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WO2012130651A1 - Differenciation diagnostique entre un syndrome coronarien aigu et une angine de poitrine stable - Google Patents

Differenciation diagnostique entre un syndrome coronarien aigu et une angine de poitrine stable Download PDF

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Publication number
WO2012130651A1
WO2012130651A1 PCT/EP2012/054767 EP2012054767W WO2012130651A1 WO 2012130651 A1 WO2012130651 A1 WO 2012130651A1 EP 2012054767 W EP2012054767 W EP 2012054767W WO 2012130651 A1 WO2012130651 A1 WO 2012130651A1
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WIPO (PCT)
Prior art keywords
sgpvi
acs
sap
living
blood
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2012/054767
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German (de)
English (en)
Inventor
Boris Bigalke
Meinrad Gawaz
Oliver Poetz
Thomas Joos
Elisabeth Kremmer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eberhard Karls Universitaet Tuebingen
Universitätsklinikum Tübingen
Original Assignee
Eberhard Karls Universitaet Tuebingen
Universitätsklinikum Tübingen
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Application filed by Eberhard Karls Universitaet Tuebingen, Universitätsklinikum Tübingen filed Critical Eberhard Karls Universitaet Tuebingen
Publication of WO2012130651A1 publication Critical patent/WO2012130651A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/324—Coronary artery diseases, e.g. angina pectoris, myocardial infarction

