WO2013056358A1 - Procédé de détermination du risque d'un événement cardiovasculaire aigu - Google Patents

Procédé de détermination du risque d'un événement cardiovasculaire aigu Download PDF

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WO2013056358A1
WO2013056358A1 PCT/CA2012/000975 CA2012000975W WO2013056358A1 WO 2013056358 A1 WO2013056358 A1 WO 2013056358A1 CA 2012000975 W CA2012000975 W CA 2012000975W WO 2013056358 A1 WO2013056358 A1 WO 2013056358A1
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glucose
biomarkers
mammal
level
sflt
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PCT/CA2012/000975
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Peter Kavsak
Andrew WORSTER
Stephen Hill
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Mcmaster University
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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
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • 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
    • 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
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/475—Assays involving growth factors
    • G01N2333/515—Angiogenesic factors; Angiogenin
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5412—IL-6
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2871—Cerebrovascular disorders, e.g. stroke, cerebral infarct, cerebral haemorrhage, transient ischemic event
    • 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
    • G01N2800/324—Coronary artery diseases, e.g. angina pectoris, myocardial infarction
    • 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
    • G01N2800/50—Determining the risk of developing a disease

Definitions

  • the present invention relates to the field of cardiology, and in particular, to a prognostic method with respect to an acute cardiovascular event.
  • MI myocardial infarction
  • heart attack For those patients presenting with chest pain, a physician's decision to discharge a patient from the hospital or admit and treat them for myocardial infarction (MI) or heart attack is often based on the patient's cardiac troponin measurement. It has been demonstrated that testing for troponins on admission and again after 6 to 12 hours provides better risk stratification than previously used algorithms based on the ECG and creatine kinase MB. The test results should be available within 30 to 60 minutes, because elevated troponins are helpful in identifying the patients who benefit most from early invasive strategies, glycoprotein Ilb/IIIa antagonists, and low-molecular-weight heparins.
  • method of determining risk of acute cardiovascular event in a mammal comprising the steps of: determining in a biological sample obtained from the mammal the level of biomarkers, wherein said biomarkers are glucose or a compound that mediates glucose metabolism, IL-6 or an IL-6 related compound and sFlt-1 or a related compound, comparing the level of the biomarkers with acceptable limits of these biomarkers in a mammal, and determining that the mammal is at risk of an acute cardiovascular event when each biomarker exceeds an acceptable limit, or determining that the mammal is not at risk of an acute cardiovascular event when the level of at least one of the biomarkers is less than the acceptable limit.
  • an article of manufacture for use in the determination of risk of an acute cardiovascular event in a mammal.
  • the article comprises packaging and a biomarker-specific reactant for at least one of the biomarkers, glucose or a compound that mediates glucose metabolism, IL-6 or an IL-6 related compound and sFlt-1 or a related compound, wherein the packaging indicates that a determination of a level of at least one of the biomarkers within acceptable limits of the biomarker in a mammal indicates that the mammal is not at risk of an acute cardiovascular event, or that a determination of each of the biomarkers above acceptable cut-off levels of the biomarker in a biological sample of a mammal indicates that the mammal is at risk of an acute cardiovascular event.
  • Figure 1 is the histogram of cardiac troponin concentrations characterized by determining levels of glucose, IL-6 and sFlt-1 biomarkers in a panel;
  • Figure 2 illustrates the evaluation of the biomarker panel with 3 different troponin assays to determine risk of an acute cardiovascular event
  • FIG. 3 illustrates the evaluation of the biomarker panel with high-sensitivity troponin I, high-sensitivity troponin T and heart-type fatty acid binding protein (H-FABP) to determine risk of an acute cardiovascular event.
  • H-FABP heart-type fatty acid binding protein
  • a method of determining risk of an acute cardiovascular event in a mammal comprises determining in a biological sample obtained from the mammal the level of a metabolic biomarker such as glucose and compounds that mediate glucose metabolism, the level of an immune-mediated biomarker such as IL-6 and related compounds, and the level of a vascular biomarker such as sFlt-1 and related compounds in the sample, comparing the level of the biomarkers with acceptable limits of these biomarkers in a mammal, and determining that the mammal is at risk of an acute cardiovascular event when each biomarker exceeds an acceptable limit or threshold cut-off value, or that the mammal is not at risk of a cardiovascular event when the level of at least one of the biomarkers is less than the acceptable limit or threshold cut-off value.
