CN115219725A - Application of cardiac adriamycin reactive protein in monitoring anthracycline cardiac toxicity - Google Patents
Application of cardiac adriamycin reactive protein in monitoring anthracycline cardiac toxicity Download PDFInfo
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Abstract
The invention discloses application of cardiac adriamycin-reactive protein in monitoring anthracycline cardiac toxicity. The research of the application shows that the change degree of the concentration of CARP in serum before and after chemotherapy can predict the anthracycline induced adverse cardiac events and is negatively related to the adverse cardiac event classification, the sensitivity and specificity of CARP for predicting myocardial damage are higher than those of the traditional serum hypersensitive troponin T, serum creatine kinase isozyme and electrocardiogram, and the CARP can become an important serological index for monitoring ANT myocardial toxicity and is beneficial for clinical doctors to carry out early recognition on the anthracycline cardiotoxicity so as to guide clinical diagnosis and treatment.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of myo-cardia doxorubicin response protein in monitoring anthracycline cardiotoxicity.
Background
Anthracyclines (ANT) are the basic drugs of chemotherapy regimens for acute lymphoblastic leukemia, the most significant adverse drug reaction being cardiotoxicity. The main mechanisms of ANT-induced cardiotoxicity are iron-mediated reactive oxygen species generation and promotion of myocardial oxidative stress. Other mechanisms of myocardial injury include topoisomerase II, calcium overload, cardiomyocyte autophagy, induction of apoptosis, increased release of mitochondrial cytochrome C, and the like.
ATN-induced cardiotoxicity is dose and cumulative dependent. Most of the ATN-related cardiotoxicity appears faster after chemotherapy, and the injury is more obvious along with the prolonging of time, mainly manifested as arrhythmia, acute left heart failure, chronic heart failure, cardiomyopathy and the like, and greatly influences the long-term prognosis of chemotherapy. Both clinical work and clinical research results suggest that most of the cardiotoxicity caused by ANT is progressive and irreversible, and therefore early monitoring and active prevention of ATN-related cardiotoxicity are particularly important. Conventional monitoring indicators for ANT-related cardiac damage include Troponin I (cTnI), serum Hypersensitive Troponin T (TNT-HS), creatine Kinase isozyme (CK-MB), N-terminal pro-B-type natural Peptide (NT-pro-BNP), electrocardiogram (ECG), cardiac ultrasound, etc., however, conventional ANT-related cardiac damage monitoring indicators lack sensitivity and specificity.
Cardiac Adriamycin Responsive Protein (CARP) is a Protein identified in Cardiac myocytes by Jeyaseelan et al in 1997 that can be rapidly inhibited by Adriamycin (ADR), and is named because it is specifically expressed in heart. CARP contains 319 amino acids, has a relative molecular weight of about 37kDa, has a nuclear localization signal, a nuclear export signal, tandem anchor repeats involved in protein-protein interactions, and PEST sequences associated with rapid degradation of CARP. Since the Protein has an anchoring Repeat sequence domain, it is also called a myocardial anchoring Repeat sequence Protein (CARP). CARP is mainly localized to and shuttles between the sarcomere and nucleus of cardiomyocytes. CARP has multiple functions of structural protein, signal molecules and transcription regulating factors, and plays an important role in maintaining the structure and function of cardiac muscle, sensing and transmitting external signals, transcriptional regulation, cardiac development and development of related diseases. The research shows that: CARP is used as stress response protein, and has effects of antagonizing apoptosis, regulating inflammatory response, and inhibiting cardiac muscle fibrosis. However, no report has been made on the effect of cardiac doxorubicin-reactive protein in anthracycline-induced cardiotoxicity.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a new application of the cardiac adriamycin reactive protein in serum in monitoring the cardiotoxicity of anthracyclines in children, and is beneficial to early recognition of the cardiotoxicity of the anthracyclines by clinicians so as to guide clinical diagnosis and treatment.
The first purpose of the invention is to provide the application of the cardiac adriamycin response protein in monitoring the cardiac toxicity of anthracyclines.
The second purpose of the invention is to provide the application of the cardiac adriamycin response protein in preparing products for monitoring the cardiac toxicity of anthracyclines.