Definitions

  • the present invention relates to a method for diagnostic differentiation between an acute coronary syndrome and a stable angina pectoris in a living being.
  • the acute coronary syndrome (English: “acute coronary syndrome", ACS) is in human medicine a collective term for various phases of acute circulatory disorders of the coronary arteries, which can be directly life threatening.
  • ACS usually involves three different clinical pictures that affect the coronary arteries, namely the ST elevation myocardial infarction (STEMI), which accounts for about 30% of all ACS cases, the non-ST elevation myocardial infarction (English: Non-ST elevation myocardial infarction (NSTEMI), which accounts for approximately 25% of ACS cases, and unstable angina pectoris (IAP), which accounts for approximately 38% of ACS cases.
  • ST elevation myocardial infarction (STEMI)
  • NSTEMI Non-ST elevation myocardial infarction
  • IAP unstable angina pectoris
  • ACS is to be distinguished from a stable angina pectoris (SAP), which is essentially noticeable only in physical activity and therefore much less critical than the ACS.
  • SAP stable angina pectoris
  • the diagnosis of ACS predominantly takes place via the creation of an electrocardiogram in which, for example, an increase of the ST segment is to be recognized.
  • an increase of the ST segment is to be recognized.
  • the distinction to an SAP is not always reliable possible.
  • pGPVI platelet-bound glycoprotein VI
  • pGPVI is the key regulator of platelet activation and aggregation Vascular damage sites where collagen exposure occurs. It has been shown that increased surface expression of pGPVI can be found in patients with ACS. It was also shown that the levels of pGPVI are significantly increased in ACS patients compared to patients with SAP. However, it has been found that the sensitivity and specificity of a diagnosis of ACS via pGPVI, for example in the context of flow cytometry studies, are too low to allow an adequate clinical decision. Furthermore, only a few clinics are technically able to determine pGPVI as a diagnostic marker of ACS.
  • ACS acute coronary syndrome
  • SAP stable angina pectoris
  • a / n-wfro method comprising the steps of: (1) providing a blood sample of the animal; (2) determining the concentration of soluble glycoprotein VI (sGPVI) in the blood sample to obtain the value of Ai; (3) comparing Ai with the concentration of sGPVI in the blood of an SAP patient (A 2 ), and (4) detecting the presence of ACS when Ai ⁇ A 2 .
  • sGPVI soluble glycoprotein VI
  • the object is further achieved by using the concentration of soluble glycoprotein VI (sGPVI) in the blood of a subject for diagnostic differentiation in vitro between ACS and SAP.
  • sGPVI soluble glycoprotein VI
  • Cardiol. 104, pages 352-357 describe elevated plasma levels of sGPVI in patients with ACS and versus patients with SAP, respectively; see. P. 355, right column, first paragraph and Fig. 1 b. Similar data can be found in Bigalke et al. (2009), Influence of Platelet Count on the Expression of Platelet Collagen Receptor Glycoprotein VI (GPVI) in Patients with Acute Coronary Syndrome, Thromb. Haemost. 101, pages 911-915, cf. in particular page 913, right column, 1st paragraph and Fig. 1 B.
  • GPVI Platelet Collagen Receptor Glycoprotein VI
  • providing a blood sample means that the method is performed in vitro, i. in a laboratory.
  • the blood sample is taken before carrying out the method according to the invention and is therefore not part of the latter.
  • the presence of a human or animal animal is not required for carrying out the method according to the invention. The same applies to the use according to the invention.
  • the blood sample is a blood plasma sample and A 2 is the concentration of sGPVI in the blood plasma of an SAP patient.
  • This measure has the advantage that due to the separation of the cellular blood components from the blood sample a simpler and more accurate determination of the concentration of sGPVI is possible and in particular prevents that falsified by a possibly presence of platelet-bound GPVI (pGPVI) the measurement becomes.
  • pGPVI platelet-bound GPVI
  • the living being is a human being with cardiac-induced breast pain.
  • This measure has the advantage that already a pre-selection of the living being to be examined is made, so that the inventive method allows an even more reliable differentiation between ACS and SAP.
  • the inventive method can be in a reliable manner with people with cardiac conditional chest pain, determine whether ACS is present and immediate therapeutic and / or pharmacological treatment is necessary or due to a far less critical SAP if necessary, no or only pain relief measures are performed.
  • the method according to the invention therefore makes it possible to make a targeted therapeutic decision at an early point in time, so that possible mistreatment and unnecessary stress on the patient can be largely avoided.
  • the living being is a human being with coronary artery disease (CAD).
  • CAD coronary artery disease
  • This measure also has the advantage that already a preselection of the living beings to be examined is carried out on such a patient population, which has been proven to already suffer from a disease of the coronary arteries. In such vulnerable patients, it is particularly important to differentiate between ACS and SAP and then take the right therapeutic measures. This is made possible with this further development of the method according to the invention.
  • the ACS includes ST elevation myocardial infarction (STEMI) and non-ST elevation infarct (NSTEMI).
  • STMI ST elevation myocardial infarction
  • NSTEMI non-ST elevation infarct
  • This measure has the advantage that the process of the invention, the largest part of the ACS patients is detected.
  • the inventors were able to determine that the plasma levels of sGPVI are significantly lower in STEMI and NSTEMI patients than in SAP patients.
  • step 2 is carried out using an antibody directed against sGPVI.
  • this is carried out using a sandwich immunoassay, preferably a bead-based sandwich immunoassay.
  • This measure has the advantage that the method according to the invention is implemented with established techniques of bioanalytics, so that a routine application in hospitals and even a large-scale application is made possible.
  • the special embodiment as a bead-based sandwich immunoassay has the advantage of facilitated preparation and handling as well as increased flexibility of the assay.
  • Another object of the present invention relates to a kit comprising reagents and devices and a description for carrying out the method according to the invention.
  • Fig. 1 shows results of the bead-based sandwich immunoassay for
  • sGPVI soluble glycoprotein VI
  • A 7 monoclonal Antibodies were screened against each other for their ability to function as scavenger or detector molecules. The best antibody pair was selected according to the best signal-to-noise ratio (S / N) by dividing the fluorescence signal obtained at standard 125 ng / l sGPVI by the fluorescence signal from phosphate buffered saline (PBS) without standard. S / N ratios of antibody pairs are shown in a bubble chart. The size of the bubbles is determined by the S / N values.
  • B Dose-response curve of sandwich immunoassay for determination of sGPVI.
  • Figure 2 shows the levels of soluble glycoprotein VI (sGPVI) and platelet-bound GPVI (pGPVI) in patients with symptomatic coronary artery disease.
  • sGPVI soluble glycoprotein VI
  • pGPVI platelet-bound GPVI
