US2013289141A1PendingUtilityA1

Assessing Cardiac Disease Via Detection and Measurement of MicroRNA

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Assignee: SPINALE FRANCIS GPriority: Nov 11, 2010Filed: Nov 11, 2011Published: Oct 31, 2013
Est. expiryNov 11, 2030(~4.3 yrs left)· nominal 20-yr term from priority
Inventors:Francis G. SpinaleMichael R. ZileRobert E. StoudJohn S. IkonomidisJeffrey A. Jones
C12Q 1/6883C12Q 2600/178C12Q 1/686C12Q 2600/112C12Q 2600/158
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Claims

Abstract

Disclosed are methods and materials for assessing cardiac disease, including cardiac failure, cardiac hypertrophy, thoracic aortic aneurysm, left ventricular remodeling using microRNA levels. The level of microRNAs can be measured in a body fluid, such as plasma and serum, or in cardiac tissue.

Claims

exact text as granted — not AI-modified
1 . A method comprising detecting one or more target microRNAs in tissue or a body fluid of a subject, wherein the level or amount of the one or more target microRNAs indicates the risk, presence, severity, or a combination, of thoracic aortic aneurysm (TAA) in the subject, of diastolic heart failure in the subject, of left ventricular hypertrophy in the absence of diastolic heart failure in the subject, of left ventricular remodeling in the subject, that the subject experienced ischemia-reperfusion, or a combination. 
     
     
         2 . The method of  claim 1 , wherein the one or more target microRNAs comprises miR-1, miR-21, miR-29a, miR-133a, and miR-486-5p, or a combination, wherein a level or amount of miR-1, miR-21, miR-29a, miR-133a, and miR-486-5p, or a combination, less than the level or amount in control subjects, reference subjects, normal subjects, or a combination, indicates the risk, presence, severity, or a combination, of TAA in the subject. 
     
     
         3 . The method of  claim 1 , wherein the one or more target microRNAs comprises miR-455-3p, miR-1268, miR-338-5p, miR-940, miR-1323, miR-768-3p, miR-574-3p, miR-106b, miR-451, miR-100, miR-125b, miR-195, miR-19b, miR-30d, miR-15b, miR-125a-5p, miR-143, miR-193b, miR-16, miR-27a, miR-29a, miR-30a, miR-27b, miR-92a, miR-140-5p, let-7i, miR-151-5p, miR-140-3p, miR-24, miR-23a, miR-145, miR-199b-3p, miR-199a-3p, miR-361-5p, miR-130a, miR-22, and miR-497,
 wherein a level or amount, for a threshold percentage or more of the target microRNAs miR-455-3p, miR-1268, miR-338-5p, miR-940, miR-1323, miR-768-3p, miR-574-3p, miR-106b, miR-451, miR-100, miR-125b, miR-195, miR-19b, miR-30d, miR-15b, miR-125a-5p, miR-143, miR-193b, miR-16, miR-27a, miR-29a, miR-30a, miR-27b, miR-92a, miR-140-5p, let-7i, miR-151-5p, miR-140-3p, miR-24, miR-23a, miR-145, miR-199b-3p, miR-199a-3p, miR-361-5p, miR-130a, miR-22, and miR-497:   (a) of less than the level or amount in control subjects, reference subjects, normal subjects, or a combination, for miR-1323, miR-768-3p, miR-574-3p, miR-106b, miR-451, miR-100, miR-125b, miR-195, miR-19b, miR-30d, miR-15b, miR-125a-5p, miR-143, miR-193b, miR-16, miR-27a, miR-29a, miR-30a, miR-27b, miR-92a, miR-140-5p, let-7i, miR-151-5p, miR-140-3p, miR-24, miR-23a, miR-145, miR-199b-3p, miR-199a-3p, miR-361-5p, miR-130a, miR-22, and miR-497, and   (b) of greater than the level or amount in control subjects, reference subjects, normal subjects, or a combination, for miR-455-3p, miR-1268, miR-338-5p, and miR-940,   indicates the risk, presence, severity, or a combination, of thoracic aortic ancurysmTAA in the subject.   
     
