Core outcome sets for myocardial infarction in clinical trials of traditional Chinese medicine and Western medicine.

BACKGROUND: Clinical trials of traditional Chinese medicine (TCM) and Western medicine showed there was heterogeneity of outcome reporting in myocardial infarction (MI). Developing a core outcome set (COS) might improve the consistency of outcome reporting in future clinical trials. METHODS: A list of outcomes was developed based on a systematic review of randomized controlled trials (RCTs) of MI and semistructured interviews with MI patients. Two rounds of Delphi survey for clinicians, researchers, journal editors, and methodologists were conducted. An online questionnaire sent to nurses. After an online consensus meeting, a COS for MI RCTs was developed. RESULTS: After extracted data from clinical trials and discussed, 216 outcomes were included in round 1 of the Delphi survey. Seventy-four participants completed round 1 of the Delphi survey. Sixty-five participants completed round 2 of the Delphi survey. Twenty-two nurses completed the online questionnaire. Fifteen participants attended the online consensus meeting, and 14 of them voted and determined the final COS. For all types of MI, it was recommended that left ventricular ejection fraction and quality of life be measured and reported. For acute MI, the participants in the consensus meeting recommended the following core outcomes: death from cardio-cerebrovascular disease, cardiogenic shock, heart failure, troponin I, troponin T, creatine kinase isoenzyme, Killip class, target vessel revascularization, and emergency CABG. For previous MI, recurrent MI, recurrent angina pectoris, and heart failure readmission were recommended. CONCLUSIONS: The COS for MI in RCTs provides recommendations for clinical trials that seek to improve outcomes for patients with MI.

The predictive value of machine learning for mortality risk in patients with acute coronary syndromes: a systematic review and meta-analysis.

BACKGROUND: Acute coronary syndromes (ACS) are the leading cause of global death. Optimizing mortality risk prediction and early identification of high-risk patients is essential for developing targeted prevention strategies. Many researchers have built machine learning (ML) models to predict the mortality risk in ACS patients. Our meta-analysis aimed to evaluate the predictive value of various ML models in predicting death in ACS patients at different times. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched systematically from database establishment to March 12, 2022 for studies developing or validating at least one ML predictive model for death in ACS patients. We used PROBAST to assess the risk of bias in the reported predictive models and a random-effects model to assess the pooled C-index and accuracy of these models. RESULTS: Fifty papers were included, involving 216 ML prediction models, 119 of which were externally validated. The combined C-index of the ML models in the validation cohort predicting the in-hospital mortality, 30-day mortality, 3- or 6-month mortality, and 1 year or above mortality in ACS patients were 0.8633 (95% CI 0.8467-0.8802), 0.8296 (95% CI 0.8134-0.8462), 0.8205 (95% CI 0.7881-0.8541), and 0.8197 (95% CI 0.8042-0.8354), respectively, with the corresponding combined accuracy of 0.8569 (95% CI 0.8411-0.8715), 0.8282 (95% CI 0.7922-0.8591), 0.7303 (95% CI 0.7184-0.7418), and 0.7837 (95% CI 0.7455-0.8175), indicating that the ML models were relatively excellent in predicting ACS mortality at different times. Furthermore, common predictors of death in ML models included age, sex, systolic blood pressure, serum creatinine, Killip class, heart rate, diastolic blood pressure, blood glucose, and hemoglobin. CONCLUSIONS: The ML models had excellent predictive power for mortality in ACS, and the methodologies may need to be addressed before they can be used in clinical practice.

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.

Metabolic profile and potential mechanisms of Wendan decoction on coronary heart disease by ultra-high-performance quadrupole time of flight-mass spectrometry combined with network pharmacology analysis.

Wendan decoction, a well-known classical traditional Chinese medicine prescription, has been widely used in the clinical application of coronary heart disease for thousands of years. However, due to a lack of research on the overall metabolism of Wendan decoction, the bioavailable components responsible for the therapeutic effects remain unclear, hindering the revelation of its mechanisms against coronary heart disease. Consequently, an efficient joint research pattern combined with characterization of the metabolic profile and network pharmacology analysis was proposed. As a result, a total of 172 Wendan decoction-related xenobiotics (57 prototypes and 115 metabolites) were detected based on the exploration of the typical metabolic pathways of representative pure compounds in vivo, describing their multi-component metabolic characteristics comprehensively. Subsequently, an integrated network of "herbs-bioavailable compounds-coronary heart disease targets-pathways-therapeutic effects" was constructed, and its seven compounds were finally screened out as the key components acting on five main targets of coronary heart disease. Overall, this work not only provided a crucial biological foundation for interpreting the effective components and action mechanisms of Wendan decoction on coronary heart disease but also showed a reference value for revealing the bioactive components of traditional Chinese medicine prescriptions.

