WO2005124362A2 - Procede et kit de test pour diagnostiquer une lesion ischemique cardiaque, notamment ses formes chroniques et latentes, par identification serologique de la chaine legere 1 de myosine - Google Patents

Procede et kit de test pour diagnostiquer une lesion ischemique cardiaque, notamment ses formes chroniques et latentes, par identification serologique de la chaine legere 1 de myosine Download PDF

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WO2005124362A2
WO2005124362A2 PCT/IB2005/002385 IB2005002385W WO2005124362A2 WO 2005124362 A2 WO2005124362 A2 WO 2005124362A2 IB 2005002385 W IB2005002385 W IB 2005002385W WO 2005124362 A2 WO2005124362 A2 WO 2005124362A2
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mlc
spect
test kit
latent
myocardial
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WO2005124362A3 (fr
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Viktor Ruzicka
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Biovendor Laboratorni Medicina AS
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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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6887—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids from muscle, cartilage or connective tissue
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • 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

Definitions

  • the invention relates to a method for the diagnosis of ischemic heart damage, in particular the latent and chronic forms, by serological detection of the myosin light chain I.
  • the method relates to a method for the diagnosis of ischemic heart damage, in particular the latent and chronic forms (Myosin Light Chain 1, MLC 1) as a diagnostic marker in the blood of affected patients and an enzyme immunoassay for the detection of MLC 1.
  • MLC 1 Myosin Light Chain 1, MLC 1
  • the field of application of the invention is medicine and here in particular medical diagnostics.
  • Circulatory disorder emerge from the heart muscle cell and, depending on the biological half-life, can be measured in the peripheral blood for a certain time. Their appearance, increase or decrease therefore indicate the occurrence, expansion and regression of an acute ischemic event.
  • cardiac troponins with whose help the existence of myocardial necrosis has been proven can be reliably recognized, but it is not possible to determine myocardial ischemia without necrosis [24]) and the fact that examinations under stress (e.g. stress tests, perfusion scintigraphy of the myocardium, etc.) must be carried out, which is time-consuming and economically expensive are [10, 11, 15, 24].
  • the object of the present invention was to provide a diagnostic marker for the detection of ischemic heart damage, in particular the latent and chronic forms, preferably by the diagnostic significance of the marker for patients with suspected myocardial ischemia, the use of the marker in Diagnostics to verify ischemic heart damage, especially latent myocardial ischemia, and a test kit to detect the marker.
  • the invention relates to a method for the diagnosis of ischemic heart damage, in particular the latent and chronic forms, by serological detection of the myosin light chain I (myosin light chain 1, MLC 1) as a diagnostic marker in the blood of affected patients, and an enzyme immunoassay for the detection of MLC
  • myosin light chain I myosin light chain 1, MLC 1
  • the enzyme immunoassay for the determination of MLC I in blood for the diagnosis of ischemic heart damage, especially of the latent and chronic forms comprises in separate packaging at least: a) a solid support with antibodies bound to it, which bind MLC I sensitively and specifically; b) MLC I as a standard for the quantitative determination of this marker; c) at least one buffer for making a standard series of MLC I; d) a buffer for diluting the sample to be examined; e) a wash buffer; f) a detectably labeled conjugate that binds to MLC I; g) and a substrate that marked the visualization of the detectable. , Conjugate allowed.
  • the antibodies which are bound to the solid support are preferably monoclonal antibodies.
  • Solid carriers microtiter plates are mainly used, and as the detectably labeled conjugate is a conjugate antibody, preferably a monoclonal antibody which binds to the MLC I.
  • Immunological standard methods for the detection of analytes from test solutions are particularly suitable for the invention, preferably if they are implemented as an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • Monoclonal antibodies that bind specifically to MLC 1 were conjugated to horseradish peroxidase (HRP) using the periodate method. Various combinations of antibodies were then tested. Both the antibodies that were bound to the microtiter plate and the conjugated antibodies were varied. It was shown that the combination of a monoclonal antibody for plate coating with an HRP-conjugated monoclonal antibody gives the best results.
  • HRP horseradish peroxidase
  • the concentration of the coating antibodies, the conjugate dilution, the buffer components, the incubation times and temperatures, as well as the stability of the reagents and components of the test kit were optimized according to known methods.
  • the MTP is incubated for 2 hours at room temperature (approx. 25 ° C) and shaken at about 300 rpm using an orbital MTP shaker. 3.. The wells are washed 3 times with 350 ⁇ l washing buffer each.
  • the MTP is incubated for 1 hour at room temperature (approx. 25 ° C.) and shaken at about 300 rpm using an orbital MTP shaker.
