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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 2  |  Page : 247-256

Danhong injection improves elective percutaneous coronary intervention in ua patients with blood stasis syndrome revealed by perioperative metabolomics


1 Department of Critical Care Medicine, Zhuhai Hospital of Guangdong Provincial Hospital of Traditional Chinese Medicine, Zhuhai, China
2 Department of Cardiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
3 Department of Traditional Chinese Medicine, Capital Medical University, Beijing, China
4 State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China

Date of Submission08-Jun-2020
Date of Acceptance31-May-2021
Date of Web Publication30-Jun-2022

Correspondence Address:
Hong-Xu Liu
Department of Cardiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing
China
Wen-Long Xing
Department of Cardiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_63_21

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  Abstract 


Objective: To observe the effect of Danhong injection (DHI) on perioperative metabolomics of unstable angina pectoris (UA) with blood stasis syndrome. Materials and Methods: A prospective, randomized, controlled, and single-blind clinical trial was conducted. Sixty-one UA patients with traditional Chinese medicine blood stasis syndrome undergoing elective percutaneous coronary intervention (PCI) were randomly divided into the Danhong and control groups, and 10 healthy volunteers were included as baseline. The Danhong group received western medicine + DHI treatment, while the control group received western medicine + saline. Nontargeted metabolomics was used to analyze the serum metabolites of healthy volunteers in the Danhong and control groups before and 5 days after PCI. Results: Before treatment, there was no significant difference in serum metabolites between the Danhong and control groups, but there was a significant difference between the two groups and the healthy group. Differential metabolites were clustered mainly in glycerophospholipid, sphingolipid, purine, and amino acid groups, which were generated in their metabolic pathways. After 5 days of PCI, the profiles of serum metabolites were significantly closer between the Danhong-or control-treated groups and that of the healthy group. Furthermore, DHI treatment converted the serum metabolite profile more to that of the healthy group than the control treatment. Conclusion: The beneficial effect of DHI on patients with unstable angina is reflected at the level of serum metabolic biomarkers.

Keywords: Danhong injection, metabolomics, perioperative percutaneous coronary intervention, unstable angina pectoris


How to cite this article:
Niu Q, Xing WL, Wang YT, Zhu Y, Liu HX. Danhong injection improves elective percutaneous coronary intervention in ua patients with blood stasis syndrome revealed by perioperative metabolomics. World J Tradit Chin Med 2022;8:247-56

How to cite this URL:
Niu Q, Xing WL, Wang YT, Zhu Y, Liu HX. Danhong injection improves elective percutaneous coronary intervention in ua patients with blood stasis syndrome revealed by perioperative metabolomics. World J Tradit Chin Med [serial online] 2022 [cited 2022 Aug 8];8:247-56. Available from: https://www.wjtcm.net/text.asp?2022/8/2/247/349267




  Introduction Top


In recent years, percutaneous coronary intervention (PCI) has become one of the important treatments for coronary heart disease (CHD). In 2018, the annual number of PCI operations in mainland China exceeded 910,000, among which angina pectoris (UA) patients accounted for 66.73%. The widespread use of PCI has also raised concerns on its clinical problems, such as no reflow, slow blood flow, perioperative myocardial injury (PMI), and reperfusion injury.

PMI refers to the high level of biomarkers associated with myocardial injury after PCI, which has a complex mechanism. Current intervention procedures cannot avoid the occurrence of PMI,[1] which provide space for the prevention and treatment by traditional Chinese medicine (TCM). Previous studies have shown that Danhong injection (DHI) has a potential myocardial protective effect during perioperative PCI.[2] Recent studies have revealed the myocardial protective mechanism and pharmacological effects of DHI during perioperative PCI, such as anti-inflammation, improvement of microcirculation, anti-oxidative stress, anticoagulation, and promotion of angiogenesis.[3],[4],[5] However, due to the complexity of TCM, there are still some deficiencies in explaining the mechanism of DHI based on the exploration of a single mechanism. On the other hand, PMI has a complicated occurrence mechanism. If a single pathological and physiological indicator is selected for the study based on a specific mechanism, it has certain limitations in explaining the overall picture of disease development.

