| 1.BackgroundVentricular premature contraction is also called ventricular premature beats,which refers to ectopic heart rhythms caused by premature contraction in the ventricle before the electrical impulse reaches the ventricle.Ventricular premature contraction is a clinical frequently-occurring disease.Among the elderly over 75,the incidence of Ventricular premature contraction is as high as 69%.Frequent or multi-source ventricular premature is likely to cause malignant arrhythmias such as ventricular tachycardia and ventricular fibrillation,which can lead to sudden cardiac death.Active treatment of ventricular premature beats can effectively reduce cardiovascular mortality.Clinical treatments for premature ventricular beats mainly include antiarrhythmic drugs and radiofrequency ablation.At present,the most commonly used drugs are sotalol,amiodarone,etc.But their clinical application is limited due to their side effects that cause arrhythmia.The long-term effective rate of radiofrequency ablation is about 75%,there is a certain recurrence rate,and it is an invasive operation,which is likely to cause a psychological burden on the patient.Therefore,in the current clinical treatment,drugs are still the main treatment method.Traditional Chinese medicine has good curative effects on the treatment of arrhythmia with low side effects.It has received increasing attention and recognition.It is the current clinical demand to promote the research of new Chinese herbal prescriptions and explore better methods for the treatment of ventricular premature beats.Professor Feng Ling used Chinese medicine to treat ventricular premature contraction under the guidance of the concept of body-mind unity,and the effect was remarkable.To further explored the core prescription and mechanism has certain clinical significance.2.PurposeThe research takes Professor Feng Ling’s clinical medical records for the treatment of ventricular premature beats as objects to organize Professor Feng Ling’s experience in treating ventricular premature beats under the guidance of the theory of body-mind unity.The purpose is to find the core prescription by data mining and determine the efficacy through retrospective research,and to reveal the mechanism of the treatment by means of network pharmacology and ion channel cell experiments.3.Methods3.1.Use data mining methods to collect the medical records of Professor Feng Ling from January 2019 to December 2020,and conduct frequency,correlation and cluster analysis of prescriptions through the traditional Chinese medicine inheritance computing platform V3.0 to find the core prescription.To filter the records,and include the cases that had continuous treatment for 8 weeks and had Holler examination information before and after treatment,to observe the efficacy of core prescriptions on ventricular premature beats.3.2 By means of network pharmacology to explore the mechanism of the core medicine in the core prescription obtained by data mining.The effective ingredients and targets of medicine are obtained through database mining and literature search.Through database mining,to find the targets of ventricular premature beats,take the intersection of the targets,and screen predictive targets.By means of protein interaction network construction,GO function enrichment analysis and KEGG signal pathway to analysis the mechanism of core prescription treatment of ventricular premature beats through.3.3 By means of whole-cell patch clamp technology;preparing cultured HEK293 and CHO cells and the core prescription(An Shen Ding lv Granule)working solution to performe electrophysiological recording.To explore the effects of different concentrations of alcohol extracts of the core prescription(An Shen Ding lv Granule)on hERG potassium channels,Kir2.1 channels,Kv 1.5 channel,Kv4.3 channel,KAch channels,KATP channels,and Nav1.5 Channel,Cav1.2 channel,Cav3.2 channel,HCN2 channel,HCN4 channel,IKs channel,Through the comparison of current peaks,4.Results4.1 Collect the diagnosis and treatment information of ventricular premature beats in the outpatient clinic of Guang’anmen Hospital by Professor Feng Ling from January 2019 to December 2020.A total of 220 cases were collected,and a total of 890 consultations were performed.Professor Feng Ling’s core prescription for the treatment of ventricular premature beats in the clinic contains 11 kinds of medicine.The prescription was named