     
         4 . The method of  claim 3 , wherein the threshold percentage is 60%. 
     
     
         5 . The method of  claim 3 , wherein the threshold percentage is 80%. 
     
     
         6 . The method of  claim 3 , wherein the threshold percentage is 90%. 
     
     
         7 . The method of  claim 1 , wherein the one or more target microRNAs comprises miR-1, miR-21, miR-29a, and miR-133a, or a combination, wherein the lower the level or amount of miR-1, miR-21, miR-29a, miR-133a, and miR-486-5p, or a combination, less than the level or amount in control subjects, reference subjects, normal subjects, or a combination, the larger the TAA in the subject. 
     
     
         8 . The method of  claim 1 , wherein the lower the level or amount of miR-29a less than the level or amount in control subjects, reference subjects, normal subjects, or a combination, the higher the level of MMP-2 in the subject. 
     
     
         9 . The method of  claim 1 , wherein the lower the level or amount of miR-133a less than the level or amount in control subjects, reference subjects, normal subjects, or a combination, the higher the level of MMP-9 in the subject. 
     
     
         10 . The method of  claim 1 , wherein prior to detection, the subject is suspected of having TAA. 
     
     
         11 . The method of  claim 1 , wherein the subject has left ventricular hypertrophy, wherein the one or more target microRNAs comprises miR-1, miR-21, miR-29a, miR-133a, and miR-760, or a combination, wherein a decrease in the level or amount of miR-1, miR-21, miR-29a, miR-133a, and miR-760, or a combination, from a level or amount greater than the level or amount in control subjects, reference subjects, normal subjects, or a combination, indicates the risk, development, presence, severity, or a combination, of diastolic heart failure in the subject. 
     
     
         12 . The method of  claim 1 , wherein the subject has left ventricular hypertrophy, wherein the one or more target microRNAs comprises miR-1, miR-21, miR-29a, miR-133a, and miR-760, or a combination, wherein a decrease in the level or amount of miR-1, miR-21, miR-29a, miR-133a, and miR-760, or a combination, from a level or amount in subjects with left ventricular hypertrophy but not diastolic heart failure, indicates the risk, development, presence, severity, or a combination, of diastolic heart failure in the subject. 
     
     
         13 . The method of  claim 11 , wherein the decrease in the level or amount of the one or more target microRNAs is determined by detecting the level or amount of the one or more target microRNAs at different times. 
     
     
         14 . The method of  claim 13 , wherein the level or amount of the one or more target microRNAs at one or more of the different times is greater than the level or amount in control subjects, reference subjects, normal subjects, or a combination. 
     
     
         15 . The method of  claim 1 , wherein the subject has left ventricular hypertrophy, wherein the one or more target microRNAs comprises miR-1, miR-21, miR-29a, miR-133a, and miR-760, or a combination, wherein a level or amount of miR-1, miR-21, miR-29a, miR-133a, and miR-760, or a combination, about the same as the level or amount in control subjects, reference subjects, normal subjects, or a combination, indicates the presence of diastolic heart failure in the subject. 
     
     
         16 . The method of  claim 1 , wherein the subject has left ventricular hypertrophy, wherein the one or more target microRNAs comprises miR-1, miR-21, miR-29a, miR-133a, and miR-760, or a combination, wherein a level or amount of miR-1, miR-21, miR-29a, miR-133a, and miR-760, or a combination, greater than the level or amount in control subjects, reference subjects, normal subjects, or a combination, indicates the absence of diastolic heart failure in the subject. 
     
     
         17 . The method of  claim 1 , wherein the one or more target microRNAs comprises miR-1, miR-133a, miR-760, or a combination, wherein a level or amount of miR-1, miR-133a, miR-760, or a combination, greater than the level or amount in control subjects, reference subjects, normal subjects, or a combination, indicates that the subject experienced ischemia-reperfusion. 
     
     
         18 . The method of  claim 1 , wherein prior to detection, the subject is suspected of having experienced ischemia-reperfusion. 
     