  • a metabolic biomarker such as glucose and compounds that mediate glucose metabolism
  • an immune-mediated biomarker such as IL-6 and related compounds
  • a vascular biomarker such as sFlt-1 and related compounds
  • cardiovascular event refers to an event involving the cardiovascular system, including the heart and blood vessels, such as myocardial infarction, unstable angina/myocardial ischemia, arrhythmia, heart failure, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), cardiac arrest, stroke or death.
  • An acute cardiovascular event is one which exhibits rapid onset from presentation of first symptoms, for example, within about 5 days or less from presentation of first symptoms, and in particular, within 1 -3 days of presentation of first symptoms.
  • symptoms may include chest pain or discomfort (angina), pain in one or both arms, the left shoulder, neck, jaw, or back, shortness of breath, dizziness, irregular or increased heartbeat, nausea and being tired.
  • IL-6 refers to the mammalian cytokine, Interleukin-6, and encompasses both human IL-6, as depicted by NCBI accession no. NP000591, as well as IL- 6 of other mammalian species, for example, mouse IL-6 as depicted by NCBI accession no. NPl 12445. Also encompassed are other members of the IL-6 family of compounds such as a gpl 30 cytokine family member (e.g. gpl30, LIF-R (NP002301), OSM-R (Q99650), and G- CSF-R (NP000751)), or a soluble gpl30 receptor (e.g., soluble IL-6 receptor).
  • a gpl 30 cytokine family member e.g. gpl30, LIF-R (NP002301), OSM-R (Q99650), and G- CSF-R (NP000751)
  • a soluble gpl30 receptor
  • glucose refers to the simple monosaccharide having the chemical formula, C 6 Hi 2 C»6, which is also known as D-glucose or dextrose. Also encompassed are biomarkers that modulate glucose metabolism, such as insulin, glucagon, amylin, GLP-1, glucose-dependent insulinotropic peptide (GIP), epinephrine, Cortisol, and growth hormone.
  • biomarkers that modulate glucose metabolism such as insulin, glucagon, amylin, GLP-1, glucose-dependent insulinotropic peptide (GIP), epinephrine, Cortisol, and growth hormone.
  • sFlt-1 refers to mammalian soluble fms-like tyrosine kinase-1 or sVEGFR-1, and encompasses both human sFlt-1 as depicted by Uniprot P 17948, as well as non-human forms thereof.
  • sFlt-1 is a soluble receptor that disables proteins that cause blood vessel growth. These proteins act as a receptor of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor.
  • VEGF vascular endothelial growth factor
  • PIGF phosphatidylinositol-glycan biosynthesis class F protein
  • troponin refers to a complex of three regulatory proteins (troponin
  • troponin T is depicted by the 298 amino acid sequence, Uniprot P45379; troponin C is depicted by the 161 amino acid sequence, Uniprot P63316; and troponin I is depicted by the 210 amino acid sequence, Uniprot PI 9429.
  • Troponin is used herein also to refer to other mammalian sources thereof.
  • mammal is used herein to refer to both human and non-human mammals including domestic animals, e.g. cats, dogs and the like, livestock and undomesticated animals.
  • a biological sample is obtained from a mammal at risk for a cardiovascular event.
  • biological sample is meant to encompass any mammalian sample that may contain the target biomarkers, e.g. glucose, IL-6, sFlt-1 or related proteins for each biomarker. Suitable biological samples include, for example, blood, serum, plasma and urine. The sample is obtained from the mammal in a manner well- established in the art.
  • a suitable biological sample is obtained, it is analyzed to determine the level or concentration of each of the biomarkers: glucose, IL-6, sFlt-1, and optionally troponin.
  • a related protein as indicated above, may be analyzed in place of any one of IL-6, sFlt-1 or glucose.
