CN110824170A - Biomarker for predicting adverse event of acute pulmonary embolism patient and application of biomarker - Google Patents
Biomarker for predicting adverse event of acute pulmonary embolism patient and application of biomarker Download PDFInfo
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention relates to a biomarker for predicting adverse events of patients with acute pulmonary embolism and application thereof, in particular to application of Lipocalin-2 (LCN-2) in predicting long-term adverse outcome of acute pulmonary embolism with stable hemodynamics, wherein the long-term adverse outcome refers to all-cause death and/or venous thromboembolic recurrence event constitution. The present application relates to: LCN-2 can independently predict the long-term adverse prognosis of acute pulmonary embolism with stable hemodynamics, and meanwhile, based on the current risk stratification, the LCN-2 (critical value of 11ng/ml) can improve the risk re-stratification capability of the long-term adverse outcome of the acute pulmonary embolism patients with middle-risk groups.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to a biomarker for predicting adverse events of acute pulmonary embolism patients and application thereof.
Background
Acute Venous Thromboembolism (VTE), including Deep Venous Thromboembolism (DVT) and acute Pulmonary Embolism (PE), is one of the important diseases causing death from cardiovascular diseases, and has clinical features of high mortality and high disability rate. The most severe form of clinical presentation of VTE, the prognosis of acute pulmonary embolism is typically heterogeneous. The vast majority of patients with acute pulmonary embolism are hemodynamically stable, accounting for about 95%, patients with hemodynamically stable patients have better prognosis, the early mortality rate is 2% -15%, and even outpatient treatment can be performed according to circumstances. Long-term death of patients with acute pulmonary embolism is mainly influenced by combined diseases, particularly, the prognosis of patients with combined tumor and cardiovascular diseases is poor, and past researches suggest that at least 1 major adverse outcome (all-cause mortality and symptomatic VTE relapse) occurs in 4 years after the first diagnosis of half of patients with acute pulmonary embolism.
Clinical risk assessment models, biomarkers, cardiac ultrasound and imaging evaluations help clinicians identify patients at high risk, however, whether biomarkers or clinical prediction models, current prognostic studies of acute pulmonary embolism are mainly based on short-term (30-day) prognosis evaluation, lacking a predictive index or model of long-term outcome. The long-term prognosis evaluation of acute pulmonary embolism patients with stable hemodynamics is not only beneficial to the prognosis evaluation of patients, but also beneficial to the promotion of clinical comprehensive management by long-term risk stratification. In order to find a method for predicting long-term adverse outcome events of acute pulmonary embolism patients with stable hemodynamics, bioinformatics reanalysis is carried out through transcriptomics of a previously published acute pulmonary embolism animal model in the early period, potential acute pulmonary embolism biomarkers (CN20171090953.6, CN201710910555.3 and CN201710909523.1) are selected through differential gene expression level and clinical applicable value, and the result shows that various protein markers, especially lipocalin-2, are possible to be candidate biomarkers for prognosis evaluation of acute pulmonary embolism patients with stable hemodynamics.
The present work is based on the above results and further through clinical studies and follow-up studies discusses the predictive value of plasma lipocalin-2 for long-term adverse events in hemodynamically stable acute pulmonary embolism patients.
Disclosure of Invention
The invention relates firstly to the use of lipocalin-2 (LCN-2),
(1) predicting whether the long-term adverse event outcome of the hemodynamically stable acute pulmonary embolism patient is high-risk;
(2) a risk stratification prediction model that improves long-term adverse event outcome for hemodynamically stable acute pulmonary embolism patients;
(3) preparing a detection kit for predicting long-term adverse event fates of acute pulmonary embolism patients with stable hemodynamics;
(4) preparing a detection reagent for predicting long-term adverse event outcome of a hemodynamically stable acute pulmonary embolism patient;
the method for predicting whether the long-term adverse event outcome of the acute pulmonary embolism patient with stable hemodynamics is high-risk or not comprises the following steps,
preferably, the hemodynamically stable acute pulmonary embolism patients are patients in the middle-risk group evaluated according to the 2014 guidelines of the European Heart Association;
preferably, the LCN-2 is free LCN-2 in the plasma of the patient;
when the LCN-2 concentration is more than or equal to 11ng/ml, the patient is a high risk group; when the LCN-2 concentration is less than 11ng/ml, the patient is a non-high risk group.
