CN112114152A - Application of serum S100A8/A9 complex level in CABG surgery prognosis judgment - Google Patents
Application of serum S100A8/A9 complex level in CABG surgery prognosis judgment Download PDFInfo
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Abstract
The invention relates to application of serum S100A8/A9 complex level in postsurgical hospitalization prognosis judgment of CABG. The prognosis judgment refers to predicting the prognosis of coronary heart disease patients after CABG surgery, and distinguishing the patients into a postoperative high adverse event risk group and a postoperative low adverse event risk group, wherein the adverse events include but are not limited to: death, low cardiac output syndrome.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to application of serum S100A8/A9 complex level in CABG surgery prognosis judgment.
Background
Ischemic Heart Disease (IHD) is one of the most common causes of death worldwide, and the mortality rate rises year by year. In 2013, ischemic heart disease has replaced stroke and is the first cause of death in China. At present, Coronary Artery Bypass Grafting (CABG) is one of the most common surgical modes for cardiac revascularization of patients with Coronary Heart Disease (CHD), especially the first choice for patients with complex lesions of multiple stenoses. However, due to aging population and increasing complications, more and more high-risk patients receive CABG surgery, and intraoperative cold injury and uneven cardioplegia cause acute ischemic injury to Cardiac muscle and failure of Cardiac pump function, which leads to the occurrence of malignant cardiovascular events such as Low Cardiac Output Syndrome (LCOS) after surgery. Therefore, there is a great need for timely intervention to reduce the incidence of hospital adverse events in patients who are at high risk for developing such acute myocardial injury after CABG surgery.
In recent years, several biomarkers have emerged internationally to predict the risk of assessing the risk of development of adverse cardiovascular events after CABG surgery. The most common of these include: troponin, NT-proBNP, and the like. In 2006, a study of Circulation was included in a total of 254 first-line emergency CABG patients, and preoperative cTnI was found to be significantly associated with both in-hospital mortality and MACE (low cardiac output syndrome, cardiopulmonary resuscitation, and new ventricular fibrillation) (P all <0.001), but inclusion of the study was limited to emergency CABG; in 2019, a study of European Heart Journal is included in 6597 patients with three-branch lesion CABG, and NT-proBNP before operation is found to have correlation with the in-hospital mortality, but the end-point event is single, and other adverse events such as low cardiac output syndrome and the like are not evaluated; in addition, the previous biomarker research lacks accurate risk stratification for the occurrence of the CABG postoperative low cardiac output syndrome of the coronary heart disease patient, and the clinical application is limited.
The S100A8 protein (Calgranulin A protein, MRP8 protein) and the S100A9 protein (Calgranulin B protein, MRP14 protein) both belong to the calcium binding protein S100 protein family members, and the two proteins form a heterodimer S100A8/A9 protein complex in a calcium ion-dependent manner. The two proteins are expressed in circulating neutrophilic granulocyte and mononuclear macrophage but not in normal macrophage and lymphocyte, and under the environment of chronic inflammation, the two proteins are also expressed in epithelial cell, can participate in inflammatory reaction, regulate cell growth and differentiation, increase and inhibit, induce apoptosis and the like. According to the previous literature report and preliminary basic experiments, S100A8/A9 is found to be a key inflammation early warning molecule and plays an important role in myocardial ischemia injury, ischemia-reperfusion injury, myocardial dysfunction and the like. In previous work, the team has already elucidated the correlation between S100A8/A9 and various cardiac events (CN108982844A, etc.), and on the basis of the correlation, the relation between S100A8/A9 and post-CABG events is continuously studied, which may bring clinical help to CABG prognosis.
Disclosure of Invention
From the perspective of effectively and quickly identifying high-risk patients clinically, the expression level of S100A8/A9 is detected at the early stage after CABG operation of coronary heart disease patients, so that the S100A8/A9 serving as an index reflecting myocardial injury possibly has a prediction value on the occurrence of low cardiac output syndrome in CABG postoperation hospitals.
The invention firstly relates to the application of the S100A8/A9 complex in serum,
as a serological diagnostic marker to predict postoperative prognosis in patients with Coronary Artery Bypass Grafting (CABG).
The S100A8/A9 complex is a heterodimer complex formed by S100A8 protein (Calgranulin A protein and MRP8 protein) and S100A9 protein (Calgranulin B protein and MRP14 protein) in a calcium ion-dependent manner.
The postoperative prognosis condition of the CABG patient refers to the fact that the patient has the following hospital events after the operation: death, low cardiac output syndrome.