  • protein biomarkers such as IL-6 or a related protein compound (e.g. gpl30, gpl30/IL-6 receptor, G-CSF receptor) sFlt-1 or a related protein (e.g. VEGF and PIGF) and glucose related proteins if required (e.g.
  • the level of protein biomarkers in a sample is measured by immunoassay using an antibody specific to the target biomarker.
  • the antibody is bound to the biomarker and bound antibody is quantified by measuring a detectable marker which may be linked to the antibody or other component of the assay, or which may be generated during the assay.
  • Detectable markers may include radioactive, fluorescent, phosphorescent and luminescent (e.g. chemiluminescent or bioluminescent) compounds, dyes, particles such as colloidal gold and enzyme labels.
  • antibody is used herein to refer to monoclonal or polyclonal antibodies, or antigen-binding fragments thereof, e.g. an antibody fragment that retains specific binding affinity for the target biomarker.
  • Antibodies to the target biomarkers are generally commercially available. For example, kits including antibody to IL-6 (Roche Diagnostics) and antibody to sFlt-1 (Roche Diagnostics) are readily available.
  • kits including antibody to IL-6 (Roche Diagnostics) and antibody to sFlt-1 (Roche Diagnostics) are readily available.
  • antibodies to the target biomarkers may also be raised using techniques conventional in the art. For example, antibodies may be made by injecting a host animal, e.g. a mouse or rabbit, with the antigen (target biomarker), and then isolating antibody from a biological sample taken from the host animal.
  • Different types of immunoassay may be used for the detection of the biomarkers, including indirect immunoassay which the biomarker is non-specifically immobilized on a surface; sandwich immunoassay in which the biomarker is specifically immobilized on a surface by linkage to a capture antibody bound to the surface; competitive binding immunoassay in which a sample is first combined with a known quantity of biomarker antibody to bind biomarker in the sample, and then the sample is exposed to immobilized biomarker which competes with the sample to bind any unbound antibody. To the immobilized biomarker/antibody is added a detectably-labeled secondary antibody that detects the amount of immobilized primary antibody, thereby revealing the inverse of the amount of biomarker in the sample.
  • indirect immunoassay which the biomarker is non-specifically immobilized on a surface
  • sandwich immunoassay in which the biomarker is specifically immobilized on a surface by linkage to a capture antibody bound to the surface
  • a preferred immunoassay for use to determine levels of protein biomarkers is an ELISA (Enzyme Linked Immunosorbent Assay) or Enzyme ImmunoAssay (EIA).
  • ELISA Enzyme Linked Immunosorbent Assay
  • EIA Enzyme ImmunoAssay
  • the biomarker to be analyzed is generally immobilized, for example, on a solid adherent support, such as a microtiter plate, polystyrene beads, nitrocellulose, cellulose acetate, glass fibers and other suitable porous polymers, which is pretreated with an appropriate ligand for the target biomarker, and then complexed with a specific reactant or ligand such as an antibody which is itself linked (either before or following formation of the complex) to an indicator, such as an enzyme.
  • a specific reactant or ligand such as an antibody which is itself linked (either before or following formation of the complex) to an indicator, such as an enzyme.
  • Detection may then be accomplished by incubating this enzyme-complex with a substrate for the enzyme that yields a detectable product.
  • the indicator may be linked directly to the reactant (e.g. antibody) or may be linked via another entity, such as a secondary antibody that recognizes the first or primary antibody.
  • the linker may be a protein such as streptavidin if the primary antibody is biotin-labeled.
  • suitable enzymes for use as an indicator include, but are not limited to, horseradish peroxidase (HRP), alkaline phosphatase (AP), ⁇ -galactosidase, acetylcholinesterase and catalase. A large selection of substrates is available for performing the ELISA with these indicator enzymes.
  • the substrate will vary with the enzyme utilized. Useful substrates also depend on the level of detection required and the detection instrumentation used, e.g. spectrophotometer, fluorometer or luminometer.
  • Substrates for HRP include 3,3',5,5'-Tetramethylbenzidine (TMB), 3,3'-Diaminobenzidine (DAB) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS).
