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Atrial fibrillation significantly increases the risk of thromboembolism and stroke. Wenxin Keli (WXKL) is a widely used Chinese patent medicine against arrhythmia but if it has antithrombotic activity is unknown. Since platelet activation is a critical factor in thrombosis and the key target for many antithrombotic drugs, this study aims to demonstrate the antithrombotic efficacy of WXKL. In vitro platelet activation experiments showed that WXKL significantly inhibited platelet adhesion and aggregation. The potential active monomers in WXKL were screened by in silico prediction and in vitro platelet aggregation/adhesion assays. From WXKL chemical fractions and more than 40 monomers, linoleic acid (LA) was identified as the strongest antiplatelet compound. Oral administration of WXKL (1.2 g/kg/day) and LA (50 mg/kg/day) for 7 days significantly improved FeCl3-induced carotid thrombus formation in ICR mice without prolonging bleeding time. Flow cytometry showed that both WXKL and LA inhibited the release of p-selectin after platelet activation. ELISA showed that WXKL and LA also inhibited the expression of 6-Keto-PGF1α in plasma of mice with thrombus, but had no obvious effect on the expression of TXB2. WXKL inhibited platelet activation by broadly inhibiting the phosphorylation of protein kinase B (Akt), mitogen-activated protein kinases (MAPKs) and phospholipase C (PLC) β3. In contrast, LA only inhibited the phosphorylation of PLCβ3. In conclusion, WXKL and its active component LA showed good antiplatelet and antithrombotic efficacy in vivo and in vitro. Mechanistically, the multicomponent Chinese medicine WXKL acts on multiple targets in the platelet activation pathway whereas its active monomer linoleic acid acts specifically on phospholipase C β3.

BackgroundWenxin Keli (WXKL) has good clinical value in the treatment of premature ventricular contractions, but there is insufficient evidence to support it. This study evaluates the efficacy and safety of WXKL combined with metoprolol tartrate in the treatment of ventricular premature beats (VPCs).MethodsWe searched seven databases to identify randomized controlled trials (RCTs) for this study. Two reviewers independently screened and extracted the data. The Cochrane Manual criteria were used for methodological quality assessment. Meta-analyses were performed using Review Manager 5.4.1 software. Risk ratios (RR) were used for effect sizes for dichotomous data, demonstrated in effect sizes and 95% confidence intervals (CIs).ResultsA total of 11 RCTs of WXKL combined with metoprolol tartrate in the treatment of premature ventricular contractions were included in this study. Meta-analysis showed that WXKL combined with metoprolol tartrate (treatment group) was more effective than metoprolol tartrate (control group) in improving premature ventricular contractions (RR = 1.32, 95% CI: [1.24, 1.40], P < 0.00001); significantly improved the rate of premature ventricular contractions (RR = 1.32, 95% CI: [1.23, 1.41], P < 0.00001); there was no difference in adverse drug reactions compared with the control group (RR = 0.61, 95% CI: [0.35, 0.1.05], P = 0.08), but the number of adverse reactions (n = 18) was less than that of the control group (n = 32), and the severity was lower than that of the control group. The included studies only mentioned randomization and did not describe the generation of random sequences in detail.ConclusionThis study found that Wenxin Keli combined with metoprolol tartrate in the treatment of premature ventricular contractions increased the efficacy of the drug, reduced the occurrence of adverse reactions, and reduced the severity of adverse reactions. Due to the quality limitations of the included studies, more high-quality RCTs are needed in the future to provide more evidence for longer-term analyses.

This study employed a systems pharmacology approach to identify the active compounds and action mechanisms of Wenxin Keli for arrhythmia treatment. Sixty-eight components identified in vivo and in vitro by UPLC/Q-TOF-MS were considered the potential active components of Wenxin Keli. Network pharmacology further revealed 33 key targets and 75 KEGG pathways as possible pathways and targets involved in WK-mediated treatment, with the CaMKII/CNCA1C/Ca2+ pathway being the most significantly affected. This finding was validated using an AC-induced rat arrhythmias model. Pretreatment with Wenxin Keli reduced the malignant arrhythmias and shortened RR, PR, and the QT interval. Wenxin Keli exerted some antiarrhythmic effects by inhibiting p-CaMKII and intracellular Ca2+ transients and overexpressing CNCA1C. Thus, suppressing SR Ca2+ release and maintaining intracellular Ca2+ balance may be the primary mechanism of Wenxin Keli against arrhythmia. In view of the significance of CaMKII and NCX identified in this experiment, we suggest that CaMKII and NCX are essential targets for treating arrhythmias. [ABSTRACT FROM AUTHOR]

This study employed a systems pharmacology approach to identify the active compounds and action mechanisms of Wenxin Keli for arrhythmia treatment. Sixty-eight components identified in vivo and in vitro by UPLC/Q-TOF-MS were considered the potential active components of Wenxin Keli. Network pharmacology further revealed 33 key targets and 75 KEGG pathways as possible pathways and targets involved in WK-mediated treatment, with the CaMKII/CNCA1C/Ca2+ pathway being the most significantly affected. This finding was validated using an AC-induced rat arrhythmias model. Pretreatment with Wenxin Keli reduced the malignant arrhythmias and shortened RR, PR, and the QT interval. Wenxin Keli exerted some antiarrhythmic effects by inhibiting p-CaMKII and intracellular Ca2+ transients and overexpressing CNCA1C. Thus, suppressing SR Ca2+ release and maintaining intracellular Ca2+ balance may be the primary mechanism of Wenxin Keli against arrhythmia. In view of the significance of CaMKII and NCX identified in this experiment, we suggest that CaMKII and NCX are essential targets for treating arrhythmias.