The risk layered prediction model for improving the long-term adverse event outcome of the hemodynamically stable acute pulmonary embolism patient is as follows;
on the basis of a danger layering model of '2014 European Heart Association guide', the middle-risk group patients are further divided into high-risk groups and low-risk groups according to plasma LCN-2 concentration, wherein the plasma LCN-2 concentration is 11ng/ml, and when the plasma LCN-2 concentration of the patients is more than or equal to 11ng/ml, the patients are high-risk groups; when the LCN-2 concentration of the blood plasma of the patient is less than 11ng/ml, the patient is a low-risk group;
the adverse event outcome includes, but is not limited to: death, thromboembolism recurrence.
The Lipocalin-2 (LCN-2) is a secretory glycoprotein composed of 198 amino acids and having a relative molecular mass of 25kDa, also called neutrophil gelatinase-Associated Lipocalin (NGAL), protooncogene 24p3 or 25kDa α -2 microglobulin-Associated subunit of MMP-9.
A test kit for predicting whether a hemodynamically stable acute pulmonary embolism patient is at high risk for long term adverse event outcome, said kit comprising:
(1) a quantitative detection reagent for LCN-2;
(2) necessary chromogenic and sample pretreatment reagents;
the method for predicting whether the long-term adverse event outcome of the acute pulmonary embolism patient with stable hemodynamics is high-risk or not comprises the following steps,
when the plasma LCN-2 concentration of the patient is more than or equal to 11ng/ml, the patient is a high risk group; when the plasma LCN-2 concentration of the patient is less than 11ng/ml, the patient is a non-high risk group.
Preferably, the hemodynamically stable acute pulmonary embolism patients are patients in the middle-risk group evaluated according to the 2014 guidelines of the European Heart Association;
preferably, the LCN-2 is free LCN-2 in the plasma of the patient.
The adverse event outcome includes, but is not limited to: death, thromboembolism recurrence.
The quantitative detection reagent aiming at the LCN-2 comprises but is not limited to:
(1) antibodies that specifically bind to LCN-2, 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 LCN-2;
(3) non-proteinaceous compounds that specifically recognize LCN-2;
the types of the detection kit include but are not limited to:
(1) enzyme linked immunosorbent assay kit;
(2) a colloidal gold test paper detection kit;
(3) a chemiluminescent detection kit;
(4) flow cytometer detection kit.
The invention has the beneficial effects that:
the relation between the expression level of LCN-2 in plasma and the long-term adverse event outcome of acute pulmonary embolism with stable hemodynamics is researched, 170 acute pulmonary embolism patients with stable hemodynamics are brought into the blood, the expression level of LCN-2 in the plasma of the acute pulmonary embolism patients with stable hemodynamics is quantified by an ELISA technology, the relation between the plasma LCN-2 level and the long-term adverse event outcome of 467 days of median follow-up is evaluated, and the ability of LCN-2 for promoting risk stratification is evaluated at the same time. The outcome of the study consisted of either all-cause mortality or Venous Thromboembolism (VTE) recurrence.
Statistical results show that the increase of plasma LCN-2 level can predict long-term adverse outcome of acute pulmonary embolism patients with stable hemodynamics, and LCN-2 is a biomarker with clinical value for risk stratification of middle-risk group population.
Lipocalin-2 (LCN-2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is one of the members of the lipocalin superfamily. Neutrophils are the major source of LCN-2 in plasma, and LCN-2 expression secretion is increased during inflammation, infection, acute injury, poisoning, oxidative stress, and ischemia reperfusion. As the most promising early diagnostic and prognostic biomarker for acute kidney injury, there is increasing fundamental and clinical evidence that LCN-2 is an important diagnostic and predictive biomarker for cardiovascular disease.
Therefore, from the perspective of predicting long-term adverse outcome of hemodynamically stable acute pulmonary embolism from clinical practice, by evaluating the expression level of LCN-2 in a hemodynamically stable acute pulmonary embolism patient during hospitalization, it is possible to independently predict long-term adverse event outcome while improving a model of risk stratification.
Drawings
Fig. 1, LCN-2 levels in long-term adverse event groups versus non-event groups for hemodynamically stable acute pulmonary embolism patients versus intermediate risk groups of acute pulmonary embolism.
FIG. 2 relationship of LCN-2 to long term adverse events in hemodynamically stable acute pulmonary embolism patients and intermediate risk group acute pulmonary embolism patients.
FIG. 3 ROC curves for patients with intermediate risk group acute pulmonary embolism.
FIG. 4, the consistency curve of LCN-2 for long-term adverse events in patients with intermediate risk group acute pulmonary embolism.
FIG. 5, Kaplan-Meier survival curves show long-term adverse events with LCN-2 ≥ 11ng/ml and LCN-2<11ng/ml for medium-risk groups of acute pulmonary embolism patients.