The low cardiac output syndrome is an acute circulatory disorder syndrome caused by incomplete revascularization or myocardial preservation, and has a post-operative incidence of about 3-14% in CABG. The occurrence of low cardiac output syndrome can further aggravate myocardial damage, cause multiple organ complications, and the mortality rate is up to 17-24%. S100A8/A9 is a key inflammation early warning molecule, is released in the early stage of an ischemic injury part, plays an important role, and therefore can reflect the degree of acute myocardial ischemic injury and predict poor prognosis in the early stage.
The invention also relates to application of the S100A8/A9 complex in preparing a detection kit for predicting postoperative prognosis of a patient with Coronary Artery Bypass Graft (CABG).
The prediction of the postoperative prognosis of the CABG patient refers to the prediction of the probability of occurrence of postoperative adverse events (MACE) of the patient, wherein the adverse events refer to the occurrence of the following hospital events after the operation of the patient: death, low cardiac output syndrome.
The S100A8/A9 complex is a heterodimer complex formed by S100A8 protein (Calgranulin A protein and MRP8 protein) and S100A9 protein (Calgranulin B protein and MRP14 protein) in a calcium ion-dependent manner.
The present invention also provides the use of the S100A8/a9 complex for predicting the post-operative prognosis of a CABG patient, by differentiating the patient into a post-operative high adverse event risk group and a post-operative low adverse event risk group, including but not limited to: death, low cardiac output syndrome.
The high risk group is: the incidence rate of adverse events after CABG surgery exceeds 30 percent;
the low risk groups are: the incidence of adverse events after CABG surgery is lower than 6%;
the judgment standard of the adverse event high risk group is as follows: the difference of the expression quantity of the S100A8/A9 complex in serum 24 hours after CABG operation of a patient is larger than or equal to 7860 ng/ml;
the judgment standard of the adverse event low risk group is as follows: the difference of the expression quantity of the S100A8/A9 complex in serum 24 hours after CABG operation of a patient is less than 7860 ng/ml.
The S100A8/A9 complex is a heterodimer complex formed by S100A8 protein (Calgranulin A protein and MRP8 protein) and S100A9 protein (Calgranulin B protein and MRP14 protein) in a calcium ion-dependent manner.
The present invention also relates to the use of the S100A8/a9 complex in the preparation of a test kit for predicting the post-operative prognosis of a CABG patient, by differentiating the patient into a post-operative high adverse event risk group and a post-operative low adverse event risk group, including but not limited to: death, low cardiac output syndrome.
The high risk group is: the incidence rate of adverse events after CABG surgery exceeds 30 percent;
the low risk groups are: the incidence of adverse events after CABG surgery is lower than 6%;
the judgment standard of the adverse event high risk group is as follows: the difference of the expression quantity of the S100A8/A9 complex in serum 24 hours after CABG operation of a patient is larger than or equal to 7860 ng/ml;
the judgment standard of the adverse event low risk group is as follows: the difference of the expression quantity of the S100A8/A9 complex in serum 24 hours after CABG operation of a patient is less than 7860 ng/ml.
The S100a8/a9 complex is a heterodimer complex formed by S100A8 protein (Calgranulin A protein and MRP8 protein) and S100A9 protein (Calgranulin B protein and MRP14 protein) in a calcium ion-dependent manner.
The detection kit also comprises a detection reagent for detecting the serum expression level of the S100A8/A9 complex, and the detection reagent comprises but is not limited to:
(1) antibodies that specifically bind to the S100A8/a9 complex, including but not limited to polyclonal antibodies, monoclonal antibodies, single chain antibodies, functional antibody fragments, antibody Fab regions, nanobodies, chimeric antibodies, multispecific antibodies, and the like;
(2) a ligand protein or polypeptide that specifically binds to the S100A8/a9 complex;
(3) a non-proteinaceous compound that specifically recognizes the S100A8/A9 complex.
The detection kit comprises a detection reagent box and a detection reagent box,
(1) enzyme linked immunosorbent assay kit;
(2) a colloidal gold test paper detection kit;
(3) a chemiluminescent detection kit;
(4) flow cytometer detection kit.
Drawings
FIG. 1, levels of serum S100A8/A9 protein complex in patients in the MACE and Non-MACE groups at 1 day post CABG.
FIG. 2 is a ROC graph showing the prediction of the incidence of MACE events after CABG surgery on the serum S100A8/A9 complex expression level 1 day after CABG surgery in patients with coronary heart disease.
FIG. 3 is a CABG operation MACE event survival chart of a coronary heart disease patient group marked by using the expression level 7860ng/ml of S100A8/A9 protein complex after CABG operation as a distinguishing value.