Objective: To evaluate the efficacy and safety of Wenxin Keli for premature beats in structurally normal heart systematically. Methods: Eight databases at home and abroad were searched to collect randomized controlled trials of Wenxin Keli for premature beats without cardiac diseases. The included literatures were systematically evaluated with Cochrane Handbook 5.1 evaluation criteria and tools, and Meta analysis was performed with software RevMan5.3. Results: A total of 13 randomized controlled trials with 1278 subjects were included. The exprimental group used Wenxin Keli alone while the control group used antiarrhythmic medicine. The Meta analysis results showed that the total effective rate(RR=1.06,95%CI [0.97,1.16],P=0.23) and clinical symptom effective rate (RR=1.16,95%CI[0.94, 1.44],P=0.18)of Wenxin Keli on idiopathic premature beats was not significantly different from western medicine group. The subgroup analysis of total effective rate showed that Wenxin Keli had no significant difference with metoprolol (RR=1.04,95%CI[ 0.95,1.15],P=0.41), bisoprolol (RR=1.32,95%CI[0.85,2.05],P=0.22) and propanone(RR=1.07, 95%CI[0.90,1.26],P= 0.44). ECG changes showed that the PR intervals (MD=-12.57,95%CI[-16.15, -8.99],P<0.00001) and QTc intervals (MD=-8.09,95%CI[-15.52, -0.65],P=0.03) in the western medicine group were prolonged significantly more than those of Wenxin Keli. In terms of safety, the incidence of adverse reactions of Wenxin Keli was significantly less than that of western medicine group (RR=0.32,95%CI[0.19, 0.54],P< 0.0001). Conclusion: The efficacy of Wenxin Keli in the treatment of premature beats with structurally normal heart is accurate, and there are no serious adverse reactions. However, because of the low quality of the included papers, which affected the reliability of the conclusions, high-quality clinical research is needed to further demonstrate. [ABSTRACT FROM AUTHOR]

Wenxin Keli (WXKL) is a widely used Chinese botanical drug for the treatment of arrhythmia, which is consisted of four herbs and amber. In the present study, we analyzed the chemical composition of WXKL using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) to tentatively identify 71 compounds. Through typical separate procession, the total extract of WXKL was divided into fractions for further bioassays. Cardiomyocytes and zebrafish larvae were applied for assessment. In vivo arrhythmia model in Cmlc2-GFP transgenic zebrafish was induced by terfenadine, which exhibited obvious reduction of heart rate and occurrence of atrioventricular block. Dynamic beating of heart was recorded by fluorescent microscope and sensitive camera to automatically recognize the rhythm of heartbeat in zebrafish larvae. By integrating the chemical information of WXKL and corresponding bioactivities of these fractions, activity index (AI) of each identified compound was calculated to screen potential active compounds. The results showed that dozens of compounds including ginsenoside Rg1, ginsenoside Re, notoginsenoside R1, lobetyolin, and lobetyolinin were contributed to cardioprotective effects of WXKL. The anti-arrhythmic activities of five compounds were further validated in larvae model and mature zebrafish by measuring electrocardiogram (ECG). Our findings provide a successful example for rapid discovery of bioactive compounds from traditional Chinese medicine (TCM) by activity index based approach coupled with in vivo zebrafish model.

Wenxin Keli (WXKL) is a widely used Chinese botanical drug for the treatment of arrhythmia, which is consisted of four herbs and amber. In the present study, we analyzed the chemical composition of WXKL using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) to tentatively identify 71 compounds. Through typical separate procession, the total extract of WXKL was divided into fractions for further bioassays. Cardiomyocytes and zebrafish larvae were applied for assessment. In vivo arrhythmia model in Cmlc2-GFP transgenic zebrafish was induced by terfenadine, which exhibited obvious reduction of heart rate and occurrence of atrioventricular block. Dynamic beating of heart was recorded by fluorescent microscope and sensitive camera to automatically recognize the rhythm of heartbeat in zebrafish larvae. By integrating the chemical information of WXKL and corresponding bioactivities of these fractions, activity index (AI) of each identified compound was calculated to screen potential active compounds. The results showed that dozens of compounds including ginsenoside Rg1, ginsenoside Re, notoginsenoside R1, lobetyolin, and lobetyolinin were contributed to cardioprotective effects of WXKL. The anti-arrhythmic activities of five compounds were further validated in larvae model and mature zebrafish by measuring electrocardiogram (ECG). Our findings provide a successful example for rapid discovery of bioactive compounds from traditional Chinese medicine (TCM) by activity index based approach coupled with in vivo zebrafish model. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the major public health problem and a leading cause of morbidity and mortality on a global basis. Wenxin Keli (WXKL), a formally classical Chinese patent medicine with obvious efficacy and favorable safety, plays a great role in the management of patients with CVDs. Accumulating evidence from various animal and cell studies has showed that WXKL could protect myocardium and anti-arrhythmia against CVDs. WXKL exhibited its cardioprotective roles by inhibiting inflammatory reaction, decreasing oxidative stress, regulating vasomotor disorders, lowering cell apoptosis, and protection against endothelial injure, myocardial ischemia, cardiac fibrosis, and cardiac hypertrophy. Besides, WXKL could effectively shorten the QRS and Q-T intervals, decrease the incidence of atrial/ventricular fibrillation and the number of ventricular tachycardia episodes, improve the severity of arrhythmias by regulating various ion channels with different potencies, mainly comprising peak sodium current (INa), late sodium current (INaL), transient outward potassium current (Ito), L-type calcium current (ICaL), and pacemaker current (If).