Figure 6, long term adverse risk re-stratification flow chart based on 2014 european heart disease association guidelines and biomarker LCN-2.
Fig. 7, risk re-stratification summary of LCN-2 for long-term adverse outcome in hemodynamically stable acute pulmonary embolism patients.
Detailed Description
Example 1: prediction of long-term adverse outcome in hemodynamically stable acute pulmonary embolism patients with elevated LCN-2 levels
170 cases of acute pulmonary embolism patients with stable hemodynamics are selected, after 467 days (four-quadrant spacing: 288-. The long-term adverse event outcome includes, but is not limited to: death, thromboembolism recurrence.
Firstly, an experiment step:
the kit comprises:
Human Lipocalin-2ELISA Kit
1. reagent preparation
1.1 Experimental materials and reagents
1.2 detection of samples: 170 haemodynamically stable sodium citrate anticoagulated plasma for acute pulmonary embolism patients.
2. Preparation of the experiment
(1) Before use, the kit and the sample are placed at normal temperature and balanced to room temperature (18-25 ℃);
(2) diluting a standard product: respectively diluting 5X Item E, 600X Item F and 20X Wash buffer to 1X for later use, and diluting plasma for 200 times of loading;
(3) assay Diluent (Item E2) was diluted 5-fold with deionized water for use;
(4) preparing standard product, namely centrifuging the Item C small tube, adding 400 uL of 1X Assay Diluent (Item E2) into the standard product small tube, mixing uniformly to obtain a 50ng/ml standard product, extracting 20ul of the 50ng/ml standard product, and adding 980ul of 1X Assay Diluent (Item E2) to obtain STD 1; preparing 7 1.5ml small centrifuge tubes, adding 300. mu.L of 1X Assay dilution (Item E2) buffer solution to all the tubes, and sequentially labeling them as STD2, STD3, STD4, STD5, STD6 and STD 7; then, the standard substance is diluted by STD1 gradient, 200 muL of STD1 is extracted and added into an STD2 small tube, after uniform mixing, 200 muL of solution in the tube is extracted and added into an STD3 small tube and then uniform mixing is carried out, the sequential method is carried out until STD7 is prepared, and STD 8 is only 300 muL of 1XAssay Diluent (Item E2), namely the standard substance is 0 pg/ml;
as shown in the following table:
(5) dilution of washing liquor: diluting the concentrated washing solution by 20 times with deionized water for later use;
(6) centrifuging the detection antibody vial (Item F), adding 100. mu.L of a Diluent 1 × Assay Diluent (Item E2), dissolving thoroughly, gently pipetting up and down with a pipette, and diluting 80-fold with the Diluent 1 × Assay Diluent (Item E2);
(7) centrifuging HRP-streptavidin (Item G), and diluting with a Diluent 1X Assay Diluent 600 times for use;
3. procedure for the preparation of the
(1) Equilibrating the kit and sample to room temperature (18-25 ℃);
(2) after the antibody-coated ELISA plate is balanced to room temperature, 100 microliter of prepared standard substance and sample are added into the corresponding hole, the whole plate strip is sealed by a sealing plate membrane, and the mixture is incubated overnight at 4 ℃;
(3) sucking the liquid in the holes into a waste liquid tank, adding prepared 1X Wash Buffer lotion to a plate washer, washing the plate strips for 4 times by the plate washer, and adding 300 mu L lotion into each hole;
(4) adding 100 μ L of prepared LCN-2 antibody (biotin labeled antibody) into each well, incubating at room temperature for 1h, and slowly shaking on a shaking table;
(5) the cleaning step is the same as 3;
(6) adding 100 mu L of prepared HRP-streptavidin into each hole, and incubating for 45min at room temperature;
(7) the cleaning step is the same as 3;
(8) adding 100 μ L of TMB color development solution into each well, incubating at room temperature in dark for 30min, and slowly shaking on a shaking table;
(9) add 50. mu.L of stop solution to each well and immediately place the plate in the microplate reader for reading, with the detection wavelength set at 450 nm.
(10) Standard Curve is drawn by using sigmaplot 12.0 software and a four-Parameter Logistic Regression Model, and the concentration value of the sample is calculated according to the light absorption value of the sample.