Metabolomics is an overall method for studying the change in metabolic products and metabolic pathways to explore pathophysiological changes, with the characteristics of integrity, dynamic, and real-time. As the development and improvement of metabolomic techniques continue, it is increasingly applied in TCM research.[6] It is possible to avoid these limitations using metabolomics, and there was no similar study conducted before. Thus, this study explored the possible myocardial protective mechanism of DHI by nontargeted metabolomics using clinically relevant patient samples.


  Materials and Methods Top


Diagnostic criteria of western medicine

  1. The UA diagnostic criteria refer to the guidelines on emergency rapid diagnosis and treatment of acute coronary syndrome issued by the emergency physicians and cardiovascular branches of the Chinese Medical Association in 2016[7] and the guidelines on the diagnosis and treatment of acute coronary syndrome issued by the cardiovascular branch of the Chinese Medical Association in 2016[8]
  2. PCI was treated according to the “guidelines for PCI in China (2016)”[9] issued by the interventional cardiology group under the cardiovascular branch of the Chinese Medical Association
  3. The diagnostic criteria of PMI are in accordance with the fourth edition of the new global definition of myocardial infarction jointly released by ESC/ACC/AHA/WHF in 2018.[10]


TCM diagnostic criteria

The diagnostic criteria of TCM patients with chest pain and blood stasis were formulated according to the national standard of the People's Republic of China-TCM clinical diagnosis and treatment terms syndrome.[11]

Inclusion criteria

(1) Accordance with the UA diagnostic criteria; (2) Accordance with the TCM diagnostic criteria; (3) Aged 18–86 years; (4) Patients to receive PCI; (5) Patients did not take any TCM preparations regularly 2 weeks before admission; and (6) Subject or their legal representative shall sign the informed consent of this study.

Exclusion criteria

(1) Patients with acute stroke, history of intracerebral hemorrhage, severe primary diseases such as liver, kidney and hematopoietic system, and mental illness (2) Combination with other diseases that can cause elevated levels of muscle enzymes or myocardial enzymes, such as myocarditis, heart failure, skeletal muscle injury; (3) Patients with chronic cardiac insufficiency and left ventricular ejection fraction of <40%; (4) Patients with severe infectious diseases, autoimmune diseases, and tumors; (5) Patients known to be allergic to DHI; (6) Patients with TCM preparations containing ingredients for activating blood circulation and removing stasis should be applied during the observation period.

Elimination criteria

(1) Those who were found to be not in conformity with the UA diagnostic criteria or coronary imaging criteria after inclusion and were mistakenly included (2) After inclusion, improvement of coronary angiography to show vascular lesions requires coronary artery bypass grafting, or the surgeon judges that PCI was unnecessary, or the patient refused to accept PCI; (3) Taking other proprietary Chinese medicine or TCM decoction during the test. The reasons for the eliminated cases were recorded, which were kept without statistical analysis of the curative effect. However, those who had received treatment and had safety records were included in the safety analysis as appropriate.

Discontinuation criteria

(1) The occurrence of allergy indications, which are considered to be caused by the test drug; (2) Those who need to readjust the treatment plan due to major sudden changes in the condition; and (3) Other unpredictable emergencies.

Termination criteria

(1) Serious safety problems occur in the test, such as severe liver and kidney function impairment and abnormal blood coagulation related to the test drug; (2) If there is evidence that the test drug is ineffective and has no clinical value, the test should be terminated to avoid delaying the effective treatment of the subject and avoiding unnecessary economic losses; (3) The safety of test subjects cannot be guaranteed for some reason; (4) If it was found in the experiment that there were major mistakes in the scheme that makes it difficult to evaluate the drug effect, or the implementation of the program resulted in a major deviation that makes it difficult to continue the evaluation. Approval Number of Ethics Committee (20171020).

General information

The subjects were UA patients with blood stasis syndrome who underwent PCI from July 2018 to January 2019 in the Beijing TCM Hospital affiliated to the Capital Medical University. A total of 61 patients were enrolled, including 31 in the Danhong group and 30 in the control group. There was no significant difference in sex, age, risk factors, and other baseline data between the Danhong and control groups (P > 0.05), indicating comparability.

