| Markers associated with arteriovascular events and methods of use thereof -> Monitor Keywords |
|
|
  Markers associated with arteriovascular events and methods of use thereofUSPTO Application #: 20080057590Title: Markers associated with arteriovascular events and methods of use thereof Abstract: Disclosed are methods of identifying subjects with arteriovascular disease, subjects at risk for developing arteriovascular disease, methods of differentially diagnosing diseases associated with arteriovascular disease from other diseases or within sub-classifications of arteriovascular disease, methods of evaluating the risk of arteriovascular events in patients with arteriovascular disease, methods of evaluating the effectiveness of treatments in subjects with arteriovascular disease, and methods of selecting therapies for treating arteriovascular disease. (end of abstract)
Agent: Mintz Levin Cohn Ferris Glovsky & Popeo - New York, NY, US Inventors: Mickey Urdea, Michael McKenna, Patrick Arensdorf USPTO Applicaton #: 20080057590 - Class: 436071000 (USPTO) Related Patent Categories: Chemistry: Analytical And Immunological Testing, Lipids, Triglycerides, Cholesterol, Or Lipoproteins The Patent Description & Claims data below is from USPTO Patent Application 20080057590. Brief Patent Description - Full Patent Description - Patent Application Claims
INCORPORATION BY REFERENCE [0001] This application claims priority from U.S. Provisional Application Ser. No. 60/811,996, filed on Jun. 7, 2006. Each of the applications and patents cited in this text, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent; "application cited documents"), and each of the U.S. and foreign applications or patents corresponding to and/or claiming priority from any of these applications and patents, and each of the documents cited or referenced in each of the application cited documents, are hereby expressly incorporated herein by reference. More generally, documents or references are cited in this text, either in a Reference List before the claims, or in the text itself; and, each of these documents or references ("herein-cited references"), as well as each document or reference cited in each of the herein-cited references (including any manufacturer's specifications, instructions, etc.), is hereby expressly incorporated herein by reference. Documents incorporated by reference into this text may be employed in the practice of the invention. FIELD OF THE INVENTION [0002] The present invention relates generally to the identification of biological markers associated with arteriovascular events and methods of using such biological markers in screening, prevention, diagnosis, therapy, monitoring, and prognosis of arteriovascular disease. BACKGROUND OF THE INVENTION [0003] Arteriovascular disease continues to be a leading cause of morbidity and mortality among adults in Europe and North America. Although age-adjusted death rates have declined over the past two decades, the absolute mortality rate from arteriovascular disease has not. Arteriovascular disease accounts for over one-half million deaths (1 out of every 5) in the U.S. yearly. The lifetime risk of arteriovascular disease after age 40 has been estimated at 49% for men and 32% for women. Even for those who survive to age 70 years, the lifetime risk for arteriovascular disease has been estimated at 35% for men and 24% for women. Arteriovascular diseases include atherosclerosis and atherothrombosis, coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease (CVD). [0004] Risk factors for arteriovascular disease currently account for a large proportion of the burden of heart disease in the United States, suggesting that risk-factor identification and risk-lowering treatments could postpone or prevent the majority of ateriovascular events. Identified risk factors for arteriovascular disease include independent risk factors, such as cigarette smoking, elevated blood pressure (hypertension), elevated serum total cholesterol (CHOL) and low-density lipoprotein (LDL) cholesterol, low serum high-density lipoprotein (HDL) cholesterol, diabetes mellitus, and advancing age. Conditional risk factors for arteriovascular disease include elevated serum triglycerides (TRIG), small LDL particles, elevated serum homocysteine levels, elevated serum lipoprotein (a) (LPA), prothrombotic factors such as fibrinogen (FGA), and inflammatory markers like C-reactive protein (CRP), whose contribution to risk may vary upon their relationship to other identified risk factors. Other risk factors include obesity (measured by weight (WT), height (HT), Body Mass Index (BMI), and abdominal girth comparisons such as waist ("Waist") or hip ("Hip") circumference, ankle-brachial index, physical inactivity, family history of arteriovascular