WO2023274296A1 - 丙酮酸激酶m2在心力衰竭诊断及预后评估中的应用 - Google Patents

丙酮酸激酶m2在心力衰竭诊断及预后评估中的应用 Download PDF

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WO2023274296A1
WO2023274296A1 PCT/CN2022/102358 CN2022102358W WO2023274296A1 WO 2023274296 A1 WO2023274296 A1 WO 2023274296A1 CN 2022102358 W CN2022102358 W CN 2022102358W WO 2023274296 A1 WO2023274296 A1 WO 2023274296A1
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heart failure
pkm2
patient
mrna encoding
level
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PCT/CN2022/102358
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English (en)
French (fr)
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王俊宏
唐波
丁强
冯速
褚明
时亚斌
曹露
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南京诺唯赞医疗科技有限公司
江苏省人民医院（南京医科大学第一附属医院）
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Publication of WO2023274296A1 publication Critical patent/WO2023274296A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • G01N2333/91205—Phosphotransferases in general
    • G01N2333/9121—Phosphotransferases in general with an alcohol group as acceptor (2.7.1), e.g. general tyrosine, serine or threonine kinases
    • G01N2333/91215—Phosphotransferases in general with an alcohol group as acceptor (2.7.1), e.g. general tyrosine, serine or threonine kinases with a definite EC number (2.7.1.-)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/325—Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present disclosure relates to methods of diagnosing and predicting heart failure. Further, the present disclosure relates to a method for the diagnosis and prognosis of pyruvate kinase M2 heart failure.
  • Heart failure is the impairment of ventricular filling and/or ejection function caused by various heart structural or functional diseases, and the cardiac output cannot meet the metabolic needs of body tissues, resulting in pulmonary circulation and (or) systemic circulation congestion , and organ and tissue hypoperfusion is a group of syndromes with clinical manifestations.
  • the main clinical manifestations are dyspnea and fluid retention (pulmonary congestion and peripheral edema) caused by blood stasis in the venous system and hypoperfusion of the arterial system.
  • HF is the terminal stage of various cardiovascular diseases and one of the important causes of death from cardiovascular diseases. It is an important issue affecting the public health of our country. Accurate diagnosis of HF is helpful for active and effective treatment of HF, reducing the occurrence of cardiovascular events, thereby reducing the social and family burden.
  • the diagnosis of HF includes clinical symptoms, signs, two-dimensional echocardiography, cardiac magnetic resonance and other imaging examinations, as well as HF-related blood markers. Among them, the detection of HF-related blood markers is an important means for the diagnosis and clinical prognosis evaluation of HF patients.
  • HF markers include brain natriuretic peptide (BNP), N-terminal precursor BNP (NT-proBNP), troponin T/I (cTnT/I), and human galectin-3 (Gal-3). , soluble ST-2, GDF-15, H-FABP and CRP, etc.
  • BNP brain natriuretic peptide
  • NT-proBNP N-terminal precursor BNP
  • cTnT/I troponin T/I
  • Gal-3 human galectin-3
  • BNP and NT-proBNP in the blood circulation are the most widely used markers in clinical practice, and their elevations are positively correlated with the severity of HF.
  • blood circulation BNP and NT-proBNP will also increase significantly, thereby Interfering with the clinical diagnosis of HF. Therefore, the detection of a single marker is often unable to determine the condition and prognosis of HF well, and combined detection of multiple biomarkers is often used in clinical testing to diagnose and guide HF.
  • PK Pyruvate kinase
  • PKM1 is expressed in most adult tissues, while PKM2 is mainly expressed in embryonic development. expressed in the process.
  • PKM2 is composed of four subunits, which exist in various forms such as monomer, dimer and tetramer. A large amount of evidence shows that the expression of PKM2 is enhanced in various tumor tissues.
  • PKM2 promotes the uptake of a large amount of glucose by tumor cells, inhibits oxidative phosphorylation, generates a large amount of lactic acid, and provides a favorable growth environment for tumor cells.
  • studies have found that PKM2 is related to myocardial reperfusion injury, activation of glycolysis pathway during myocardial ischemia and hypoxia, myocardial cell cycle and myocardial oxidative stress.
  • US20070238781A1 discloses a method for in vitro detection of cardiac insufficiency or chronic heart failure, which comprises comparing the level of pyruvate kinase type M2 in a patient's plasma sample with a predetermined standard level, wherein the level of pyruvate kinase type M2 in the plasma sample Detection is performed by an immunological assay using a monoclonal antibody to detect M2-type pyruvate kinase.
  • One aspect of the present disclosure provides a method for predicting, diagnosing, assisting in diagnosing or prognosing heart failure by detecting the level of PKM2 or mRNA encoding PKM2 protein in a subject, including detecting PKM2 or mRNA encoding PKM2 protein in a subject sample mRNA levels compared to predetermined standard levels of PKM2 or mRNA encoding PKM2 protein, relative to which a detectable increase in the predetermined standard level indicates the possibility of heart failure.
  • Another aspect of the present disclosure also provides the use of a reagent for detecting PKM2 or mRNA encoding PKM2 protein in the preparation of a kit for prediction, diagnosis, auxiliary diagnosis or prognosis assessment of heart failure, using the reagent to detect The level of PKM2 or the mRNA encoding PKM2 protein, and compared with the predetermined standard level of PKM2 or the mRNA encoding PKM2 protein, and the predictable level of PKM2 or the mRNA encoding PKM2 protein in the subject sample relative to the predetermined standard level An increase in detection indicates the possibility of heart failure.