The above object of the present invention is achieved by the following technical solutions:
according to the invention, by observing the clinical manifestations of the cardiotoxicity before and after ANT chemotherapy, the levels of serum CARP, hypersensitive Troponin T-High Sensitivity (TNT-HS), creatine Kinase isoenzyme (CK-MB) and QTc interval are measured within 24-48 hours before and after the chemotherapy, the serum CARP changes before and after the chemotherapy are compared according to the occurrence condition of the heart adverse events, and the clinical value of the ANT cardiotoxicity is predicted by comparing the change levels of all indexes through a Receiver Operating Characteristic (ROC) curve.
The results show that after ANT chemotherapy, the serum CARP expression of the cardiac adverse event group is increased, the serum CARP of the cardiac adverse event group with grade 1 and grade 2 is reduced after the chemotherapy, the degree of reduction of the cardiac adverse event group with grade 2 is more obvious, and the difference has statistical significance. And statistical analysis shows that the CARP change degree after chemotherapy has negative correlation with the adverse cardiac event grading. The results suggest that the CARP expression of the ANT chemotherapy-free cardiac adverse event group is increased, so that ANT cardiotoxicity is antagonized, and the protective effect is exerted on the heart without causing cardiotoxicity, while the CARP expression is reduced to cause cardiotoxicity in the myocardial damage group after ANT chemotherapy, and the reduction degree of the CARP expression is positively correlated with the degree of myocardial damage. The degree of CARP change after chemotherapy is linearly inversely correlated with the degree of QTc interval prolongation. The CARP change degree after chemotherapy can predict the adverse cardiac events through ROC curve analysis, the critical value is 1% lower than that before chemotherapy after chemotherapy, the sensitivity and specificity are 88.64% and 91.67% respectively, and the sensitivity and specificity for predicting myocardial damage are higher than those of a Delta QTc interval and Delta TNT-HS. CARP can be an important serological index for monitoring ANT myocardial toxicity.
Accordingly, the present invention provides the use of cardiac doxorubicin response protein in the following aspects:
the application of cardiac adriamycin response protein as a marker (specifically a serum marker) in monitoring the cardiac toxicity of anthracyclines.
Application of cardiac adriamycin reactive protein as a marker (specifically a serum marker) in preparation of monitoring anthracycline cardiotoxicity.
The application of the reagent for detecting the expression quantity of the cardiac adriamycin response protein in monitoring the cardiac toxicity of anthracyclines. In particular to the application of a reagent for detecting the concentration of adriamycin reactive protein in serum in monitoring the cardiotoxicity of anthracycline drugs.
Application of a reagent for detecting the expression quantity of cardiac adriamycin response protein in preparation of monitoring anthracycline cardiotoxicity. Application of a reagent for detecting concentration of cardiac adriamycin reactive protein in serum in preparation of monitoring anthracycline cardiotoxicity.
A method for monitoring the cardiotoxicity of anthracycline medicines for non-disease treatment and diagnosis comprises the steps of detecting the change direction and the change degree of the concentration of cardiac adriamycin reactive protein in the serum of a patient before and after anthracycline medicine chemotherapy to reflect whether cardiotoxicity exists or not and grading the cardiotoxicity; if the CARP concentration after chemotherapy is reduced by 1% compared with that before chemotherapy, the cardiotoxicity is present, and the lower the reduction degree, the higher the grade of cardiotoxicity. Specifically, if the CARP concentration after chemotherapy is reduced by more than 1% (less than 13%) compared to before chemotherapy, it is a grade 1 cardiac adverse event; if the CARP concentration after chemotherapy is reduced by more than 13% compared with that before chemotherapy, the adverse event of the heart is more than grade 2.
Preferably, in order to extract peripheral blood of a patient, serum is separated after centrifugation, and the concentration of CARP in the serum is detected by adopting a biotin double-antibody sandwich enzyme-linked immunosorbent assay.
The invention also provides a product for monitoring the cardiotoxicity of anthracyclines, which comprises a reagent for detecting the expression level of cardiac adriamycin response protein.
Preferably, the reagent is an enzyme-linked immunoassay reagent of cardiac doxorubicin response protein.
Preferably, the product is a kit.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a new application of cardiac adriamycin response protein in monitoring anthracycline cardiac toxicity. The research of the application shows that the change direction and degree of the concentration of the CARP content in the serum before and after chemotherapy can predict the cardiac adverse events induced by anthracycline drugs and the classification of the cardiac adverse events; and the sensitivity and specificity of CARP for predicting myocardial damage are higher than those of conventional serum hypersensitive troponin, serum creatine kinase isozyme and electrocardiogram, so that the CARP can become an important serological index for monitoring ANT myocardial toxicity, and is favorable for clinicians to perform early identification on anthracycline cardiotoxicity so as to guide clinical diagnosis and treatment.