  • the MTP is incubated for 15 min at room temperature (approx. 25 ° C).
  • the color development is stopped by adding 100 ⁇ l stop solution.
  • the optical density is measured with a photometer at a wavelength of 450 nm.
  • MLC I was added to two sera in different concentrations and examined.
  • Serum samples with different concentrations were diluted and measured.
  • the sample recovery rate ranged from 97.5% to 117.2%.
  • a group of 80 subjects was tested.
  • the group consisted of three sub-groups.
  • Echocardiography and exercise tests All subjects were tested echocardiographically (calculation of the left ventricular ejection fraction - LVEF - according to Simpson), followed by an examination using bicycle ergometry. Ergometry was carried out according to the recommendation of the Czech Cardiological Society (Chaloupka, 2000). The initial load was 50 W, increased by 25 W every minute until the subject felt a maximum load.
  • SPECT Single SPECT was performed in all subjects.
  • Stress tests Physical stress was achieved using a bicycle ergometer. Radiopharmaceuticals were administered after 85% of maximum aerobic capacity was reached, or when angina pectoris resilience, ischemic changes on the ECG, severe arrhythmia, low blood pressure, etc. were limited the patient was not physically resilient, pharmacological exposure to dipyridamole (0.56 mg / kg body weight over 4 min) was generated.
  • Gated SPECT The gated SPECT was reached 15 minutes after the administration of 740 MBq 99tn Tc-MIBI at the highest load. With heterogeneous perfusion, the resting examination was carried out on another day (gated SPECT 1 hour after administration of 99m Tc-MIBI). 8-frame gating was used to record data on a double detection scintillation camera Siemens e.cam (Siemens Medical Solutions, Erlangen, Germany) equipped with a parallel collimator of the LEHR type, rotation angle 180 °, a total of 64 projections in a 64 x 64 matrix the right anterior oblique projection of 45 ° to the left posterior oblique projection of 45 °.
  • Coronary angiography In people with typical CAD findings or unclear findings, a freely selectable coronary chart was performed through the femoral with a 6 or 7F instrumentation. Obliteration of the coronary artery and stenosis was assessed by an invasive cardiologist who was not informed about the patient's other risks. "An angiographically positive result was considered when at least one stenosis narrowed the lumen of a major coronary artery or one of its branches by more than 60%.
  • the entire group was divided into subgroups according to the SPECT results (persons with signs of myocardial ischemia in the SPECT examination). Patients with a positive SPECT result were compared with patients with a positive ergometric result, regardless of the SPECT result. The division into the above Groups were also used to plot the ROC curve for diagnostic validity of MLC-1, considering the presence of myocardial ischemia under stress.
  • MLC-1 Laboratory determination of MLC-1 - The removal for MLC-1 was carried out from peripheral venous blood, the determination was carried out from the serum. After sampling, each sample was kept at room temperature for 60 minutes. The samples were then centrifuged (10 min, 1100 g at 4 ° C) and frozen at -80 ° C.
  • MLC-1 was determined 3 months after collection after the samples were warmed to room temperature (25 ° C). All samples were run twice examined.
  • the data was processed using the Medcalc software. Unless otherwise indicated, related content was expressed by mean ⁇ standard deviation and median.
  • the MLC-1 concentration in the subgroups was compared by analysis of variance (ANOVA, Kruskal-Wallis according to the distribution type) and ROC analysis. The concentration of MLC-1 and other values were compared with the Spearmann correlation coefficient. Category data were compared using the x 2 test. A value of p ⁇ 0.05 was considered to be statistically significant. Normal values were determined using the x 2 test.
  • Table 1 shows the statistical course of the entire group. It shows an abnormal distribution of most parameters.
  • the MLC-1 concentrations in the initially determined subgroups (A, B, C) did not show any significant differences with no withdrawal.
  • Figure 1 shows a 91% sensitivity and 98% specificity when diagnosing myocardial ischemia for MLC-1 above its determinability limit shown in Figure 2 (AUC 0.94; 95% CI 0.86-0.98; LR + 36.3; PPV + in the group with one Prevalence of 44.4% 96.7% and NPV- 93%).
  • Myosin is a contractile protein consisting of two heavy chains (MW 200 kD) and two light chains. Light chains are designated MLC-1 (MW 25 kD) and MLC-2 (MW 19 kD).
