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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]

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. [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). [ABSTRACT FROM AUTHOR]

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 wasmore 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. [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]

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]