Drawings
FIG. 1 shows CARP expression before and after chemotherapy for various levels of cardiac adverse events. * Expressed as P < 0.05, expressed as P < 0.01, expressed as P < 0.001, expressed as P < 0.0001.
FIG. 2 is an analysis of the differences in the degree of CARP expression before and after differential adverse cardiac event stratification chemotherapy. A: comparing log2 (FC) values of the extent of CARP expression change before and after different levels of adverse cardiac event chemotherapy; b: the degree of CARP change is graded with cardiac adverse events.
FIG. 3 is a graph of Δ CARP between the presence and absence of adverse cardiac events.
FIG. 4 is a graph of ROC for different indices.
Detailed Description
The invention is further described with reference to the drawings and specific examples, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Human Cardiac Anchor Repeat Protein (CARP) enzyme-linked immunoassay kit (enzyme immunoassay, cat # MM-2280H 1).
Example 1
1. Study object and method
The study protocol was reviewed and approved by the ethical committee of medical science of the affiliated hospital of Guangdong medical university.
1. Study object
ALL was confirmed at the hematological tumor center of children in our hospital and clinical data (including name, sex, age, ALL risk, cumulative dose of chemotherapy, etc.) of children receiving ANT chemotherapy were collected.
(1) Subjects included criteria: (1) determining the infant to be the acute lymphocytic leukemia patient through morphology-immunology-cytogenetics-molecular biology (MICM) typing; (2) ANT chemotherapy is carried out in the induction stage and the re-induction stage of the 2016 scheme for treating and cooperating acute lymphoblastic leukemia of children in south China; (3) the age is less than or equal to 14 years old, and the nature is not limited; (4) the guardian signs an informed consent.
(2) Subject exclusion criteria: (1) severe cardiovascular disease prior to chemotherapy: severe congenital heart disease such as atrial septal defect, ventricular septal defect, patent ductus arteriosus, etc., rheumatic heart disease, previous acquired diseases such as hypertension, myocardial damage and various cardiomyopathies caused by virus infection before chemotherapy, severe electrolyte disorder, etc.; (2) other cardiotoxic drugs are being used; (3) critical clinical data is missing.
2. Chemotherapy regimen: each chemotherapy of daunorubicin is 30mg/m2; cardiac adverse event evaluation criteria the assessment of the cardiac toxicity rating was performed according to the New York Heart Association (NYHA) classification evaluation on cardiac status or adverse event evaluation criteria (CTC AE 4.0) in the category of cardiac adverse event groups and cardiac adverse event free groups.
3. Cardiotoxicity monitoring
(1) Monitoring of pre-chemotherapy cardiotoxicity: (1) clinical evaluation, wherein the children patients who meet the inclusion standard and do not meet the exclusion standard are selected into the study by screening; (2) and (3) completing examination of serum myocardial injury markers (TNT-HS, CK-MB) and electrocardiogram (QTc interval) before chemotherapy. The range of the reference value of the detection index is shown in table 1 below.
TABLE 1 detection index reference value range
(2) post-ANT chemotherapy cardiotoxicity monitoring: (1) clinical evaluation: heart muscle damage clinical manifestations such as palpitations, chest distress, shortness of breath, hypotension, heart rate changes, etc.; (2) completing serum TNT-HS, CK-MB and electrocardiogram (QTc interval) examination within 24-48 hours after chemotherapy; (3) assessment of the cardiotoxicity rating was performed according to the new york heart association of america (NYHA) classification assessment on cardiac status or adverse event assessment criteria (CTC AE 4.0).
4. Serum CARP assay
(1) Collecting and storing specimens
Before chemotherapy, 2mL venous blood was collected 24-48 hours after chemotherapy. The specimen was left to stand at about 25 ℃ for about 20 minutes until it was coagulated, and centrifuged at 2500rpm at 4 ℃ for about 25 minutes. Transferring the centrifuged supernatant to a test tube, marking, and storing in a refrigerator at minus 80 ℃.