Deciphering mechanism of the herbal formula WuShen in the treatment of postinfarction heart failure.

BACKGROUND: Numerous clinical studies reported the effectiveness of herbal formula WuShen (WS) in treating cardiovascular diseases, yet relevant basic research was rarely conducted. METHODS AND RESULTS: Twelve main bioactive compounds of WS decoction were identified using the ultra-performance liquid chromatography-LTQ-Orbitrap mass spectrometer. A total of 137 active compounds with 613 targets were predicted by network pharmacology; their bioinformatic annotation and human microarray data suggested that wounding healing, inflammatory response, and gap junction were potentially the major therapeutic modules. A rat model of post-myocardial infarction (MI) heart failure (HF) was used to study the effects of WS on cardiac function, adverse cardiac remodeling, and experimental arrhythmias. Rats treated with WS led to a significantly improved pump function and reduced susceptibility to both ventricular tachycardia and atrial fibrillation, and restricted adverse cardiac remodeling partly via inhibiting TGFß1/SMADs mediated extracellular matrix deposition and Rac1/NOX2/CTGF/Connexin43 -involved gap junction remodeling. CONCLUSIONS: The present study highlights that WS can be applied to the treatment of heart failure and the upstream therapy for atrial fibrillation and ventricular tachycardia through its preventive effect on adverse cardiac remodeling.

[Therapeutic effect of auriculotherapy with miniature bian needle on anxiety in the patients after percutaneous coronary intervention].

OBJECTIVE: To observe the effect of auriculotherapy with miniature bian needle on anxious emotion, the condition of angina pectoris attack and sleep quality in the patients with anxiety after percutaneous coronary intervention (post-PCI). METHODS: A total of 74 eligible patients of post-PCI combined with anxious depression were randomized into an auriculotherapy group (37 cases, 2 cases dropped out) and a control group (37 cases, 3 cases dropped out). In the auriculotherapy group, on the base of the conventional secondary prevention medication for coronary heart disease (CHD), auriculotherapy with miniature bian needle was supplemented. In the control group, a proper physical exercise was combined on the base of the secondary prevention medication for CHD. The duration of treatment was 4 weeks in two groups. Separately, the score of Hamilton anxiety scale (HAMA), the score Seattle angina questionnaire (SAQ) and the score of Pittsburgh sleep quality index (PSQI) were assessed in the patients of the two groups before and after treatment. RESULTS: After treatment, the score of HAMA, the score of each item of SAQ and PSQI score were all improved significantly as compared with those before treatment respectively in both the auriculotherapy group and the control group (P<0.001, P<0.05). After treatment, HAMA score, PSQI score and the scores of physical limitation (PL), anginal stability (AS), anginal frequency (AF) and treatment satisfaction (TS) in SAQ in the auriculotherapy group were all better than those in the control group (P<0.001, P<0.05). The total effective rate was 91.43% (32/35) in the auriculotherapy group, obviously higher than 58.82% (20/34) in the control group (P<0.001). CONCLUSION: Auriculotherapy with miniature bian needle effectively relieves anxious emotions and the condition of angina pectrois attack and improves sleep quality in the post-PCI patients with anxiety.

Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) /System xc-/ glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis.