  • the reagent comprises an antibody or antigen-binding fragment thereof capable of specifically binding to PKM2. In some embodiments, the reagent comprises a reagent capable of specifically detecting mRNA encoding a PKM2 protein. In some embodiments, the reagents comprise specific primers for amplifying mRNA encoding PKM2 protein, or specific probes or chips for detecting mRNA encoding PKM2 protein.
  • Another aspect of the present disclosure also provides the use of a reagent for detecting PKM2 or mRNA encoding PKM2 protein in the preparation of a kit for evaluating the prognosis of heart failure patients.
  • the patient is receiving anti-heart failure therapy, and the prognosis evaluation includes: a. Measuring the level of PKM2 or mRNA encoding a PKM2 protein in at least two biological samples obtained from a patient at different times, wherein the different times are a first time point and a second time point, wherein the second time point later than the first time point, and wherein the patient is being treated for heart failure; and b.
  • comparing the levels of PKM2 or mRNA encoding PKM2 protein in the at least two biological samples wherein compared to the first time point A reduction in the level of PKM2 or mRNA encoding a PKM2 protein collected at the point compared to the second time point in which the PKM2 collected at the second time point compared to the first time point in which the PKM2 Or an increase in the level of mRNA encoding the PKM2 protein indicates that the treatment is not effective.
  • Another aspect of the present disclosure also provides the use of reagents for detecting PKM2 or mRNA encoding PKM2 protein in the preparation of kits for diagnosis and auxiliary diagnosis of heart failure.
  • the diagnosis includes: a. the level of PKM2 or mRNA encoding a PKM2 protein in a sample from the subject; and b. compared to a predetermined standard level of PKM2 or mRNA encoding a PKM2 protein, wherein PKM2 or mRNA encoding a PKM2 protein in said sample is relative to said predetermined standard
  • a detectable increase in levels indicates the possibility of heart failure.
  • the heart failure symptoms are selected from the group consisting of dyspnea, cough, expectoration, hemoptysis, fatigue, dizziness, palpitation, decreased exercise, oliguria, symptoms of kidney damage, cold extremities, forced sitting, confusion, Cyanosis of the lips, pale complexion, profuse sweating, irritability, pulmonary edema, lower extremity edema, hepatosplenomegaly, hydroperitoneum, chest tightness, and shortness of breath.
  • the heart failure symptom is dyspnea.
  • the dyspnea is acute dyspnea.
  • the present disclosure also relates to the use of a reagent for detecting PKM2 or mRNA encoding PKM2 protein in the preparation of a kit for evaluating the prognosis of heart failure patients.
  • the patient is receiving anti-heart failure therapy, and the prognosis evaluation includes:
  • the patient's prognosis is poor; if the patient's PKM2 level is lower than 50% of the reference value, the patient's prognosis is better.
  • the poor prognosis means that the incidence of death within one year is greater than 20%, greater than 25%, or greater than 30%.
  • the better prognosis means that the incidence of death within one year is less than 15%, less than 10%, or less than 8%.
  • the good prognosis means that the incidence of cardiovascular death and heart failure readmission within 1 year is less than 10%; the poor prognosis means that the incidence of cardiovascular death and heart failure readmission within 1 year higher than 30%.
  • the reference value is an average of the levels of PKM2 or mRNA encoding a PKM2 protein in a population of heart failure patients. In some embodiments, the reference value of PKM2 is selected from 15-25 U/L. In some embodiments, the reference value of PKM2 is selected from 15-20 U/L. In some embodiments, the reference value of PKM2 is selected from 18-20 U/L.
  • the reference value of PKM2 is selected from 18.0U/L, 18.1U/L, 18.2U/L, 18.3U/L, 18.4U/L, 18.5U/L, 18.6U/L, 18.7U/L, 18.8U/L, 18.9U/L, 19.0U/L, 19.1U/L, 19.2U/L, 19.3U/L, 19.4U/L, 19.5U/L, 19.6U/L, 19.7U/L, 19.8U/L, 19.9U/L or 20.0U/L.
  • the heart failure is left heart failure, global heart failure, acute heart failure, chronic heart failure, heart failure caused by ischemic myocardial injury, heart failure caused by high heart disease, alcoholic cardiomyopathy heart failure due to dilated cardiomyopathy, heart failure due to hypertrophic cardiomyopathy, heart failure due to valvular cardiomyopathy, heart failure due to other types of heart disease, heart failure with preserved systolic function (HFpEF), Heart failure with intermediate systolic function (HFmEF) or heart failure with reduced systolic function (HFrEF).
  • HFpEF preserved systolic function
  • HFmEF Heart failure with intermediate systolic function
  • HFrEF reduced systolic function
  • the heart failure patient is heart failure caused by dilated cardiomyopathy.
  • the heart failure is not right heart failure.
  • the heart failure is left heart failure. In some embodiments, the heart failure is global heart failure.
  • the heart failure is acute heart failure. In some embodiments, the heart failure is chronic heart failure. In some embodiments, the heart failure is acute onset of chronic heart failure or acute onset heart failure.
  • the heart failure is heart failure caused by ischemic myocardial injury, heart failure caused by high heart disease, heart failure caused by alcoholic cardiomyopathy, heart failure caused by dilated cardiomyopathy, hypertrophic myocardium Heart failure caused by heart disease, heart failure caused by valvular cardiomyopathy, or heart failure caused by other types of heart disease.
  • the heart failure is heart failure with preserved systolic function (HFpEF), heart failure with intermediate systolic function (HFmEF), or heart failure with reduced systolic function (HFrEF).
  • HFpEF preserved systolic function
  • HFmEF heart failure with intermediate systolic function
  • HFrEF heart failure with reduced systolic function
  • the PKM2 level in the subject's sample increases by more than 10% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient. In some embodiments, the level of PKM2 in the subject's sample increases by more than 20% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient. In some embodiments, the level of PKM2 in the subject's sample increases by more than 30% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient. In some embodiments, the PKM2 level in the subject sample is increased by more than 50% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient.