An Shen Ding lv Granule.This study analyzed the 24-hour Holter results before and after treatment of 60 patients with premature ventricular contractions who had been treated for more than 8 weeks.Among them,before treatment,20 people had more than 20,000 premature beats,and 38 people had more than 10,000 but less than 20,000 premature beats before treatment.They were treated withAn Shen Ding lv Granule.After 8 weeks,0 people had more than 20,000 premature beats,and 12 people had more than 10,000 but less than 20,000 premature beats,and 48 people had less than 10,000 premature beats.According to the criterion of efficacy,the results of the study show that after 8 weeks of treatment,the total effective rate was 86.67%,of which 33.33%were markedly effective and 53.33%were effective.The results show that the difference in total heart rate before and after treatment is statistically significant(P<0.01);before and after treatment,the frequency of premature ventricular contractions is statistically significant(P<0.01);the difference of heart rate variability index SDNN before and after treatment is statistically significant(P<0.01),indicating that An Shen Ding lv Granule can reduce the number of ventricular premature beats and significantly increase the number of ventricular premature patients SDNN,improving the function of the autonomic nerves of the heart and playing an anti-arrhythmic effect.4.2 This study conducted a network pharmacological mechanism study on the core medicines of Professor Feng Ling’s treatment core prescription(An Shen Ding lv Granule),and found 499 targets for core medicines and 896 targets for premature ventricular contractions.There are 112 targets for the intersection of medicines and premature beats.These 112 targets are the predictive targets of core medicines for the treatment of ventricular premature beats.The network of core medicines components and prediction targets show that the prediction targets are concentrated in quercetin,luteolin,bilene,aristolochne,angelin,cryptotanshinone and other components,and the targets of medicines are concentrated in sodium,calcium and potassium channels,suggesting that this formula may have a regulatory effect on sodium,calcium and potassium ion channels.It directly inhibits ion currents and reduces ventricular premature beats.It also has regulatory effects on neuromodulation genes.It may be the mechanism that An Shen Ding lv Granule regulate nerves.In addition,after constructing a protein interaction network for the predicted target,it was found that the target was concentrated on anti-inflammatory mechanisms.This prescription may have a better effect on ventricular premature beats caused by inflammation,such as myocardial ischemic premature ventricular beats.The GO enrichment analysis and signal pathway research found that the biological processes,molecular functions and cellular components of the target are concentrated in the cell membrane,ion channel transport-related genes,and the signal pathway includes the calcium ion signal pathway and the adrenaline signal pathway.Corresponding to the predicted target,it clarifies that An Shen Ding lv Granule has a regulatory effect on ion channels and the nervous system.4.3 The regulation of the alcohol extract of An Shen Ding lv Granule on ion channels is as follows:The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on hERG current,and the inhibition rate of hERG current at a concentration of 1 mg/mL is 66.51%±3.07%.The inhibitory rate of hERG current was 91.14%± 1.04%at the concentration of l0mg/mL.At a concentration of 0.1mg/mL,the effect is weak,and the inhibitory rate was not measured.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on Kir2.1 current.The inhibitory rate of Kir2.1 current at a concentration of 1 mg/mL is 2.85%±2.33%,and the inhibitory rate of Kir2.1 current at a concentration of 10 mg/mL is 22.67%± 3.43%,the effect is weak at a concentration of 0.1 mg/mL,and the inhibition rate has not been measured.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on Kv1.5 current.At a concentration of 1mg/mL,the inhibition rate of Kv1.5 current is 44.60%± 4.08%.At a concentration of 0.1mg/mL,the effect is weak.At a concentration of 10mg/mL,the damage to the cells is large,and the inhibition rate is not measured.