Method of prognosis

Abstract

Provided is a method for prognosing ACS in a subject, the method comprising determining plasma MIF and Nt-ProBNP (or BNP) concentrations in a sample from the subject, diagnosing ACS when the subject plasma concentrations are greater than a reference MIF and Nt-proBNP (or BNP) plasma concentration, and prognosing the magnitude of ACS from the subject plasma MIF and Nt-proBNP (or BNP) concentrations. Also provided are a device, a kit and a cardiac biomarker panel related to the methods of prognosing ACS.

1 . A method for providing a prognosis of acute coronary syndrome (ACS) in a subject comprising
 determining the concentration of (a) macrophage migration inhibitory factor (MIF) or fragment thereof, and (b) N-terminal prohormone of brain natriuretic peptide (Nt-proBNP) or a fragment thereof, in a sample from the subject, and   prognosing ACS when the subject plasma MIF and Nt-proBNP concentration is greater than a reference plasma MIF and Nt-proBNP concentration.   
     
     
         2 . A method for providing a prognosis of a subject having acute coronary syndrome (ACS), the method comprising:
 determining the concentration of (a) macrophage migration inhibitory factor (MIF) or fragment thereof, and (b) N-terminal prohormone of brain natriuretic peptide (Nt-proBNP) or a fragment thereof, in a sample from the subject,   comparing the concentration of MIF or fragment thereof to a reference MIF concentration,   comparing the concentration of Nt-proBNP or fragment thereof to a reference Nt-proBNP concentration,   
       wherein the concentration of MIF or fragment thereof and Nt-proBNP or fragment thereof compared to their respective reference concentrations is indicative of the subject's prognosis. 
     
     
         3 . A method for providing a prognosis of a subject having ACS, the method comprising
 determining the concentration of (a) macrophage migration inhibitory factor (MIF) or fragment thereof, and (b) N-terminal prohormone of brain natriuretic peptide (Nt-proBNP) or a fragment thereof, in a sample from the subject,   comparing the concentration of MIF or fragment thereof to a reference MIF concentration,   comparing the concentration of Nt-proBNP or fragment thereof to a reference Nt-proBNP concentration,   
       wherein the reference concentrations of MIF and Nt-proBNP are concentrations below which correlate with an increased probability of survival and a decreased probability of non-fatal cardiac events at a later time, and above which correlate with a decreased probability of survival and an increased probability of non-fatal cardiac events at a later time, 
       thereby providing a prognosis of a subject having ACS. 
     
     
         4 . A method for providing a prognosis of a subject having ACS, the method comprising
 analysing levels of (a) macrophage migration inhibitory factor (MIF) or fragment thereof and (b) B N-terminal prohormone of brain natriuretic peptide (Nt-proBNP) or a fragment thereof, in a sample from the subject   determining the concentration of macrophage migration inhibitory factor (MIF) or fragment thereof and N-terminal prohormone of brain natriuretic peptide (Nt-proBNP) or a fragment thereof in the sample from the subject,   comparing the concentration of MIF or fragment thereof to a reference MIF concentration,   comparing the concentration of Nt-proBNP or fragment thereof to a reference Nt-proBNP concentration,   assigning the subject to a risk group based on whether the concentration of MIF or fragment thereof is higher or lower than the reference concentration, and whether the concentration of Nt-proBNP or fragment thereof is higher or lower than the reference concentration,   
       wherein a concentration of MIF or fragment thereof that is higher than the reference MIF concentration indicates a low likelihood of survival and high likelihood of non-fatal cardiac events, 
       wherein a concentration of Nt-proBNP or fragment thereof that is higher than the reference Nt-proBNP concentration indicates a low likelihood of survival and high likelihood of non-fatal cardiac events, 
       thereby providing a prognosis of a subject having ACS. 
     
     
         5 . A method for providing a prognosis of a subject having ACS, the method comprising
 determining the concentration of macrophage migration inhibitory factor (MIF) or a fragment thereof in a sample from the subject,   
       wherein if the concentration of MIF or fragment thereof from the sample from the subject is equal to or higher than about 70 ng/ml the subject is determined to have a decreased probability of survival and an increased probability of non-fatal cardiac events at a later time, 
       wherein if the concentration of MIF or fragment thereof from the sample from the subject is lower than about 70 ng/ml the subject is determined to have an increased probability of survival and a decreased probability of non-fatal cardiac events at a later time, 
       thereby providing a prognosis of a subject having ACS. 
     