  • the PKM2 level in the subject sample is increased by more than 60% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient. In some embodiments, the PKM2 level in the subject's sample increases by more than 70% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient. In some embodiments, the level of PKM2 in the subject's sample increases by more than 80% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient. In some embodiments, the level of PKM2 in the subject sample is increased by more than 90% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient.
  • the level of PKM2 in the subject's sample increases by more than 100% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient. In some embodiments, the level of PKM2 in the subject's sample increases by more than 150% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient. In some embodiments, the PKM2 level in the subject sample is increased by more than 200% relative to the predetermined standard level, suggesting that the subject may be a heart failure patient.
  • the PKM2 level of the subject sample or patient sample is determined by a PKM2 detection kit, which includes a reagent capable of recognizing PKM2.
  • the reagent capable of recognizing PKM2 comprises an antibody or antigen-binding fragment thereof capable of specifically binding to PKM2 or a biologically active fragment thereof.
  • the predetermined standard level of PKM2 is the level of PKM2 from a population of healthy individuals without heart failure.
  • the predetermined standard level of PKM2 is less than 10 U/ml. In some embodiments, the predetermined standard level of PKM2 is selected from 7-10 U/ml. In some embodiments, the predetermined standard level of PKM2 is selected from 7.5U/ml, 7.6U/ml, 7.7U/ml, 7.8U/ml, 7.9U/ml, 8.0U/ml, 8.1U/ml, 8.2U/ml ml, 8.3U/ml, 8.4U/ml, 8.5U/ml, 8.6U/ml, 8.7U/ml, 8.8U/ml, 8.9U/ml, 9.0U/ml, 9.1U/ml, 9.2U/ml ml, 9.3U/ml, 9.4U/ml, 9.5U/ml, 9.6U/ml, 9.7U/ml, 9.8U/ml, 9.9U/ml.
  • the test results show that the PKM2 level of the subject is higher than 10U/ml, 11U/ml, 12U/ml, 13U/ml, 14U/ml, 15U/ml, 16U/ml, 17U/ml, 18U/ml, 19U/ml ml, 20U/ml, 21U/ml, 22U/ml, 23U/ml, 24U/ml, 25U/ml, 26U/ml, 27U/ml, 28U/ml, 29U/ml, 30U/ml, 31U/ml, When the concentration is 32U/ml, 33U/ml, 34U/ml, 35U/ml, 36U/ml, 37U/ml, 38U/ml, 39U/ml or 40U/ml, it indicates that the subject may be a patient with heart failure.
  • the test results show that the PKM2 level of the subject is higher than 10U/ml, 11U/ml, 12U/ml, 13U/ml, 14U/ml, 15U/ml, 16U/ml, 17U/ml, 18U/ml, 19U/ml ml, 20U/ml, 21U/ml, 22U/ml, 23U/ml, 24U/ml, 25U/ml, 26U/ml, 27U/ml, 28U/ml, 29U/ml, 30U/ml, 31U/ml, When the concentration is 32U/ml, 33U/ml, 34U/ml or 35U/ml, it indicates that the subject may be a patient with left heart failure.
  • the test results show that the PKM2 level of the subject is higher than 10U/ml, 11U/ml, 12U/ml, 13U/ml, 14U/ml, 15U/ml, 16U/ml, 17U/ml, 18U/ml, 19U/ml ml, 20U/ml, 21U/ml, 22U/ml, 23U/ml, 24U/ml, 25U/ml, 26U/ml, 27U/ml, 28U/ml, 29U/ml, 30U/ml, 31U/ml, 32U/ml, 33U/ml, 34U/ml, 35U/ml, 36U/ml, 37U/ml, 38U/ml, 39U/ml or 40U/ml, suggesting that the subject may be a patient with heart failure.
  • the level of PKM2 in the sample of the acute heart failure patient described in the present disclosure is between 10-100 U/ml. In some embodiments, the level of PKM2 in the sample of the acute heart failure patient described in the present disclosure is between 10-80 U/ml. In some embodiments, the level of PKM2 in the sample of the acute heart failure patient described in the present disclosure is between 10-60 U/ml. In some embodiments, the level of PKM2 in the sample of the acute heart failure patient described in the present disclosure is between 10-40 U/ml.
  • the PKM2 level in the acute heart failure patient sample described in the present disclosure is higher than 10U/ml, 11U/ml, 12U/ml, 13U/ml, 14U/ml, 15U/ml, 16U/ml, 17U /ml, 18U/ml, 19U/ml, 20U/ml, 21U/ml, 22U/ml, 23U/ml, 24U/ml, 25U/ml, 26U/ml, 27U/ml, 28U/ml, 29U/ml , 30U/ml, 31U/ml, 32U/ml, 33U/ml, 34U/ml, 35U/ml, 36U/ml, 37U/ml, 38U/ml, 39U/ml or 40U/ml.
  • the level of PKM2 in the sample of the chronic heart failure patient described in the present disclosure is between 10-30 U/ml. In some embodiments, the level of PKM2 in the sample of the chronic heart failure patient described in the present disclosure is between 10-20 U/ml. In some embodiments, the level of PKM2 in the chronic heart failure patient sample of the present disclosure is higher than 10U/ml, 11U/ml, 12U/ml, 13U/ml, 14U/ml, 15U/ml, 16U/ml, 17U /ml, 18U/ml, 19U/ml or 20U/ml.
  • the subject sample or patient sample described in the present disclosure is a biological sample.