  • MLC-1 MW 25 kD
  • MLC-2 MW 19 kD
  • MLC-1 MW 25 kD
  • MLC-2 MW 19 kD
  • MLC-1 MW 25 kD
  • MLC-2 MW 19 kD
  • MLC-1 MW 25 kD
  • MLC-2 MW 19 kD
  • MLC-1 MW 25 kD
  • MLC-2 MW 19 kD
  • MLC-1 MW 25 kD
  • MLC-2 MW 19 kD
  • There are different types of MLC in the organism e.g. skeletal muscle MLC - sMLC, ventricular MLC - vMLC, atrial MLC - aMLC
  • a disturbed cardiomyocyte integrity e.g. myocardial necros
  • MLC-1 occurs mainly in the ventricular myocardium, it is not myocardial-specific (it also occurs in skeletal muscle) (2, 4, 7). An increased MLC-1 value has also been described in other cases of myocardial involvement, in addition to ischemic necrosis (myocarditis). (1).
  • Structural damage is a prerequisite.
  • MLC-1 is also a substrate of caspase-3, which is activated after the apoptotic cascade has been triggered. Activated caspase-3 cleaves vMLC-1, destroying the biologically active vMLC-1, which leads to reduced contractility of the myocardium.
  • a direct cleavage of vMLC-1 by caspase-3 can cause a restriction of the myocardial function by changing the cross-linking contacts between actin and myosin molecules. It is possible that the activation of apoptosis in the heart leads to contractile dysfunction even before cell death. (4, 6).
  • a group of 176 high-risk subjects was evaluated, who were divided into two subgroups based on the result of myocardial SPECT (single-photon emission computed tomography): people with and people without myocardial ischemia.
  • a stress test and a myocardial SPECT (99mTc-MIBI) were carried out in all subjects. Subsequently, the subjects who had shown relevant SPECT results were subjected to an elective coronary angiography.
  • the laboratory markers in the venous blood were examined several times in all subjects: a) immediately before the stress test: C-reactive protein (CRP), hemoglobin (Hb), hematocrit (Htk), lactate, MLC-1; b) on the subjective maximum: Hb, Htk, lactate, MLC-1; c) 30 min after reaching the maximum load: MLC-1 and d) 60 min after the maximum load: MLC-1.
  • CRP C-reactive protein
  • Hb hemoglobin
  • Htk hematocrit
  • lactate lactate
  • MLC-1 a) on the subjective maximum: Hb, Htk, lactate, MLC-1
  • the ROC for diagnostic efficacy of MLC-1 was established from the point of view of myocardial ischemia under stress.
  • the subgroups differed in their MLC-1 concentrations in all 4 blood samples (median in mg / 1; 3.1 versus 0.5 for blood sample 1; 3.1 versus 1.1 for blood sample 2; 2.9 versus 0, 5 for blood sample 3; 3.4 versus 0.5 for blood sample 4) and their gender distribution (a positive SPECT result was more common in men).
  • MLC-1 values did not change either during the exercise test or 60 minutes after, i.e. H. taking into account the changes in blood volume during the stress test, no changes were recorded.
  • latent myocardial ischemia individuals with numerous risk factors and a risk of> 20% / 10 years according to the Framingham algorithm or> 5% / 10 years according to the Cardioscore algorithm
  • IVS ischemic heart disease
  • Myocardial SPECT Stress tests: The physical stress was exerted on a bicycle ergometer, the radiopharmaceutical was applied when 85% of the maximum aerobic capacity was exceeded or when the stress was caused by more pronounced angina pectoris, ischemic changes in the ECG, more serious rhythm, a drop in blood pressure etc. was limited. The applicable international and Czech recommendations were used for the approach used [10, 11].
  • Gated SPECT The gated SPECT examination (synchronized recording of ECG and SPECT) was carried out 15 min after the application of 740 MBq 99mTc-MIBI at the peak of the load, if there was a heterogeneity of perfusion, supplemented by an examination at rest the next day (gated SPECT 1 after the application of 99mTc-MIBI).
  • the data was recorded via 8-frame gating using the e.cam double-head scintillation camera from Siemens (Siemens Medical Solutions, Erlangen, Germany), equipped with parallel LEHR collimators (collimators with low energy consumption and high resolution), rotation angle 180 ° , a total of 64 projections with a matrix of 64x64 from 45 ° oblique projection from right to 45 ° oblique projection behind left.
  • the summary stress score (SSS, Summed Stress Score) was evaluated from the parameters, which represents the extent of the perfusion defect after exercise. The higher the SSS value, the worse the patient prognosis, regardless of whether the defect is manifest (scar) or reversible (ischemia) [15]. Values of ⁇ 3 are considered normal, values between 4 and 8 indicate a moderate defect, values between 9 and 13 indicate a moderate defect, and values> 13 indicate a severe defect.