Objectives: To evaluate possible adverse effects and efficacy of Wenxin keli (WXKL)-amiodarone combination on heart failure complicated by ventricular arrhythmia.Methods: Nine electronic literature databases (the Cochrane Library, PubMed, EMBASE, IPA, AMED, CBM, CNKI, VIP, and WanFang) were searched up to February 2018. Two authors extracted data and assessed risk of bias of the included studies independently. Randomized controlled trials (RCTs) and quasi-RCTs about WXKL-amiodarone combination and amiodarone alone were eligible for comparison.Results: Thirteen trials involving 1,126 patients were included. Risk of bias was assessed as high in three studies and unclear in the remaining 10 studies. Six trials reported adverse events (AE). There was no obvious difference between WXKL-amiodarone combination group and amiodarone group in reported AEs (OR 0.64; 95%CI 0.39–1.07). The total effective rate of WXKL-amiodarone combination group was greater than that of amiodarone group (RR 1.22; 95%CI 1.16–1.29). The pooled results showed that the combination group was more effective in reducing heart rate (MD −2.25; 95%CI −2.61 to −1.88, P = 0.46, I2 = 0%), the frequency of ventricular premature complexes (MD −2.03; 95%CI −2.41 to −1.65) and QT dispersion (MD 5.59; 95%CI 3.60–7.58).Conclusion: The WXKL-amiodarone combination is safe and shows more protective effects on heart failure combined with ventricular arrhythmia compared with amiodarone alone. Further research is warranted, ideally involving large, prospective, rigorous trials, in order to confirm these findings.

Background: Premature ventricular contractions (PVCs) are common in the general population, and frequent PVCs may result in the poor quality of life or even the damage of cardiac function. We examined the efficacy and safety of a traditional Chinese medicine Wenxin Keli for the treatment of frequent PVCs among a relatively large Chinese cohort. Methods: We performed a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 1200 eligible participants were randomly assigned in a ratio of 1:1 to receive Wenxin Keli or the placebo for 4 weeks. The primary and secondary endpoint was the change of PVC numbers and PVC-related symptoms after a 4-week treatment compared with baseline, respectively. In addition, vital signs, laboratory values, and electrocardiographic parameters were assessed in a safety analysis. Results: At the initial evaluation, no significant differences in the baseline characteristics were observed between the Wenxin Keli group and the placebo group. A smaller number of PVCs was observed after the 4-week treatment than at baseline, in both the Wenxin Keli group (5686 ± 5940 vs. 15,138 ± 7597 beats/d, P < 0.001) and the placebo group (10,592 ± 8009 vs. 14,529 ± 5929 beats/d, P < 0.001); moreover, the Wenxin Keli group demonstrated a significantli greater reduction in the frequency of PVCs than the placebo group (P < 0.001). In a full analysis set, patients in the Wenxin Keli group exhibited significantly higher total effective responses in the reduction of PVCs compared to those in the placebo group (83.8% vs. 43.5%,P < 0.001). The per-protocol analysis yielded similar results (83.0% vs. 39.3%,P < 0.001). Treatment with Wenxin Keli also demonstrated superior performance compared to the placebo with respect to PVC-related symptoms. No severe adverse effects attributable to Wenxin Keli were reported. Conclusions: Wenxin Keli treatment effectively reduced the overall number of PVCs and alleviated PVC-related symptoms in patients without structural heart diseases and had no severe side effects.