disease, ethnicity, and psychosocial factors. Arteriovascular disease risk factors have been the subject of many studies, including those presented in Pasternak, R. C. et al (2003) JACC 41(11): 1855-1917 and Grundy, S. M. (1999) Circulation 100: 988-998. [0005] Typically, a patient suspected of having arteriovascular disease is assessed on several of the "traditional" or "conventional" risk factors: age, sex, total cholesterol concentration, HDL and LDL cholesterol concentration, smoking status, diabetic status, and blood pressure (systolic and diastolic), as well as many of the above conditional risk factors, such as LPA, FGA, CRP, and homocysteine, amongst others. These risk factors have been incorporated into useful predictive models of future arteriovascular events, such as the Framingham Risk Score presented in Wilson, P. W., et al (1998) Circulation 97: 1837-1847, however this "evidence-based" multiple risk factor or "global risk assessment" approach is only moderately accurate for predicting short- and long-term risk of manifesting a major arteriovascular event, particularly an event such as acute coronary syndromes (ACS, comprising myocardial infarction and unstable angina), stroke or sudden death, in healthy populations or asymptomatic individuals. In particular, while such approaches may, at typical clinical measurement cut-off levels, be relatively sensitive to individuals who have multiple risk factors, experienced past arteriovascular events or who have already confirmed arteriovascular disease (who would be "true positives" if they subsequently experience an acute arteriovascular event), they suffer from specificity, also identifying large portions of the population who do not subsequently experience acute arteriovascular events ("false positives"). In the typical adult population, these algorithms yield many more false positives than true positives, particularly in the low (<6% ten year risk of an acute event) and intermediate risk (6-20% ten year risk of an acute event) populations that make up the majority of those tested. While performance metrics for global risk assessment indices may evidence high clinical utility in the population in which the index algorithm was trained, occasionally exhibiting an AUC as high as 0.8, but more commonly an AUC around 0.7 (Wilson et al. above reported 0.74 for men and 0.77 for females for the Framingham Risk Score), such predictive models show relatively low transferability between populations, which may differ based on genetic and other factors, and absent substantial recalibration and re-optimization, often the AUC will drop to below 0.65, as shown in the example. They also are often difficult for clinicians to effectively implement and perform within an active clinical environment, involving complex calculations and numerical manipulations. [0006] Thus, the general concept of applying one or more biomarkers to the task of classifying current and predicting future arteriovascular disease or risk of future arteriovascular events is not new in the clinical practice, literature or patent art. Several specific biomarkers, biomarker combinations, and methods have been proposed over time, with limited adoption to date due to several issues including technical difficulty, analytical performance, clinical performance, reliability, and practical clinician application of complex algorithms combining more than one such biomarker. By way of example, Ridker, P. et al. in U.S. Pat. No. 6,040,147 dated Mar. 21, 2000, suggested the use of a marker of systemic inflammation (including the use of CRP, a cytokine or a cellular adhesion marker such as soluble ICAM-1) could be useful in assessing the risk profile of an apparently healthy individuals risk profile for developing a future myocardial infarction, either alone or in combination with traditional risk factors such as CHOL or HDLC; such use of CRP has now become routine. Schonbeck, U. et al., in U.S. Pat. No. 7,189,518 B2 dated Mar. 13, 2007, suggested similar usage for soluble CD40 ligand (CD40LG) in predicting future cardiovascular disorders, such as myocardial infarction or stroke, in apparently healthy individuals; this has not been clinically adopted due to inadequate performance as a single marker. Anderson, L. (2004) in J. Physiological Society 563.1: 23-60, suggested 177 individual candidate biomarker proteins with reported associations to cardiovascular disease and stroke that might be of use in constructing panels of disease-related proteins for several applications, including the anticipation of future myocardial infarction or stroke, if it were found that several of the biomarkers were independent and not strongly correlated with each other, and thus able to be combined together into panels and "composite indices" more useful