  • SDS Summed Difference Score
  • LK defect area of the left chamber
  • TID Transient Ischemic Dilatation
  • the ejection fraction of the left chamber was evaluated at the peak of the stress and after calming down (in the gated-SPECT examination). If the ejection fraction of the left ventricle decreased by more than 5% after exercise, the finding was interpreted as transient dilatation of the left ventricle after exercise, which is a symptom of anesthesia of the left ventricle after exercise [15-18, 20-23].
  • the specified data were determined using 4D-MSPECT, software for automatic quantification (University of Michigan, Ann Arbor, USA) [16]. The SPECT results were assessed as decisive for ICHS diagnostics.
  • latent myocardial ischemia was defined as the positivity of myocardial SPECT for the detection of ischemia (SSS> 3) with a negative ECG result and absence of ICHS symptoms [15].
  • Laboratory examination and blood sampling technique To examine the biological material, vein samples of non-clotting blood (for serum extraction) and blood with a solution of the salt of " ethylenediaminetetraacetic acid (EDTE) as an anticoagulant (for the examination of the blood picture and plasma extraction) were used.
  • EDTE ethylenediaminetetraacetic acid
  • MLC- 1 All parameters except MLC- 1 were determined within 120 min from the blood collection. All subjects were given the following laboratory tests with venous blood: a) immediately after the stress test: C-reactive protein (CRP - Advia 1650 analyzer, immunoturbidimetry, manufacturer of the Diasys system), hemoglobin (Hb .
  • CRP - Advia 1650 analyzer C-reactive protein
  • Hb hemoglobin
  • MaxM Coulter analyzer manufacturer of the Beckman Coulter system
  • hematocrit Htk, MaxM Coulter analyzer, manufacturer of the Beckman Coulter system
  • lactate Advanced 1650 analyzer, enzymatic determination, manufacturer of the Biovendor system
  • MLC-1 Marc + ELISA line
  • MaxM Coulter analyzer manufacturer of the Beckman Coulter system
  • MLC-1 peripheral venous blood was drawn using the serum. The blood sample was kept at room temperature for 60 minutes after collection. It was then centrifuged (10 min at 1100 g and 4 ° C) and frozen at a temperature of -80 ° C. The MLC-1 determination took place within 3 months from the removal of the material, namely after it had been tempered to room temperature (25 ° C.). All samples were examined twice.
  • the ventricular shape of the MLC-1 (vMLC-1) was determined using the ELISA technique (Biovendor GmbH) in a sandwich structure. A "combination of monoclonal mouse and chicken antibodies was used for the determination.
  • the MLC-1 values were determined between the two subgroups using the scatter analysis method (ANOVA, Kruskal-Wallis according to the type of distribution) and by
  • the MLC-1 concentration and other quantities were correlated with the Spearmann correlation coefficient with regard to the data distribution.
  • the categorical data were compared using the ⁇ 2 test. A value of p ⁇ 0.05 was considered statistically significant.
  • the normality was also assessed using the ⁇ 2 test.
  • Table 4 shows the basic statistical properties of the entire group. As can be seen from this table, the majority of the parameters have an abnormal distribution. Table 4: - Basic characteristics of the study group, 176 subjects
  • DeltaPV - change in plasma volume SSS - summary stress score; SDS - summary diff. Score; StressEF - left ventricular ejection fraction at auxiliary; RestEF - left ejection fraction
  • Myocardial ischemia in the SPECT were 37 patients (27%) as individuals with
  • Table 7 MLC-1 values before the start of exercise in patients after the appearance of a manifest or reversible defect in SPECT
  • Table 8 Differences in the MLC-1 values before the start of exercise after the appearance of symptoms of a manifest or reversible defect in SPECT
  • the area under the ROC curve (AUC) was 0.81 with a 95% confidence interval 0.72-0.88.
  • the positive test result (LR +) was 5.9; the positive predictor value (PPV +) in the group examined (with a prevalence of 27%) was 68% and the negative predictor value (NPV-) 87% ( Figure 4, Figure 5).
  • myocardial ischemia ischemic heart disease
  • SPECT single-photon emission computer tomography
  • Recent work confirms the increasing number of SPECT for myocardial perfection and its importance both in the diagnosis of myocardial ischemia and in the risk stratification and planning of a possible therapy [15, 20].
  • Patients with normal myocardial perfection after exercise have from
  • Symptoms of post-ischemic myocardial anesthesia appear), which are characterized by SSS values of 4-8, a defect of ⁇ 10% of the area of the left ventricle, a TLD value of ⁇ 1.17 and no decrease in the ejection fraction of the left chamber at maximum load is defined; if these conditions are met, drug therapy can be preferred.