4. The experimental results are as follows:
(1) in hemodynamically stable acute pulmonary embolism patients, plasma LCN-2 expression levels are higher in patients with long-term adverse events groups than in non-event groups:
for the hemodynamically stable acute pulmonary embolism study population, the expression level difference of LCN-2 protein in the tested plasma is shown in figure 1, the expression level of LCN-2 in the long-term adverse outcome event group is obviously higher than that in the non-event group (13.23[ IQR,7.39-19.97] vs.8.55[ IQR,5.99-13.81] ng/ml, P is 0.022, the result is shown in figure 1A, the result after natural logarithm conversion is shown in figure 1C, and P is 0.011);
in the middle-risk group (panel a and C are all study populations (middle-risk and low-risk), B and D are only middle-risk group study populations), LCN-2 was also statistically significantly higher in the long-term adverse outcome event group expression level than in the non-event group (13.52[ IQR,7.96-20.22] vs.8.41[ IQR,6.31-11.93] ng/ml, P0.005, results are shown in fig. 1B; and LCN-2 results after natural log transformation are shown in fig. 1D, P0.003).
The intermediate-risk group hemodynamically stable acute pulmonary embolism patients are defined by the 2014 European Heart Association guide, and comprise patients in the intermediate-low risk group and the intermediate-high risk group, which are detailed as follows. Middle-low risk group: hemodynamics are stable, the score of sPESI is more than or equal to 1, and the blood flow is accompanied by right ventricular insufficiency or the level rise of cardiac biomarkers, or the blood flow is not accompanied by the right ventricular insufficiency or the cardiac biomarkers; and an spisi score of 0, hemodynamically stable, acute pulmonary embolism patients with right ventricular dysfunction or elevated cardiac biomarker levels. Middle-high risk group: hemodynamics were stable with an sPISi score of 1 or more, accompanied by right ventricular dysfunction and elevated levels of cardiac biomarkers.
(2) LCN-2 is an independent predictive biomarker for long-term adverse outcome of hemodynamically stable acute pulmonary embolism:
the study population shown in fig. 2A was all hemodynamically stable acute pulmonary embolism patients (N170), and the study population of fig. 2B was intermediate risk acute pulmonary embolism (N126). The single-factor Cox regression model results show that LCN-2 is predictive of long-term adverse outcome in hemodynamically stable acute pulmonary embolism (HR 4.15, 95% CI: 1.84-8.35; P0.001) and acute pulmonary embolism patients in intermediate risk group (HR 4.56, 95% CI: 2.01-10.32; P0.002).
Similarly, after the correction of model 1 and model 2 (the correction model 1 includes two indexes of age and gender, the correction model 2 includes five correction parameters of age, gender, malignancy, pulmonary hypertension and oxygen partial pressure <60 mmHg), the multi-factor Cox regression analysis result shows that the LCN-2 level rise after the correction of model 1 can independently predict the long-term adverse outcome of the acute pulmonary embolism patients (the hemodynamically stable HR is 4.23, 95% CI is 1.84-9.72; P is 0.001; the middle risk group HR is 4.68, 95% CI is 2.06-10.65; P is 0.000); elevated levels of LCN-2 also independently predicted long-term adverse outcome in patients with acute pulmonary embolism corrected by model 2 (hemodynamically stable HR 3.40, 95% CI: 1.46-7.91; P0.004; intermediate risk HR 3.88, 95% CI: 1.63-9.23; P0.000). As a result, LCN-2 is an independent predictive biomarker for long-term adverse outcome of acute pulmonary embolism in all hemodynamic-stable and intermediate-risk groups.
(3) Elevated LCN-2 levels predict long-term adverse outcome in hemodynamically stable acute pulmonary embolism patients:
FIG. 3 shows the ROC curves demonstrating the ability of the clinical variable model, biomarker LCN-2 and the clinical variable model + LCN-2 global model to discriminate long-term adverse events; the area under the curve AUC of the clinical variable model is 0.686, the area under the curve AUC of the LCN-2 is 0.734, and the full model AUC of the clinical variable model + LCN-2 is 0.802, which is significantly higher than the AUC level of the pure clinical variable model (P is 0.017). Wherein the clinical variable model analyzes Pvalue according to one-factor Cox regression<0.10 malignancy, pulmonary arterial hypertension and PaO2<60 mmHg.
The consistency graph result in fig. 4 shows that the equation Y of the predicted value trend line of LCN-2 is 0.8937 × X +0, the Slope is 0.89, and the Intercept is 0.00. Chi of goodness of fit test of Hosmer-Lemeshow2The value of 5.582 (P0.509) indicates that the LCN-2 biomarker has a good accuracy in predicting the outcome of long-term adverse events (MAEs) in the intermediate-risk group of acute pulmonary embolism patients.