  • Substrates for AP include para-Nitrophenylphosphates.
  • Substrates for ⁇ -galactosidase include galactosides; the substrate for acetylcholinesterase is acetylcholine, and the substrate for catalase is hydrogen peroxide.
  • the level of protein biomarkers in a biological sample from a mammal may be determined based on the levels of nucleic acid encoding the target protein biomarkers.
  • Methods of determining DNA or mRNA levels are known in the art, and include, for example, PCR-based techniques (such as RT-PCR) and Northern or Southern blotting techniques which generally include the application of gel electrophoresis to isolate the target nucleic acid, followed by hybrization with specific labeled probes. Probes for use in these methods can be readily designed based on the known sequences of the protein biomarkers. Suitable labels for use are well-known, and include, for example, fluorescent, chemiluminescent and radioactive labels.
  • the level or concentration of the glucose biomarker in a sample may be determined using methods more appropriate for this biomarker such as enzyme assays including glucose oxidase methods, hexakinase methods and glucose dehydrogase methods.
  • enzyme assays including glucose oxidase methods, hexakinase methods and glucose dehydrogase methods.
  • glucose oxidase method the sample is treated with glucose oxidase and glucose in the sample is oxidized to yield hydrogen peroxide which is combined with a chromogenic substance such as O-dianizidine, ABTS (2,2"-azino-di-3-ethylbenzothiazoline sulfonic acid - 6-diammonium salt), 4-aminoantipyrine - dimethylanilline and 4-aminoantipyrine to yield a chromogen which is measurable photometrically and which corresponds with the amount of glucose in the sample.
  • a chromogenic substance such as O-dianizid
  • the sample is treated with hexokinase enzyme and D-glucose is phosphorylated with ATP to form glucose-6-phosphate.
  • D-glucose is phosphorylated with ATP to form glucose-6-phosphate.
  • G-6-PDH glucose-6-phosphate dehydrogenase
  • glucose- 6-phosphate is transformed to 6-phosphogluconate and NADPH is formed.
  • the absorbance of NADPH is measured in the UV region (334, 340 or 365 nm) and is proportional to glucose content.
  • D-glucose and NAD are transformed to D- gluconolactone and NADH.
  • the change in NADH absorbance is measured in the UV region (334, 340 or 365 nm) which is proportional to the concentration of glucose.
  • troponin levels in a mammalian sample may also be utilized in the present method.
  • Troponin levels including the determination of one of troponin T, troponin I and troponin C, is sufficient for use in the present.
  • the level of any one of these troponins may also be determined by immunoassay using an antibody directed to troponin T, troponin I or troponin C. Such antibodies may be prepared using standard methods.
  • Commercial immunoassay kits are also available including, for example, cardiac specific troponin T antibody (Roche Diagnostics) and cardiac specific troponin I antibody (Abbott, Siemens, Beckman, Ortho Clinical Diagnostics, Alere, bioMerieux, Instrument Laboratories, Roche Diagnostics and Singulex).
  • biochip arrays provide a means to simultaneously determine the level of multiple biomarkers in a given sample. These arrays may utilize ELISA technology and, thus, the biochip may be modified to incorporate capture antibodies at pre-defined sites on the surface.
  • a determination of a level or concentration of at least one of glucose, IL-6, sFlt-1 , or a related biomarker to glucose, IL-6 or sFlt-1 , which is within acceptable limits of the biomarker in a mammal indicates that the mammal is not at risk of an acute cardiovascular event, particularly when cardiac troponin levels of the mammal are also below the acceptable troponin limit.
  • acceptable limit or “acceptable cut-off level” it is meant the upper-most level or concentration of the biomarker that is considered to be normal, for example, a serum concentration that does not exceed the median biomarker concentration level of the population.
  • sFlt-1 biomarkers or a related biomarkers to glucose, IL-6 or sFlt-1, and optionally troponin, which is above acceptable limits of the biomarker in a biological sample of a mammal indicates that the mammal is at risk of an acute cardiovascular event, regardless of cardiac troponin levels of the mammal.