Ferroptosis is an important form of myocardial cell death in myocardial ischemia-reperfusion injury (MIRI). Naringenin (NAR), as a flavonoid, has a significant advantage in improving MIRI. But the regulatory effect and mechanism of NAR on ferroptosis in MIRI have not been reported. After the rats were given NAR and induced to form myocardial ischemia-reperfusion (MI/R) injury, Tetrazolium chloride (TTC) staining was used to detect the myocardial infarction area of rats, and Hematoxylin-eosin (H&E) staining was used to detect myocardial injury. The markers of tissue inflammation were detected by ELISA. Serum creatine kinase Serum creatin kinase (CPK), Lactate dehydrogenase (LDH), and lipid peroxide (LPO) and oxidative stress related levels were measured. In addition, iron detection kits were used to detect total iron and Fe2+ levels in cardiac tissues, and western blot was used to detect the expression of ferroptosis-related proteins and the expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4). At the cellular level, H9C2 cardiomyocytes were induced by hypoxia/reoxygenation (H/R), and ferroptosis inducer Erastin was administered to detect cell viability, ferroptosis-related indicators, oxidative stress related indicators, and expressions of Nrf2 and GPX4, to explore the mechanisms involved. NAR alleviated MI/R-induced pathological damage, inflammation and lipid peroxidation in myocardial tissue of rats. NAR adjusted the NRF2 /System xc - /GPX4 axis and improved ferroptosis. At the cellular level, ferroptosis inducer Erastin reversed the protective effect of NAR on H/R-induced H9C2 cardiomyocytes. In conclusion, NAR can alleviate MIRI by regulating the Nrf2/System xc-/GPX4 axis to inhibit ferroptosis.

Naringenin Inhibits Platelet Activation and Arterial Thrombosis Through Inhibition of Phosphoinositide 3-Kinase and Cyclic Nucleotide Signaling.

Citrus flavanoids intake can reduce the risk of cardiovascular diseases. Naringenin, a natural predominant flavonoid abundant in citrus fruits, possesses protective effects against atherothrombotic diseases. As platelet activation plays central roles in atherothrombogenesis, we studied the effects of naringenin on platelet activation, signaling, thrombosis and hemostasis. Naringenin dose-dependently inhibited agonist-induced platelet aggregation in vitro, and exhibited more-potent efficacy on ADP-induced platelet aggregation. It also suppressed platelet aggregation stimulated by ADP ex vivo. Naringenin inhibited ADP-induced platelet α-granule secretion, fibrinogen binding, intracellular calcium mobilization and platelet adhesion on collagen-coated surface. Naringenin also inhibited platelet spreading on fibrinogen and clot retraction, processes mediated by outside-in integrin signaling. Mechanism studies indicated that naringenin suppressed PI3K-mediated signaling and phosphodiesterase activity in platelets, in addition to increasing cGMP levels and VASP phosphorylation at Ser239. Furthermore, naringenin-induced VASP phosphorylation and inhibition of platelet aggregation were reversed by a PKA inhibitor treatment. Interestingly, naringenin inhibited thrombus formation in the (FeCl3)-induced rat carotid arterial thrombus model, but not cause a prolonged bleeding time in mice. This study suggests that naringenin may represent a potential antiplatelet agent targeting PI3K and cyclic nucleotide signaling, with a low bleeding risk.

Hesperetin inhibits foam cell formation and promotes cholesterol efflux in THP-1-derived macrophages by activating LXRα signal in an AMPK-dependent manner.

Cholesterol efflux from macrophages is the first step of reverse cholesterol transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Hesperetin has been reported to exert several protective effects on cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism in macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin on foam cell formation and cholesterol efflux by using human macrophages, focusing on liver X receptor alpha (LXRα) and AMPK. We found that hesperetin treatment reduced foam cell formation, intracellular cholesterol levels and the cholesterol esterification rate, and increased cholesterol efflux in THP-1 macrophages. Hesperetin increased the levels of LXRα protein and its targets, including ABCA1, ABCG1, SR-BI, and phosphorylated-AMPK. Meanwhile, the hesperetin-induced increase in LXRα expression was further increased by the AMPK agonist and inhibited by an AMPK inhibitor. Meanwhile, hesperetin increased the levels of LXRα mRNA and its target genes, all of which were decreased in cells transfected with the AMPKα1/α2 small interfering RNA (siRNA). Furthermore, the hesperetin-induced inhibition of foam cell formation and promotion of cholesterol efflux were decreased by transfection of AMPKα1/α2 siRNA. In conclusions, We are the first to report that hesperetin activate AMPK in THP-1-derived macrophages. This activation upregulats LXRα and its targets, including ABCA1, ABCG1 and SR-BI, which significantly inhibits foam cell formation and promotes cholesterol efflux. Our results highlight the therapeutic potential of hesperetin to possibly reduce foam cell formation. This new mechanism might contribute the anti-atherogenic effects of hesperetin.

