-component-target-disease" network map was constructed by Cytoscape 3.7.2 software. The DAVID online platform was used to analyze the function of Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) at the intersection of targets of drugs and diseases. RESULTS: A total of 27 articles were searched for GLXBGZD, including 111 potential targets, 5521 disease targets, 100 drug and disease intersection targets. The core target network map shows that Interleukin (IL)-6, TNF, vascular endothelial growth factor (VEGFA), TP53, EGF, JUN, MAPK1, Catalase (CAT), and prostaglandin-endoperoxide synthase 2 (PTGS2) may be the key targets in CHD therapy. GO functional enrichment analysis revealed that the biological functions of GLXBGZD involved biological processes such as response to drugs, positive regulation of nitric oxide biosynthesis process, and response to hypoxia. KEGG pathway enrichment analysis showed that GLXBGZD might participate in CHD treatment through Hypoxia-inducible factor-1 (HIF-1), Tumor necrosis factor (TNF), PhosphoInositide-3 Kinase--Threonine protein kinase (PI3K-Akt), and the calcium signal pathway. CONCLUSIONS: This study reveals that the GLXBGZD mechanism in CHD treatment has the characteristics of multi-components, multi-targets, and multi-pathways, which provides a theoretical basis for its clinical application and subsequent experimental verification.

Effect of berberine on global modulation of lncRNAs and mRNAs expression profiles in patients with stable coronary heart disease.

BACKGROUND: Berberine (BBR) is an isoquinoline alkaloid found in the Berberis species. It was found to have protected effects in cardiovascular diseases. Here, we investigated the effect the regulatory function of long noncoding RNAs (lncRNAs) during the treatment of stable coronary heart disease (CHD) using BBR. We performed microarray analyses to identify differentially expressed (DE) lncRNAs and mRNAs between whole blood samples from 5 patients with stable CHD taking BBR and 5 no BBR volunteers. DE lncRNAs and mRNAs were validated by quantitative real-time PCR. RESULTS: A total of 1703 DE lncRNAs and 912 DE mRNAs were identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated DE mRNAs might be associated with mammalian target of rapamycin and mitogen-activated protein kinase pathway. These pathways may be involved in the healing process after CHD. To study the relationship between mRNAs encoding transcription factors (DNA damage inducible transcript 3, sal-like protein 4 and estrogen receptor alpha gene) and CHD related de mRNAs, we performed protein and protein interaction analysis on their corresponding proteins. AKT and apoptosis pathway were significant enriched in protein and protein interaction network. BBR may affect downstream apoptosis pathways through DNA damage inducible transcript 3, sal-like protein 4 and estrogen receptor alpha gene. Growth arrest-specific transcript 5 might regulate CHD-related mRNAs through competing endogenous RNA mechanism and may be the downstream target gene regulated by BBR. Verified by the quantitative real-time PCR, we identified 8 DE lncRNAs that may relate to CHD. We performed coding and non-coding co-expression and competing endogenous RNA mechanism analysis of these 8 DE lncRNAs and CHD-related DE mRNA, and predicted their subcellular localization and N6-methyladenosine modification sites. CONCLUSION: Our research found that BBR may affect mammalian target of rapamycin, mitogen-activated protein kinase, apoptosis pathway and growth arrest-specific transcript 5 in the process of CHD. These pathways may be involved in the healing process after CHD. Our research might provide novel insights for functional research of BBR.

The mechanism of Epimedium in the treatment of coronary atherosclerotic heart disease based on network pharmacology, molecular docking, and in vitro studies.