  • the subject sample or patient sample is a blood sample.
  • the subject sample or patient sample is a sample of myocardial tissue.
  • the subject sample or patient sample is a serum sample.
  • the subject sample or patient sample is a plasma sample.
  • the level of PKM2 described in the present disclosure is obtained by detecting the content of PKM2 in plasma, and the plasma sample is obtained by: collecting anticoagulated whole blood from a subject, and centrifuging the whole blood get plasma.
  • blood is collected from a subject into a blue cap vacuum blood collection tube (containing the anticoagulant sodium citrate in a 1:9 ratio of anticoagulant to blood), and the blood in the blood collection tube is centrifuged Plasma was obtained after processing.
  • the subject or heart failure patient of the present disclosure is not a patient with malignancy.
  • the detection methods include but are not limited to colloidal gold immunochromatography, immunoblotting, immunohistochemistry, immunofluorescence, enzyme-linked immunoassay, nucleic acid probe method or real-time quantitative q-PCR method.
  • the "detectable increase” in the present disclosure refers to an increase of more than 5% relative to the predetermined standard level of PKM2. For example, increase by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300% or more.
  • the present disclosure finds that the content of PKM2 in the plasma of patients with heart failure is higher than that of non-heart failure patients, especially in patients with left heart failure and total heart failure, which is significantly higher than that in non-heart failure patients, and the content in plasma of patients with acute heart failure is significantly higher
  • PKM2 as a marker of heart failure, has high accuracy in the diagnosis of heart failure and prognosis of heart failure, and provides a new and better choice for the prediction, diagnosis, auxiliary diagnosis, and prognosis of heart failure.
  • FIG 1 PKM2 expression levels in heart failure patients (HF) and normal non-HF patients
  • FIG. 1 PKM2 expression levels in heart failure patients (HF) with different systolic function
  • FIG. 3 Expression levels of PKM2 in different types of heart failure patients (HF)
  • FIG. 5 Correlation between central function level and PKM2 expression level in patients with heart failure (HF)
  • FIG. 7 Correlation between cardiac end-diastolic diameter and PKM2 expression level in heart failure patients (HF)
  • FIG. 8 Expression of PKM2 in patients with acute heart failure and chronic heart failure
  • Figure 10 The ability of PKM2 to assess the prognosis of patients with heart failure
  • the PKM2 detection kit used in this disclosure was purchased from Nanjing Nuoweizan Medical Technology Co., Ltd., and the pyruvate kinase isoenzyme 2 detection kit (enzyme-linked immunosorbent assay): EL101.