Characterization of chemical profile and quantification of major representative components of Wendan decoction, a classical traditional Chinese medicine formula.

Wendan decoction, a classical traditional Chinese medicine formula consisting of six herbal medicines, has been widely used in clinical treatments for thousands of years due to the expectorant effects. However, the chemical basis of Wendan decoction remains unclear, which hinders the elucidation of the scientific connotation and mechanism of its effective components. In this study, an ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry method was first developed for characterization of its chemical profile, and a total of 142 chemical components including flavonoids, triterpenoids, alkaloids, coumarins, pungent phytochemicals, and other types were detected, among which 41 components were definitively identified with authentic standards. Furthermore, 14 major representative components were simultaneously quantified by high-performance liquid chromatography with ultraviolet detector, indicating that the content levels of flavonoids were the most abundant in Wendan decoction. In summary, this study established sensitive and practical methods to systematically characterize chemical profile for the first time and simultaneous quantify representative components of Wendan decoction. These findings above would provide a solid chemical basis for disclosure of potential effective components by further in vivo disposal study, and promote therapeutic mechanism researches of Wendan decoction.

Prevention of platelet aggregation and arterial thrombosis using a modified Shenzhu Guanxin Formula.

OBJECTIVE: Modified Shenzhu Guanxin Formula (mSGF) has beneficial effects in coronary artery disease. Previously, we found that mSGF inhibited platelet aggregation in rats. In the present study we further investigated the antiplatelet and antithrombotic activities of mSGF in rats. METHODS: Rats were orally administered mSGF (4.2, 8.4, or 16.8 g crude drug/kg), the adenosine 5'-diphosphate (ADP) receptor antagonist clopidogrel (7.875 mg/kg), or saline once a day for 7 days. The effects of mSGF on platelet aggregation were measured. Levels of cyclic adenosine monophosphate (cAMP) and phosphoinositide 3-kinase (PI3K) signaling were analyzed by ELISA and western blotting, respectively. The antithrombotic effect of mSGF was investigated using a FeCl3-induced carotid arterial thrombosis model and effects on bleeding time were assessed in a rat tail transection model. RESULTS: mSGF significantly inhibited ADP-induced platelet aggregation in a dose-dependent manner, elevated cAMP levels and inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and PI3K/protein kinase B (Akt). Moreover, mSGF dose-dependently inhibited thrombosis in a FeCl3-induced carotid arterial thrombus model and had a significantly smaller effect on bleeding time compared with clopidogrel. CONCLUSIONS: mSGF represents a potent and safe antithrombotic agent whose antiplatelet activity is probably mediated through blockade of PI3K/Akt signaling and increased cAMP generation.

Investigation of the Cellular Pharmacological Mechanism and Clinical Evidence of the Multi-Herbal Antiarrhythmic Chinese Medicine Xin Su Ning.

Xin Su Ning (XSN), a China patented and certified multi-herbal medicine, has been available in China since 2005 for treating cardiac ventricular arrhythmia including arrhythmia induced by ischemic heart diseases and viral myocarditis, without adverse reactions being reported. It is vitally important to discover pharmacologically how XSN as a multicomponent medicine exerts its clinical efficacy, and whether the therapeutic effect of XSN can be verified by standard clinical trial studies. In this paper we report our discoveries in a cellular electrophysiological study and in a three-armed, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Conventional electrophysiological techniques were used to study the cellular antiarrhythmic mechanism of XSN. Data was then modeled with computational simulation of human action potential (AP) of the cardiac ventricular myocytes. The clinical trial was conducted with a total of 861 eligible participants randomly assigned in a ratio of 2:2:1 to receive XSN, mexiletine, or the placebo for 4 weeks. The primary and secondary endpoint was the change of premature ventricular contraction (PVC) counts and PVC-related symptoms, respectively. This trial was registered in the Chinese Clinical Trial Register Center (ChiCTR-TRC-14004180). We found that XSN prolonged AP duration of the ventricular myocytes in a dose-dependent, reversible manner and blocked potassium channels. Patients in XSN group exhibited significant total effective responses in the reduction of PVCs compared to those in the placebo group (65.85% vs. 27.27%, P < 0.0001). No severe adverse effects attributable to XSN were observed. In conclusion, XSN is an effective multicomponent antiarrhythmic medicine to treat PVC without adverse effect in patients, which is convincingly supported by its class I & III pharmacological antiarrhythmic mechanism of blocking hERG potassium channels and hNaV1.5 sodium channel reported in our earlier publication and prolongs AP duration both in ventricular myocytes and with computational simulation of human AP presented in this report.

