Predicting heart failure following myocardial infarction by protease and protease inhibitor profiling
Inventors
Spinale, Francis G. • Stroud, Robert E. • Zile, Michael R.
Assignees
Medical University of South Carolina MUSC • MUSC Foundation for Research and Development
Publication Number
US-8445222-B2
Publication Date
2013-05-21
Expiration Date
2027-07-11
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Abstract
Disclosed herein are methods of detecting or predicting diastolic heart failure in a subject, comprising identifying a profile of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) from a body fluid of the subject that is associated herein with the existence of likely development of left ventricular dilation (LVD).
Core Innovation
This invention provides methods of detecting or predicting diastolic heart failure in a subject by identifying a profile of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) from a body fluid of the subject, where such a profile is associated with the existence or likely development of left ventricular dilation (LVD). The key focus is on measuring specific MMPs and TIMPs—such as MMP-9, MMP-8, MMP-2, TIMP-1, TIMP-2, TIMP-4—and calculating their ratios, notably the MMP-9/TIMP-4 ratio, to diagnose or predict adverse LV remodeling after myocardial infarction.
The problem addressed is the lack of practicable methods for identifying patients at greatest risk for developing post-myocardial infarction (MI) remodeling, a critical predictor of morbidity and mortality. The patent points out that while LV remodeling is an important event after MI, current approaches do not provide reliable or timely identification of those at risk for subsequent left ventricular dilation and heart failure.
The disclosed methods involve detection and quantification of MMPs and TIMPs in bodily fluids such as blood, plasma, urine, synovial fluid, or saliva, using immunoassays or other suitable techniques. The invention also encompasses the use of ratios between MMPs and TIMPs (e.g., MMP-9/TIMP-4, MMP-9/TIMP-1, MMP-9/TIMP-2) as indicators for identifying or predicting the presence or risk of left ventricular dilation in subjects following myocardial infarction.
Claims Coverage
The patent contains multiple independent claims which set out methods for detecting or predicting left ventricular dilation in a subject following myocardial infarction based on specific biomarker measurements.
Detection of MMP-9 elevation relative to normal reference values
A method comprising detecting in a body fluid from a subject following myocardial infarction the amount of Matrix Metalloproteinase-9 (MMP-9) and identifying the subject for the presence or risk of left ventricular dilation if the detected amount of MMP-9 is greater than the normal reference value.
Detection of increased MMP-9 to TIMP-4 ratio
A method comprising identifying the subject for the presence or risk of left ventricular dilation by detecting an increase in the ratio of MMP-9 to TIMP-4 in a body fluid from the subject following myocardial infarction compared to the normal ratio calculated from normal reference values.
Detection of increased MMP-9 to TIMP-1 ratio
A method comprising identifying the subject for the presence or risk of left ventricular dilation by detecting an increase in the ratio of MMP-9 to TIMP-1 in a body fluid from the subject following myocardial infarction compared to the normal ratio calculated from normal reference values.
Detection of increased MMP-9 to TIMP-2 ratio
A method comprising identifying the subject for the presence or risk of left ventricular dilation by detecting an increase in the ratio of MMP-9 to TIMP-2 in a body fluid from the subject following myocardial infarction compared to the normal ratio calculated from normal reference values.
Detection of increased MMP-9 to TIMP-4 and MMP-8 to TIMP-4 ratios
A method comprising identifying the subject for the presence or risk of left ventricular dilation by detecting an increase in the ratio of MMP-9 to TIMP-4 and an increase in the ratio of MMP-8 to TIMP-4 in a body fluid from the subject following myocardial infarction compared to the normal ratios calculated from normal reference values.
Combinatorial increase of MMP-9, MMP-8, TIMP-1, and multiple MMP-9/TIMP ratios
A method comprising identifying the subject for the presence or risk of left ventricular dilation by detecting in a body fluid from the subject following myocardial infarction an increased amount of MMP-9, an increased amount of MMP-8, an increased amount of TIMP-1, and an increase in the ratios of MMP-9 to TIMP-4, MMP-9 to TIMP-1, and MMP-9 to TIMP-2 compared to normal ratios calculated from reference values.
The claims cover methods for detecting or predicting left ventricular dilation by measuring individual levels of MMP-9, assessing its increase relative to normal, and by measuring increases in the ratios of MMP-9 (and, in some cases, MMP-8) to TIMP-4, TIMP-1, and TIMP-2 in body fluids post-myocardial infarction.
Stated Advantages
Provides a rapid and simplified process to identify patients at risk for developing adverse LV remodeling post-MI or in which this process is occurring at an accelerated pace.
Enables both diagnostic and prognostic information regarding the underlying myocardial remodeling process after MI by plasma profiling of specific proteolytic enzymes.
Allows for use in diagnosis, prognosis, and guiding therapeutic interventions by monitoring MMP and TIMP profiles and ratios.
Enables the use of reliable biomarkers for assessing the degree of myocardial remodeling and informing adjustments in medical therapy post-MI.
Documented Applications
Detection and prediction of diastolic heart failure and left ventricular dilation in subjects after myocardial infarction.
Diagnostic stratification of post-MI patients to identify those at greatest risk for adverse LV remodeling and heart failure progression.
Guiding clinical management, including monitoring and adjusting pharmacological therapies, by serial measurement of MMP and TIMP profiles following myocardial infarction.
Differential diagnosis of heart failure etiology, distinguishing between systolic (post-MI) and diastolic (hypertensive heart disease) heart failure based on specific MMP/TIMP profiles.
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