Methods of diagnosing acute cardiac disorders using bnp-sp

Abstract

The invention provides methods for predicting, diagnosing or monitoring acute cardiac disorders, cardiac transplant rejection, or distinguishing acute cardiac disorders from pulmonary disorders, by measuring BNP signal peptide levels in a sample taken from a subject shortly after onset of, or presentation with the disorder or transplant rejection.

We claim: 
     
         1 . An assay method for diagnosing an acute cardiac disorder in a subject, the method comprising:
 a. obtaining a biological sample from the subject;   b. contacting the sample with a BNP-SP fragment binding agent;   c. determining the level of a BNP-SP fragment in the biological sample obtained from the subject; and   d. comparing the level of said BNP-SP fragment in the sample with the level of said BNP-SP fragment in a control or reference value,   wherein a level of BNP-SP fragment in the sample that is higher than the control level is diagnostic of an acute cardiac disorder.   
     
     
         2 . A method according to  claim 1 , wherein said method is used to evaluate or monitor a response to treatment of an acute cardiac disorder, wherein said assay method is carried out on one or more biological samples from said subject and a change in the measured level of BNP-SP fragment from said control or reference value is determined, said method further comprising the step of determining whether to adjust treatment for said acute cardiac disorder based on a change in the measured level of BNP-SP fragment from the control or reference value and, optionally, adjusting said treatment. 
     
     
         3 . A method according to  claim 1 , which further comprises the step of providing therapy to the subject for treatment of an acute cardiac disorder. 
     
     
         4 . A method according to  claim 1  that further comprises the step of evaluating one more risk factors and/or test results in conjunction with determining the level of BNP-SP fragment in the sample. 
     
     
         5 . A method according to  claim 1 , wherein the control is an individual or group from which BNP-SP fragment samples are obtained and a mean BNP-SP fragment level is determined. 
     
     
         6 . A method according to  claim 5 , wherein the individual or group comprises normal healthy individuals or a group of individuals not known to be suffering from an acute cardiac disorder. 
     
     
         7 . A method according to  claim 5 , wherein the control BNP-SP fragment levels are between 0 to 15 pmol/L. 
     
     
         8 . A method according to  claim 5 , wherein the control or reference value is derived from BNP-SP fragment level in a cardiac control population. 
     
     
         9 . A method according to  claim 8 , wherein the BNP-SP fragment level in the cardiac control population is in the order of 1.5 to 3, 2 to 3, or 2.5 to 3 times higher than BNP-SP fragment levels in a normal control population. 
     
     
         10 . A method according to  claim 1 , wherein repeat BNP-SP fragment level determinations are carried out on separate samples from the subject. 
     
     
         11 . A method according to  claim 1  wherein a sample level of BNP-SP fragment in the range of any of 20 to 300 pmol/L, 25 to 250 pmol/L, 20 to 180 pmol/L, 30 to 180 pmol/L, 35 to 150 pmol/L, 40 to 130 pmol/L, 40 to 120 pmol/L, 40 to 90 pmol/L, 45 to 80 pmol/L, 45 to 160 pmol/L, 50 to 100 pmol/L and 50 to 200 pmol/L is diagnostic of an acute cardiac disorder. 
     
     
         12 . A method according to  claim 1 , wherein a level of BNP-SP fragment in the sample which is five to eight times higher, or four to ten times higher, than the control or reference level is diagnostic of acute cardiac disorder. 
     
     
         13 . A method according to  claim 1 , wherein the acute cardiac disorder is unstable angina. 
     
     
         14 . A method according to  claim 1 , wherein the acute cardiac disorder is an acute myocardial infarction. 
     
     
         15 . A method according to  claim 14 , wherein the acute myocardial infarction is an acute myocardial infarction with ST-elevation on presenting ECG. 
     
     
         16 . A method according to  claim 14 , wherein the acute cardiac disorder is non-ST elevated myocardial infarction. 
     
     
         17 . A method as claimed in  claim 1  wherein the acute cardiac disorder is acute cardiac ischemia. 
     
     
         18 . A method according to  claim 1 , wherein the acute cardiac disorder is an acute cardiac injury, acute cardiac damage resulting from acute drug toxicity, an acute cardiomyopathy or a cardiac transplant rejection episode. 
     
     
         19 . A method according to  claim 1 , wherein the biological sample is blood. 
     
     
         20 . A method according to  claim 1 , wherein the biological sample is plasma. 
     
     
         21 . A method according to  claim 1 , wherein the level of the BNP-SP fragment in the biological sample is determined by immunoassay. 
     
     
         22 . A method according to  claim 21 , wherein the immunoassay is a competitive binding assay, a non-competitive assay, a sandwich assay, a fluoroimmunoassay, a immunofluorometric assay, an immunoradiometric assay, a luminescence assay or a chemiluminescence assay. 
     
     
         23 . A method according to  claim 21 , wherein the immunoassay is a quantitative immunoassay. 
     
     
         24 . A method according to  claim 21 , wherein the immunoassay comprises an antibody or an antibody binding fragment. 
     
     
         25 . A method according to  claim 24 , wherein the antibody or antibody binding fragment is attached to a solid phase. 
     
     
         26 . A method according to  claim 21 , wherein the immunoassay comprises a labeled antibody or a labeled antibody binding fragment. 
     
     
         27 . A method according to  claim 1 , wherein the BNP-SP fragment level is evaluated by mass spectroscopy. 
     
     
         28 . A method according to  claim 1 , wherein the BNP-SP fragment is BNP-SP (17-26) (SEQ ID NO:19). 
     
     
         29 . A method according to  claim 1 , wherein the BNP-SP fragment is selected from the group consisting of BNP-SP (1-10) (SEQ ID NO:13), BNP-SP (1-17) (SEQ ID NO:15) and BNP-SP (12-23) (SEQ ID NO:17). 
     
     
         30 . A method according to  claim 1 , wherein the assay method is carried out using a device for sample analysis comprising a disposable testing cartridge. 
     
     
         31 . A method according to  claim 1 , which further comprises the step of determining the level of one or more non-BNP-SP markers associated with an acute cardiac disorder. 
     
     
         32 . A method according to  claim 31  wherein the non-BNP-SP marker is selected from the group consisting of troponin, troponin T, troponin I, creatine kinase-MB, myoglobin, BNP, NT-BNP, and H-FABP.