CN105486778B - The metabolic markers of stable angina cordis and acute coronary syndrome are distinguished in diagnosis - Google Patents
The metabolic markers of stable angina cordis and acute coronary syndrome are distinguished in diagnosis Download PDFInfo
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Abstract
The invention discloses the metabolic markers that stable angina cordis and acute coronary syndrome are distinguished in diagnosis, including 1, one or more of 3 octadienes, methyl amimoacetic acid, phosphocholine, 2 hydroxylauric acids and tryptophan.It is single be used to diagnose distinguish patients with stable angina pectoris and during Acute Coronary Syndrome Patients, area (AUC) is all higher than 0.7 under ROC curve, with clinical diagnosis meaning；Combine for when diagnosing, with the increase of joint number, AUC is further improved, highest during 5 whole joints, and AUC is up to 0.987, and under optimal cutoff values, sensitivity and specificity are respectively 96.9% and 97.6%.The metabolic markers that the present invention is provided can diagnose differentiation stable angina cordis and acute coronary syndrome exactly, and accuracy is high, and sensitivity and specificity are strong.
Description
Technical field
The invention belongs to biochemical field, it is related to the metabolic markers of diagnosis of coronary heart disease parting, and in particular to one group of use
The metabolic markers of stable angina cordis and acute coronary syndrome are distinguished in diagnosis.
Background technology
Coronary heart disease is also known as ischemic heart disease, and atherosis occurs for the artery for being related to supply myocardial blood, i.e., coronal dynamic
Pulse atherosclerosis lesion causes lumen of vessels narrow or patch formation even ruptures, completely plugged, causes myocardial ischemia, anoxic or bad
Extremely cause heart ischemia disease, so as to cause a series of clinically serious cardiovascular events such as angina pectoris, myocardial infarction.
Coronary heart disease is the primary killers of human health, the tool incidence of disease height, disability rate height, high recurrence rate, case fatality rate height, the spy such as more than complication
Point, has become the principal disease for threatening our people's health.
At present, based on pathophysiological mechanism, by coronary heart disease be divided into chronic stable coronary heart disease (i.e. stable angina cordis) and
Acute coronary syndrome；Acute coronary syndrome is further divided into unstable angina pectoris and acute myocardial infarction AMI.Coronary heart disease
From without to having, from gently to generally including following developing stage again：Coronary artery is normal → coronary atherosclerosis → stable type
Angina pectoris → unstable angina pectoris → acute myocardial infarction AMI.
Coronary atherosclerosis is the Etiological of coronary heart disease, is the early stage illness of coronary heart disease.Coronary artery is athero- hard
Change is a kind of common progressive arterial disease, and lesion mainly involves medium sized muscle layer artery, endarterium lipidosis,
Smooth muscle cell proliferation, forms limitation patch, arterial wall can be made to be hardened, plaque rupture causes thrombus, embolism, gone out when serious
Blood, involvement or is entirely shut at luminal part, and clinical manifestation is the generation of atherosclerotic blood vessel complication.Atherosclerosis
Early lesion can occur before 10 years old, and lesion causes arteriarctia to undergo for 20 to 30 years, in early days without clinical symptoms, no
Easily it is found and payes attention to, therefore early prevention to coronary atherosclerosis and diagnosis can effectively prevent the hair of coronary heart disease
It is raw.
Coronarography can make accurate judgement to stenosis coronarius, be the gold mark of diagnosis of coronary heart disease
Accurate [coronarography goldstandard and clinical routine diagnostics coronary heart disease otherness comparative studies, Shu Rongwen etc., naval medicine magazine
04 phase in 2015].As the goldstandard of diagnosis of coronary heart disease, coronary angiography can only find hemadostewnosis degree, and it or one
Intervention measurement means are planted, it is necessary to intervene operation, and diagnosis is expensive.On the other hand, doctor also need to according to the electrocardiogram of patient,
The inspection results such as cardiogram, Treadmill Exercise Test, CT make last diagnostic, because doctor's subjectivity judges, patient describes unclear
Situations such as appearance, larger mistaken diagnosis is still suffered to the diagnosis of coronary heart disease and is failed to pinpoint a disease in diagnosis, this influence prognosis to patient is very big.For
Improve the quality of life of patient, the life threat that reduction patient is subject to, we need badly, and development is a kind of to have that diagnosis is high, warp
Ji, the diagnostic method without the characteristic such as invasive, easy to operate.
