Future cardiac event biomarkers

Abstract

The present invention relates to the identification of chemokine biomarkers predictive of future acute coronary syndromes including unstable angina pectoris (UAP). The present invention also identifies particular chemokines as potential therapeutic targets for intervention in cardiovascular diseases.

What is claimed is: 
     
         1 . A method for identifying a subject at increased risk of a future acute cardiovascular syndrome or event, the method comprising:
 a) determining an amount of at least one compound selected from the group consisting of CCL3 (chemokine (C—C motif) ligand 3), CCL18 (chemokine (C—C motif) ligand 18), and CCL5 (chemokine (C—C motif) ligand 5) in a sample obtained from the subject by contacting the sample with:   i) an antibody specific for CCL3, and quantifying the amount of CCL3 bound to the antibody,   ii) an antibody specific for CCL18, and quantifying the amount of CCL18 bound to the antibody, or   iii) an antibody specific for CCL5, and quantifying the amount of CCL5 bound to the antibody; and   b) identifying the subject as having an increased risk of a future acute cardiovascular syndrome or event if the sample from the subject was determined to have greater CCL3, greater CCL5, or greater CCL18 relative to a subject with no risk.   
     
     
         2 . The method according to  claim 1 , wherein the cardiovascular syndrome or event may comprise coronary artery disease, atherosclerosis, acute myocardial infarction, arteriosclerosis, unstable angina pectoris, embolism, deep vein thrombosis, stroke, congestive heart failure or arrhythmia. 
     
     
         3 . The method according to  claim 1 , wherein the indication of an increased risk of a future acute cardiovascular syndrome or event may be used for monitoring the status and/or progression of said syndrome or event. 
     
     
         4 . The method according to  claim 1 , wherein the indication of an increased risk of a future acute cardiovascular syndrome or event may be used for monitoring therapeutic regimes and/or clinical trials in order to detect whether or not a particular treatment may be effective in reducing an increased risk of an acute cardiovascular syndrome or event. 
     
     
         5 . The method according to  claim 1 , wherein the sample is a cell taken from the subject or a sample of a body fluid of the subject, which may be derived from blood or from a blood fraction. 
     
     
         6 . The method according to  claim 1 , wherein the amount of compound bound to an antibody is detected by a method selected from the group consisting of an immunoassay, an enzyme linked immunoassays (ELISA), a fluorescence based assay, a dissociation enhanced lanthanide fluoroimmunoassay (DELFIA), a radiometric assay, a multiplex immunoassay, and a cytometric bead assay (CBA). 
     
     
         7 . The method according to  claim 1 , further comprising assessing clinical symptoms, determining the level of at least one other compound in the subject, or a combination thereof, wherein the at least one other compound is a biomarker indicative of cardiovascular disease or a predisposition thereto. 
     
     
         8 . The method according to  claim 7 , wherein the at least one other compound is selected from the group consisting of CXSCL 10 (IP-10), C-Reactive Protein, troponin I, creatine kinase, creatine kinase MB, CD40L, high density lipoprotein (HDL), myoglobin and interleukin-6. 
     
     
         9 . The method according to  claim 1 , wherein the method comprises determining the amount of each compound selected from the group consisting of CCL3, CCL18, and CCL5. 
     
     
         10 . The method according to  claim 1 , wherein the subject is identified as having an increased risk of a future acute cardiovascular syndrome or event if the sample from the subject was determined to have greater than 41 pg/ml CCL3, greater than 40.3 ng/ml CCL5, and/or greater than 39.3 ng/ml CCL18. 
     
     
         11 . A method for identifying a subject at increased risk of a future acute cardiovascular syndrome or event, the method comprising:
 a) determining an amount of at least one compound selected from the group consisting of CCL3 (chemokine (C—C motif) ligand 3), CCL18 (chemokine (C—C motif) ligand 18), and CCL5 (chemokine (C—C motif) ligand 5) in a sample obtained from the subject by contacting the sample with:   i) an antibody specific for CCL3, and quantifying the amount of CCL3 bound to the antibody,   ii) an antibody specific for CCL18, and quantifying the amount of CCL18 bound to the antibody, or   an antibody specific for CCL5, and quantifying the amount of CCL5 bound to the antibody;   b) identifying the subject as having an increased risk of a future acute cardiovascular syndrome or event if the sample from the subject was determined to have greater CCL3, greater CCL5, or greater CCL18 relative to a subject with no risk; and   c) performing follow-up on the subject identified with an increased risk using standard medical therapy.   
     
     
         12 . A method for identifying a subject at increased risk of a future acute cardiovascular syndrome or event, the method comprising:
 a) analyzing a sample obtained from the subject, in vitro, by mass spectrometry to determine an amount of at least one compound selected from the group consisting of CCL18 (chemokine (C—C motif) ligand 18) and CCL5 (chemokine (C—C motif) ligand 5);   b) identifying the subject as having an increased risk of a future acute cardiovascular syndrome or event if an elevated amount of CCL18 or CCL5 is detected in the sample from the subject relative to a subject with no risk; and   c) performing follow-up on the subject identified with an increased risk using standard medical therapy.   
     
     
         13 . The method according to  claim 12 , wherein the detection of a peak with m/z at approximately 7,860 Da detects CCL18 and CCL5. 
     
     
         14 . The method according to  claim 13 , further comprising the detection of a minor peak with m/z at approximately 15,730 Da. 
     
     
         15 . The method according to  claim 12 , further comprising analyzing the sample obtained from the subject, in vitro, by mass spectrometry to determine an amount of CCL3 (chemokine (C—C motif) ligand 3). 
     
     
         16 . The method according to  claim 12 , wherein the cardiovascular syndrome or event may comprise coronary artery disease, atherosclerosis, acute myocardial infarction, arteriosclerosis, unstable angina pectoris, embolism, deep vein thrombosis, stroke, congestive heart failure or arrhythmia. 
     
     
         17 . The method according to  claim 12 , wherein the sample is a cell taken from the subject or a sample of a body fluid of the subject, which may be derived from blood or from a blood fraction. 
     
     
         18 . A method for identifying a subject at increased risk of a future acute cardiovascular syndrome or event, the method comprising:
 a) determining an amount of at least one compound selected from the group consisting of CCL3 (chemokine (C—C motif) ligand 3), CCL18 (chemokine (C—C motif) ligand 18), and CCL5 (chemokine (C—C motif) ligand 5) in a sample obtained from the subject by measuring the level of expression of CCL3 mRNA, CCL18 mRNA or CCL5 mRNA;   b) identifying a subject as having an increased risk of a future acute cardiovascular syndrome or event if the sample from the subject was determined to have elevated CCL3 mRNA, elevated CCL5 mRNA, or elevated CCL18 mRNA relative to a subject with no risk; and   c) performing follow-up on the subject identified with an increased risk using standard medical therapy.   
     
     
         19 . The method according to  claim 18 , wherein the cardiovascular syndrome or event may comprise coronary artery disease, atherosclerosis, acute myocardial infarction, arteriosclerosis, unstable angina pectoris, embolism, deep vein thrombosis, stroke, congestive heart failure or arrhythmia. 
     
     
         20 . The method according to  claim 18 , wherein the sample is a cell taken from the subject or a sample of a body fluid of the subject, which may be derived from blood or from a blood fraction.