Cardiovascular risk event prediction and uses thereof

Abstract

Biomarkers, methods, devices, reagents, systems, and kits used to assess an individual for the prediction of risk of developing a Cardiovascular (CV) Event over a 1 to 5 year period are provided.

1 . A method for screening a subject for the risk of a cardiovascular event (CV) event or for predicting the likelihood that a subject will have a CV event, comprising:
 (a) forming a biomarker panel comprising at least one biomarker selected from cardiac troponin I and angiopoietin-related protein 4 and N biomarkers selected from MMP12, angiopoietin-2, complement C7, CCL18/PARC, alpha-1-antichymotrypsin complex, GDF11 and alpha-2-antiplasmin, wherein N is an integer from 1 to 7; and   (b) detecting the level of each of the N biomarkers of the panel in a sample from the subject.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the biomarker panel comprises at least five biomarkers selected from MMP12, angiopoietin-2, complement C7, cardiac troponin I, angiopoietin-related protein 4, CCL18/PARC, alpha-1-antichymotrypsin complex, GDF11 and alpha-2-antiplasmin. 
     
     
         4 . (canceled) 
     
     
         5 . A method for screening a subject for the risk of a cardiovascular event (CV) or predicting the likelihood that a subject will have a CV event comprising detecting the level of GDF11 and FSTL3 in a sample from the subject. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 3 , wherein the likelihood of the subject having a CV event within 4 years is high if the level of at least five biomarkers selected from the level of MMP12, angiopoetin-2, complement C7, cardiac troponin I, angiopoietin-related protein 4, CCL18/PARC and alpha1-antichymotrypsin complex is higher than a control level of the respective protein, and if the level of at least one biomarker or both biomarkers selected from GDF11 and alpha2-antiplasmin is lower than a control level of the respective protein. 
     
     
         8 . The method of  claim 5 , wherein the likelihood of the subject having a CV event within 4 years is high if the level of GDF11 is lower than a control level of GDF11 and/or the level of FSTL3 is higher than a control level of FSTL3. 
     
     
         9 . The method of  claim 5 , wherein the CV event is a thrombotic event. 
     
     
         10 . The method of  claim 9 , wherein the thrombotic event is selected from myocardial infarction, stroke, and transient ischemic attack. 
     
     
         11 .- 19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the method comprises detecting the level of MMP12, angiopoietin-2, complement C7, cardiac troponin I, angiopoietin-related protein 4, CCL18/PARC, alpha-1-antichymotrypsin complex, GDF11 and alpha-2-antiplasmin. 
     
     
         21 . The method of  claim 1 , wherein the subject has coronary artery disease. 
     
     
         22 . The method of  claim 1 , wherein the subject does not have a history of CV events. 
     
     
         23 . The method of  claim 22 , wherein the subject has a high American College of Cardiology (ACC) risk score. 
     
     
         24 . The method of  claim 22 , wherein the subject has an intermediate ACC risk score. 
     
     
         25 . The method of  claim 22 , wherein the subject has a low ACC risk score. 
     
     
         26 . The method of  claim 1 , wherein the subject has had at least one CV event. 
     
     
         27 . The method of  claim 26 , wherein the CV event is selected from myocardial infarction, stroke, congestive heart failure, transgenic ischemic attack, and death. 
     
     
         28 . The method of  claim 1 , wherein the sample is selected from a blood sample, a serum sample, a plasma sample, and a urine sample. 
     
     
         29 . The method of  claim 28 , wherein the sample is a plasma sample. 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein each biomarker is a protein biomarker. 
     
     
         32 . The method of  claim 31 , wherein the method comprises contacting biomarkers of the sample from the subject with a set of biomarker capture reagents, wherein each biomarker capture reagent of the set of biomarker capture reagents specifically binds to a different biomarker being detected. 
     
     
         33 . The method of  claim 32 , wherein each biomarker capture reagent is an antibody or an aptamer. 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 33 , wherein each biomarker capture reagent is a slow off-rate aptamer. 
     
     
         36 . The method of  claim 35 , wherein at least one slow off-rate aptamer comprises at least one nucleotide with a modification. 
     
     
         37 . The method of  claim 35 , wherein each slow off-rate aptamer binds to its target protein with an off rate (t 1/2 ) of ≧30 minutes. 
     
     
         38 . The method of  claim 1 , wherein the likelihood of a CV event is based on the biomarker levels and at least one item of additional biomedical information selected from
 a) information corresponding to the presence of cardiovascular risk factors selected from the group consisting of prior myocardial infarction, angiographic evidence of greater than 50% stenosis in one or more coronary vessels, exercise-induced ischemia by treadmill or nuclear testing or prior coronary revascularization,   b) information corresponding to physical descriptors of said individual,   c) information corresponding to a change in weight of said individual,   d) information corresponding to the ethnicity of said individual,   e) information corresponding to the gender of said individual,   f) information corresponding to said individual's smoking history,   g) information corresponding to said individual's alcohol use history,   h) information corresponding to said individual's occupational history,   i) information corresponding to said individual's family history of cardiovascular disease or other circulatory system conditions,   j) information corresponding to the presence or absence in said individual of at least one genetic marker correlating with a higher risk of cardiovascular disease in said individual or a family member of said individual,   k) information corresponding to clinical symptoms of said individual,   l) information corresponding to other laboratory tests,   m) information corresponding to gene expression values of said individual, and   n) information corresponding to said individual's consumption of known cardiovascular risk factors such as diet high in saturated fats, high salt, high cholesterol,   o) information corresponding to the individual's imaging results obtained by techniques selected from the group consisting of electrocardiogram, echocardiography, carotid ultrasound for intima-media thickness, flow mediated dilation, pulse wave velocity, ankle-brachial index, stress echocardiography, myocardial perfusion imaging, coronary calcium by CT, high resolution CT angiography, MM imaging, and other imaging modalities,   p) information regarding the individual's medications, and   q) information regarding the individual's kidney function.   
     
     
         39 . The method of  claim 1 , wherein the method comprises determining the likelihood of a CV Event for the purpose of determining a medical insurance premium or life insurance premium. 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 1 , wherein the method further comprises using information resulting from the method to predict and/or manage the utilization of medical resources. 
     
     
         42 . The method of  claim 1 , wherein the method further comprises using information resulting from the method to enable a decision to acquire or purchase a medical practice, hospital, or company. 
     
     
         43 . A computer-implemented method for evaluating the risk of a cardiovascular (CV) event, the method comprising:
 retrieving on a computer biomarker information for a subject, wherein the biomarker information comprises the levels of at least five, at least six, at least seven, at least eight, or all nine biomarkers selected from MMP12, angiopoietin-2, complement C7, cardiac troponin I, angiopoietin-related protein 4, CCL18/PARC, alpha-1-antichymotrypsin complex, GDF11 and alpha-2-antiplasmin in a sample from the subject;   performing with the computer a classification of each of said biomarker values; and   indicating a result of the evaluation of risk for a CV event for said individual based upon a plurality of classifications.   
     
     
         44 . (canceled)