Metabolism group is the science studied the entirety of organism endogenous metabolism material and its changed with internal cause and external cause, is
One important component of systems biology.It can be carried out quickly and without invasive point to body fluids such as blood and urine
Analysis, the metabolic markers of various biochemical reactions can be indicated by being obtained by the difference of metabolism spectrum.The analytical technology bag commonly used at present
Include nuclear magnetic resonance (NMR), mass spectrum (LC-MS/GC-MS) etc..LC-MS/GC-MS have to sample preparation require low, sensitivity it is high,
The features such as wide dynamic range, the metabolin differed greatly available for concentration in detection sample, thus in the research as metabolism group
Using increasing technology platform.Plasma analysis is a kind of clinically conventional methods for the diagnosis of diseases, because it is easy, it is quick,
The economic and advantage of relative noninvasive and be widely adopted.
Not yet someone carries out diagnosis typing using blood plasma metabolite level to coronary heart disease at present.Sought using blood plasma metabolism group
Look for the level error of coronary artery normal person and coronary atherosclerosis patients and different parting Patients Plasma with Coronary Heart Disease metabolins
It is different quickly to make a definite diagnosis coronary heart disease for clinical early stage and to carry out parting significant.
The content of the invention
In order to overcome the deficiencies in the prior art, an object of the present disclosure is that providing one group is used to diagnose the differentiation stable type heart
The metabolic markers of angina and acute coronary syndrome, this group of metabolic markers are present in blood plasma simultaneously, and survey can be analyzed simultaneously
It is fixed；The second object of the present invention, which is that offer is a kind of, can delicately analyze the method for detecting the metabolic markers；The present invention
The 3rd purpose be to provide a kind of detection kit based on the metabolic markers, distinguish stable angina cordis for diagnosing
And acute coronary syndrome, diagnosis convenience is improved, promotes diagnostic method standardization.
Above-mentioned purpose is achieved by following technical solution：
One group is used to diagnose the metabolic markers for distinguishing stable angina cordis and acute coronary syndrome, including one or many
Individual metabolic markers as described below：1,3- octadienes, methyl amimoacetic acid, phosphocholine, 2- hydroxylauric acids and tryptophan.
Further, described one group is used to diagnose the metabolic indicator for distinguishing stable angina cordis and acute coronary syndrome
Thing, including the metabolic markers described in any two.
Further, described one group is used to diagnose the metabolic indicator for distinguishing stable angina cordis and acute coronary syndrome
Thing, including the metabolic markers described in any three.
Further, described one group is used to diagnose the metabolic indicator for distinguishing stable angina cordis and acute coronary syndrome
Thing, including the metabolic markers described in any four.
Further, described one group is used to diagnose the metabolic indicator for distinguishing stable angina cordis and acute coronary syndrome
Thing, including all metabolic markers described in five.
Further, described metabolic markers derive from blood plasma.
Being used for described in a kind of qualitative or quantitative analysis diagnoses the generation for distinguishing stable angina cordis and acute coronary syndrome
The method for thanking to mark is：Described metabolic markers are qualitatively or quantitatively divided using LC-MS and/or gas chromatography mass spectrometry
Analysis.The low, sensitivity of the gentle quality detection limit of liquid matter is high, can delicately analyze the metabolic markers in detection biological specimen and it is determined
Amount.
It is a kind of to be used to diagnose the detection kit for distinguishing stable angina cordis and acute coronary syndrome, including described generation
Thank to the standard items of mark, the standard items are the chemical monomer or mixture of each metabolic markers.Can be right using standard items
Metabolic markers in biological specimen carry out rapidly and accurately qualitative and quantitative analysis.Kit helps to realize standardized testing,
Improve detection convenience and reappearance.