  • Example 1 Analysis of the expression of PKM2 in the blood of heart failure patients and non-heart failure patients

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Abstract

本公开涉及丙酮酸激酶M2在心力衰竭诊断及预后评估中的应用，属于体外诊断技术领域。本公开在排除了恶性肿瘤患者之后，发现丙酮酸激酶M2在心衰患者血浆中含量高于正常非心衰患者，尤其是在左心衰和全心衰患者中含量显著高于正常非心衰患者，在急性心衰患者血浆中的含量显著高于正常非心衰患者，PKM2作为心衰标记物在诊断心衰、心衰预后方面准确性高，为心衰疾病的预测、诊断、辅助诊断、预后判断提供了新的、更好的选择。

Description

丙酮酸激酶M2在心力衰竭诊断及预后评估中的应用 技术领域
本公开涉及诊断和预测心力衰竭的方法。更进一步的，本公开涉及丙酮酸激酶M2诊断及预后评估心力衰竭的方法。
背景技术
心力衰竭(heart failure，HF)是各种心脏结构或功能性疾病导致的心室充盈和(或)射血功能受损，心排血量不能满足机体组织代谢需要，导致肺循环和(或)体循环淤血，而器官及组织血液灌注不足为临床表现的一组综合征。临床主要表现为静脉系统血液瘀滞和动脉系统灌注不足所致呼吸困难及液体潴留(肺淤血和外周水肿)。
HF是各种心血管疾病的终末阶段，也是心血管疾病的重要死亡原因之一。它是影响我国公共卫生健康的重要问题。对于HF的准确诊断有助于积极有效的治疗HF，减少心血管事件的发生，从而减轻社会和家庭负担。HF的诊断包括临床症状、体征、二维超声心动图、心脏磁共振等影像学检查以及HF相关血液标志物。其中HF相关的血液标志物检测是HF患者诊断及临床预后评估的重要手段。目前常用的HF标志物有脑利钠肽(BNP)、N端前体BNP(NT-proBNP)、肌钙蛋白T/I(cTnT/I)、人半乳糖凝集素-3(Gal-3)、可溶性ST-2、GDF-15、H-FABP及CRP等。这些血液标志物的水平反映了HF各个环节的病理生理学变化情况，它与HF过程中的压力负荷变化、炎症反应、心肌损伤、心肌重构及心肌纤维化相关联，可以从不同层面诊断和指导HF治疗，对HF急性危险分层及预后判断。其中血循环中BNP及NT-proBNP为临床应用最为广泛的标志物，其升高程度和HF的严重程度呈正相关。但在某些肺部疾病、神经内分泌疾病及多种器官功能衰竭(肾衰，肝衰竭)及某些严重感染性疾病等情况下，血液循环BNP及NT-proBNP也会出现显著升高，从而干扰临床对HF的诊断。因此，单一标志物检测往往不能很好的确定HF的病情及预后，临床检测中常使用多个生物标志物联合检测来诊断及指导HF。
丙酮酸激酶(pyruvate kinase，PK)是糖酵解途径的关键限速酶，通过催化磷酸烯醇式丙酮酸生成丙酮酸。它在细胞能量代谢中居于中心地位。目前已发现哺乳动物体内有四种同工酶(PKM1,PKM2,PKR,PKL),PK的分布具有组织特异性，生理状态下,PKM1在大多数成体组织中表达,而PKM2则主要在胚胎发育的过程中表达。PKM2由四个亚基组成,有单体、二聚体及四聚体等多种存在形式。大量证据表明,PKM2在各类肿瘤组织中表达增强,PKM2促使肿瘤细胞摄取大量葡萄糖,并遏制氧化磷酸化,生成大量乳酸,为肿瘤细胞提供有利的生长环 境。近年来有研究发现，PKM2与心肌再灌注损伤、心肌缺血缺氧过程中糖酵解途径的活化、心肌细胞周期及心肌的氧化应激过程相关。
Biochem Biophys Res Commun.2015 April 10；459(3):430–436，公开了心力衰竭患者心脏组织中的PKM2表达显著增加，但并未研究血液或者血浆中PKM2的表达情况。US20070238781A1公开了一种体外检测心脏不足或慢性心力衰竭的方法，其包括将患者血浆样品中的丙酮酸激酶类型M2的水平与预定标准水平进行比较，其中血浆样品中的丙酮酸激酶类型M2的水平为通过使用单克隆抗体检测M2型丙酮酸激酶的免疫学测定法进行检测。
发明内容
本公开一方面提供了通过检测受试者的PKM2或编码PKM2蛋白的mRNA的水平，预测、诊断、辅助诊断或者预后心衰疾病的方法，包括检测受试者样品中的PKM2或编码PKM2蛋白的mRNA的水平，并与PKM2或编码PKM2蛋白的mRNA的预定标准水平进行比较，相对于所述预定标准水平的可检测的提高表明心衰的可能性。
本公开另一方面还提供了检测PKM2或编码PKM2蛋白的mRNA的试剂在制备用于预测、诊断、辅助诊断或者预后评估心衰的试剂盒中的用途，使用所述试剂检测受试者样品中的PKM2或编码PKM2蛋白的mRNA的水平，并与PKM2或编码PKM2蛋白的mRNA的预定标准水平进行比较，所述受试者样品中PKM2或编码PKM2蛋白的mRNA相对于所述预定标准水平的可检测的提高表明心衰的可能性。
在一些实施方案中，所述的试剂包含能够与PKM2特异结合的抗体或其抗原结合片段。在一些实施方案中，所述的试剂包含能够特异性检测编码PKM2蛋白的mRNA的试剂。在一些实施方案中，所述的试剂包含用于扩增编码PKM2蛋白的mRNA的特异性引物、或用于检测编码PKM2蛋白的mRNA的特异性探针或芯片。
本公开另一方面还提供了检测PKM2或编码PKM2蛋白的mRNA的试剂在制备用于心衰患者预后评估的试剂盒中的用途，所述患者正在接受抗心衰治疗，所述预后评估包括：a.测量在不同的时间获自患者的至少两个生物样品中PKM2或编码PKM2蛋白的mRNA的水平，其中所述不同的时间是第一时间点和第二时间点，其中所述第二时间点晚于所述第一时间点，以及其中所述患者正被治疗心衰；和b.比较所述至少两个生物样品中PKM2或编码PKM2蛋白的mRNA的水平，其中与所述第一时间点相比在所述第二时间点采集的PKM2或编码PKM2蛋白的mRNA水平的降低表明所述治疗是有效的，其中与所述第一时间点相比在所述第二时间点采集的PKM2或编码PKM2蛋白的mRNA水平的提高表明所述治疗不是有效的。
本公开另一方面还提供了检测PKM2或编码PKM2蛋白的mRNA的试剂在制备用于诊 断、辅助诊断心衰的试剂盒中的用途，所述诊断包括：a.测量获自呈现心衰症状的受试者样品中PKM2或编码PKM2蛋白的mRNA的水平；和b.与PKM2或编码PKM2蛋白的mRNA的预定标准水平比较，其中所述样品中PKM2或编码PKM2蛋白的mRNA相对于所述预定标准水平的可检测的提高表明心衰的可能性。
在一些实施方案中，所述的心衰症状选自呼吸困难、咳嗽、咳痰、咯血、乏力、头晕、心慌、运动量减低、少尿、肾损害症状、四肢发冷、强迫坐位、神志模糊、口唇发绀、面色灰白、大汗、烦躁、肺水肿、下肢水肿、肝脾肿大、腹腔积水、胸闷、气短。在一些实施方案中，所述的心衰症状是呼吸困难。在一些实施方案中，所述的呼吸困难是急性呼吸困难。