The efficacy and safety of Shenzhu Guanxin Recipe Granules for the treatment of patients with coronary artery disease: protocol for a double-blind, randomized controlled trial.

BACKGROUND: Coronary artery disease (CAD) is one of the most common types of the cardiovascular disease. Previous pilot trials have suggested that Traditional Chinese Medicine (TCM) has brought clinical benefits for patients with CAD. We will conduct this trial to determine the efficacy and safety of Shenzhu Guanxin Recipe Granules (SGR) for the treatment of patients with CAD. METHODS: This randomized controlled trial recruited 190 patients who were diagnosed with CAD by clinical manifestation and examination and in which coronary computed tomography angiography (CCTA) showed 50-70% stenosis, with soft or mixed plaque types. The included participants were randomly assigned to the case group and control group using a 1:1 allocation ratio; patients in the case group received SGR and usual care, and those in the control group received placebo (6 g/day for 6 months) and usual care. The endpoint of the study included Calcium Coverage Score (CCS), C-reactive protein (CRP) level, and the levels of blood lipids, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and ATP-binding membrane cassette transporter A1 (ABCA1) were calculated before recruiting and at the sixth month. The indicators were Seattle Angina Questionnaire (SAQ) and TCM Syndrome Questionnaire scores at 0, 3, and 6 months. DISCUSSION: This clinical trial may provide reliable evidence regarding the clinical effectiveness and safety of SGR therapy for patients with CAD diagnosed by clinical manifestation and examination, in which CCTA showed 50-70% stenosis, with soft or mixed plaque types. TRIAL REGISTRATION: ClinicalTrials.gov, ID: ChiCTR1900020501 . The trial was registered on 25 December 2018.

Functional suppression of Epiregulin impairs angiogenesis and aggravates left ventricular remodeling by disrupting the extracellular-signal-regulated kinase1/2 signaling pathway in rats after acute myocardial infarction.

Acute myocardial infarction (AMI), a severe consequence of coronary atherosclerotic heart disease, is often associated with high mortality and morbidity. Emerging evidence have shown that the inhibition of the extracellular-signal-regulated kinase (ERK) signaling pathway appears to protect against AMI. Epiregulin (EREG) is an autocrine growth factor that is believed to activate the MEK/ERK signaling pathway. Therefore, the aim of the present study was to determine the expression patterns of EREG in AMI and to further study its effects on AMI induced experimentally in rats focusing on angiogenesis and left ventricular remodeling. Microarray-based gene expression profiling of AMI was used to identify differentially expressed genes. To understand the biological significance of EREG and whether it is involved in AMI disease through the ERK1/2 signaling pathway, rats after AMI were treated with small interfering RNA (siRNA) against EREG, an ERK1/2 pathway inhibitor, PD98059, or both of them. The microarray data sets GSE66360 and GSE46395 showed that EREG was robustly induced in AMI. Both siRNA-mediated depletion of EREG and PD98059 treatment were shown to significantly increase infarct size and left ventricular cardiomyocyte loss and enhance left ventricular remodeling. In addition, we also found that the ERK1/2 signaling pathway was inhibited following siRNA-mediated EREG inhibition and PD98059 could enhance the effects of EREG inhibition on AMI. In conclusion, these findings highlight that the silencing of EREG inhibits angiogenesis and promotes left ventricular remodeling by disrupting the ERK1/2 signaling pathway, providing a novel therapeutic target for limiting AMI.