  • the inventors evaluated the concentration of sGPVI in a total of 2,438 consecutive patients with symptomatic coronary artery disease (CAD) undergoing coronary angiography. 1,371 patients had an SAP, 724 non-ST elevation myocardial infarction (NSTEMI) and 343 ST elevation myocardial infarction (STEMI).
  • the categorization of acute coronary syndrome (ACS) was performed according to the AHA / ACC guidelines; Braunwald et al. (2000), ACC / AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: executive summary and recommendations.
  • the exclusion criteria were an age under 18 years, inability and absence of informed consent, patients with non-cardiac chest pain.
  • Troponin-I was immediately determined by performing the troponin I ultraassay on an Advia Centaur system (both from Siemens Healthcare Diagnostics, Kunststoff, Germany).
  • the C-reactive protein (CRP) was determined using a Siemens hsCRP Advia2120 (Siemens Medical, Solutions Diagnostics GmbH, Fernwald, Germany).
  • the platelet biomarker blood was filled into 5 ml heparinized vials (for determination of sGPVI) and in 5 ml vials of citrate, phosphate, dextrose and adenine (for the determination of pGPVI), processed and analyzed immediately by flow cytometry to determine the surface expression of platelet receptors (pGPVI and GPIb) as previously described in Bigalke et al. (2006), Expression of platelet collagen receptor VI is associated with acute coronary syndrome, Eur. Heart J. 27, pp. 2165-2169, and Bigalke et al. (2008), Platelet Collagen Receptor Glycoprotein VI as a Possible Novel Indicator for the Acute Coronary Syndrome, Am. Heart J. 156, pages 193-200.
  • heparin anticoagulated blood was centrifuged at 3000 g for 15 minutes at 4 ° C. Two thirds of the supernatant were aliquoted and frozen immediately in liquid nitrogen. The samples were stored at -78 ° C until analysis. After thawing the samples, they were centrifuged at 13000 rcf for 10 minutes at 4 ° C. The heparin plasma samples were used throughout the assay development and study for measurements of sGPVI.
  • a 1 ml NHS-activated HiTrap HP column (GE Healthcare, USA) was prepared according to the manufacturer's instructions using 1 mg mAB (5C4) which is reactive with human sGPVI. 800 ⁇ plasma was added to the column and depleted for sGPVI. sGPVI-depleted plasma was used as a matrix for the determination of assay precision, assay accuracy and analyte stability.
  • the plasma concentration of sGPVI was determined using a bead-based sandwich immunoassay.
  • the capture antibody used was the monoclonal antibody 8E9, which is reactive with human GPVI.
  • the antibody was covalently coupled to color-coded polystyrene magnetic microspheres (Luminex, Austin, TX, USA) as described in Carson and Vignali (1999). Simultaneous Quantification of Cytokines Using a Multiplexed Flow Cytometric Assay, J. Immunol. Methods 227, p. 41-52.
  • Plasma or standard dilutions were co-incubated with 2000 antibody-coated microspheres in a 96-well PCR plate (Thermo Fisher, Waltham, MA, USA) in a magnetic particle holder (King Fisher 96, Thermo Fisher, Waltham, MA) for one hour at 25 ° C and incubated by mixing at a medium frequency. Microspheres coated with bovine serum albumin were used as a negative control. After the capture step, the microspheres were transferred to another PCR plate containing a biotinylated detection GPVI-specific detection antibody (1 mg / l, mAB 8A2) using a magnetic particle holder (King Fisher 96, Thermo Fisher, Waltham, MA, USA ).
  • the final detection step was performed by transferring the microspheres to a third PCR plate containing a solution of streptavidin-phycoerythrin conjugate (2.5 mg / l, Prozyme, Hayward, CA, USA) for 45 minutes at 25 ° C.
  • the microtiter plate was transferred to a Luminex 100 instrument (Luminex, Austin, TX) and the data were obtained according to the manufacturer's instructions.
  • Assay background data were obtained using microspheres incubated with 10% mouse plasma in Roche blocking buffer for ELISA (Roche, Mannheim, Germany) containing 0.1% Tween were.
  • Recombinant sGPVI was prepared as described in the prior art and used as a reference; see.
  • GDVI GDVI standard was diluted in blocking buffer from Roche for ELISA plus 10% mouse serum (Sigma, St. Louis, MO, USA). Plasma concentrations of sGPVI were calculated by referring to a four parametric logarithmic fit of standard fluorescence.
  • the precision and accuracy were determined by the analysis of three samples containing three different concentrations of recombinant sGPVI.
  • the sGPVI was added to 2% sGPVI-depleted human plasma in high, medium and low concentrations (25, 6.25 and 1.55 ⁇ 9 / ⁇ ). Aliquots of the samples were prepared, frozen and analyzed in 5 replicates on five days.
  • the surface expression of pGPVI and GPIb was determined by a two-color whole blood flow cytometry as previously described; see.
  • the mean fluorescence intensity (MFI) was used as an index of receptor expression.
  • the GPVI-directed fluorescein isothiocyanate (FITC) conjugated mAB 4C9 was prepared and characterized as previously described; see. Bigalke et al. (2006, supra) and Bigalke et al. (2008, supra).
  • a CD42b-directed, phycoerythrin (PE) conjugated mAB (clone SZ2) was purchased from Immunotec (Beckman, Coulter, Inc., Fullerton, CA, USA).
  • a probability value less than 0.05 was considered statistically significant and evaluated with appropriate non-parametric tests. The values are shown as mean ⁇ standard deviation (SD). Consequently, a Kruskall-Wallis test was used for the pairwise comparisons of SAP, NSTEMI and STEMI. Bonferroni Holm correction was performed to correct the multiple pairwise comparison testing. An adaptation by possible disturbances such as a Medical treatment at the time of admission, classical cardiovascular risk factors and laboratory markers, was performed by multifactorial analysis of covariance for the decadic logarithm of sGPVI. Predictive values of sGPVI and pGPVI for the development of ACS were assessed using binary logistic regression analysis. Using ROC curves, the optimal cutoff value of sGPVI and pGPVI was determined for an ACS.
  • the study population included 2,438 consecutive patients with symptomatic CAD undergoing coronary angiography.
  • SAP 1,371
  • ACS 1,067
  • 724 had NSTEMI and 343 had STEMI. Details of the demographic data are shown in Table 1 below.
  • Hyperlipidemia 1705 (69.9) 770 (72.2) 935 (68.2)
  • ACE inhibitors 1372 (56.3) 654 (61, 3) 718 (52.4)
  • Angiotensin Receptor Blocker 284 (1 1, 7) 1 14 (10,7) 170 (12,4)
  • Beta Blocker 1609 (66) 687 (64.4) 922 (67.3)
  • Vitamin K Antagonist 236 (9,7) 97 (9,1) 139 (10,1)
  • Table 1 Characteristics of the patients and medical treatment during the
  • the inter-assay precision was calculated from five independent assays.
  • the co-efficacy of the intra-assay variability did not exceed 7% and the inter-assay values were not higher than 14% (Table 2).
  • the values for the assay accuracy are identical to the intra-assay precision, as no certified standard is available.
  • Intra and inter-assay precision was determined by testing three samples containing high, medium and low levels of recombinant soluble glycoprotein VI (sGPVI).
  • sGPVI recombinant soluble glycoprotein VI
  • sGPVI was added in 2% human plasma depleted in GPVI, frozen and stored at -20 ° C. The samples were independently measured five times in five replicates.
  • the stability of the analyte was determined by testing three samples containing high, medium and low levels of recombinant soluble glycoprotein VI (sGPVI) after each cycle, one, two, three or four cycles of freezing and thawing.
  • the inventors provide a method with which reliable distinction can be made between ACS and SAP.
  • the method is superior in terms of sensitivity and accuracy to the prior art methods.