In addition, 10 healthy subjects were included as the baseline group. They were healthy volunteers who underwent routine physical examination from June 2018 to December 2018 in the physical examination center of the Beijing TCM Hospital affiliated to the Capital Medical University. They were aged 45–85 years and in good health. There were no significant differences in sex and age between the Danhong group and the baseline group.

Research methods

Randomization and blinding

This study was designed as a prospective, randomized, controlled, and single-blind clinical trial. We set and selected 180 random numbers generated by random seeds, with 120 prestored supplement doses. The 180 random numbers were arranged into rank order and then divided into groups according to the parity of rank order. Those with odd numbers were assigned to the Danhong group, while those with even numbers were assigned to the control group. The distribution sequence table, which was the rank matching with the random number, corresponded to the test group. According to the order of enrollment, the serial number in the ascending order and the corresponding drugs were assigned to patients by their attending physicians. Personal information of each subject and the number of obtained drugs were recorded. Nurses were responsible for each usage and record of the drugs, and records were kept for checking the possible problems during and at the end of the test. In both groups, brown bags to cover the infusion bottles and brown infusion apparatus were used to keep the subjects in a blind state.

Intervention

Both groups received standard western medicine treatment according to the guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndrome (2016).[8] Before PCI, the Danhong group was given 40 mL DHI + 250 mL saline, via intravenous drip (drip rate controlled at approximately 100 mL/h), twice daily for 2–3 days. After PCI paracentesis, DHI was used once, and postoperative application should not be <5 days. The control group was treated with 40 mL saline + 250 mL saline at the same time point.

Serum sample collection and preliminary treatment

Fasting serum samples were collected from healthy subjects, and serum samples were collected from the Danhong and control groups before and 5 days after PCI. Serum samples of all patients and healthy subjects were collected in the fasting state, more than 8 h after the meal, without using other TCM or TCM preparations that promotes blood circulation and removes stasis, and without drinking strong tea, coffee, and other beverages within 1 week. Then, 4 mL of venous blood was collected at room temperature by the nurse using a coagulant tube. Blood samples were naturally coagulated for 1 h at room temperature, centrifuged at 3,000 rpm for 10 min at 4°C, and the supernatant was collected and stored in a freezer at −80°C for later testing.

Observation indices of curative effect

Change in creatine kinase-MB level and incidence of perioperative myocardial injury during perioperative percutaneous coronary intervention

The changes in creatine kinase-MB (CK-MB) during the perioperative period of PCI in the two groups were observed, and the occurrence of PMI in the two groups was compared and analyzed.

Major cardiovascular events 30 days after surgery

The incidence of major adverse cardiac events (MACE) within 30 days after surgery was recorded by telephone follow-up, WeChat follow-up, outpatient follow-up, etc. In this study, the MACE included recurrent angina pectoris, recurrent myocardial infarction, coronary revascularization, non-fatal stroke, and all-cause death.

Statistical method

SPSS 15.0 (PN: 32119001, SN: 5045602) statistical software (Chicago, IL,USA) was used for data analysis. Measurement data were expressed as mean ± standard deviation (x¯ ± s). The t-test was used for the comparison of continuous variables with normal distribution and homogeneity of variance between the two groups, and the paired sample t-test was used for comparison between the two groups before and after surgery. Enumeration data were expressed as percentage, and comparison between groups was performed by χ2 test. P < 0.05 was defined as a statistically significant difference.

Metabolomics methods

Samples were analyzed by the ultra-high performance liquid chromatography with quadrupole/time-off-flight mass spectrometer (UPLC-Q/TOF-MS).

Preparation of serum samples

Samples to be tested were taken out of the −80°C freezer and thawed in ice water at 4°C for 30–60 min. In a 1.5-mL labeled centrifuge tube, 100 μL of serum and 200 μL of acetonitrile were mixed, fully oscillated for 10 min for protein precipitation, centrifuged at 12,000 rpm, 4°C for 10 min, and 100 μL top solution was transferred into a 200 μL lining tube for test.