  • Myosin is a contractile structural protein (heteropolymer), which consists of two heavy amino acid chains (relative molecular weight about 200 kDa) and two pairs of light amino acid chains.
  • the pairs of light amino acid chains are called MLC-1 (rel. Mol. Wt. 25 kDa) and MLC-2 (rel. Mol. Wt. 19 kDa).
  • the MLC-1 is also referred to as an essential chain, and although its complete
  • MLC-1 myocardial necrosis
  • MLC-1 myocardial stress besides ischemic necrosis (myocarditis) [1, 2, 4, 7].
  • Another possible reason could be, for example, excessive gene expression for MLC-1, which would cause excessive stress (e.g. by stimulation, etc.) of the cardiomyocytes. This phenomenon could lead to an excessive synthesis of the protein in the myocardial cells with its passage into the circulation (e.g. via a slightly disturbed cell membrane). Of course, the question remains to some extent whether this transfer is associated with a disruption of the cardiac myocyte structure (whether a disruption of the structure is a condition at all).
  • the programmed cell death includes the activation of the prosthease (caspase), which leads to a cleavage of the vital proteins of the cytoskeleton. It has been described that there is activation of caspase-3 (associated with a decrease in contractile performance) in failing myocytes.
  • caspase-3 associated with a decrease in contractile performance
  • the activated caspase-3 cleaves vMLC-1, which leads to an interruption of the biologically active vMLC-1, which is associated with a reduction in the contractile performance of the myocardium.
  • IHK ischemic heart disease
  • HN hypertension
  • 252 subjects were examined, including 240 asymptomatic subjects with a high risk of ischemic heart disease (Framingham or Score Algorithm) or subjects with a history of IHK, and 12 healthy volunteers. None of the subjects examined showed signs of acute coronary syndrome or heart failure (medical history, heart and lung Rtg, EKG, NT-proBNP and troponin I level).
  • ECG Ergometric examinations with an ECG recording (exercise ECG) were carried out on the test subjects (50 W with an increase of 10 W per minute until exhaustion), 15 minutes after reaching 85% of the aerobic capacity or after the appearance of ischemic symptoms ( angina pectoris, EKG) 740 MBq 99Tc-MIBI administered intravenously and a SPECT examination was carried out. 38 subjects had a circulatory defect, determined with the help of both SPECT and exercise ECG. The SPECT analysis showed that in 14 cases it was a fixed and in 27 cases a temporary circulatory defect.
  • the basal MLC-1 determination can be used to predict a latent
  • Cardiac ischemia can be used, with negative predictive values of 88% (fixed and temporary circulatory defects) and 92% (transient circulatory defects) being achieved (Table 9, Figures 8A, 8B, 9A and 9B).
  • Transient ischemic dilation ratio of the left ventricle is a significant predictor of future cardiac events in patients with otherwise normal myocardial perfusion.
  • SPECT. JACC. 2003; 42: 1818 - 1825. 15 Kammek M, Myslivecek M, Husäk V. Kvantitativni hodnoceni myokardiälni perfuze, funkce a viability pomoci jednofotonove emisni vypocetai tomography. Interv acute cardiol. 2003; 2: 190-197. 16) Kaminek M, Skvarilovä M, Ostransky J et al.
  • Illustration 1
  • the ROC analysis showed a diagnostic sensitivity of 91% with a specificity of 86% for values above "0".
  • FIG. 5 Graphical comparison of the MLC-1 values at rest before the start of exercise (the median is given at a 95% confidence interval) in patients after the occurrence of mocardial ischemia in SPECT.
  • Figure 6 Graphical comparison of the MLC-1 values at rest before the start of exercise (the median is given at a 95% confidence interval) in patients after the occurrence of mocardial ischemia in SPECT.

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Abstract

La présente invention concerne un procédé pour diagnostiquer des lésions ischémiques cardiaques, notamment ses formes chroniques et latentes, par identification sérologique de la chaîne légère I de myosine (MLC 1) qui sert de marqueur diagnostique dans le sang des patients touchés. Cette invention concerne également une analyse immuno-enzymatique pour identifier MLC 1. La présente invention s'applique au domaine de la médecine, en particulier au domaine du diagnostic médical.
PCT/IB2005/002385 2004-06-17 2005-06-17 Procede et kit de test pour diagnostiquer une lesion ischemique cardiaque, notamment ses formes chroniques et latentes, par identification serologique de la chaine legere 1 de myosine Ceased WO2005124362A2 (fr)

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