The effects of traditional Chinese exercise on hypertension: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Several studies have reported the benefits of traditional Chinese exercises (TCEs) on hypertension; however, a consensus regarding the effectiveness and safety of TCEs for patients with hypertension has not been reached. METHODS AND RESULTS: Only randomized controlled trials were included in our study. A total of 16 articles involving 1164 patients with hypertension met the inclusion criteria. The results showed that TCEs can reduce BP, blood lipids (including total cholesterol and triglyceride levels) and endothelin levels and improves quality of life in hypertensive patients, however, the low-quality of the included studies made the results be of questionable significance. CONCLUSIONS: The results of this review suggest that there is no firm evidence to support the objective effectiveness and safety of TCEs for hypertension because of the poor quality of the studies. Well-designed, randomized placebo-controlled trial with objective outcome measures should be conducted in the future.

Shenzhu Guanxin Recipe Granules () for Improving Exercise Tolerance in Patients with Stable Angina (SERIES Trial): A Protocol of Multicenter, Randomized, Double-Blind, Placebo Parallel Controlled Clinical Trial.

BACKGROUND: Many patients with chronic angina experience anginal episodes despite successful recanalization, antianginal and antiischemic medications. Empirical observations suggested that Shenzhu Guanxin Recipe Granules (, SGR), a Chinese herbal compound, exerted potential impacts on increased treadmill exercise performance and angina relieve. However, there has been no systematic study to clarify the impact of SGR on exercise tolerance in patients with stable angina. The SERIES (ShEnzhu guanxin Recipe for Improving Exercise tolerance in patients with Stable angina) trial is designed to determine the effects of SGR on exercise duration, electrocardiographic (ECG) evidence of myocardial ischemia, and incidence of major adverse cardiac events (MACE) in stable anginal patients. METHODS: A total of 184 eligible patients with stable angina will be randomly assigned to receive placebo or SGR (10 g/day for 12 weeks) in a 1:1 ratio. The primary outcome will be the change from baseline in total exercise tolerance duration, time to onset of angina and ECG ischemia during exercise treadmill testing performed over a 12-week study period. The secondary outcome will include ECG measures, the occurrence and composite of MACE and the Seattle Angina Questionnaire score. Moreover, the coronary microcirculation will be evaluated to explore the possible effects in response to treatment of SGR. After the procedure, all participants will be followed up by interview at 3 and 6 months, enquiring about any cardiac events, hospitalizations, cardiac functional level and medication usage. Additionally, the occurrence of adverse events will be evaluated at each follow-up. DISCUSSION: This study may provide novel evidence on the efficacy of SGR in improving exercise tolerance and potentially reducing clinical adverse events. (Trial registration No. ChiCTR-TRC-14004504).

Chronic Kidney Disease Increases Atrial Fibrillation Inducibility: Involvement of Inflammation, Atrial Fibrosis, and Connexins.

Chronic kidney disease (CKD) causes atrial structural remodeling and subsequently increases the incidence of atrial fibrillation (AF). Atrial connexins and inflammatory responses may be involved in this remodeling process. In this study, nephrectomy was used to produce the CKD rat model. Three months post-nephrectomy, cardiac structure, function and AF vulnerability were quantified using echocardiography and electrophysiology methods. The left atrial tissue was tested for quantification of fibrosis and inflammation, and for the distribution and expression of connexin (Cx) 40 and Cx43. An echocardiography showed that CKD resulted in the left atrial enlargement and left ventricular hypertrophy, but had no functional changes. CKD caused a significant increase in the AF inducible rate (91.11% in CKD group vs. 6.67% in sham group, P < 0.001) and the AF duration [107 (0-770) s in CKD vs. 0 (0-70) s in sham, P < 0.001] with prolonged P-wave duration. CKD induced severe interstitial fibrosis, activated the transforming growth factor-ß1/Smad2/3 pathway with a massive extracellular matrix deposition of collagen type I and α-smooth muscle actin, and matured the NLR (nucleotide-binding domain leucine-rich repeat-containing receptor) pyrin domain-containing protein 3 (NLRP3) inflammasome with an inflammatory cascade response. CKD resulted in an increase in non-phosphorylated-Cx43, a decrease in Cx40 and phosphorylated-Cx43, and lateralized the distribution of Cx40 and Cx43 proteins with upregulations of Rac-1, connective tissue growth factor and N-cadherin. These findings implicate the transforming growth factor-ß1/Smad2/3, the NLRP3 inflammasome and the connexins as potential mediators of increased AF vulnerability in CKD.

Salvianolate reduces atrial fibrillation through suppressing atrial interstitial fibrosis by inhibiting TGF-ß1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in post-MI rats.