  • a determination of a level of glucose that is greater than the acceptable limit of about 5.6 mmol/L, a determination of a level of IL-6 that is greater than the acceptable limit of about 2.9 ng/L and a determination of a level of sFlt-1 that is greater than the acceptable limit of about 70 ng/L, or a concentration that exceeds that of the median concentration in chest pain patients that did not have a myocardial infarction indicates that the mammal is at significant risk (e.g. greater than 50% chance) of an acute cardiovascular event.
  • biomarkers involved in acute cardiovascular pathologies e.g., metabolic, vascular, and immune-mediated
  • This combination of biomarkers is also useful to identify patients who, despite presentation of certain symptoms, can safely be discharged from hospital when the level of at least one of these biomarkers is below the acceptable cut-off limit thereof combined with a determination of a cardiac troponin level that is below current guideline recommended cutoffs (i.e., below the 99 th percentile).
  • determination that each of these biomarkers exceeds the acceptable cut-off limits, regardless of troponin levels identifies patients that require continued observation as significant risk of an acute cardiovascular event exists.
  • an article of manufacture that is useful to practice the present diagnostic/prognostic method.
  • the article of manufacture comprises biomarker-specific reactants for each of glucose, IL-6, and sFlt-1 biomarkers, or for related biomarkers, as described above.
  • suitable reactants include antibodies that specifically bind to the biomarker.
  • a glucose-specific reactant includes glucose oxidase, hexakinase and glucose dehydrogase.
  • the reactants may or may not be associated with an indicator that reveals the level of the biomarker and whether or not the biomarker exceeds acceptable cut-off levels as described.
  • a given indicator is measurable to indicate the concentration of the biomarker that interacts with the reactant associated with that indicator.
  • Suitable indicators are described herein.
  • glucose oxidase may be associated with a chromogenic indicator such as O-dianizidine or 4- aminoantipyrine
  • antibody reactants may be associated with enzyme labels such as horseradish peroxidase (HRP) and alkaline phosphatase (AP), with or without suitable substrates, or with labeled or unlabeled secondary antibody.
  • HRP horseradish peroxidase
  • AP alkaline phosphatase
  • the article of manufacture may additionally include a microtitre plate or other support surface, to conduct the assays, and the support surface may modified to include bound reactant for one or more of the biomarkers, or a non-specific binding material useful to conduct an assay such as an indirect assay.
  • the article of manufacture will generally indicate that a determination of a level or concentration of at least one of glucose, IL-6, sFlt-1, or a related biomarker to glucose, IL-6 or sFlt-1 , which is within acceptable limits of the biomarker in a mammal indicates that the mammal is not at risk of an acute cardiovascular event, particularly when cardiac troponin levels of the mammal are also below the acceptable troponin limit, or that determination of a level or concentration of each of glucose, IL-6, sFlt-1 biomarkers, or biomarkers related to glucose, IL-6 or sFlt-1 as above, which is above acceptable cut-off levels of the biomarkers in a biological sample of a mammal indicates that the mammal is at risk of an acute cardiovascular event, regardless of cardiac troponin levels of the mammal.
  • the specimens were processed without compromising the integrity of the sample (this type of specimen is preferred if testing is delayed). After processing, the separated serum specimens were transported to the Clinical Research and Clinical Trials Laboratory (CRCTL) at the Hamilton General Hospital for storage (below -80°C) until measurements for different biomarkers and cardiac troponin assays were completed.
  • CCTL Clinical Research and Clinical Trials Laboratory
  • biomarkers measured using the following immunoassays (analyte/platform/company): enhanced AccuTnl (cardiac troponin I -cTnl/Access II instrument/Beckman Coulter); Interleukin-6 (IL-6/ Access II instrument/Beckman Coulter), high-sensitivity cardiac troponin I (hs-cTnl/ Access II instrument/Beckman Coulter), and high-sensitivity cardiac troponin T (hs-cTnT/ Elecsys 2010 instrument/Roche Diagnostics). The performance of these analytes on these platforms has been previously described (Kavsak et al. Clin Chem. (2012);58:298-302).