(2) The CARP determination method and the experimental principle are as follows: (1) the determination method comprises the following steps: adopting biotin double antibody sandwich Enzyme-Linked Immunosorbent Assay (ELISA); (2) the experimental principle is as follows: the method comprises the steps of coating a microporous plate with a purified human ankyrin (CARP) antibody to form a solid-phase antibody, adding the CARP into a micropore coated with a monoclonal antibody, then combining the monoclonal antibody with an HRP-labeled CARP antibody to form an antibody-antigen-enzyme-labeled antibody complex, and then adding a TMB substrate for color development. Catalyzed by HRP, TMB turns blue and finally turns yellow in an acidic environment. The hue is positively correlated with the concentration of CARP in the sample. Measuring absorbance (OD value) at the wavelength of 450nm by using an enzyme-labeling instrument, calculating a standard curve according to the concentration of a standard substance, and finally calculating the CARP concentration of a corresponding sample through the standard curve;
(3) The operation steps of the determination of serum CARP concentration are as follows: (1) sign boardDiluting a standard product; (2) adding a sample: blank wells (blank control wells without sample or enzyme labeling reagent, other steps are the same), standard wells and sample wells are set. Add exactly 50. Mu.L of standard to the ELISA coated plate, add 40. Mu.L of sample diluent to the sample wells, and then 10. Mu.L of sample. Adding the sample to the bottom of the wells of the microtiter plate, so as not to contact the walls of the wells as much as possible; (3) and (3) incubation: slightly shaking and mixing the mixture by using a sealing film sealing plate, and incubating the mixture in a constant temperature box at 37 ℃ for 30 minutes; (4) preparing liquid: diluting the washing liquid by 30 times with distilled water for later use; (5) washing: carefully taking down the sealing film, quickly pouring out liquid in the holes to avoid repeated pouring so as to avoid cross contamination among the holes, then vigorously drying the sealing film to avoid liquid remaining in the holes as much as possible, adding 200 mu L of washing liquid into each hole, standing for 30 seconds, then removing the washing liquid, drying the sealing film again, and repeating the process for 5 times; (6) adding an enzyme: adding 50 mu L of enzyme labeling reagent into each hole except for blank holes; (7) and (3) incubation: the operation is the same as the step 3; (8) washing: the operation is the same as the step 5; (9) color development: add 50. Mu.L of each of developer A and developer B to each well in sequence, gently shake the ELISA plate to mix well, at 37.C, incubation in an incubator for 10 minutes, wherein the step must be carried out in the dark; r terminates: after reaction for 10 minutes, the color of each hole of the ELISA plate is changed, 50 mu L of acid stop solution is added into each hole of the ELISA plate, the solution is changed into yellow, and the reaction is stopped;
and (3) determination: the CARP OD value should be determined within 15 minutes of the addition of stop solution. Zeroing an enzyme-labeling instrument by using blank holes, setting the wavelength to be 450nm, and then sequentially measuring the OD value of a CARP sample in each plate hole of the enzyme-labeling instrument;
and (3) calculating: firstly, calculating a linear regression equation of a standard curve according to the relation between the concentration and the OD value of a standard substance, and then calculating the corresponding sample concentration, namely the CARP concentration on the regression equation according to the measured OD value of the sample;
human CARP detection range: 18pg/mL-650pg/mL.
5. Statistical method
Data analysis was performed using SPSS 22.0 statistical software. The metrology data is normally distributed as mean and standard deviation
Expressed as median, quartile if not normal distribution; the counting data is represented by frequency. The data which are in accordance with normal distribution and homogeneity of variance are compared between the measurement data groups, and the samples are compared and matched between the two groups for t test; the counting data is checked by chi-square. The difference of the degree of serum CARP change before and after chemotherapy among the adverse cardiac event groups was examined by the Scheffe method. And (3) evaluating the values of serum CARP, TNT-HS, CK-MB, QTc interval and PR interval change degree for predicting myocardial damage by using the ROC curve. P < 0.05 is statistically significant.