     
         6 . A method for providing a prognosis of a subject having ACS, the method comprising
 determining the concentration of macrophage migration inhibitory factor (MIF) or a fragment thereof in a sample from the subject,   comparing the concentration of MIF or fragment thereof to reference MIF concentrations of about 40 ng/ml and about 70 ng/ml,   wherein if the concentration of MIF or fragment thereof from the sample from the subject is equal to or lower than about 40 ng/ml the subject is determined to have a high probability of survival and a low probability of non-fatal cardiac events at a later time,   wherein if the concentration of MIF or fragment thereof from the sample from the subject is equal to or higher than about 70 ng/ml the subject is determined to have a low probability of survival and a high probability of non-fatal cardiac events at a later time,   thereby providing a prognosis of a subject having ACS.   
     
     
         7 . The method according to any one of  claims 1  to  6 , further comprising determining the concentration of troponin or a fragment thereof. 
     
     
         8 . The method according to any one of  claims 1  to  7 , wherein the concentrations of MIF, Nt-proBNP and/or troponin or fragments thereof are determined from plasma. 
     
     
         9 . The method according to any one of  claims 1  to  8 , wherein ACS is acute myocardial infarction (AMI). 
     
     
         10 . The method according to  claim 9 , wherein the AMI is ST elevation myocardial infarction (STEMI). 
     
     
         11 . The method according to any one of  claims 1  to  10 , comprising determining MIF concentration of the subject in a sample taken less than 4 hours after symptom onset. 
     
     
         12 . The method of  claim 11 , wherein the MIF sample is taken 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less after symptom onset. 
     
     
         13 . The method of any one of  claims 1  to  12 , wherein instead of the concentration of N-terminal prohormone of brain natriuretic peptide (Nt-proBNP), the concentration of brain natriuretic peptide (BNP) is determined. 
     
     
         14 . The method of any one of  claims 7  to  13 , wherein the troponin is high sensitive-troponin T (hs-TnT). 
     
     
         15 . The method according to any one of  claims 1  to  14 , wherein prognosis is determined by assessing MACE-Free survival, All-cause mortality free survival, cardiac death free survival or HF rehospitalisation free survival. 
     
     
         16 . The method according to any one of  claims 1  to  15 , wherein Nt-proBNP (or BNP) and MIF are measured in the same sample. 
     
     
         17 . The method according to any one of  claims 1  to  16 , further comprising performing a step of performing percutaneous coronary intervention (PCI) and/or thrombinolysis on the subject. 
     
     
         18 . A method of treating acute coronary syndrome (ACS) in a subject, the method comprising:
 (a) determining macrophage migration inhibitory factor (MIF) or fragment thereof and N-terminal prohormone of brain natriuretic peptide (Nt-proBNP) or fragment thereof concentration in a sample taken from the subject, and prognosing ACS when the subject MIF and Nt-proBNP concentration is greater than a reference MIF and Nt-proBNP concentration; and   (b) performing percutaneous coronary intervention (PCI) and/or thrombinolysis on the subject.   
     
     
         19 . A device comprising means for determining concentration of macrophage migration inhibitory factor (MIF) or fragment thereof and N-terminal prohormone of brain natriuretic peptide (Nt-proBNP) or fragment thereof in a sample from a subject, for use in a method according to any one of  claims 1  to  18 . 
     
     
         20 . The device of  claim 19 , comprising means for performing an immunoassay for determining concentrations of MIF and Nt-proBNP (or BNP). 
     
     
         21 . The device of  claim 19  or  20 , wherein the device is a point of care device. 
     
     
         22 . The method according to  claim 18 , or device according to any one of  claims 19  to  21 , further comprising determining the concentration of troponin or a fragment thereof. 
     
     
         23 . The method or device of  claim 22 , wherein the troponin is high sensitive-troponin T (hs-TnT). 
     
     
         24 . The method according to any one of  claims 7  to  17 , wherein if the concentration of troponin from the sample from the subject is equal to or higher than about 4.5 ng/ml the subject is determined to have a decreased probability of survival and an increased probability of non-fatal cardiac events at a later time,
 wherein if the concentration of troponin from the sample from the subject is lower than about 4.5 ng/ml the subject is determined to have an increased probability of survival and a decreased probability of non-fatal cardiac events at a later time, 
 thereby providing a prognosis of a subject having ACS. 
 