Chromatographic conditions

Thermo Scientific U3000 ultra-rapid liquid chromatography was used to analyze the samples by reversed-phase chromatography. The conditions of the gradient system are shown in [Table 1] of attachment.
Table 1: Comparison of basic data of included subjects

Click here to view


Separation conditions of reversed-phase chromatography

Waters UPLC HSS T3 (1.8 μm, 2.1 mm × 100 mm) was used as the chromatographic column with the following mobile phase settings: A (methanol, 0.1% formic acid, 10 mM ammonium acetate) and B (water, 0.1% formic acid, 10 mM ammonium acetate). Elution procedure with a flow rate of 0.3 mL/min; injection volume of 1.0 L and column temperature of 50°C, as shown in [Table 1] of attachment.

Hydrophilic chromatographic separation conditions

Waters UPLC BEH Amide (1.7 μm, 2.1 mm × 100 mm) was used as the chromatographic column with the following mobile phase settings: A (acetonitrile, 0.1% formic acid, and 10 mM ammonium acetate) and B (water, 0.1% formic acid, 10 mM ammonium acetate). The elution procedure includes a flow rate of 0.3 mL/min, injection volume of 1 L, and column temperature of 40°C, as shown in [Table 2] of attachment.
Table 2: Comparison of perioperative myocardial injury incidence

Click here to view


Mass spectrometry conditions

Mass spectrometry was performed using a quadrupole orbiting ion trap mass spectrometer equipped with a thermoelectric spray ion source (Q Exactive, ThermoFisher Scientific), with the following parameters: Voltage of the positive ion source, 3.7 kV; capillary heating temperature, 320°C; warping pressure, 30 psi; auxiliary pressure, 10 psi; volume heating evaporation temperature, 300°C; warping gas, auxiliary gas, and collision gas was nitrogen; and collision gas pressure, 1.5 mTorr. The first full scan parameters were as follows: Resolution 70,000; automatic gain control target, 1 × 106; maximum isolation time, 50 ms; and mass-to-charge scanning range, 50-1,500 da. The liquid mass system was controlled by the Xcalibur 2.2 SP1.48 software.

Identification of differential metabolic markers

According to the first order accurate molecular weight of differentially selected substances and MS/MS secondary scanning of the quality control samples, we obtained the second order mass spectrogram. Online database HMDB was searched to compare the mass-to-charge ratio (m/z) or accurate molecular mass of mass, with an error limit of 0.01 da. The secondary spectrum and molecular weight of the corresponding metabolites were obtained through structural derivation, and the preliminary results were finally identified by comparing with the MS/MS mass spectrometry of the standard.

Metabolomics indicators

By analyzing the metabolomic indices of the Danhong, control, and healthy groups, the possible regulatory effect of DHI on the perioperative metabolites and pathways of PCI in patients with UA blood stasis syndrome were explored.

Statistical analysis method of metabolomics data

The collected liquid-mass spectrometry data were processed by Progenesis QI software, and the original data were imported, with peak alignment, peak extraction, and normalization, to form a table of retention time, mass charge ratio, and peak strength. The peak extraction time of reversed-phase chromatography and hydrophilic chromatography were 1–18 min and 1–12 min, respectively. Various additive ions were deconvolved to each ion characteristic.

All samples in each group were taken and mixed evenly with 5 μL each and pretreated as quality control samples (pretreated in the same way as other samples). First, five blank samples were used to balance the chromatographic column, and three quality control samples were used to balance the column conditions. Then, a quality control sample was inserted every six to eight samples to monitor the stability and repeatability of the whole liquid-mass system. The coefficient of variation value of the metabolic features extracted from the quality control samples was calculated. The metabolic features with a coefficient of variation of >15% were deleted.

Principal component analysis (PCA), partial least square discriminant analysis (PLS-DA), orthogonal PLS-DA (OPLS-DA), one-sample analysis of variance, and t-test were performed by SIMCA14.1 (Umetrics). The VIP value (threshold > 1) of the PLS-DA model, P value (P < 0.05) of the t-test and fold change value (FC < 0.75, 1.3< FC value) of the t-test were combined to search for differential expression metabolites. It contained the name of the differential metabolite, HMDB code, mass-charge ratio, retention time, VIP value, and P value of the one-way differential analysis.