Detailed Description
Example 1: 688 coronary heart disease patients had 1 day post CABG operation in hospital period, expression of S100A8/A9
688 coronary heart disease patients CABG 1 day postoperative serum samples, by ELISA test detection of S100A8/A9 expression level. 688 patients with row CABG surgery were divided into MACE group (65 patients) and Non-MACE group (623 patients) according to the occurrence of MACE events (death, low cardiac output syndrome) in the hospital.
Firstly, an experiment step:
the kit comprises: r & D Systems, Inc, Human S100A8/S100A9, Heterodeimer Immunoassay
Reagent preparation:
1. all reagents were equilibrated to room temperature before use.
2. Wash (Wash Buffer): if crystals had formed in the concentrate, equilibrate to room temperature and shake gently until the crystals were completely dissolved, add ionized or distilled water to dilute 20ml of the wash to 500 ml.
3. Substrate Solution (Substrate Solution): the chromogenic reagents A and B should be mixed in equal volumes 15min before use and stored protected from light, requiring 200ul of an equal volume mixture of the chromogenic reagents A and B per well.
4. S100A8/A9 Standard (S100A8/9 Standard): the S100A8/A9 standard was reconstituted with standard Diluent RD5-10 (calibration dilution RD 5-10). The reconstituted product was a 40ng/ml stock solution. The standards were gently stirred for at least 15min prior to dilution.
5. 250ul of the appropriate standard dilution RD5-10 (calibration dilution RD5-10) was pipetted into each tube. Stock solutions were used to prepare a series of dilutions (20ng/ml, 10ng/ml, 5ng/ml, 2.5ng/ml, 1.25ng/ml, 0.625ng/ml), with undiluted standard (40ng/ml) as the high standard and standard dilutions as the 0 standard (0 pg/ml).
(II) a measuring step:
all reagents and samples were equilibrated to room temperature before use and all samples, standards and controls were assayed in duplicate.
1. All reagents and working standards were prepared and serum samples were diluted 150-fold.
2. The excess microplate strips were removed, placed back in a tin foil bag containing desiccant, and resealed.
3. 50ul of Assay dilution RD1-34 was added to each well.
4. 50ul of standards, samples and controls were added to each well in sequence. Sealed with rubber strips, incubated at room temperature for 2 hours and the distribution of the assay standards and samples recorded.
5. And (3) absorbing liquid in the holes, removing 400ul of cleaning solution in each hole, completely removing the liquid after fully washing, drying on clean paper, and repeatedly washing for 4 times.
6. 200ul of S100A8/A9 Conjugate was added to each well and sealed with a new strip of mastic. And carrying out warm bath at room temperature for 2 hours.
7. And (5) repeating the step.
8. 200ul of Substrate Solution was added to each well and incubated for 30 minutes at room temperature in the absence of light.
9. 50ul of Stop Solution was added to each well and the color in the wells should change from blue to yellow. If the color in the wells is green, or if the color change is not uniform, the plate is tapped gently to ensure adequate mixing.
10. The absorbance of each well was measured at 450nm using a microplate reader within 30 minutes and set to 540nm or 570nm if wavelength correction is effective. If wavelength correction is not available, either 540nm or 570nm wavelength readings are subtracted from the 450nm wavelength reading. This method can correct optical defects of the board. Readings directly at 450nm without correction may be higher or lower.
(III) calculating the result:
1. the OD value of the standard, control, sample minus the OD value of the zero standard is taken as the mean of two duplicate wells.
2. The standard curve was established using computer software with a 4 parameter curve.
3. If the sample has been diluted, the concentration from the standard curve must be multiplied by the dilution factor.
II, experimental results:
688 patients with coronary heart disease were classified post-CABG surgery into MACE group (65 patients) and Non-MACE group (623 patients) according to the incidence of MACE events (death, low cardiac output syndrome) in the post-CABG hospital. Compared with the Non-MACE group, the serum S100A8/A9 content of the patients in the MACE group is obviously increased within 24 hours after CABG operation. The MACE group was 2.41-fold higher (P <0.001) than the Non-MACE group, and the results are shown in FIG. 1 and Table 1 below.
TABLE 1 serum S100a8/9 levels in patients of MACE and Non-MACE group 1 day post CABG surgery
Example 2: S100A8/A9 prognostic assessment of hospital MACE events
688 patients were identical to example 1. The experimental results are as follows:
through establishing a COX regression model to explain the relationship between the marker level and the hospital MACE event, nine factors of age, sex, Euroscore II score, pre-operative NT-proBNP, post-operative creatinine, pre-operative and post-operative cTnI and pre-operative and post-operative ejection fraction are corrected, S100A8/A9 has independent prediction value for the occurrence of the hospital MACE event, and the result is shown in the following table 2.