Background An increase in the late sodium current (INaL) causes intracellular Na+ overload and subsequently intracellular Ca2+ ([Ca2+]i) overload via the stimulated reverse Na+-Ca2+ exchange (NCX). Wenxin Keli (WXKL) is an effective antiarrhythmic Chinese herb extract, but the underlying mechanisms are unclear. Methods and results The INaL, NCX current (INCX), L-type Ca2+ current (ICaL), and action potentials were recorded using the whole-cell patch-clamp technique in rabbit ventricular myocytes. Myocyte [Ca2+]i transients were measured using a dual excitation fluorescence photomultiplier system. WXKL decreased the enhanced INaL, reverse INCX, diastolic [Ca2+]i, and the amplitude of Ca2+ transients induced by sea anemone toxin II (ATX II, a specific INaL channel opener) in a concentration-dependent manner. Hypoxia increased INaL, INCX, and diastolic [Ca2+]i, and decreased amplitude of [Ca2+]i transients. Hypoxia-reoxygenation aggravated these changes and induced spontaneous [Ca2+]i transients and hypercontraction in 86% cells (6/7). The application of WXKL during hypoxia or reoxygenation periods decreased the increased INaL, INCX, and diastolic [Ca2+]i, and prevented those events in 82% cells (9/11) under hypoxia-reoxygenation conditions. WXKL also inhibited the ICaL in a dose-dependent manner. Furthermore, WXKL shortened the action potential duration and completely abolished ATX II-induced early afterdepolarizations from 9/9 to /9. In isolated heart electrocardiogram recordings, WXKL inhibited ischemia-reperfusion induced ventricular premature beats and tachycardia. Conclusions WXKL attenuated [Ca2+]i overload induced by hypoxia-reoxygenation in ventricular myocytes through inhibiting INaL and ICaL and prevents arrhythmias. This could, at least partly, contribute to the antiarrhythmic effects of WXKL. [ABSTRACT FROM AUTHOR]

Background An increase in the late sodium current (INaL) causes intracellular Na+ overload and subsequently intracellular Ca2+ ([Ca2+]i) overload via the stimulated reverse Na+-Ca2+ exchange (NCX). Wenxin Keli (WXKL) is an effective antiarrhythmic Chinese herb extract, but the underlying mechanisms are unclear. Methods and results The INaL, NCX current (INCX), L-type Ca2+ current (ICaL), and action potentials were recorded using the whole-cell patch-clamp technique in rabbit ventricular myocytes. Myocyte [Ca2+]i transients were measured using a dual excitation fluorescence photomultiplier system. WXKL decreased the enhanced INaL, reverse INCX, diastolic [Ca2+]i, and the amplitude of Ca2+ transients induced by sea anemone toxin II (ATX II, a specific INaL channel opener) in a concentration-dependent manner. Hypoxia increased INaL, INCX, and diastolic [Ca2+]i, and decreased amplitude of [Ca2+]i transients. Hypoxia-reoxygenation aggravated these changes and induced spontaneous [Ca2+]i transients and hypercontraction in 86% cells (6/7). The application of WXKL during hypoxia or reoxygenation periods decreased the increased INaL, INCX, and diastolic [Ca2+]i, and prevented those events in 82% cells (9/11) under hypoxia-reoxygenation conditions. WXKL also inhibited the ICaL in a dose-dependent manner. Furthermore, WXKL shortened the action potential duration and completely abolished ATX II-induced early afterdepolarizations from 9/9 to /9. In isolated heart electrocardiogram recordings, WXKL inhibited ischemia-reperfusion induced ventricular premature beats and tachycardia. Conclusions WXKL attenuated [Ca2+]i overload induced by hypoxia-reoxygenation in ventricular myocytes through inhibiting INaL and ICaL and prevents arrhythmias. This could, at least partly, contribute to the antiarrhythmic effects of WXKL. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of Wenxin Keli (WXKL) alone or combined with Western medicine in treating ventricular premature complexes (VPCs) with heart failure (HF).Methods: We searched five databases to identify relevant randomized controlled trials (RCTs) published before May 2016. Two review authors independently searched and screened the literature, extracted the data as well as assessed the methodological quality of the included studies by using criteria from the Cochrane Handbook, and analyzed via using Review Manager 5.3 software.Results: Eight studies of WXKL were included. The results of the Meta-analysis showed that WXKL was more significant on the frequency of VPCs (MD=-427.08, 95% CI: -526.73∼-327.43, P<0.01), left ventricular ejection fraction (LVEF) (MD=-4.12, 95% CI: 2.97∼5.27, P<0.01), the total effect of VPCs (RR=0.48, 95% CI: 0.34∼0.69, P<0.01) and 6-min walking test (MD=28.05, 95% CI: 19.56∼36.54, P<0.01). The treatment group presented a significant reduction at left ventricular end-diastolic diameter (LVED) (MD=-3.94, 95% CI: -6.57∼-1.31, P<0.01) when treatment time was 12 weeks, however, there was no statistical difference at 8 weeks. In addition, the included trials generally showed low methodological quality.Conclusions: Wenxin Keli may be effective and safe for treating VPCs and HF. However, further RCTs of larger scale, multi-center/country, longer follow-up periods, and higher quality are still required to verify the efficacy of Wenxin Keli in ventricular premature beat with heart failure. [ABSTRACT FROM AUTHOR]