  Results Top


Curative effect index

Comparison of perioperative myocardial injury incidence

PMI occurred in 6 of the 61 enrolled subjects during the observation period, with an overall incidence of 9.83%. Among them, there was one case in the Danhong group and five cases in the control group (3.23% vs. 16.67%), P = 0.18 > 0.05. There was no statistical significance between the two groups, and the incidence of PMI in the Danhong group was lower than that in the control group.

Comparison of creatine kinase-MB levels between the two groups during the perioperative period

There was no significant difference in CK-MB level between the Danhong group and the control group before PCI (P = 0. 83).

Within the two groups, the levels of CK-MB 24 h and 5 days after surgery in the Danhong group were higher than those before surgery, and the difference was not statistically significant (P = 0.36, P = 0.78, respectively). In the control group, the difference was statistically significant (P = 0.01, P = 0.04, respectively), and the difference between the two groups was statistically significant (P = 0.04). The difference between the Danhong group and the Danhong group was not statistically significant (P = 0.23). The difference between the Danhong group and the Danhong group was statistically significant (P = 0.04), while the difference between the Danhong group and the control group was statistically significant (P = 0.04).

Postoperatively, the CK-MB level of the Danhong group was lower than that of the control group 24 h after surgery, with a statistically significant difference (P = 0.04), while there was no statistically significant difference between the two groups 5 days after surgery (P = 0.38).

Comparison of the incidence of MACE 30 days after percutaneous coronary intervention

The researchers followed up 61 subjects 30 days after PCI. As a result, five subjects in both groups developed recurrent angina pectoris, including one in the Danhong group and four in the control group (3.2% vs. 13.3%); the total incidence of MACE within 30 days after surgery was 8.3%. There was no statistical difference in the incidence of MACE between the two groups (P > 0.05). The number of MACE in the Danhong group was less than that in the control group. There was no death, recurrent myocardial infarction, coronary revascularization, or nonfatal stroke in the two groups.

During the test, no drug eruption, bleeding, and other manifestations were found in patients of the two groups, and no abnormalities were found in routine hematuria and stool, liver and kidney function, or blood coagulation function caused by the test drugs. No obvious abnormalities were observed during the general physical examination of the subjects in both groups, and no adverse reactions related to DHI occurred during the trial.

Metabolomics analysis results

[Figure 1]a and [Figure 1]b, respectively, shows the total ion flow diagrams of positive ions TIC by reversed-phase chromatography and by hydrophilic chromatography of the test samples. The metabolites were well separated, and differences between groups were clearly identified. The parameters of the PCA analysis model are shown in [Table 3] of attachment.
Figure 1: Profiles of (a) reverse-phase chromatography and (b) hydrophilic chromatography positive ions

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Table 3: Creatine kinase–myocardial band levels at different times during the perioperative period of percutaneous coronary intervention (X¯±S)

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PCA and OPLS-DA analyses of the preoperative Danhong group, preoperative control group, and healthy group. The parameters of (a) PCA analysis model and (b) OPLS-DA analysis models are shown in [Figure 2] of attachment.
Figure 2: Reverse-phase chromatography (a) and Hydrophilic chromatography (b) of positive ions

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Displacement verification test was used to evaluate the model overfitting. R2X represented the interpretation rate of the model to the samples on the X-axis, while Q2 represented the prediction rate of the model to the samples. The analysis results showed that the R2X of the Danhong group before operation and the control group before operation in the OPLS-DA model were low (Q2 <0), suggesting that the model was not excessive fitting, as shown in the [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d. Displacement verification test was used to evaluate the model overfitting, as shown in [Figure 3]e and [Figure 3]f. Thus, the preoperative serum metabolites of the Danhong group and the control group had no obvious statistical significant differences in types and quantities. The metabolic profiles of the two groups' preoperative serum samples were relatively close and comparable.
Figure 3: Principal component analysis positive ions by (a) reverse-phase chromatography and (b) hydrophilic chromatography, orthogonal partial least square discriminant analysis positive ions by (c) reverse-phase chromatography and (d) hydrophilic chromatography, Displacement test of orthogonal partial least square discriminant analysis positive ions by (e) reversed-phase chromatography and (f) hydrophilic chromatography

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PCA and OPLS-DA analysis of the disease groups (preoperative Danhong group and preoperative control group) and the healthy group. The PCA (A) and OPLS-DA (B) model parameters of the preoperative disease and healthy groups are shown in [Figure 2] of attachment.

