| BackgroundCardiovascular disease is the leading cause of death worldwide,and the prevalence of cardiovascular disease in China is still rising.Coronary heart disease(CHD)has become a major public health problem in China and even globally,and needs to be urgently addressed.Borderline Coronary Lesions(BCL)is a lesion with 30%-70%coronary stenosis under coronary angiography detection.At this stage,because the plaque causing the stenosis is mostly unstable,it is very easy to rupture and form thrombus causing myocardial infarction.Therefore,early intervention of critical lesions in coronary arteries is the key to prevent and treat coronary heart disease.From the analysis of Chinese medicine theory,the formation of atherosclerotic plaque is due to the weakening of internal qi or the attachment of phlegm,blood stasis and heat toxin on the blood vessel wall,the imbalance of local micro environment of blood vessels,the blockage of qi and blood,the poor circulation of qi,blood and fluid,and the loss of nourishment of heart vessels,and then the accumulation of phlegm,blood stasis and heat in the blood vessels.Xuanbi Antong Formula is formulated to invigorate blood circulation,resolve phlegm and clear heat,and has proven efficacy in clinical use.Therefore,in this study,a randomized double-blind placebo-parallel controlled clinical trial was used to investigate the clinical efficacy and safety of the method of invigorating blood,resolving phlegm and clearing heat in the treatment of phlegm,stagnation and heat interconnection in critical lesions of coronary arteries.At the same time,metabolomics techniques were used to identify and analyze the changes in the levels and types of small molecule metabolites before and after the intervention of Chinese medicine,to screen the plasma differential metabolites in patients with BCL before and after the intervention of Chinese medicine,and to reveal the expression profile of the mechanism changes at the molecular biology level,so as to provide a reliable basis for identifying metabolic markers for the diagnosis and treatment of BCL.ObjectiveTo observe the clinical effectiveness and medication safety of the method of activating blood,resolving phlegm and clearing heat in patients with BCL through clinical trials;to investigate the effect of the method of activating blood,resolving phlegm and clearing heat on the metabolic pathways of BCL through metabolomics to detect the differential changes of plasma metabolites before and after medication in patients in the treatment group.The study aimed to provide high-quality evidence to support the clinical practice of the method of activating blood,resolving phlegm and clearing heat to intervene in critical lesions of coronary arteries,and to explore the possible pharmacological mechanisms of action of Chinese medicine.Methods1.A randomized,double-blind,placebo-parallel controlled clinical trial of activating blood,resolving phlegm and clearing heat to intervene in critical lesions of coronary arteries.Sixty patients with coronary artery critical lesions with phlegm-stasis-heat interjunction evidence were clinically included,and were divided into test and control groups using the principle of randomized,double-blind,placebo-controlled clinical experiment.The test and control groups were given Xuanbi Antong Formula granules and placebo respectively on the basis of conventional Western medical treatment,and the duration of treatment for both groups was 6 months,with a follow-up of 6 months.The incidence of target plaque area stenosis,diameter stenosis,target plaque mean CT value,target plaque calcification score,blood lipid level,TCM evidence score,individual symptom-sign score,Seattle Angina Scale score,as well as vital signs,blood routine,urine routine,stool routine,liver function,kidney function and major adverse cardiovascular events within 6 months were observed before and after the trial.SPSS Statistics 26.0 was used for statistical analysis of the data,and the measurement data were expressed as mean±standard deviation or median and quartiles,the count data were expressed as number and percentage,and the statistical test was a two-sided test,and P<0.05 was considered a statistically significant difference.2.Exploring the intervention effect of blood activation,phlegm removal and heat clearing method on critical lesions of coronary arteries based on metabolomics technology.Twenty patients with good clinical results,with coronary artery stenosis between 30%and 70%by coronary angiography or coronary CTA,with clear TCM diagnosis and evidence of phlegm-stasis-heat interaction,were selected from the experimental group in Study one.Using non-targeted metabolomics techniques,the plasma differential metabolites before and after treatment were screened by liquid chromatography-mass spectrometry,and the matched endogenous differential metabolite names were analyzed by MetaboAnalyst 5.0 for metabolic pathway analysis using multidimensional statistical analysis,to observe the changes of plasma differential small molecule metabolites in patients before and after treatment with Xuanbi Antong Formula,and to investigate the relevant mechanism of drug action.Results1.Clinical study on the intervention of the method of activating blood,resolving phlegm and clearing heat in critical lesions of coronary arteries.The general baseline conditions such as gender,age,BMI,history of smoking and alcohol,type of angina pectoris,past history and combined medications were comparable between the two groups of subjects.As for the main outcome index plaque,the stenosis of the lumen area where the target plaque was located was significantly lower in the test group than before treatment(P=0.002),and the reduction was more significant in the test group than in the control group after treatment(P=0.026);the stenosis of the lumen diameter where the target plaque was located was significantly lower in the test group than before treatment(P=0.001),and the differences between the groups was not significant;the calcification score of the target plaque in the test group after treatment was There was a statistically significant difference in the mean CT values of the target plaques in the test group before and after treatment(P=0.006).In terms of lipid levels,TG and VLDL indexes in the Xuanbi Antong Formula test group decreased(P<0.05);in terms of symptom efficacy,the test group could significantly improve the TCM clinical symptoms of chest pain,chest tightness and phlegm in patients,and improve the degree of limitation of physical activity,stable state of angina,angina attack,treatment satisfaction and disease awareness in the Seattle Angina Scale(P<0.01 or P<0.05).With regard to safety,no adverse effects were observed in the two groups in terms of blood routine,liver and kidney function,and urine and stool routine.2.Plasma differential metabolism and pathway changes before and after intervention of activating blood,resolving phlegm and clearing heat method on critical lesions of coronary arteries.A total of 163 differential metabolites were screened in positive and negative ion mode.The main differential metabolites were phosphoenolpyruvate,dihydrosphingosine,L-homoserine,S1P sphingosine,3-dehydrosphingo sine,L-carnitine,tetraethyleneglycol monododecyl ether,and 3-hydroxyvaleric acid(VIP>1 and P<0.05).The key pathways enriched were sphingolipid metabolic pathway,glycine-serine-threonine metabolic pathway,cysteine and methionine metabolic pathway,which are mainly involved in the regulation of cell growth,differentiation,aging,programmed death and other signaling processes.Among them,sphingolipid signaling pathway(P<0.001)is the key pathway,and sphingolipids,ceramides,sphingosine and sphingosine 1-phosphate(VIP>1 and P<0.05)in sphingolipid metabolic pathway have the role of contributing to the inflammatory response and instability of atherosclerotic plaques,and are involved in the regulation of unstable plaques during the development of coronary artery disease.Conclusion1.The treatment of BCL with phlegm-stasis-heat interconnection using blood activation and phlegm-clearing treatment has good clinical efficacy and safety,2.The herbal medicine of activating blood,resolving phlegm and clearing heat can stabilize coronary plaque,improve the degree of coronary stenosis,reduce lipid TG and VLDL levels,improve symptoms of coronary artery disease such as chest pain and chest tightness,and improve patients’ quality of life.3.Based on Untargeted Metabolomics Analysis,the study of plasma differential metabolites in patients before and after treatment with Xuanbi Antong Formula revealed that multiple classes of differential metabolites are involved in regulating energy metabolism through different targets of action and signaling pathways,exerting antioxidant,antithrombotic and anti-inflammatory effects.Among them,sphingolipid metabolites such as sphingomyelin,ceramide,sphingosine and sphingosine 1-phosphate could affect the progression of atherosclerotic plaques. |
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