TABLE 2 relationship between COX regression model statistical marker levels and in-hospital MACE events
(uncorrected HR is the placement of a marker in a COX regression model only corrected HR is the placement of a marker and the aforementioned correction factors in a COX regression model)
Example 3: S100A8/A9 Risk stratification for post-CABG hospital adverse event prediction
688 patients were identical to example 1.
The experimental results are as follows:
1. in the hospital MACE event analysis, the cut-off values predicted for hospital adverse events 24 hours after CABG surgery S100A8/A9 were determined using ROC curve analysis, see FIG. 2 for a specific ROC curve, the ROC data of which are shown in Table 3 below.
TABLE 3 data relating CABG 24 hours post-operative S100A8/A9 to MACE events
2. The predicted cut-off versus adverse events for MACE events in the S100A8/A9 hospital was evaluated using the Kaplan-Meier survival curve. Patient prognosis with marker levels <7860ng/ml was better than patients with elevated marker levels (P <0.001), and the results are shown in figure 3.
Finally, it should be noted that the above embodiments only help those skilled in the art understand the essence of the present invention, and are not intended to limit the protection scope of the present invention.
Claims (5)
- Use of the S100A8/A9 complex in the preparation of a test kit for predicting the postoperative prognosis of a patient with Coronary Artery Bypass Grafting (CABG),the prediction of the postoperative prognosis of the CABG patient refers to the prediction of the probability of occurrence of adverse events after the operation of the patient, wherein the adverse events comprise: death, low cardiac output syndrome;the S100A8/A9 complex is a heterodimer complex formed by S100A8 protein (Calgranulin A protein and MRP8 protein) and S100A9 protein (Calgranulin B protein and MRP14 protein) in a calcium ion-dependent manner.
- 2. The kit according to claim 1,the judgment standard of the adverse event high probability group is as follows: the difference of the expression quantity of the S100A8/A9 complex in serum 24 hours after CABG operation of a patient is larger than or equal to 7860 ng/ml;the judgment criteria of the adverse event low probability group are as follows: the difference of the expression quantity of the S100A8/A9 complex in serum 24 hours after CABG operation of a patient is less than 7860 ng/ml.
- 3. The kit according to claim 1,the high probability group is: the incidence rate of adverse events after CABG surgery exceeds 30 percent;the low probability group is: the incidence of adverse events after CABG surgery was less than 6%.
- 4. The detection kit according to any one of claims 1 to 3, further comprising a detection reagent for detecting the serum expression level of the S100A8/A9 complex, wherein the detection reagent includes but is not limited to:(1) antibodies that specifically bind to the S100A8/a9 complex, including but not limited to polyclonal antibodies, monoclonal antibodies, single chain antibodies, functional antibody fragments, antibody Fab regions, nanobodies, chimeric antibodies, multispecific antibodies, and the like;(2) a ligand protein or polypeptide that specifically binds to the S100A8/a9 complex;(3) a non-proteinaceous compound that specifically recognizes the S100A8/A9 complex.
- 5. The test kit according to any one of claims 1 to 3, wherein the test kit is:(1) enzyme linked immunosorbent assay kit;(2) a colloidal gold test paper detection kit;(3) a chemiluminescent detection kit;(4) flow cytometer detection kit.
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Citations (4)
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| WO2007014434A1 (en) * | 2005-08-04 | 2007-02-08 | Newsouth Innovations Pty Limited | Biomarker for cardiovascular disease |
| US20110184712A1 (en) * | 2007-10-11 | 2011-07-28 | Cardiodx, Inc. | Predictive models and methods for diagnosing and assessing coronary artery disease |
| US9925160B1 (en) * | 2017-01-16 | 2018-03-27 | Universita' Degli Studi Di Milano | Methods for treating cardiac reperfusion injury |
| CN108982844A (en) * | 2018-08-17 | 2018-12-11 | 北京市心肺血管疾病研究所 | Application of the serum S100a8/9 complex level in Diagnosis of Acute Myocardial Infarction and Index for diagnosis |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007014434A1 (en) * | 2005-08-04 | 2007-02-08 | Newsouth Innovations Pty Limited | Biomarker for cardiovascular disease |
| US20110184712A1 (en) * | 2007-10-11 | 2011-07-28 | Cardiodx, Inc. | Predictive models and methods for diagnosing and assessing coronary artery disease |
| US9925160B1 (en) * | 2017-01-16 | 2018-03-27 | Universita' Degli Studi Di Milano | Methods for treating cardiac reperfusion injury |
| CN108982844A (en) * | 2018-08-17 | 2018-12-11 | 北京市心肺血管疾病研究所 | Application of the serum S100a8/9 complex level in Diagnosis of Acute Myocardial Infarction and Index for diagnosis |
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