OBJECTIVE: There are many challenges related to the treatment of coronary atherosclerotic heart disease (CAD). Studies have confirmed that Epimedium extract inhibits myocardial injury induced by myocardial ischaemia, but the mechanism of action remains unclear. This study aimed at analysed the effective components and mechanisms of Epimedium in treating CAD based on network pharmacology and molecular docking studies and to verify the mechanism in vitro. MATERIALS AND METHODS: The TCMSP and UniProt databases were used to filter for the active components and drug targets of Epimedium. The GeneCards database was used to screen disease targets associated with CAD. The intersection of the drug targets of Epimedium and the disease targets of coronary heart disease was studied to identify the targets of Epimedium in the treatment of CAD. Cytoscape software was used to establish and analyse an activity-target network. The STRING database was used to analyse a protein-protein interaction (PPI) network, and proteins in the PPI network were visualized in the R language. Bioconductor software was used for GO function and KEGG pathway enrichment analyses, and visualization analysis was performed in the R language. PyMOL software was used to verify the molecular docking between selected active components of Epimedium and the targets of CAD, and the potential key effective components of Epimedium in the treatment of coronary heart disease were identified. The involvement of the PI3K/Akt pathway was validated by Western blot analysis. RESULTS: (1) Twenty-three active compounds, including Epimedium glycoside, quercetin, luteolin, and olive resin, were screened out. There were 68 common targets of Epimedium and CAD, including IL-6, ESR1, RELA, FOS, NCOA1, CCND1, EGFR, MAPK8, VEGFA, and CASP8. The potential signaling pathways involved in the treatment of CAD by Epimedium included the human cytomegalovirus infection pathway, the PI3K-Akt signaling pathway, the TNF signaling pathway, and the HIF-1 signaling pathway. (2) Luteolin, quercetin, sitosterol, and anhydroicaritin showed strong binding to targets of CAD based on molecular docking studies. (3) Epimedium extract increased the expression of PI3K, Akt and P-Akt but decreased the expression of IL-6  in vitro. CONCLUSIONS: (1) Icariin, quercetin and luteolin may act on target proteins, including IL-6, ESR1, EGFR, MAPK8, VEGFA and CASP8, to participate in the regulation of the human cytomegalovirus infection pathway, the PI3K-Akt signaling pathway, the TNF signaling pathway and other signaling pathways in order to effectively treat CAD. (2) In vitro studies confirmed that Epimedium extract can treat CAD by upregulating PI3K, Akt and P-Akt protein expression and downregulating IL-6 protein expression in SD rat cardiomyocytes.

Proton Pump Inhibitor and Clopidogrel Use After Percutaneous Coronary Intervention and Risk of Major Cardiovascular Events.

PURPOSE: Due to shared hepatic metabolism, concomitant medication with a proton pump inhibitor (PPI) and clopidogrel might reduce the effectiveness of clopidogrel in the prevention of cardiovascular events after percutaneous coronary intervention (PCI). We aimed to examine the risk of major cardiovascular events after PCI comparing patients who used clopidogrel together with PPI with those who used clopidogrel alone. METHODS: This Swedish nationwide cohort study included patients who received clopidogrel after primary PCI in 2005-2019. Patients were followed for up to 12 months after PCI. Data were retrieved from the Swedish Prescribed Drug Registry, Patient Registry, Cancer Registry, and Cause of Death Registry. Multivariable Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular events comparing PPI users (exposed) with non-users of PPI (non-exposed). The HRs were adjusted for sex, age, comorbidity, calendar period, obesity, diabetes, anti-diabetic medication, tobacco-related diseases, hypertension, and congestive heart failure. RESULTS: The cohort included 99,836 patients who received clopidogrel after primary PCI. Among these, 35,772 (35.8%) received concomitant PPI. Compared to non-users, PPI users had increased adjusted HRs of all study outcomes, i.e., the main outcome myocardial infarction (HR = 1.23, 95% CI 1.15-1.32) and the secondary outcomes coronary heart disease (HR = 1.28, 95% CI 1.24-1.33), stroke (HR = 1.21, 95% CI 1.05-1.40), and death due to coronary heart disease (HR = 1.52, 95% CI 1.37-1.69). The results were similar in analyses including both primary and secondary PCIs. CONCLUSIONS: In patients who receive clopidogrel after PCI, concomitant use of PPI seems to increase the risk of major cardiovascular events.