Background: To evaluate the efficacy and safety of the Chinese herbal extract Wenxin Keli, alone or in combination with Western medicine, for ventricular premature beats.Methods: This systematic review was registered at PROSPERO (registration number CRD42013003200). A systematic literature search of 8 core electronic databases and 3 clinical trial registries in Chinese and English, yielded 10 trials whose randomness verified by contacting the authors. The included trials were assessed by the Cochrane risk of bias tool.Results: Wenxin Keli might be more efficacious than placebo (Change of VPBs numbers, RR, 1.61, 95%CI, 1.48-1.76, P<0.00001, I2=0%;VPBs- related symptom, RR, 2.10, 95%CI, 1.91-2.30, P<0.00001, I2=0%), and the dual therapy of Wenxin Keli plus amiodarone might also be more effective than the monotherapy of amiodarone (Change of VPBs numbers, RR, 1.23, 95%CI, 1.10-1.39, P=0.0005, I2=0%; VPBs- related symptom, RR, 1.51., 95%CI, 1.30-1.76, P<0.00001, I2=0%), whereas Wenxin Keli might be comparable to metoprolol, propafenone or mexiletine (Change of VPBs numbers: metoprolol, RR, 1.01, 95%CI, 0.91-1.11, P=0.88, I2=0%; propafenone, RR, 1.05, 95%CI, 0.93-1.19, P=0.44, I2=0%; mexiletine, RR, 1.06, 95%CI, 0.96-1.17, P=0.28. VPBs- related symptom: metoprolol, RR, 0.95, 95%CI, 0.87-1.04, P=0.27, I2=0%, propafenone. RR, 1.10, 95%CI, 0.93-1.30, P=0.29, I2=29%, mexiletine,RR, 0.94, 95%CI, 0.78-1.12, P=0.47). Participants with ventricular premature beats' numbers<360 beats/h or with coronary heart disease benefited the most of the Wenxin Keli therapy (Change of VPBs numbers:RR, 1.10, 95%CI, 1.02-1.20, P=0.02, I2=44%; RR, 1.71, 95%CI, 1.18-2.49, P=0.005, I2=54%, respectively). The safety analysis revealed that Wenxin Keli did not statistically significant differed from the Western medicine in respect of the incidence of total adverse drug reactions (RR, 0.59, 95%CI, 0.35-1.01, P=0.05, I2=0%), but Wenxin Keli might be associated with a reduced risk of proarrhythmic reactions (P=0.007). The quality of the methodology of included trials was generally low. Several limitations existed that affected the validity of the findings, including the small sample size, insufficient randomization methods, poorly defined eligibility criteria, short duration of follow-up, absence of hard endpoints, and high risk of publication bias(P=0.013).Conclusions: Wenxin Keli might be a promising alternative and complementary medicine for ventricular premature beats. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that WenXin KeLi (WXKL), a traditional Chinese medicine, can exert antiarrhythmic properties through complex multichannel inhibition, but its pharmacologic effect remains to be elucidated, especially in the cardiac conductive system.Objective: To explore the antiarrhythmic property of WXKL in cardiac Purkinje cells (PCs).Methods: PCs were isolated from rabbit hearts and action potentials (APs) and ion currents were recorded by whole-cell patch clamp technique. Anemonia toxin II (ATX-II) and isoproterenol (ISO) were used to induce early or delayed afterdepolarizations (EADs, DADs) or triggered activities (TAs).Results: WXKL (1 g/L and 5 g/L) significantly abbreviated the action potential duration (APD) of PCs in a dose- and rate-dependent manner. Treatment of PCs with ATX-II (2 nM) prolonged APD and induced EADs, which were significantly suppressed by WXKL. WXKL (1, 5 g/L) also inhibited ISO-induced EADs, DADs, and TAs. To reveal the ionic mechanisms, we studied the effects of WXKL on late sodium current (I(NaL)), peak sodium current (I(NaP)), and L-type calcium currents (ICaL) in PCs. WXKL-attenuated ATX-II (5 nM) induced I(NaL) augmentation and blocked I(NaL) with an IC50 of 4.3 ± 0.5 g/L, which is 3- to 4-fold more selective than that of I(NaP) (13.3 ± 0.9 g/L) and ICaL (17.6 ± 1.4 g/L). Moreover, WXKL exerted significantly less use-dependent block of I(NaP) than that of flecainide, indicating its lower proarrhythmic effect.Conclusions: WXKL exhibits antiarrhythmic properties in cardiac PCs via selective inhibition of I(NaL). [ABSTRACT FROM AUTHOR]