本公开还涉及检测PKM2或编码PKM2蛋白的mRNA的试剂在制备用于心衰患者预后评估的试剂盒中的用途，所述患者正在接受抗心衰治疗，所述预后评估包括：
a.测量入院时患者样品中的PKM2或编码PKM2蛋白的mRNA的水平；和
b.将所述患者入院时的PKM2或编码PKM2蛋白的mRNA的水平与参考值比较。
在一些实施方案中，其中如果患者的PKM2水平高于参考值的50％，则其预后不良；如果患者的PKM2水平低于参考值的50％，则其预后较好。在一些实施方案中，所述预后不良意味着一年内死亡发生率高于20％、高于25％或高于30％。在一些实施方案中，所述预后较好意味着一年内死亡发生率低于15％、低于10％或低于8％。在一些实施方案中，所述预后较好意味着1年内心血管死亡和心衰再入院事件发生率低于10％；所述预后不良意味着1年内心血管死亡和心衰再入院事件发生率高于30％。
在一些实施方案中，参考值是心衰患者群体PKM2或编码PKM2蛋白的mRNA的水平的平均值。在一些实施方案中，所述的PKM2的参考值选自15～25U/L。在一些实施方案中，所述的PKM2的参考值选自15～20U/L。在一些实施方案中，所述的PKM2的参考值选自18～20U/L。在一些实施方案中，所述的PKM2的参考值选自18.0U/L、18.1U/L、18.2U/L、18.3U/L、18.4U/L、18.5U/L、18.6U/L、18.7U/L、18.8U/L、18.9U/L、19.0U/L、19.1U/L、19.2U/L、19.3U/L、19.4U/L、19.5U/L、19.6U/L、19.7U/L、19.8U/L、19.9U/L或20.0U/L。
在一些实施方案中，所述的心衰是左心衰、全心衰、急性心衰、慢性心衰、缺血性心肌损伤导致的心衰、高心病导致的心衰、酒精性心肌病导致的心衰、扩张性心肌病导致的心衰、肥厚性心肌病导致的心衰、瓣膜性心肌病导致的心衰、其他类型的心脏病导致的心衰、收缩功能保留心衰(HFpEF)、中间型收缩功能心衰(HFmEF)或收缩功能下降的心衰(HFrEF)。
在一些实施方案中，所述的心衰患者是扩张性心肌病引发的心衰。
在一些实施方案中，所述的心衰不是右心衰。
在一些实施方案中，所述的心衰是左心衰。在一些实施方案中，所述的心衰是全心衰。
在一些实施方案中，所述的心衰是急性心衰。在一些实施方案中，所述的心衰是慢性心衰。在一些实施方案中，所述的心衰是慢性心衰急性发作或急性初发心衰。
在一些实施方案中，所述的心衰是缺血性心肌损伤导致的心衰、高心病导致的心衰、酒精性心肌病导致的心衰、扩张性心肌病导致的心衰、肥厚性心肌病导致的心衰、瓣膜性心肌病导致的心衰或者是其他类型的心脏病导致的心衰。
在一些实施方案中，所述的心衰是收缩功能保留心衰(HFpEF)、中间型收缩功能心衰(HFmEF)或收缩功能下降的心衰(HFrEF)。
在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高10％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高20％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高30％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高50％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高60％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高70％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高80％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高90％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高100％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高150％以上，提示受试者可能是心衰患者。在一些实施方案中，受试者样品中的PKM2水平相对于预定标准水平升高200％以上，提示受试者可能是心衰患者。
在一些实施方案中，受试者样品或者患者样品的PKM2水平是通过PKM2的检测试剂盒确定的，检测试剂盒中包括能够识别PKM2的试剂。在一些实施方案中，所述能够识别PKM2的试剂包括能够特异性结合PKM2或其生物活性片段的抗体或其抗原结合片段。
在一些实施方案中，所述PKM2预定标准水平是来自非心衰健康个体的群体的PKM2水平。
在一些实施方案中，PKM2预定标准水平低于10U/ml。在一些实施方案中，PKM2预定标准水平选自7～10U/ml。在一些实施方案中，PKM2预定标准水平选自7.5U/ml、7.6U/ml、7.7U/ml、7.8U/ml、7.9U/ml、8.0U/ml、8.1U/ml、8.2U/ml、8.3U/ml、8.4U/ml、8.5U/ml、8.6U/ml、8.7U/ml、8.8U/ml、8.9U/ml、9.0U/ml、9.1U/ml、9.2U/ml、9.3U/ml、9.4U/ml、9.5U/ml、9.6U/ml、9.7U/ml、9.8U/ml、9.9U/ml。当检测结果显示受试者的PKM2水平高 于10U/ml、11U/ml、12U/ml、13U/ml、14U/ml、15U/ml、16U/ml、17U/ml、18U/ml、19U/ml、20U/ml、21U/ml、22U/ml、23U/ml、24U/ml、25U/ml、26U/ml、27U/ml、28U/ml、29U/ml、30U/ml、31U/ml、32U/ml、33U/ml、34U/ml、35U/ml、36U/ml、37U/ml、38U/ml、39U/ml或40U/ml时，提示受试者可能是心衰患者。当检测结果显示受试者的PKM2水平高于10U/ml、11U/ml、12U/ml、13U/ml、14U/ml、15U/ml、16U/ml、17U/ml、18U/ml、19U/ml、20U/ml、21U/ml、22U/ml、23U/ml、24U/ml、25U/ml、26U/ml、27U/ml、28U/ml、29U/ml、30U/ml、31U/ml、32U/ml、33U/ml、34U/ml或35U/ml时，提示受试者可能是左心衰患者。当检测结果显示受试者的PKM2水平高于10U/ml、11U/ml、12U/ml、13U/ml、14U/ml、15U/ml、16U/ml、17U/ml、18U/ml、19U/ml、20U/ml、21U/ml、22U/ml、23U/ml、24U/ml、25U/ml、26U/ml、27U/ml、28U/ml、29U/ml、30U/ml、31U/ml、32U/ml、33U/ml、34U/ml、35U/ml、36U/ml、37U/ml、38U/ml、39U/ml或40U/ml时，提示受试者可能是全心衰患者。