2. Results
1. CARP expression changes before and after chemotherapy for different levels of cardiac adverse events
The paired t test was used to compare the differences in serum CARP expression before and after chemotherapy. The results are shown in table 2 and fig. 1, showing that serum CARP levels are elevated after chemotherapy compared to before chemotherapy in the grade 0 cardiac adverse event group; in the grade 1 cardiac adverse event group, post-chemotherapy serum CARP levels decreased compared to pre-chemotherapy; the group of adverse events of 2 grades has more significant decrease of serum CARP level after chemotherapy than before chemotherapy, and the difference is statistically significant (P is less than 0.05)
TABLE 2 CARP expression levels before and after chemotherapy for various grades of cardiac adverse events (C:)
pg/mL)
2. Differential analysis of CARP expression change degree before and after chemotherapy for different grading adverse cardiac events
Fold difference (FC) was used to indicate the extent of CARP change before and after chemotherapy, log2 (FC) data was normalized and Scheffe was used to test for differences between groups. The results are shown in Table 3 and FIG. 2, which show that the differences among the groups are significant and all have statistical significance (P < 0.05). The correlation between the degree of serum CARP change after chemotherapy and the grading of the cardiac adverse events is tested by using Spearman, and the result shows that the cardiac adverse events are graded at 0 grade, 1 grade and more than 2 grades, and the degree of serum CARP change before and after chemotherapy is in negative correlation with the grading of the cardiac adverse events (r = -0.754.
TABLE 3 Log2 (FC) values for the extent of CARP expression change before and after chemotherapy for different grades of adverse cardiac events
Note that: FC is post-chemotherapy serum CARP expression level/pre-chemotherapy serum CARP expression level; n table number of examples
3. CARP predictive of cardiotoxicity value
The value of predicting myocardial damage occurrence by evaluating serum CARP, TNT-HS, CK-MB and QTc interval change degree by using an ROC curve. The results are shown in Table 4 and FIG. 4, and the area under the curve (AUC) and 95% CI were 0.9094 (0.8225-0.9963), 0.7348 (0.5613-0.9084), 0.5316 (0.3022-0.7609), 0.8469 (0.7416-0.9522), respectively, which indicate that Δ CARP, Δ QTc interval, and Δ TNT-HS can predict the occurrence of myocardial damage well. The critical value of the predicted myocardial damage of the delta CARP is-0.0094 (table 4, figure 3), the sensitivity and specificity of the predicted myocardial damage of the delta CARP are respectively 88.64% and 91.67% which are reduced by 1% compared with that before chemotherapy after chemotherapy, and the sensitivity and specificity of the predicted myocardial damage of the delta CARP are higher than those of a delta QTc interval and delta TNT-HS.
TABLE 4 prediction of cardiotoxicity values for the extent of change before and after chemotherapy with different indices
The results show that the monitoring of the concentration change of the CARP in serum before and after ATN chemotherapy can reflect ATN cardiotoxicity and cardiotoxicity grading, the sensitivity and the specificity are higher than those of TNT-HS, CK-MB in serum and electrocardiogram, and the CARP can be an important serological index for monitoring ANT cardiotoxicity. The invention provides a new direction for clinically monitoring the cardiotoxicity of anthracyclines, and has clinical practicability.
The above embodiments are only preferred embodiments and some applications of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention and are intended to be equivalent substitutions are included in the scope of the present invention.
Claims (10)
1. Application of cardiac adriamycin reactive protein as a marker in monitoring anthracycline cardiotoxicity.
2. Application of cardiac adriamycin reactive protein as a marker in preparation of monitoring anthracycline cardiotoxicity.
3. The application of the reagent for detecting the expression quantity of the cardiac adriamycin response protein in monitoring the cardiac toxicity of anthracyclines.
4. Application of a reagent for detecting the expression quantity of cardiac adriamycin response protein in preparation of monitoring anthracycline cardiotoxicity.
5. A method for monitoring the cardiotoxicity of anthracycline medicines for non-disease treatment and diagnosis comprises the steps of detecting the change direction and the change degree of the concentration of cardiac adriamycin reactive protein in the serum of a patient before and after anthracycline medicine chemotherapy to reflect whether cardiotoxicity exists or not and grading the cardiotoxicity; if the CARP concentration after chemotherapy is reduced by 1% compared with that before chemotherapy, the cardiotoxicity is present, and the lower the reduction degree, the higher the grade of cardiotoxicity.
6. The method of claim 5, wherein the serum CARP concentration is measured by biotin-diabody sandwich ELISA for drawing peripheral blood from the patient and separating the serum after centrifugation.
7. A product for monitoring the cardiotoxicity of anthracycline drugs is characterized by comprising a reagent for detecting the expression level of cardiac adriamycin response protein.
8. The product of claim 7, wherein the reagent is an enzyme-linked immunoassay for cardiac doxorubicin reactive protein.
9. The product according to claim 7 or 8, wherein the product is a kit.
10. Use of the product according to claim 7 or 8 for monitoring the cardiotoxicity of anthracyclines.
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Application publication date: 20221021 |