Atrial fibrillation significantly increases the risk of thromboembolism and stroke. Wenxin Keli (WXKL) is a widely used Chinese patent medicine against arrhythmia but if it has antithrombotic activity is unknown. Since platelet activation is a critical factor in thrombosis and the key target for many antithrombotic drugs, this study aims to demonstrate the antithrombotic efficacy of WXKL. In vitro platelet activation experiments showed that WXKL significantly inhibited platelet adhesion and aggregation. The potential active monomers in WXKL were screened by in silico prediction and in vitro platelet aggregation/adhesion assays. From WXKL chemical fractions and more than 40 monomers, linoleic acid (LA) was identified as the strongest antiplatelet compound. Oral administration of WXKL (1.2 g/kg/day) and LA (50 mg/kg/day) for 7 days significantly improved FeCl3-induced carotid thrombus formation in ICR mice without prolonging bleeding time. Flow cytometry showed that both WXKL and LA inhibited the release of p-selectin after platelet activation. ELISA showed that WXKL and LA also inhibited the expression of 6-Keto-PGF1α in plasma of mice with thrombus, but had no obvious effect on the expression of TXB2. WXKL inhibited platelet activation by broadly inhibiting the phosphorylation of protein kinase B (Akt), mitogen-activated protein kinases (MAPKs) and phospholipase C (PLC) β3. In contrast, LA only inhibited the phosphorylation of PLCβ3. In conclusion, WXKL and its active component LA showed good antiplatelet and antithrombotic efficacy in vivo and in vitro. Mechanistically, the multicomponent Chinese medicine WXKL acts on multiple targets in the platelet activation pathway whereas its active monomer linoleic acid acts specifically on phospholipase C β3. [Display omitted] • Anti-arrhythmic compound Chinese medicine Wenxin Keli has significant antithrombotic effect in vitro and in vivo, providing an experimental basis for its use in treatment of myocardial infarction. • Antithrombotic activity screen of WXKL components identified linoleic acid as a main active ingredient. • WXKL and its active ingredient linoleic acid exert antithrombotic effect via selectively inhibiting P-selectin-mediated platelet activation. [ABSTRACT FROM AUTHOR]

Background Wenxin Keli is a popular Chinese herb extract that approximately five million Asians are currently taking for the treatment of a variety of ventricular arrhythmias. However, its electrophysiological mechanisms remain poorly understood. Methods and results The concentration-dependent electrophysiological effects of Wenxin Keli were evaluated in the isolated rabbit left ventricular myocytes and wedge preparation. Wenxin Keli selectively inhibited late sodium current (INa) with an IC50 of 3.8 ± 0.4 mg/mL, which was significantly lower than the IC50 of 10.6 ± 0.9 mg/mL (n = 6, P < 0.05) for the fast INa. Wenxin Keli produced a small but statistically significant QT prolongation at 0.3 mg/mL, but shortened the QT and Tp-e interval at concentrations ≥1 mg/mL. Wenxin Keli increased QRS duration by 10.1% from 34.8 ± 1.0 ms to 38.3 ± 1.1 ms (n = 6, P < 0.01) at 3 mg/mL at a basic cycle length of 2,000 ms. However, its effect on the QRS duration exhibited weak use-dependency, that is, QRS remained less changed at increased pacing rates than other classic sodium channel blockers, such as flecainide, quinidine, and lidocaine. On the other hand, Wenxin Keli at 1-3 mg/mL markedly reduced dofetilide-induced QT and Tp-e prolongation by attenuation of its reverse use-dependence and abolished dofetilide-induced early afterdepolarization (EAD) in four of four left ventricular wedge preparations. It also suppressed digoxin-induced delayed afterdepolarization (DAD) and ventricular tachycardias without changing the positive staircase pattern in contractility at 1-3 mg/mL in a separate experimental series (four of four). Conclusions Wenxin Keli suppressed EADs, DADs, and triggered ventricular arrhythmias via selective inhibition of late INa. [ABSTRACT FROM AUTHOR]