Further, the detection kit also includes dissolving generation described in the solvent and/or Extraction and enrichment of the standard items
Thank to the solvent of mark.
Advantages of the present invention：
(1) metabolic markers that the present invention is provided can diagnose differentiation stable angina cordis and Acute Coronary Syndrome exactly
Levy.In ROC curve evaluation method, area AUC is in the case of more than 0.5 under ROC curve, closer to 1, illustrates diagnosis effect
Better.AUC has relatively low accuracy at 0.5~0.7, and AUC has certain accuracy at 0.7~0.9, had when AUC is more than 0.9
High accuracy.Empirical tests, the metabolic markers that the present invention is provided are single for diagnosing differentiation stable angina cordis and acute hat
During arteries and veins syndrome, AUC is more than 0.7；During multiple use in conjunction, AUC is than single closer to 1, and diagnosis effect is more preferable；Eight
During use in conjunction, AUC is closest to 1, and it is best that effect is distinguished in diagnosis.
(2) the method sensitivity for the analysis detection metabolic markers that the present invention is provided is high, as a result accurately and reliably.
(3) detection kit that the present invention is provided can be used for diagnosis differentiation stable angina cordis and Acute Coronary Syndrome
Levy, improve diagnosis convenience, promote diagnostic method standardization.
Embodiment
Essentiality content of the present invention is further illustrated with reference to embodiment.The instrument or reagent used does not elaborate
Be conventional instrument and reagent；The experimental working technique not specifically described is routine known to a person of ordinary skill in the art
Operating method.
Embodiment 1：The screening of blood plasma difference metabolin between patients with stable angina pectoris and Acute Coronary Syndrome Patients
Characterize
First, object and method
1st, Specimen origin
After patient's agreement is obtained, Jiangsu Prov. People's Hospital in September, 2010~2015 year 280 stable type hearts in June are collected
The peripheric venous blood blood plasma of angina patient, 320 Acute Coronary Syndrome Patients and 350 Healthy Peoples, all patients or health
Confirmed per capita through coronary angiography.Age of Healthy People, sex and patients with stable angina pectoris, Acute Coronary Syndrome Patients phase
Match somebody with somebody.All patients with stable angina pectoris, Acute Coronary Syndrome Patients and health have normal cardiopulmonary liver kidney and hematopoiesis function per capita.
Blood sampling time is early morning fasted conditions.
2nd, main agents
Acetonitrile and formic acid (UPLC is pure) are purchased from ROE companies of the U.S.；Chromatogram rank methanol and chloroform are purchased from Jiangsu Chinese nation science and technology
Co., Ltd；Chlorination methoxamine and N- methyl-N- (trimethyl silane) trifluoroacetamide (containing 1% trim,ethylchlorosilane) are purchased from U.S.
Sigma-Aldrich companies of state；Deionized water by U.S. Mi Libo (Millipore) company MIlli-Q ultrapure water system systems
It is standby；Standard items include 1,3- octadienes, methyl amimoacetic acid, phosphocholine, 2- hydroxylauric acids and tryptophan, are purchased from U.S. Sigma-
Aldrich。
3rd, the screening of blood plasma difference metabolin is characterized
3.1 UPLC-Q/TOF-MS screenings are characterized
3.1.1 sample preparation
Extraction solvent optimization is carried out using response phase method：With the peak number and Zong Feng under mass spectrum ESI+ and ESI- detection pattern
Area is that factor investigates Extraction and enrichment efficiency of the different solvents (acetonitrile, methanol, ethanol, chloroform, water) to metabolin in blood plasma.Will
Test data measured and carry out multi-variables analysis, utilize (the variable importance to of importance factor in PLS models
Projection, VIP value) reflect the importance that variable is responded to model.Acetonitrile, methanol, ethanol, chloroform, water VIP values successively
For 1.503,0.802,0.651,0.688 and 0.987, the extraction efficiency highest of acetonitrile, therefore selection acetonitrile is used as plasma sample
Extraction solvent.
