Diagnosis of cardiovascular disease

Abstract

This invention relates to methods for the detection of cardiovascular disease, e.g., acute coronary syndrome, heart failure and/or pulmonary embolism, in high body mass index (BMI) individuals, e.g., with a BMI of 25-29, or 30 or above, and those with impaired renal function.

What is claimed is: 
     
         1 . A kit for diagnosing cardiovascular disease (CVD), the kit comprising antibodies that specifically bind to ST2, BNP, and D-dimer, or nucleic acid probes that specifically bind to nucleic acids encoding ST2, BNP, and D-dimer, and instructions for use in a method of diagnosing heart failure (HF) or a pulmonary embolism (PE) in a subject who has one or both of (i) a body mass index (BMI) of greater than or equal to 25, or (ii) impaired renal function. 
     
     
         2 . A method of diagnosing cardiovascular disease (CVD) in a subject who has one or both of (i) a body mass index (BMI) of greater than or equal to 25, or (ii) impaired renal function, the method comprising:
 one or both of:
 (A) determining the subject's BMI, and if the subject's BMI is equal to or greater than 25, selecting the subject; or 
 (B) evaluating the subject's renal function, and if the subject has impaired renal function, selecting the subject; and 
   determining levels of BNP, D-dimers, and ST2 in a biological sample from the subject;   wherein the subject's BNP level, D-dimer level, and ST2 level indicates whether the subject has CVD.   
     
     
         3 . The kit of  claim 1  or the method of  claim 2 , wherein the CVD is heart failure (HF) or pulmonary embolism (PE). 
     
     
         4 . The kit of  claim 1  or the method of  claim 2 , wherein the BNP level, D-dimer level, and ST2 level are detected in a biological sample comprising blood, plasma, or serum. 
     
     
         5 . The method of  claim 2 , wherein if the subject's BNP level is less than 500 pg/mL, and the D-dimer level is less than 500 μg/L, then the relationship of the ST2 level to a reference level of ST2 indicates whether the subject has HF. 
     
     
         6 . The method of  claim 2 , wherein if the subject's BNP level is less than 100 pg/mL, and the D-dimer level is 500-4000 μg/L, then the relationship of the ST2 level to a reference level of ST2 indicates whether the subject has PE. 
     
     
         7 . The method of  claim 5 , wherein the reference level of ST2 represents a level in a subject who does not have HF. 
     
     
         8 . The method of  claim 5 , wherein the reference level of ST2 is about 0.2 to 0.3 ng/ml of serum, and values above that level indicate the presence of HF. 
     
     
         9 . The method of  claim 6 , wherein the reference level of ST2 represents a level in a subject who does not have PE. 
     
     
         10 . The method of  claim 6 , wherein the reference level of ST2 is about 0.2 to 0.3 ng/ml of serum, and values above that level indicate the presence of PE. 
     
     
         11 . The method of  claim 2 , wherein the subject's BNP level is 100-500 pg/mL. 
     
     
         12 . The method of  claim 2 , further comprising determining a level in the subject of one or more other biomarkers. 
     
     
         13 . The method of  claim 12 , wherein the other biomarkers are selected from the group consisting of NT-proANP, ANP, troponin, CRP, creatinine, Blood Urea Nitrogen (BUN), liver function enzymes, albumin, and bacterial endotoxin. 
     
     
         14 . The method of  claim 2 , wherein determining whether the subject has impaired renal function comprises determining glomerular filtration rate (GFR) and/or serum creatinine level, and the subject has impaired renal function if they have a GFR or serum creatinine level shown in the following table: 
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Grade 
                   GFR (ml/minute) 
                   Serum Creatinine (μmol/litre) 
                 
                     
                     
                 
                     
                   mild 
                   20-50 
                   150-300 
                 
                     
                   moderate 
                   10-20 
                   300-700 
                 
                     
                   severe 
                   <10 
                   >700 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
               
            
           
         
       
     
     
         15 . The kit of  claim 1 , wherein a subject has impaired renal function if they have a GFR or less than 50 ml/minute. 
     
     
         16 . The kit of  claim 1  or the method of  claim 2 , wherein the subject has a BMI of greater than or equal to 30. 
     
     
         17 . The kit of  claim 1  or method of  claim 2 , wherein the subject has a BMI of 25 to 29. 
     
     
         18 . A method of diagnosing cardiovascular disease (CVD) in a subject who has impaired renal function, the method comprising:
 evaluating the subject's renal function, and if the subject has impaired renal function, selecting the subject; and   determining an ST2 level in a biological sample from the subject;   wherein the relationship of the ST2 level to a reference level of ST2 indicates whether the subject has CVD.   
     
     
         19 . The method of  claim 18 , wherein the reference level of ST2 represents a level in a subject who does not have CVD. 
     
     
         20 . The method of  claim 18 , wherein the reference level of ST2 is about 0.2 to 03 ng/ml of serum, and values above that level indicate the presence of CVD. 
     
     
         21 . The method of  claim 18 , wherein the reference level of ST2 represents a level in a subject who does not have CVD. 
     
     
         22 . The method of  claim 18 , wherein the CVD is heart failure (HF) or pulmonary embolism (PE). 
     
     
         23 . The method of  claim 18 , wherein the biological sample comprises blood, plasma, or serum. 
     
     
         24 . The method of  claim 18 , further comprising determining a level in the subject of one or more other biomarkers. 
     
     
         25 . The method of  claim 24 , wherein the other biomarkers are selected from the group consisting of BNP, D-Dimer, NT-proANP, and ANP troponin, CRP, creatinine, Blood Urea Nitrogen (BUN), liver function enzymes, albumin, and bacterial endotoxin. 
     
     
         26 . The method of  claim 18 , wherein determining whether the subject has impaired renal function comprises determining glomerular filtration rate (GFR) and/or serum creatinine level, and the subject has impaired renal function if they have a GFR or serum creatinine level shown in the following table: 
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Grade 
                   GFR (ml/minute) 
                   Serum Creatinine (μmol/litre) 
                 
                     
                     
                 
                     
                   mild 
                   20-50 
                   150-300 
                 
                     
                   moderate 
                   10-20 
                   300-700 
                 
                     
                   severe 
                   <10 
                   >700