Methods for assessing modified LDL immune complexes in subjects having or at risk of coronary artery disease
Inventors
Lopes-Virella, Maria F. • Virella, Gabriel T.
Assignees
MUSC Foundation for Research and Development • US Department of Veterans Affairs
Publication Number
US-8568995-B2
Publication Date
2013-10-29
Expiration Date
2030-09-17
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Abstract
The present invention relates to the analysis of modified LDL in the context of immune complexes. In particular, ox-LDL and AGE-LDL are shown to predict the development of coronary artery disease and other micro- and macrovascular disorders, particularly in the context of diabetes.
Core Innovation
The present invention provides methods for predicting the risk of coronary artery disease (CAD) and micro- and macrovascular complications in subjects, particularly those with type 1 diabetes, by analyzing modified low density lipoprotein-immune complexes (mod-LDL-IC) in biological samples such as serum or plasma. Specifically, the invention focuses on measuring oxidized-LDL immune complexes (ox-LDL-IC) and advanced glycation endproduct-LDL immune complexes (AGE-LDL-IC) as biomarkers to predict disease risk and assess therapeutic efficacy.
The problem addressed by the invention arises from the strong involvement of modified LDL forms in the inflammatory and immune processes underlying atherosclerosis and its complications. Although modified LDL and corresponding immune complexes have been associated with CAD, technical difficulties in measuring these complexes and antibodies in large patient cohorts have hindered reliable clinical assessment. Conventional methods used surrogate markers such as cholesterol in immune complexes, limiting predictive accuracy and temporal assessment in disease progression.
This invention overcomes such limitations by providing specific methods for isolating mod-LDL-IC from biological samples via precipitation and affinity chromatography, separating mod-LDL from antibodies, and accurately quantifying ox-LDL and AGE-LDL content using capture immunoassays, competitive immunoassays, gas chromatography, mass spectrometry, gel electrophoresis, or column chromatography. The invention thereby enables early prediction of CAD risk, micro- and macrovascular complications in T1D, and monitoring of treatment efficacy through longitudinal assessment of mod-LDL-IC levels.
Claims Coverage
The claims set forth three main inventive features related to methods of predicting coronary artery disease risk, predicting micro- and macrovascular complications risk in type 1 diabetes, and predicting treatment efficacy in type 1 diabetes complications.
Method of predicting coronary artery disease risk using mod-LDL-IC levels
A method comprising providing a mod-LDL-IC-containing serum or plasma sample from a subject; measuring ox-LDL-IC and/or AGE-LDL-IC in the sample by isolating mod-LDL-IC (e.g., precipitation), separating mod-LDL from antibodies (e.g., affinity chromatography), and determining ox-LDL and/or AGE-LDL levels (e.g., capture immunoassay, competitive immunoassay, gas chromatography, mass spectrometry, gel electrophoresis, or column chromatography); comparing these levels to a normal standard; and predicting the subject's risk of developing CAD based on elevated levels of ox-LDL-IC and/or AGE-LDL-IC.
Method of predicting micro- and macrovascular complication risk in type 1 diabetes using mod-LDL-IC levels
A method that includes providing a mod-LDL-IC-containing serum or plasma sample from a subject with or at risk of T1D, measuring ox-LDL-IC and/or AGE-LDL-IC levels by isolating, separating, and determining mod-LDL as above, comparing these levels to a normal standard, and predicting the subject's risk of developing micro- and/or macrovascular complications where elevated ox-LDL-IC and/or AGE-LDL-IC levels are observed.
Method of predicting treatment efficacy for T1D complications using sequential mod-LDL-IC measurements
A method comprising providing a first mod-LDL-IC-containing serum or plasma sample from a subject, measuring ox-LDL-IC and/or AGE-LDL-IC levels, administering treatment for a T1D complication, providing a second mod-LDL-IC-containing sample after treatment, measuring ox-LDL-IC and/or AGE-LDL-IC levels in the second sample, comparing the two measurements, and determining treatment efficacy by observing reduction in ox-LDL-IC and/or AGE-LDL-IC levels; optionally, making decisions to continue, discontinue, or provide additional treatments based on these results.
The claims collectively cover novel methods employing measurement of oxidized and advanced glycation endproduct LDL immune complexes isolated from biological samples to predict coronary artery disease risk, predict risk of diabetic vascular complications, and evaluate treatment efficacy, utilizing specific isolation and detection techniques.
Stated Advantages
High levels of oxLDL and AGE-LDL immune complexes measured early in life strongly predict accelerated progression of carotid intima-media thickness, a surrogate marker of coronary artery disease.
Measurement of mod-LDL in immune complexes provides better predictive power for cardiovascular disease risk than classical risk factors such as LDL-cholesterol, albumin excretion rate, hemoglobin A1c, and blood pressure.
The use of mod-LDL-immune complex measurements enables identification of subjects at high risk before macrovascular disease manifestation, facilitating early intervention.
Monitoring changes in mod-LDL-IC levels allows assessment of treatment efficacy in type 1 diabetes complications, potentially guiding therapeutic decisions.
Documented Applications
Prediction of coronary artery disease (CAD) risk in subjects, including those with or at risk of type 1 diabetes, type 2 diabetes, or chronic autoimmune disorders.
Prediction of risk for developing micro- and macrovascular complications in subjects with type 1 diabetes, such as cardiovascular disease, peripheral vascular disease, neuropathy, retinopathy, and nephropathy.
Assessment of efficacy of treatments for complications associated with type 1 diabetes by measuring changes in ox-LDL-IC and AGE-LDL-IC levels before and after treatment.
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