Sample treatment：100 μ L blood plasma are taken in 1.5mL centrifuge tubes, 400 μ L acetonitriles are added, mixed after being vortexed 30 seconds,
13000rpm × 10min centrifuges (4 DEG C), takes 200 μ L of supernatant in 1.5mL centrifuge tubes, is dried up at room temperature with nitrogen evaporator, gained
Residue 300 μ L 20% acetonitrile solution dissolves, and produces.
3.1.2 experimental condition and parameter
UPLC-Q/TOF-MS conditions：
Chromatographic isolation uses ultra performance liquid chromatography (UPLC, Agilent 1290, USA).Chromatographic column is Waters BEH
C18 posts (100mm × 2.1mm, 1.7 μm), 25 DEG C of column temperature, sample introduction room temperature is room temperature, the μ L of sample size 2.Positive and negative ion pattern stream
Dynamic phase composition is that A is the aqueous formic acid of volumetric concentration 0.1%, and B is the formic acid acetonitrile solution of volumetric concentration 0.1%.Gradient elution
Condition：0~1min is 0~30%B phases, and B is phase linear in 2min increases to 60%, 3~8min linear changes to 90%B phases, so
100%B phases are linearly increasing in 8~9min and keep 1min afterwards；Efflux is direct without shunting after flow velocity 0.3mL/min, post
Import mass spectrometer system detection.
Mass spectral analysis uses level Four bar-flight time mass spectrum (Agilent 6530Q-TOF/MS, USA).With electron spray from
Component (ESI) positive and negative ion mode detection；Dry gas stream speed is 7L/min, and it is 300 DEG C to dry temperature degree, dries gas and taper hole
Gas is high pure nitrogen；Capillary voltage is 3000V under 100 DEG C of ion source temperature, cation and negative ion mode, collision electricity
Press as 100V；Three data acquisitions, quality of scanning scope are carried out using full scan pattern is per second：M/z 100-1000 dalton.
3.2 GC-Q/MS screenings are characterized
3.2.1 sample preparation
200 μ L blood plasma are taken in 1.5mL centrifuge tubes, 50 μ L 1mg/mL 2- isopropylmalate acid solution internal standards, whirlpool is added
Rotation is mixed for 20 seconds, the mixed solution (ratio is 2.5: 1: 1) of 400 μ L methanol, chloroform and water is added, then in 70 DEG C of metal bath
Upper shaking 30min (1200rpm), 16000g × 5min centrifugations (4 DEG C), takes 500 μ L of supernatant in 1.5mL centrifuge tubes, adds 500
μ L distilled water, is vortexed and mixes, and then 16000g × 5min centrifuges (4 DEG C), 500 μ L of supernatant is taken in 1.5mL centrifuge tubes, in room temperature
Lower to be dried up with nitrogen evaporator, the residue obtained methoxamine pyridine solution with 80 μ L dissolves, and the oximate 8h under the conditions of 50 DEG C adds 60 μ L
N- methyl-N- trimethyl silicon substrate trifluoroacetamides, derivatization 2h, is produced under the conditions of 70 DEG C.
3.2.2 experimental condition and parameter
GC-Q/MS conditions：U.S.'s Agilent 7890B-5977A gas chromatograph-mass spectrometer (GC-MS)s.HP-5MS maos of chromatographic column
Capillary column (30.0m × 0.25mm, 0.25 μm of capillary thickness)；Carrier gas is high-purity helium, flow velocity 1.0mL/min；The μ of sample size 2
L；Temperature programming：80 DEG C of constant temperature 2min, 80 DEG C -300 DEG C (5 DEG C/min) constant temperature 6min；Do not shunt, 300 DEG C of injector temperature；Interface
300 DEG C of temperature；200 DEG C of ion source temperature；Electron energy 50eV；Solvent delay 3min；Using full scan pattern, quality of scanning model
Enclose：M/z 30-600 dalton.