Based on the PCA score chart, the preoperative Danhong group and the preoperative control group were significantly separated from the healthy group, as shown in the [Figure 4]a,[Figure 4]b,[Figure 4]c,[Figure 4]d,[Figure 4]e,[Figure 4]f. Combined with the analysis results, the metabolic network of the disease groups were disordered compared with that of the healthy group, and there were significant differences in types and quantities.
Figure 4: Positive ions Principal component analysis by (a) reversed-phase chromatography and (b) P hydrophilic chromatography, orthogonal partial least square discriminant analysis positive ions by (c) reverse-phase chromatography and (d) hydrophilic chromatography, Permutation test of positive ion orthogonal partial least square discriminant analysis model by (e) reversed-phase chromatography and (f) hydrophilic chromatography

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PLS-DA analysis of the postoperative Danhong group, the postoperative control group and the healthy group. The PLS-DA analysis model parameters of the postoperative disease and healthy groups are shown in [Table 4] of attachment.
Table 4: Differential metabolites identification results by reversed-phase chromatography

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From the relative position of the metabolic profile, the postoperative metabolic profile of the Danhong group was closer to that of the healthy group, as shown in the [Figure 5] indicating that DHI had a certain callback effect on disease-related biomarkers.
Figure 5: Partial least square discriminant analysis of positive ions by (a) reverse-phase chromatography and (b) hydrophilic chromatography

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The identification results of differential metabolites are shown in [Table 4],[Table 5].
Table 5: Differential metabolites identification results by hydrophilic chromatography

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  Discussion Top


This study showed that the incidence of PMI in the Danhong group was lower than that in the control group when the basic conditions of subjects in the Danhong group and the control group were the same. The degree of CK-MB increase in the Danhong group after PCI was lower than that in the control group, and the decrease time of CK-MB in the Danhong group after PCI was earlier than that in the control group, suggesting that the application of DHI during the perioperative period of PCI in patients with UA blood stasis syndrome can inhibit the increase of myocardial injury markers and has a certain perioperative myocardial protection effect. There was no significant difference in the incidence of PMI between the two groups, which may be related to the fact that this is an exploratory study with a small sample size.

Previous studies suggested that the incidence of PMI was related to the long-term prognosis of patients after PCI. The present study was an exploratory study with a small sample size, and due to the limited experimental conditions, the follow-up observation time was short, making it impossible to explain whether there was a statistical difference in the incidence of MACE between the two groups.

Our analysis identified significant differences in serum metabolites between the preoperative disease group and the healthy group, and these metabolites included multiple metabolic pathways such as the metabolism of glycerophospholipid, sphingolipid, purine, and amino acid.

Previous studies have shown that lipid metabolic disorder plays a critical role in the pathogenesis of CHD.[12],[13] In the glycerophospholipid metabolic pathways, the content of C18:1, C18:2 lysophosphatidylcholine (LPC) and C18:0, C18:1 lysophosphatidylthanolamine (LPE) in serum of the preoperative disease groups were significantly lower than that of the healthy group. These metabolites were closely related to lipid metabolism and had a significant negative correlation with insulin resistance index.[14] The content of glycerophosphorylcholine, C18:3/C16:0, C22:6/C14:0, C20:4/C16:1, and C20:4/C16:0 phosphatidylcholine in the preoperative disease groups decreased significantly compared with that in the healthy group. In addition, there is a significant positive correlation between C14:0 LPC and the index of insulin resistance.[15] The present study showed that the serum LPC content in the preoperative disease group was significantly higher than that in the healthy group.