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Abstract

La présente invention concerne un procédé de différenciation diagnostique entre un syndrome coronarien aigu (ACS) et une angine de poitrine stable (SAP) chez un être vivant.
PCT/EP2012/054767 2011-03-25 2012-03-19 Differenciation diagnostique entre un syndrome coronarien aigu et une angine de poitrine stable Ceased WO2012130651A1 (fr)

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DE201110016143 DE102011016143A1 (de) 2011-03-25 2011-03-25 Diagnostische Differenzierung zwischen einem akuten Koronarsyndrom und einer stabilen Angina pectoris

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN115356486A (zh) * 2022-08-19 2022-11-18 华中科技大学同济医学院附属同济医院 一种变异型心绞痛的辅助诊断试剂、试剂盒及其应用

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EP2000802A4 (fr) * 2006-03-31 2009-04-15 Mochida Pharm Co Ltd Nouveau marqueur de l'activation plaquettaire et son procédé de détermination

Non-Patent Citations (9)

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Title
B BIGALKE: "Lower platelet count is associated with an enhanced platelet surface expression of collagen receptor glycoprotein VI in patients with symptomatic coronary artery disease", 24. JAHRESTAGUNG DER DEUTSCHEN GESELLSCHAFT FÜR ARTERIOSKLEROSEFORSCHUNG, 23 March 2011 (2011-03-23), XP055025571, DOI: 10.3205/10dgaf08 *
BIGALKE ET AL.: "Expression of platelet collagen receptor VI is associated with acute coronary syndrom", EUR. HEART J., vol. 27, 2006, pages 2165 - 2169, XP055025583, DOI: doi:10.1093/eurheartj/ehl192
BIGALKE ET AL.: "Influence of Platelet Count on the Expression of Platelet Collagen Receptor Glycoprotein VI (GPVI) in Patients with Acute Coronary Syndrome", THROMB. HAEMOST., vol. 101, 2009, pages 911 - 915, XP009174397
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BIGALKE ET AL.: "Regulation of platelet glycoprotein VI (GPVI) surface expression and of soluble GPVI in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS", BASIC RES. CARDIOL., vol. 104, 2009, pages 352 - 357, XP055025591, DOI: doi:10.1007/s00395-009-0779-7
BORIS BIGALKE ET AL: "Regulation of platelet glycoprotein VI (GPVI) surface expression and of soluble GPVI in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS)", BASIC RESEARCH IN CARDIOLOGY, vol. 104, no. 3, 3 February 2009 (2009-02-03), pages 352 - 357, XP055025591, ISSN: 0300-8428, DOI: 10.1007/s00395-009-0779-7 *
BRAUNWALD ET AL.: "ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: executive summary and recommendations. A Report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on the management o", CIRCULATION, vol. 102, 2000, pages 1193 - 1209
CARSON; VIGNALI: "Simultaneous quantitation of 15 Cytokines using a multiplexed flow cytometric assay", J. IMMUNOL. METHODS, vol. 227, 1999, pages 41 - 52, XP004178041, DOI: doi:10.1016/S0022-1759(99)00069-1
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115356486A (zh) * 2022-08-19 2022-11-18 华中科技大学同济医学院附属同济医院 一种变异型心绞痛的辅助诊断试剂、试剂盒及其应用

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