4th, data processing and analysis
The data that UPLC-Q/TOF-MS and GC-Q/MS are obtained import SIMCA softwares (version 13.0.2,
Umetrics multi-variate statistical analysis) is carried out.By setting up OPLS-DA (orthogonal ginsenoside) model, find
Metabolic profile is contributed larger (VIP ＞ 1.0 and p ＜ 0.01) between patients with stable angina pectoris and acute coronary artery syndrome patient
Metabolin.
Pass through HMDB (http：//www.hmdb.ca/) and Metline (http：//metlin.scripps.edu/) etc.
Database carries out the retrieval of the structure of matter, using at the beginning of the MS/MS collection of illustrative plates obtained by the accurate molecular weight and mass spectrum provided in database
The structure of the above-mentioned difference metabolin of step identification.Eventually through purchase standard items, with the molecular weight of standard items, chromatographic retention and
Corresponding multistage MS fragmentation patterns are compared, and confirm the structure of difference metabolin.
2nd, result
Screening symbolizes 5 difference metabolins, is respectively：1,3- octadienes, methyl amimoacetic acid, phosphocholine, 2- hydroxylaurics
Acid and tryptophan.
Compared with patients with stable angina pectoris, above-mentioned 5 difference metabolins are in acute coronary artery syndrome patients blood plasma
Expression is lowered.Quantitatively detected by standard items, compared with patients with stable angina pectoris, above-mentioned difference metabolin is acute
Expression in coronary syndrome patients blood plasma lowers 0.7~0.8 times.As can be seen here, above-mentioned 5 difference metabolins are stable
Expression in type patient with angina pectoris and acute coronary artery syndrome patients blood plasma is significantly different, can be used for diagnosis and distinguishes stable
Type angina pectoris and acute coronary artery syndrome.
Embodiment 2：Build ROC curve and verify that 5 difference metabolins are used to diagnose differentiation stable angina cordis and acute hat
The ability of arteries and veins syndrome
Verified using receiver operating curves (ROC) method, pass through patients with stable angina pectoris and Acute Coronary Syndrome
The expression of difference metabolin judges that it is used to diagnose differentiation patients with stable angina pectoris and acute coronary in disease patients blood plasma
The ability of syndrome patients.As a result show, 1,3- octadiene, methyl amimoacetic acid, phosphocholine, 2- hydroxylauric acids and tryptophan this 5
The single ability that patients with stable angina pectoris and acute coronary artery syndrome patient are distinguished for diagnosing of individual difference metabolin is stronger,
Area (AUC) is all higher than 0.7 under ROC curve, with clinical diagnosis meaning；Combine for when diagnosing, with the increasing of joint number
Plus, AUC is further improved, 5 all joint when highest, AUC is up to 0.987, under optimal cutoff values, sensitivity and specificity
Respectively 96.9% and 97.6%.Single and any 2~4 Combining diagnosis the results are shown in Table 1~3.
Patients with stable angina pectoris and acute coronary artery syndrome patient are distinguished in the single difference metabolin diagnosis of table 1
| Single difference metabolin | AUC | Sensitivity | Specificity |
| 1,3- octadienes | 0.873 | 87.0% | 87.2% |
| Methyl amimoacetic acid | 0.858 | 84.5% | 85.1% |
| Phosphocholine | 0.803 | 81.0% | 80.6% |
| 2- hydroxylauric acids | 0.756 | 76.3% | 76.9% |
| Tryptophan | 0.734 | 74.1% | 73.7% |
2 two difference metabolin Combining diagnosis of table distinguish patients with stable angina pectoris and acute coronary artery syndrome patient
3 any three~tetra- difference metabolin Combining diagnosis of table distinguish patients with stable angina pectoris and Acute Coronary Syndrome
Disease patient
| Joint number | AUC | Sensitivity | Specificity |
| Three | ≥0.911 | >=92.2% | ≥91.3 |
| Four | ≥0.945 | >=94.3% | ≥95.8 |
It is used to diagnose differentiation patients with stable angina pectoris and acute hat as it can be seen from table 1 this 5 difference metabolins are single
The ability of arteries and veins syndrome patients is stronger, and AUC is all higher than 0.7, and sensitivity is higher, specific relatively strong, with clinical diagnosis meaning；From
Table 2 as can be seen that this 5 difference metabolins combine two-by-two for diagnose when, AUC than it is single be used for diagnose when higher, sensitivity
High, specificity is higher, with clinical diagnosis meaning；From table 3 it can be seen that being combined with 3~4 in this 5 difference metabolins
During for diagnosing, AUC is further improved, and sensitivity is high, high specificity, with clinical diagnosis meaning.