It is shown that sphingolipid is closely related to CHD, and the accumulation of sphingosine is related to myocardial cell apoptosis and plays an important role in the occurrence and development of CHD.[16] The level of SM (d18:1/22:1(13Z)) in the preoperative disease groups was significantly higher than that in the healthy group. The abnormal metabolite level indicated that lipid metabolism disorder occurred in the disease groups.

After the standardized drugs and PCI therapy, the above indicators in the disease group were close to the level of the healthy group, suggesting that the standardized treatment improved the disorder of lipid metabolism in UA patients. Importantly, the level of the Danhong group was closer to that of the healthy group than that of the control group, suggesting that DHI, in combination with the modern medical standard treatment, could better regulate the disorder of lipid metabolism, which might be one of the mechanisms of DHI in treating UA blood stasis syndrome.

Branched chain amino acid (BCAA), as an essential amino acid in the human body, plays various important roles in physiological state, such as regulating glycolipid metabolism, cell apoptosis, and mitochondrial autophagy as a signal molecule.[17],[18] However, when its metabolism is disordered, it may lead to insulin resistance, abnormal glucose tolerance, and diabetes[19],[20] It is also closely related to atherosclerosis and CHD, and high level of BCAA has been shown as an independent risk factor for myocardial infarction and CHD.

This study showed that the level of L-leucine in the serum samples of the preoperative disease group was significantly higher than that of the healthy group, suggesting that there might be abnormal BCAA metabolism in the pathogenesis of UA blood stasis syndrome. However, the serum L-leucine content in the Danhong group and the control group after treatment was lower than that before treatment. Compared with the control group, the decreased level in the Danhong group was closer to that in the healthy group, suggesting that DHI facilitated the regulation of BCAA metabolism in UA patients with blood stasis syndrome.

L-octanoylcarnitine, hypoxanthine, decanoylcarnitine, 9-decenoylcarnitine, DL-2-aminooctanoic acid, L-phenylalanine, L-tryptophan, and other metabolic components in the Danhong group and the control group before PCI were significantly increased compared to that in the healthy group, suggesting that the pathogenesis of UA was accompanied by the disorder of purine, carnitine, and amino acid metabolisms. Carnitine plays an important role in body fat metabolism and energy production. It can transport acyl coenzyme through the mitochondrial membrane to the mitochondrial matrix, improving the body's energy supply and promoting fat metabolism of ischemic myocardial. In this study, the carnitine level of patients in the disease group was higher than that in the healthy group, and the metabolic process might be that the long-term abnormal utilization of glucose and fat existed in patients with UA blood stasis syndrome, which resulted in increased fat synthesis and decreased catabolic metabolism in the liver, and compensatory increase in free carnitine level in the body. Drug treatment and PCI lowered the levels of these metabolites, with a stronger effect in the Danhong group compared to that of the controls.

Studies have shown that by analyzing the serum metabolites of perioperative UA patients with blood stasis syndrome and healthy people by non-targeted metabolomics methods, we identified several potential biomarkers strongly associated with the pathophysiological process of UA blood stasis, which provided a basis for exploring the pathophysiological mechanism of UA and seeking new therapeutic approaches. The study also suggested that DHI protection of the myocardium of UA patients with blood stasis syndrome during the perioperative period of PCI was accomplished at least in part by regulating the metabolism of glycerolipid, sphingolipid, purine, amino acid, and other metabolic pathways. Metabolomics has a great advantage in the research of TCM, and further investigations combining multiple omics techniques and multidimensional cross-study will reveal the myocardial protective mechanism of DHI in a deeper and more comprehensive way. In summary, DHI has a certain myocardial protection effect on patients with UA blood stasis syndrome during the perioperative period of PCI. However, due to the limitations of the experimental conditions such as the limited number of included subjects and short follow-up time, the above conclusions still have some limitations. Further confirmation is expected from larger randomized controlled studies and further related basic studies.

Financial support and sponsorship

Nil.

Conflicts of interest

Prof. Yan Zhu is an Editorial Board member of World Journal of TCM. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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