Fangji is an ancient combinatorial formula. The compatibility mechanisms that how component herbs of Fangji work cooperatively to achieve the executive framework remain unexplored. Toexplore compatibility mechanism and systematical effects of Fangjis by taking Wenxin Keli decoction (WXKL), a classical Fangji constituted by Codonopsis Radix, PolygonatiRhizoma, Notoginseng Radix Et Rhizoma, Ambrum, and Nardostachyos Radix Et Rhizoma., as example. Here, we employed bioinformatics approach, including cluster analysis, cooperative module pair analysis, primary module identification, and proximity examination among target profile of herbs, to investigate compatibility characterization and anti-arrhythmia mechanism of WXKL. Finally, core mechanisms of WXKL were validatedby in vivo experiments. As a result, we identified 695 putative target proteins and 27 clusters (W-modules) inWXKL target network (W-network), in which W-module 1, 2, 4, 8, 10 were primary modules. The cooperative module pairs were W-module 2 and 4, W-module 2 and 8, and W-module 2 and 1, all of which existed in Codonopsis Radix- or Notoginseng Radix Et Rhizoma.-condition. And Nardostachyos Radix Et Rhizoma only yielded cooperation between W-module 1 and 2. The proximity of herbs' target profiles of Codonopsis Radix and Notoginseng Radix Et Rhizoma were similar, and Nardostachyos Radix Et Rhizoma and Ambrum were similar. For the compatibility framework, Codonopsis Radix general regulated 70.67% targets and majority W-modules (81.48%) as sovereign herb, contributing to primary therapeutic effect, mainly involving neurohormonal regulation, vasomotor, inflammation and oxidative stress. Other herbs assisted Codonopsis Radix to enhance major outcomes through common modules, and acted as complementary roles through unique process including mitotic cell cycle, biosynthetic and catabolic process, etc. Furthermore, WXKL regulated 66.67% hub proteins of arrhythmia-network, 68.18% and 47.37% proteins in primary arrhythmia-module 1 and 2, mainly involving ion channel activity, neurohormonal regulation, and stress response processes, to constitute regulatory network focusing on cardiovascular, renal, nervous system, to reverse the pathological process of arrhythmia. In vivo experiments demonstrated WXKL can attenuate adrenergic activation induced sympathetic atrial fibrillation by inhibiting calmodulin expression (CaM) and ryanodine receptor 2 (RYR2) phosphorylation to regulate neurohormonal action. This strategy provided an overarching view of anti-arrhythmia mechanism of WXKL and its internal compatibility, and may facilitate the understanding of compatibility in Fangjis from the perspectives of modern biology. [Display omitted] • We introduce an approach for systematical exploration of interaction and integration among herbs' target sets of fangjis. • This strategy may facilitate the understanding of compatibility mechanism that how herbs of a fangji work cooperatively. • This may improve the network-based drug discovery for fangjis as a combinatorial therapy. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the major public health problem and a leading cause of morbidity and mortality on a global basis. Wenxin Keli (WXKL), a formally classical Chinese patent medicine with obvious efficacy and favorable safety, plays a great role in the management of patients with CVDs. Accumulating evidence from various animal and cell studies has showed that WXKL could protect myocardium and anti-arrhythmia against CVDs. WXKL exhibited its cardioprotective roles by inhibiting inflammatory reaction, decreasing oxidative stress, regulating vasomotor disorders, lowering cell apoptosis, and protection against endothelial injure, myocardial ischemia, cardiac fibrosis, and cardiac hypertrophy. Besides, WXKL could effectively shorten the QRS and Q-T intervals, decrease the incidence of atrial/ventricular fibrillation and the number of ventricular tachycardia episodes, improve the severity of arrhythmias by regulating various ion channels with different potencies, mainly comprising peak sodium current (I Na ), late sodium current (I NaL ), transient outward potassium current (I to ), L-type calcium current (I CaL ), and pacemaker current (I f ).

Objectives: To evaluate possible adverse effects and efficacy of Wenxin keli (WXKL)-amiodarone combination on heart failure complicated by ventricular arrhythmia. Methods: Nine electronic literature databases (the Cochrane Library, PubMed, EMBASE, IPA, AMED, CBM, CNKI, VIP, and WanFang) were searched up to February 2018. Two authors extracted data and assessed risk of bias of the included studies independently. Randomized controlled trials (RCTs) and quasi-RCTs about WXKL-amiodarone combination and amiodarone alone were eligible for comparison. Results: Thirteen trials involving 1,126 patients were included. Risk of bias was assessed as high in three studies and unclear in the remaining 10 studies. Six trials reported adverse events (AE). There was no obvious difference between WXKL-amiodarone combination group and amiodarone group in reported AEs (OR 0.64; 95%CI 0.39-1.07). The total effective rate of WXKL-amiodarone combination group was greater than that of amiodarone group (RR 1.22; 95%CI 1.16-1.29). The pooled results showed that the combination group was more effective in reducing heart rate (MD -2.25; 95%CI -2.61 to -1.88, P = 0.46, I 2 = 0%), the frequency of ventricular premature complexes (MD -2.03; 95%CI -2.41 to -1.65) and QT dispersion (MD 5.59; 95%CI 3.60-7.58). Conclusion: The WXKL-amiodarone combination is safe and shows more protective effects on heart failure combined with ventricular arrhythmia compared with amiodarone alone. Further research is warranted, ideally involving large, prospective, rigorous trials, in order to confirm these findings.

Background: An increase in the late sodium current (I NaL ) causes intracellular Na + overload and subsequently intracellular Ca 2+ ([Ca 2+ ] i ) overload via the stimulated reverse Na + -Ca 2+ exchange (NCX). Wenxin Keli (WXKL) is an effective antiarrhythmic Chinese herb extract, but the underlying mechanisms are unclear., Methods and Results: The I NaL , NCX current (I NCX ), L-type Ca 2+ current (I CaL ), and action potentials were recorded using the whole-cell patch-clamp technique in rabbit ventricular myocytes. Myocyte [Ca 2+ ] i transients were measured using a dual excitation fluorescence photomultiplier system. WXKL decreased the enhanced I NaL , reverse I NCX , diastolic [Ca 2+ ] i , and the amplitude of Ca 2+ transients induced by sea anemone toxin II (ATX II, a specific I NaL channel opener) in a concentration-dependent manner. Hypoxia increased I NaL , I NCX , and diastolic [Ca 2+ ] i , and decreased amplitude of [Ca 2+ ] i transients. Hypoxia-reoxygenation aggravated these changes and induced spontaneous [Ca 2+ ] i transients and hypercontraction in 86% cells (6/7). The application of WXKL during hypoxia or reoxygenation periods decreased the increased I NaL , I NCX , and diastolic [Ca 2+ ] i , and prevented those events in 82% cells (9/11) under hypoxia-reoxygenation conditions. WXKL also inhibited the I CaL in a dose-dependent manner. Furthermore, WXKL shortened the action potential duration and completely abolished ATX II-induced early afterdepolarizations from 9/9 to /9. In isolated heart electrocardiogram recordings, WXKL inhibited ischemia-reperfusion induced ventricular premature beats and tachycardia., Conclusions: WXKL attenuated [Ca 2+ ] i overload induced by hypoxia-reoxygenation in ventricular myocytes through inhibiting I NaL and I CaL and prevents arrhythmias. This could, at least partly, contribute to the antiarrhythmic effects of WXKL., (© 2017 Wiley Periodicals, Inc.)