Therefore, this 5 difference metabolins, which can be used as to be used to diagnose, distinguishes stable angina cordis and acute coronary artery syndrome
Metabolic markers.
Embodiment 3：The preparation of detection kit
The metabolic markers provided based on the present invention are prepared for detection kit, and the kit includes following composition：
The standard items of metabolic markers：Including 1,3- octadienes, methyl amimoacetic acid, phosphocholine, 2- hydroxylauric acids and color ammonia
Acid, each standard items are encapsulated respectively；
Blood plasma metabolin Extraction solvent：100% acetonitrile and 20% acetonitrile solution (are used for UPLC-Q/TOF-MS sample systems
It is standby)；Mixed solution, methoxamine pyridine and the N- methyl-N- trimethyls silicon substrate three of methanol, chloroform and water that ratio is 2.5: 1: 1
Fluorakil 100 (is used for GC-Q/MS sample preparations)；During UPLC-Q/TOF-MS screenings are characterized, 20% acetonitrile solution may be used as
Dissolve the solvent of standard items；During GC-Q/MS screenings are characterized, prepared and marked by the method for sample preparation with blood plasma metabolin Extraction solvent
Quasi- product solution；
Internal standard：2- isopropylmolic acids.
Certainly, when designing detection kit, and the standard items of above-mentioned 5 metabolic markers need not be completely included, can be with
It is combined using only wherein several.These standard items can be encapsulated individually, and mixture encapsulation can also be made.
The kit is designed based on the metabolic markers that the present invention is provided, and be can be used for diagnosis and is distinguished the stable type heart
Angina patient and acute coronary artery syndrome patient.
In summary, the present invention effectively overcomes deficiency of the prior art, and tool high industrial utilization.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but the protection of the present invention is not limited with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent substitution,
Without departing from the essence and protection domain of technical solution of the present invention.
Claims (3)
1. one group of blood plasma metabolic indicator compositions distinguishes examining for stable angina cordis and acute coronary syndrome preparing diagnosis
Application in disconnected reagent, it is characterised in that：Said composition includes methyl amimoacetic acid, phosphocholine, 2- hydroxylauric acids and tryptophan.
2. application according to claim 1, it is characterised in that：Said composition also includes 1,3- octadienes.
3. a kind of be used to diagnose the kit for distinguishing stable angina cordis and acute coronary syndrome, it is characterised in that：Containing having the right
Profit requires the metabolic indicator compositions described in 1 or 2.
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| CN111505131B (en) * | 2020-01-02 | 2023-03-31 | 东莞东华医院有限公司 | Clinical model for predicting coronary heart disease plaque instability based on serum metabonomics change |
| CN114938659B (en) * | 2021-02-05 | 2025-03-04 | 中国医学科学院阜外医院 | Cardiovascular disease risk assessment markers based on metabolomics data and their applications |
| CN115856275B (en) * | 2023-02-15 | 2024-01-30 | 南京医科大学附属逸夫医院 | Markers used to screen for sudden cardiac death caused by acute coronary syndrome and their applications |
| CN117385024B (en) * | 2023-11-29 | 2024-04-19 | 梅州市人民医院(梅州市医学科学院) | A lncRNA marker and its application in preparing a product for diagnosing, screening or evaluating acute coronary syndrome |
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