在一些实施方案中，本公开所述的急性心衰患者样品中PKM2水平在10～100U/ml之间。在一些实施方案中，本公开所述的急性心衰患者样品中PKM2水平在10～80U/ml之间。在一些实施方案中，本公开所述的急性心衰患者样品中PKM2水平在10～60U/ml之间。在一些实施方案中，本公开所述的急性心衰患者样品中PKM2水平在10～40U/ml之间。在一些实施方案中，本公开所述的急性心衰患者样品中PKM2水平高于10U/ml、11U/ml、12U/ml、13U/ml、14U/ml、15U/ml、16U/ml、17U/ml、18U/ml、19U/ml、20U/ml、21U/ml、22U/ml、23U/ml、24U/ml、25U/ml、26U/ml、27U/ml、28U/ml、29U/ml、30U/ml、31U/ml、32U/ml、33U/ml、34U/ml、35U/ml、36U/ml、37U/ml、38U/ml、39U/ml或40U/ml。在一些实施方案中，本公开所述的慢性心衰患者样品中PKM2水平在10～30U/ml之间。在一些实施方案中，本公开所述的慢性心衰患者样品中PKM2水平在10～20U/ml之间。在一些实施方案中，本公开所述的慢性心衰患者样品中PKM2水平高于10U/ml、11U/ml、12U/ml、13U/ml、14U/ml、15U/ml、16U/ml、17U/ml、18U/ml、19U/ml或20U/ml。
本公开所述受试者样品或者患者样品为生物样品。在一些实施方案中，所述受试者样品或者患者样品为血液样品。在一些实施方案中，所述受试者样品或者患者样品为心肌组织样品。在一些实施方案中，所述受试者样品或者患者样品为血清样品。在一些实施方案中，所述受试者样品或者患者样品为血浆样品。
在一些实施方案中，本公开所述的PKM2水平是通过检测血浆中PKM2含量得到的，所述的血浆样品通过以下途径获得：从受试者处采集抗凝全血，全血经离心处理后得到血浆。在一些实施方案中，从受试者处采集血液至蓝色头帽真空采血管(含抗凝剂枸橼酸钠，抗凝 剂与血液比例为1：9)，采血管中的血液经离心处理后得到血浆。
在一些实施方案中，本公开所述的受试者或者心衰患者不是恶性肿瘤患者。
在一些实施方案中，所述检测的方法包括但不限于胶体金免疫层析法、免疫印迹法、免疫组化、免疫荧光、酶联免疫法、核酸探针法或实时定量q-PCR法。
本公开所述的“可检测的提高”是指相对于PKM2预定标准水平提高5％以上。例如提高10％、20％、30％、40％、50％、60％、70％、80％、90％、100％、110％、120％、130％、140％、150％、160％、170％、180％、190％、200％、250％、300％以上。
发明的有益效果
本公开发现PKM2在心衰患者血浆中含量高于非心衰患者，尤其是在左心衰和全心衰患者中含量显著高于非心衰患者，在急性心衰患者血浆中的含量显著高于非心衰患者，PKM2作为心衰标记物在诊断心衰、心衰预后方面准确性高，为心衰疾病的预测、诊断、辅助诊断、预后判断提供了新的、更好的选择。
附图说明
图1：PKM2在心衰患者(HF)和正常非心衰患者中表达水平
图2：PKM2在心脏收缩功能不同的心衰患者(HF)中表达水平
图3：PKM2在不同类型心衰患者(HF)中表达水平
图4：PKM2在不同病因心衰患者(HF)中表达水平
图5：心衰患者(HF)中心功能水平与PKM2表达水平的相关性
图6：心衰患者(HF)中心脏收缩末期内径与PKM2表达水平的相关性
图7：心衰患者(HF)中心脏舒张末期内径与PKM2表达水平的相关性
图8：PKM2在急性心衰和慢性心衰患者中的表达
图9：PKM2与其他心衰血液标记物诊断能力比较
图10：PKM2评估心衰患者预后的能力
具体实施方式
本公开所用PKM2检测试剂盒购自南京诺唯赞医疗科技有限公司，丙酮酸激酶同工酶2检测试剂盒(酶联免疫吸附法)：EL101。
下面将结合实施例对本公开的实施方案进行详细描述，但是本领域的技术人员将会理解，下列实施例仅用于说明本公开，而不应视为限定本公开的范围。
实施例1：心衰患者和非心衰患者血液中PKM2的表达分析
排除明确有恶性肿瘤病史患者，连续收集新发心衰或心衰恶化入院接受药物治疗患者共126名，其他心内科住院非心衰患者共46名(冠心病，高血压，晕厥，房颤室早及肺动脉高压患者)，采集入院次日清晨空腹血，2,500g，10min离心获得血浆，采用ELISA方法检测两组患者血浆PKM2的表达水平，T检验比较两组患者PKM2水平差异。结果：与非心衰患者(NC)相比，PKM2在心衰患者(HF)中表达水平显著升高，如附图1所示。
对所有心衰患者按心衰类型分类，采用单因素方差分析方法比较不同类型及不同心衰病因各组PKM2水平差异。结果：收缩功能保留心衰患者(HFpEF)与中间型收缩功能心衰(HFmEF)及收缩功能下降的心衰(HFrEF)患者血浆中PKM2水平无明显差异(见附图2)，而单纯右心衰患者的血浆PKM2水平与正常对照组无显著性差异患(见附图3)，不同病因心衰患者PKM2水平无显著差异(见附图4)。
采用Pearson相关性分析对126例心衰患者的PKM2水平与心脏结构及功能相关性进行分析。结果：血浆PKM2水平与心衰患者的心功能水平(r＝-0.335，p<0.01)相关，但与心脏收缩末期内径(r＝0.01，p>0.05)及心脏舒张末期内径(r＝0.03，p>0.05)则无显著相关性。见附图5、6、7。
排除明确有恶性肿瘤病史患者，连续收集急性心衰患者共54名，急性心衰患者经治疗后转为稳定期慢性心衰患者17名，采集空腹血，2,500g，10min离心获得血浆，采用ELISA方法检测两组患者血浆PKM2的表达水平，T检验比较两组心衰患者PKM2水平差异。结果：与慢性心衰患者(CHF)相比，PKM2在急性心衰患者(AHF)中表达水平明显较高，如附图8所示。
实施例2
连续收集急诊室因急性呼吸困难入院患者65名(排除各种恶性肿瘤病史)，其中急性心衰患者43名，22名非心源性呼吸困难(16名为呼吸系统疾病，包括气胸，急性哮喘发作，肺气肿，肺部感染，胸腔积液，1名肺栓患者，2名心包积液和3名不明原因患者)。采集抗凝全血，2,500g，10min离心获得血浆，采用ELISA方法检测患者血浆PKM2，NT-proBNP和ST-2的水平，采用ROC方法计算曲线下面积，比较三种不同标志物对急性心衰的鉴别诊断价值。结果：与NT-proBNP(ROC曲线下面积：0.827 95％CI(0.700-0.955)和ST-2(ROC曲线下面积：0.686，95％CI(0.529-0.844))相比，PKM2的ROC曲线下面积：0.910，95％CI (0.818-1.00)显著升高(p<0.01)。见附图9.