Example 2: predictive model of plasma LCN-2 levels in intermediate risk groups of acute pulmonary embolism patients capable of improving risk stratification of adverse events
(1) The long-term adverse events of the acute pulmonary embolism patients in the middle-risk group with LCN-2 level more than or equal to 11ng/ml are worse than those of the patients in the middle-risk group with LCN-2<11 ng/ml:
the cutoff value (cut-off value) was determined to be 11ng/ml by calculating the Youden index from the ROC curve of FIG. 3, 43 patients were present in the middle-risk group of 126 patients with LCN-2 ≧ 11ng/ml and 83 patients were present with LCN-2<11 ng/ml.
The long-term MAEs fate of the acute pulmonary embolism patients with the middle risk group, wherein the LCN-2 is more than or equal to 11ng/ml and the LCN-2 is less than 11ng/ml, is shown in a Kaplan-Meier survival curve of a figure 5, and the survival curve of the acute pulmonary embolism patients with the middle risk group, wherein the LCN-2 is more than or equal to 11ng/ml, is obviously worse than that of the acute pulmonary embolism patients with the middle risk group, wherein the LCN-2 is less than 11ng/ml (Log-rank test, P is less than 0.0001).
(2) LCN-2 can improve the danger layering model of long-term adverse events of the medium-risk group:
figure 6 shows a long-term adverse risk re-stratification flow chart based on 2014 european heart disease association guidelines and the biomarker LCN-2. The study included 170 patients with hemodynamically stable acute pulmonary embolism with 17 (10%) long-term adverse outcome events; as evaluated by the 2014 european heart disease association guidelines, 16 of 126 patients with intermediate-risk acute pulmonary embolism (12.7%) had long-term adverse outcome events, and 1 of 44 patients with low-risk acute pulmonary embolism (2.3%) had long-term adverse outcome events.
LCN-2 was able to further classify acute pulmonary embolism patients in the medium-risk group into a medium-high risk group of long-term adverse outcomes (43 people total, event incidence 25.6%) and a medium-low risk group of long-term adverse outcomes (83 people total, event incidence 6.0%).
It can be seen that LCN-2 contributes to the long-term adverse risk re-stratification of acute pulmonary embolism in the medium-risk group, a summary of which is shown in fig. 7.
Finally, it should be noted that the above embodiments only help those skilled in the art understand the essence of the present invention, and do not limit the protection scope.
Claims (6)
1. The use of lipocalin-2 (LCN-2),
(1) preparing a detection kit for predicting long-term adverse event fates of acute pulmonary embolism patients with stable hemodynamics;
(2) preparing a detection reagent for predicting long-term adverse event outcome of a hemodynamically stable acute pulmonary embolism patient;
the adverse event outcome includes, but is not limited to: death, thromboembolic recurrence;
the Lipocalin-2 (LCN-2) is a secreted glycoprotein composed of 198 amino acids and having a relative molecular mass of 25 kDa.
2. The use according to claim 1,
the hemodynamically stable acute pulmonary embolism patient is a patient which is evaluated as a medium-risk group according to the guidance of 2014 European Heart Association;
the LCN-2 is free LCN-2 in the plasma of the patient.
3. A test kit for predicting whether a hemodynamically stable acute pulmonary embolism patient is at high risk for long term adverse event outcome, said kit comprising:
(1) a quantitative detection reagent for LCN-2;
(2) necessary chromogenic and sample pretreatment reagents;
the Lipocalin-2 (LCN-2) is a secretory glycoprotein which is composed of 198 amino acids and has a relative molecular mass of 25 kDa;
the adverse event outcome includes, but is not limited to: death, thromboembolic recurrence;
the method for predicting whether the long-term adverse event outcome of the acute pulmonary embolism patient with stable hemodynamics is high-risk or not comprises the following steps: when the plasma LCN-2 concentration of the patient is more than or equal to 11ng/ml, the patient is a high risk group; when the plasma LCN-2 concentration of the patient is less than 11ng/ml, the patient is a non-high risk group.
4. The kit according to claim 3,
the hemodynamically stable acute pulmonary embolism patient is a patient which is evaluated as a medium-risk group according to the guidance of 2014 European Heart Association;
preferably, the LCN-2 is free LCN-2 in the plasma of the patient.
5. The kit according to claim 3 or 4, wherein the quantitative detection reagent for LCN-2 comprises but is not limited to:
(1) antibodies that specifically bind to LCN-2, including but not limited to polyclonal antibodies, monoclonal antibodies, single chain antibodies, functional antibody fragments, antibody Fab regions, nanobodies, chimeric antibodies, multispecific antibodies;
(2) a ligand protein or polypeptide that specifically binds to LCN-2;
(3) non-proteinaceous compounds that specifically recognize LCN-2.
6. The kit according to claim 3 or 4, wherein the types of the detection kit include but are not limited to:
(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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