     
         19 . The method of  claim 1 , wherein the one or more target microRNAs are detected following myocardial infarction. 
     
     
         20 . The method of  claim 19 , wherein the one or more target microRNAs comprises miR-1, miR-21, or a combination, wherein the one or more target microRNAs are detected on or about 2 days following myocardial infarction, wherein a level or amount of miR-1, miR-21, or a combination, less than the level or amount in control subjects, reference subjects, normal subjects, or a combination, indicates a higher risk of left ventricular remodeling in the subject. 
     
     
         21 . The method of  claim 19 , wherein the one or more target microRNAs comprises miR-29a, wherein the one or more target microRNAs are detected on, about, or between 4 and 10 days following myocardial infarction, wherein a level or amount of miR-29a more than the level or amount in control subjects, reference subjects, normal subjects, or a combination, indicates a higher risk of increased left ventricular end diastolic volume developing in the subject. 
     
     
         22 . The method of  claim 21 , wherein the one or more target microRNAs are detected on, about, or between 5 and 8 days following myocardial infarction. 
     
     
         23 . The method of  claim 21 , wherein the one or more target microRNAs are detected on or about 5 days following myocardial infarction. 
     
     
         24 . The method of  claim 1 , wherein the one or more target microRNAs are detected in a tissue. 
     
     
         25 . The method of  claim 24 , wherein the tissue is cardiac tissue. 
     
     
         26 . The method of  claim 24 , wherein the tissue is thoracic aortic tissue. 
     
     
         27 . The method of  claim 1 , wherein the one or more target microRNAs are detected in a body fluid. 
     
     
         28 . The method of  claim 27 , wherein the body fluid is plasma. 
     
     
         29 . The method of  claim 1 , wherein the one or more target microRNAs are detected in a tissue sample or a body fluid sample collected from the subject. 
     
     
         30 . The method of  claim 1 , wherein detection of the one or more microRNAs is accomplished by altering the tissue or body fluid so that the microRNAs produce a signal. 
     
     
         31 . The method of  claim 1 , wherein the alteration of the tissue or body sample comprises amplifying the microRNAs. 
     
     
         32 . The method of  claim 1 , wherein the level of the one or more target microRNAs comprises the measured level of the one or more target microRNAs normalized to the measured level of a reference RNA in the tissue or body fluid. 
     
     
         33 . The method of  claim 32 , wherein the reference RNA is snRNA U6. 
     
     
         34 . The method of  claim 1 , wherein the level of the one or more target microRNAs comprises the measured level of the one or more target microRNAs expressed as the fold difference of the measured level of the one or more target microRNAs to the measured level of the one or more target microRNAs in a reference subject. 
     
     
         35 . The method of  claim 1 , wherein the level of the one or more target microRNAs comprises the measured level of the one or more target microRNAs normalized to the measured level of a reference RNA in the tissue or body fluid expressed as the fold difference of the normalized level of the one or more target microRNAs to the measured level of the one or more target microRNAs in the same tissue or body fluid of reference subject normalized to the measured level of a reference RNA in the tissue or body fluid of the reference subject. 
     
     
         36 . The method of  claim 34 , wherein the level of the one or more target microRNAs in a reference subject is measured at the same time as the level of the one or more target microRNAs is measured in the subject. 
     
     
         37 . The method of  claim 34 , wherein the level of the one or more target microRNAs in a reference subject is measured at a different time than the level of the one or more target microRNAs is measured in the subject. 
     
     
         38 . The method of  claim 34 , wherein the level of the one or more target microRNAs in a reference subject is a reference level. 
     
     
         39 . The method of  claim 1  further comprising treating the subject for thoracic aortic ancurysmTAA. 
     
     
         40 . The method of  claim 1  further comprising treating the subject for diastolic heart failure. 
     
     
         41 . The method of  claim 1  further comprising treating the subject for ischemia-reperfusion injury. 
     
     
         42 . The method of  claim 1  further comprising treating the subject for left ventricular remodeling.

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