实施例3
排除明确有恶性肿瘤病史患者，连续收集新发心衰或心衰恶化入院接受治疗的扩张性心肌病患者共59名，采集入院次日清晨空腹血，2,500g，10min离心获得血浆，采用ELISA方法检测患者血浆PKM2的表达水平。心衰患者入院血浆PKM2水平的按中位数(18.18U/L)分为两组(High PKM2：高于>50％中位数；Low PKM2：低于<50％中位数)以1年内心血管死亡和心衰再入院事件作为复合终点，所有心衰患者随访1年，采用COX生存分析比较High PKM2与Low PKM2组心衰患者1年内无事件生存率的差异。结果：High PKM2组患者复合终点事件发生率显著高于Low-PKM2组心衰患者(HR 4.82(95％CI 1.18-14.18),p＝0.02)。见附图10.(percent survival(％)是指无事件生存率)

Claims (13)

  1. 检测PKM2或编码PKM2蛋白的mRNA的试剂在制备用于预测、诊断、辅助诊断或者预后评估心衰的试剂盒中的用途，使用所述试剂检测受试者样品中的PKM2或编码PKM2蛋白的mRNA水平，并与预定标准水平进行比较，所述受试者样品中PKM2或编码PKM2蛋白的mRNA相对于所述预定标准水平的可检测的提高表明心衰的可能性。
  2. 检测PKM2或编码PKM2蛋白的mRNA的试剂在制备用于诊断、辅助诊断心衰的试剂盒中的用途，所述诊断、辅助诊断包括：
    a.测量获自呈现心衰症状的受试者样品中PKM2或编码PKM2蛋白的mRNA的水平；和
    b.与PKM2或编码PKM2蛋白的mRNA的预定标准水平比较，其中所述样品中PKM2或编码PKM2蛋白的mRNA相对于所述预定标准水平的可检测的提高表明心衰的可能性。
  3. 根据权利要求2所述的用途，其中心衰症状选自呼吸困难、咳嗽、咳痰、咯血、乏力、头晕、心慌、运动量减低、少尿、肾损害症状、四肢发冷、强迫坐位、神志模糊、口唇发绀、面色灰白、大汗、烦躁。
  4. 根据权利要求3所述的用途，其中所述的呼吸困难是急性呼吸困难。
  5. 检测PKM2或编码PKM2蛋白的mRNA的试剂在制备用于心衰患者预后评估的试剂盒中的用途，所述患者正在接受抗心衰治疗，所述预后评估包括：a.测量入院时患者样品中的PKM2或编码PKM2蛋白的mRNA的水平；和b.将所述患者入院时的PKM2或编码PKM2蛋白的mRNA的水平与参考值比较。
  6. 根据权利要求5所述的用途，其中如果患者的PKM2水平高于参考值的50％，则其预后不良；如果患者的PKM2水平低于参考值的50％，则其预后较好。
  7. 根据权利要求5所述的用途，其中所述心衰患者选自缺血性心肌损伤导致的心衰、高心病导致的心衰、酒精性心肌病导致的心衰、扩张性心肌病导致的心衰、肥厚性心肌病导致的心衰、瓣膜性心肌病导致的心衰或者是其他类型的心脏病导致的心衰。
  8. 根据权利要求1、2、5任一项所述的用途，其中所述的心衰选自左心衰、全心衰、急性心衰、慢性心衰、缺血性心肌损伤导致的心衰、高心病导致的心衰、酒精性心肌病导致的心衰、扩张性心肌病导致的心衰、肥厚性心肌病导致的心衰、瓣膜性心肌病导致的心衰、其他类型的心脏病导致的心衰、收缩功能保留心衰、中间型收缩功能心衰或收缩功能下降的心衰。
  9. 根据权利要求1、2、5任一项所述的用途，其中所述的心衰是收缩功能保留心衰、中间型收缩功能心衰或收缩功能下降的心衰。
  10. 根据权利要求1、2、5任一项所述的用途，其中所述的检测PKM2的试剂包括能够特异性结合PKM2或其生物活性片段的抗体或其抗原结合片段。
  11. 根据权利要求1、2、5任一项所述的用途，其中所述的检测编码PKM2蛋白的mRNA的试剂包括用于扩增编码PKM2蛋白的mRNA的特异性引物、或用于检测编码PKM2蛋白的mRNA的特异性探针或芯片。
  12. 根据权利要求1、2、5任一项所述的用途，其中所述受试者样品或者患者样品是血清样本、血浆样品或心肌组织样本。
  13. 根据权利要求1、2、5任一项所述的用途，其中所述受试者或者患者不是恶性肿瘤患者。
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