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on Kv4.3 current.The inhibition rate of Kv4.3 current at a concentration of 1 mg/mL is 68.74%± 1.17%,and the inhibition rate of Kv4.3 current at a concentration of 10 mg/mL is 89.06%±3.33%,the effect is weak at 0.1mg/mL,and the inhibition rate is not measured.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on the KAch current.The inhibitory rate of the KAch current at a concentration of 1 mg/mL is 53.16%± 9.06%.The effect is weak at 0.1 mg/mL,and the cell damage is greater at a concentration of 10 mg/mL,so the inhibition rate has not been measured.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on KATP current.The inhibitory rate of KATP current is 79.94%±4.11%at a concentration of 1 mg/mL,and the inhibitory rate of KATP current is 93.11%±1.30%at a concentration of 10 mg/mL.The effect is weak at the concentration of 0.1mg/mL,and the inhibition rate has not been measured.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on the Nav1.5 current.The inhibition rate on the Nav 1.5 current at a concentration of 1 mg/mL is 67.36%± 0.64%,and the inhibition rate on the Nav1.5 current at a concentration of 10 mg/mL is 95.66%The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on Cav1.2 current.The inhibitory rate of Cav1.2 current at a concentration of 0.1 mg/mL is-2.32%±1.89%,and it inhibits Cav1.2 current at a concentration of 1 mg/mL.The rate was 6.84%±0.78%,and the inhibition rate of Cav1.2 current at a concentration of 10mg/mL was 25.55%±0.22%.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on Nav1.5 current.The inhibitory rate of the alcohol extract of An Shen Ding lv Granule on Nav1.5 current at a concentration of 1 mg/mL is 67.36%± 0.64%.And at a concentration of 10 mg/mL,the inhibition rate of Nav1.5 current is 95.66%±1.80%.At 0.1mg/mL concentration,the effect is weak,and the inhibition rate has not been measured.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on Cav3.2 current,the inhibition rate of Cav3.2 current at 0.1 mg/mL is 13.27%±0.76%,and the inhibition rate on Cav3.2 current at 1 mg/mL concentration is 82.62%±0.01%,the inhibition rate of Cav3.2 current is 100.00%at a concentration of 10mg/mL.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on HCN2 current.The inhibition rate of HCN2 current at 0.1 mg/mL is 1.78%± 4.32),and the inhibition rate of HCN2 current at 1 mg/mL is 28.01%± 3.85%.At a concentration of 10mg/mL,it will damage the cells greatly and easily lead to cell shedding,and the inhibitory rate has not been measured.The alcohol extract of An Shen Ding lv Granule has an inhibitory effect on HCN4 current.The inhibition rate of HCN4 current at 0.1 mg/mL is 25.18%±4.60%,and the inhibition rate of HCN4 current at 1 mg/mL is 40.63%± 3.62%.At a concentration of 10mg/mL,it will damage the cells greatly and easily lead to cell shedding,and the inhibitory rate has not been measured.The alcohol extract of An Shen Ding lv Granule has an activating effect on IKs current.The activation rate of IKs current at 0.1 mg/mL is 93.71%± 6.67%,and the activation rate of IKs current at 1 mg/mL is 199.28%± 4.15%,At a concentration of 10mg/mL,it will damage the cells greatly and easily lead to cell shedding,and the activation rate has not been measured.5.Conclusions5.1 Professor Feng Ling’s core prescription of traditional Chinese medicine for the treatment of ventricular premature contractions by adjusting the pulse and mind contains 11 medicines and is named An Shen Ding lv Granules.The retrospective study has shown that An Shen Ding lv Granules can reduce the number of ventricular premature beats,significantly increase SDNN in patients with premature ventricular contractions,improve cardiac autonomic nerve function,and play an anti-arrhythmic effect.5.2 The core medicine of An Shen Ding lv Granule may inhibit premature ventricular contractions by regulating sodium,potassium,and calcium ions and anti-inflammatory effects.The targets and pathways of the core drugs include CHRM1,CHRM2,CHRM3,SLC6A,and the signal pathway of adrenaline in cardiomyocytes,indicating that An Shen Ding lv Granule has a regulatory effect on the nervous system.These targets and pathway may be its mechanism of regulating mind.5.3 An Shen Ding lv Granule has inhibitory effects for the hERG potassium channel,Kir2.1 channel,Kv1.5 channel,Kv4.3 channel,KAch channel,KATP channel,Nav1.5 channel,Cav1.2 channel,Cav3.2 channel,HCN2 Channel,HCN4 channel and has activating effects on IKs channel. |
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