  • the population was classified into the following 3 groups: ⁇ 0.02; 0.02-0.04;
  • the highest cardiac troponin group represents concentrations exceeding their respective 99 th percentiles (>0.04 ug/L for cTnl, >10 ng/L for hs-cTnl, >14 ng/L for hs-cTnT).
  • Cardiac troponin is a marker of cardiac injury. The reason for this elevated concentration may, however be due to an acute injury (e.g., myocardial infarction) or some other chronic condition.
  • Biomarkers that assessed metabolic, vascular and inflammatory abnormalities were then used to characterize a low cardiac troponin concentration. The following biomarkers were selected: sFlt-1 (soluble fms-like tyrosine kinase-1), Interleukin- 6, and glucose, representing the vascular, inflammatory and metabolic components, respectively. No previous studies have assessed all 3 biomarkers together in this context.
  • a positive result was obtained if all 3 individual tests are elevated (i.e., above the cutoffs): a glucose >5.6 mmol/L (normal glucose is less than 5.6 mmol/L as per the American Diabetes Association guidelines); IL-6 >2.9 ng L (the upper limit of normal for the Beckman IL-6 assay - refer to manufacturer's package insert); and sFlt-1 > median concentration in chest pain patients that did not have an MI, which corresponded to >134 ng/L with the sFlt-1 assay on the MSD platform as the median established with the Roche sFlt-1 assay was 70 ng/L in this non-MI chest pain group.
  • the sensitivity of the biomarker panel for the composite cardiac outcome was 92% with a corresponding specificity of 72%.
  • the sensitivity/specificity for the composite cardiac outcome was 62%/88% for cTnl alone, 92%/57% for hs-cTnl alone, and 85%/55% for hs- cTnT alone, each using the 99 th percentile cutoffs.
  • the sensitivity/specificity for the composite cardiac outcome was 64%/33% for H-FABP (positive >2.0 ug/L), 86%/38% for hs-cTnl alone (positive >6.0 ng/L), and 85%/37% for hs-cTnT alone (positive >3.0 ng/L).
  • sFlt-1 is effective to identify patients at risk of an acute cardiovascular event, as well as identifying those that can be discharged after their initial cardiac troponin result.
  • This combination of biomarkers is involved in acute cardiovascular pathologies (e.g., metabolic, vascular, and immune-mediated) and, thus, can properly identify patients which can be safely discharged home when combined with cardiac troponin results that are below current guideline recommended or outcome based cutoffs (i.e., low cardiac troponin concentrations).
  • a negative result on presentation in the biomarker panel i.e.
  • a determination that the level of any one of glucose, IL-6 or sFlt-1 is below the cut-off level, in conjunction with a low cardiac troponin concentration indicates that there is little or no risk of an acute cardiovascular event and the patient may be discharged.
  • a positive result on presentation in the biomarker panel i.e. a determination that the level of each of glucose, IL-6 or sFlt-1 is above the cut-off levels, whether or not the troponin level is high, indicates that there is a significant risk of an acute cardiovascular event and the patient should not be discharged but should be further clinically evaluated.

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Abstract

La présente invention concerne un procédé de détermination du risque d'un événement cardiovasculaire aigu chez un mammifère. Le procédé comprend les étapes consistant à déterminer, dans un échantillon biologique obtenu du mammifère, le niveau de biomarqueurs, lesdits biomarqueurs étant le glucose ou un composé de médiation du métabolisme du glucose, IL-6 ou un composé associé à l'IL-6 et sFlt-1 ou un composé associé, à comparer le niveau des biomarqueurs avec les limites acceptables de ces biomarqueurs chez un mammifère, et à déterminer que le mammifère présente un risque d'avoir un événement cardiovasculaire aigu lorsque chaque biomarqueur dépasse une limite acceptable, ou à déterminer que le mammifère ne présente pas de risque d'avoir un événement cardiovasculaire aigu lorsque le niveau d'au moins un des biomarqueurs est inférieur à la limite acceptable.
PCT/CA2012/000975 2011-10-19 2012-10-19 Procédé de détermination du risque d'un événement cardiovasculaire aigu WO2013056358A1 (fr)

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