     
     
         25 . The method or device of any one of  claims 19  to  23 , wherein instead of the concentration of N-terminal prohormone of brain natriuretic peptide (Nt-proBNP), the concentration of BNP is determined, or the device comprises a means for determining the concentration of BNP. 
     
     
         26 . The method according to any one of  claims 1  to  18 , wherein if the concentration of Nt-proBNP (or BNP) from the sample from the subject is equal to or higher than about 1200 pg/ml the subject is determined to have a decreased probability of survival and an increased probability of non-fatal cardiac events at a later time,
 wherein if the concentration of Nt-proBNP (or BNP) from the sample from the subject is lower than about 1200 pg/ml the subject is determined to have an increased probability of survival and a decreased probability of non-fatal cardiac events at a later time, 
 thereby providing a prognosis of a subject having ACS. 
 
     
     
         27 . The method or device of any one of  claims 18  to  26 , wherein the concentrations of MIF, Nt-proBNP (or BNP) and/or troponin are determined from plasma. 
     
     
         28 . A kit comprising a reagent for measuring macrophage migration inhibitory factor (MIF) and Nt-proBNP (or BNP) concentrations in a sample from a subject,
 for use in a method for prognosing ACS in the subject, the method comprising determining MIF and Nt-proBNP (or BNP) concentrations in the sample, prognosing ACS when the subject MIF and Nt-proBNP (or BNP) concentrations are greater than a reference MIF and Nt-proBNP (or BNP) concentration; and/or   comprising the device of any one of  claims 19  to  21 .   
     
     
         29 . The kit of  claim 28 , further comprising determining the concentration of troponin or a fragment thereof. 
     
     
         30 . The kit of  claim 28  or  29 , wherein the reagent comprises an anti-MIF antibody, an anti-Nt-proBNP (or BNP) antibody and/or and anti-troponin antibody. 
     
     
         31 . The kit of  claim 29 , wherein the troponin is high sensitive-troponin T (hs-TnT). 
     
     
         32 . The kit of any one of  claims 28  to  31 , wherein instead of the concentration of N-terminal prohormone of brain natriuretic peptide (Nt-proBNP), the concentration of BNP is determined, or the kit comprises a reagent for measuring BNP. 
     
     
         33 . A cardiac biomarker panel comprising plasma macrophage migration inhibitory factor (MIF) and N-terminal prohormone of brain natriuretic peptide (Nt-proBNP) in a sample from a subject, wherein MIF and Nt-proBNP concentrations greater than reference MIF and Nt-proBNP concentrations are prognostic of the magnitude of ACS in the subject. 
     
     
         34 . The cardiac biomarker panel of  claim 33 , further comprising troponin in a sample from a subject, wherein MIF, Nt-proBNP and troponin concentrations greater than reference MIF, Nt-proBNP and troponin concentrations are prognostic of the magnitude of ACS in the subject. 
     
     
         35 . The cardiac biomarker panel of  claim 33  or  34 , wherein the ACS is AMI. 
     
     
         36 . The cardiac biomarker panel of any one of  claims 33  to  35 , wherein the AMI is ST elevation myocardial infarction (STEMI). 
     
     
         37 . The method according to any one of  claims 1  to  18 , or  22  to  27 , wherein the concentration of BNP is determined in plasma derived from a blood sample obtained from a patient 3 days following symptom onset. 
     
     
         38 . The method according to any one of  claims 1  to  18 ,  22  to  27  or  37 , further comprising determining the concentration of another biomarker selected from the group consisting of myoglobin, creatine kinase (CK) or C reactive protein (CRP). 
     
     
         39 . The method according to  claim 5  or  6 , wherein a MIF level greater than about 70 ng/ml is indicative of a 5 year MACE prognosis rate of about 35% and death prognosis rate of about 20%. 
     
     
         40 . The method according to  claim 26 , wherein a MIF level greater than about 70 ng/ml and a Nt-proBNP level greater than about 1200 pg/ml is indicative of a 5 year MACE prognosis rate of about 50% and death prognosis rate of about 25%. 
     
     
         41 . The method according to  claim 40 , wherein a troponin level greater than about 4.5 ng/ml is indicative of a 5 year MACE prognosis rate of about 50% and death prognosis rate of about 25%.