Objective: To evaluate the efficacy and safety of Wenxin Keli (WXKL) alone or combined with Western medicine in treating ventricular premature complexes (VPCs) with heart failure (HF)., Methods: We searched five databases to identify relevant randomized controlled trials (RCTs) published before May 2016. Two review authors independently searched and screened the literature, extracted the data as well as assessed the methodological quality of the included studies by using criteria from the Cochrane Handbook, and analyzed via using Review Manager 5.3 software., Results: Eight studies of WXKL were included. The results of the Meta-analysis showed that WXKL was more significant on the frequency of VPCs (MD=-427.08, 95% CI: -526.73∼-327.43, P<0.01), left ventricular ejection fraction (LVEF) (MD=-4.12, 95% CI: 2.97∼5.27, P<0.01), the total effect of VPCs (RR=0.48, 95% CI: 0.34∼0.69, P<0.01) and 6-min walking test (MD=28.05, 95% CI: 19.56∼36.54, P<0.01). The treatment group presented a significant reduction at left ventricular end-diastolic diameter (LVED) (MD=-3.94, 95% CI: -6.57∼-1.31, P<0.01) when treatment time was 12 weeks, however, there was no statistical difference at 8 weeks. In addition, the included trials generally showed low methodological quality., Conclusions: Wenxin Keli may be effective and safe for treating VPCs and HF. However, further RCTs of larger scale, multi-center/country, longer follow-up periods, and higher quality are still required to verify the efficacy of Wenxin Keli in ventricular premature beat with heart failure., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: The aim of the study was to evaluate the effectiveness, safety, and cost associated with Wenxin keli in the treatment of cardiovascular diseases based on meta-analysis., Methods: The terms "Wenxin keli" and "Wenxin" were used as the search terms in the PubMed, ProQuest, Springer, the Cochrane Library, CNKI (China National Knowledge Infrastructure), VIP (Chinese Scientific Journals Database), and Wan fang electronic databases (from January 2000 to October 2015). Relevant print journals and conference papers were also searched. Studies on randomized controlled trials (RCTs) of Wenxin keli used in the treatment of cardiovascular diseases were screened, and its indications were classified. Meta-analysis of these studies was conducted using the RevMan 5.2 software., Results: A total of 49 RCTs (n=4,610) were included, 29 of which focused on arrhythmia, seven on angina, seven on heart failure, two on viral myocarditis, and four on menopausal syndrome. Analysis of the therapeutic indications of Wenxin keli showed that it was comparatively more curative and effective than other available treatments for cardiovascular diseases., Conclusion: Wenxin keli showed better clinical efficacy in the treatment of arrhythmia, angina, and heart failure; however, more high-quality evidence is needed to support its use in the clinical setting., Competing Interests: The authors report no conflicts of interest in this work.

Background: The chronic effects of ganglionic plexi (GP) ablation on atrial fibrillation (AF) inducibility have not been elucidated., Objective: To investigate the effect of Wenxin Keli (WK) on the inducibility of AF and atrial substrate remodelling after epicardial GP ablation., Methods: Twenty dogs were randomly divided into a sham-operated group, a GP ablation group and a WK-treated group. All animals underwent a left thoracotomy at the fourth intercostal space. AF inducibility was assessed by burst rapid pacing at the right atrium. Both the GP ablation group and the WK-treated group received four major GP ablations. In the WK-treated group, dogs were treated with oral WK once per day, and all animals were allowed to recover for eight weeks, after which AF inducibility and AF duration were measured again., Results: After eight weeks of WK treatment, AF inducibility was lower than in the GP ablation group, and was similar to that of the sham-operated group. Compared with the sham-operated group, the levels of atrial natriuretic peptide (ANP), tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in right atrial tissues were increased in GP ablation group (143.6±33.7 pg/mg versus 206.2±41.4 pg/mg, P=0.02; 75.3±12.1 pg/mg versus 141.3±64 pg/mg, P=0.03; and 175.1±42.5 pg/mg versus 351.7±101 pg/mg, P<0.01, respectively). There were no significant differences in levels of ANP, TNF-α and IL-6 in atrial tissues between the sham-operated group and WK treated group. Expression of connexin 43 in atrial tissues was increased after eight weeks of GP ablation, while WK administration inhibited connexin 43 remodelling., Conclusions: Epicardial GP ablation can induce atrial substrate remodelling, including Cx43 upregulation and increased levels of ANP, TNF-α and IL-6. These changes may be suppressed by long-term oral WK administration.