BACKGROUND: Salvianolate is the main water-soluble bioactive compound of Salvia Miltiorrhiza Bunge and is now clinically used in the treatment of cardiovascular diseases in China. However, its applications in the prevention of atrial interstitial fibrosis (AIF) and atrial fibrillation (AF) are not fully revealed. PURPOSES: To investigate the preventive effect of salvianolate on the pathogenesis of AF in post-myocardial infarction (MI) rats and to elucidate the potential mechanisms. MATERIALS AND METHODS: Rats underwent left anterior descending coronary artery ligation were randomized into four groups and administered intraperitoneally with vehicle (MI group, n = 13), or 10, 20 and 40 mg/kg salvianolate (Sal-L, Sal-M and Sal-H group, n = 13, 14 and 13 respectively) for totally five weeks. Rats underwent sham operation was used as control group (Sham, n = 10). Then, echocardiography and AF inducibility test were detected. Tissues and serum were collected for Sirius red and fast green counter stain or hematoxylin-eosin to assess atrial interstitial fibrosis and hypertrophy, or for western blot and ELISA analysis. RESULTS: Salvianolate injection significantly improved cardiac function, reduced left atrial enlargement and P-wave duration, and decreased not only the vulnerability to AF but also AF duration. Histologic analysis showed that salvianolate mitigated AIF and atrial hypertrophy. Western blot analysis found that salvianolate inhibited the TGFß1/Smad2/3 mediated-collagen deposition and inhibited the TXNIP/NLRP3 inflammasome /IL-1ß and IL-18 signal pathway. ELISA analysis showed that salvianolate significantly reduced the serum concentrations of BNP, IL-6, CRP and TGFß1. CONCLUSIONS: Salvianolate may constitute a novel upstream therapy for AF by suppressing AIF. The underlying mechanism may be attributable to its inhibitory effects on TGF-ß1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathway.

Relationship between short telomere length and stroke: A meta-analysis.

BACKGROUND: Several epidemiological studies had been carried out in different population cohorts to estimate the relationship between the shortened telomere length and stroke. However, the results still remained dispute. Consequently, we conducted this meta-analysis to estimate the relationship between them. METHODS: PubMed, EMBASE, and Web of Science were systematically searched for related articles to evaluate the association between "stroke" and "telomere length. STATA 12.0 software was used to perform the meta-analysis. The Cochran Q test and inconsistency index (I) were used to assess the heterogeneity. Begg funnel plot and Egger test were used to assess publication bias. RESULTS: The meta-analysis was composed of 11 studies, consisting of 25,340 participants. We found a significant relationship between shortened telomere length and stroke (OR: 1.50, 95% CI: 1.13-2.0; P = .005); however, in the prospective and retrospective study subgroup, we did not find a statistical significant relationship between shortened telomere length and stroke (the prospective subgroup: OR: 1.41, 95% CI: 1-1.98; P = .051) (the retrospective subgroup: OR: 1.89, 95% CI: 0.96-3.72; P = .067).

Systems Pharmacology Dissection of Traditional Chinese Medicine Wen-Dan Decoction for Treatment of Cardiovascular Diseases.

Cardiovascular diseases (CVDs) have been recognized as first killer of human health. The underlying mechanisms of CVDs are extremely complicated and not fully revealed, leading to a challenge for CVDs treatment in modern medicine. Traditional Chinese medicine (TCM) characterized by multiple compounds and targets has shown its marked effects on CVDs therapy. However, system-level understanding of the molecular mechanisms is still ambiguous. In this study, a system pharmacology approach was developed to reveal the underlying molecular mechanisms of a clinically effective herb formula (Wen-Dan Decoction) in treating CVDs. 127 potential active compounds and their corresponding 283 direct targets were identified in Wen-Dan Decoction. The networks among active compounds, targets, and diseases were built to reveal the pharmacological mechanisms of Wen-Dan Decoction. A "CVDs pathway" consisted of several regulatory modules participating in therapeutic effects of Wen-Dan Decoction in CVDs. All the data demonstrates that Wen-Dan Decoction has multiscale beneficial activity in CVDs treatment, which provides a new way for uncovering the molecular mechanisms and new evidence for clinical application of Wen-Dan Decoction in cardiovascular disease.