METHODS OF DIAGNOSING ACUTE CARDIAC DISORDERS USING BNP-SP
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.
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 a 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.