than the information gathered from the single biomarkers used individually; beyond referencing the previously mentioned relationships with CRP and cholesterol, no such useful individual panel involving was disclosed by Anderson, and several technical barriers and shortcomings of existing multi-marker analytical techniques in future discovery of such multi-marker associations were mentioned. Puskas, R. et al., in US Patent Publication 2006/0078998 A1 published Apr. 13, 2006, disclosed an technical technique useful for such single or multiplexed biomarker single molecule counting in samples, and mentions a wide analytical range of potential biomarkers and functional biomarker groupings potentially useful in multiple diseases, including cardiovascular disease; no specific combination of biomarkers for predicting the future risk of arteriovascular events was mentioned, nor were all of the individual biomarkers of the current invention disclosed therein. [0007] Tabibiazar, R. et al., in US Patent Publication 2007/0070099239 A1 published May 3, 2007, disclosed the use of several specific panels of biomarkers combined with various algorithms and analytical processes, in the discrimination and classification of atherosclerotic patients with past acute myocardial infarction from such patients with known stable cardiovascular disease, from those with no history of cardiovascular disease or atherosclerosis, or amongst various classification of atherosclerotic staging and current medication use within known atherosclerotic patients. Although various "predictive" algorithms are mentioned therein, and the suggestion made that certain of such disclosed biomarker panels may be useful in the prediction of future cardiovascular events, no specific panel for prediction of future cardiovascular events or future cardiovascular status tested within an asymptomatic and previously undiagnosed population is disclosed. Nor is such clearly claimed in the application as filed, nor are any examples given within the published patent of study designs involving the measurement of apparently healthy and asymptomatic individuals prior to known cardiovascular events (or confirmed symptoms and/or diagnosed atherosclerosis) and then subsequently following their health status for a sufficient longitudinal time period allowing the development of subsequent cardiovascular events. Although certain of the individual panels of biomarkers disclosed therein may be useful in such applications, it is unlikely that the panels, algorithms and analytical processes disclosed therein, selected and trained on past events and known symptomatic disease, will successfully predict the future risk of cardiovascular events in asymptomatic and previously undiagnosed subjects with as high a degree of diagnostic accuracy as is presented and claimed in Tabibiazar over a specific multi-year time horizon, absent substantial and predictive model re-training, re-modeling, optimization and re-purposing likely not possible absent inputs from such longitudinal studies, which may include changes to cutoffs, reference values and other formula. Although overlap of certain individual biomarkers disclosed in Tabibiazar with individual biomarkers and a subset of the panels of the current invention is acknowledged, each of the individual biomarkers mentioned in Tabibiazar which are also claimed herein in specific panel combinations of the current invention (and specifically CCL2, IGF1, LEP, VEGF, and IL8) were also previously disclosed in the prior published art as associated with cardiovascular disease (each of them were notably mentioned and reviewed in the aforementioned Anderson reference, amongst others). Such specific clinical applications, additional biomarkers, specific biomarker combination panels, study designs, and analytical techniques and formula are key aspects of the current invention. [0008] Recently, several studies in the scientific literature have been published examining various individual and multiple biomarker strategies, most notably Folsom, A. R. et al. (2006) Arch. Intern Med 166:1368-1373 and Wang, T. J. et al. (2006) N Eng J Med 355: 2631-2639. These studies, utilizing retrospective samples from longitudinal clinical studies such as the Atherosclerosis Risk in Communities Study and the Framingham Heart Study, combined subject clinical parameters and traditional laboratory risk factors (including using such traditional laboratory based biomarkers such as CHOL, CRP, FGA, HDLC, LPA, and Homocysteine), as well as novel markers such as Albumin-to-creatine ratios, Aldosterone, ANP (NPPA), BNP (NPPB), D-dimer, ICAM1, IL6, LEP, MMP1, PLA2G7, PLAT, PLG, REN, SELE, SERPINE1, TIMP1, THBD, amongst others, both as individual markers and incrementally as additions to multi-marker indices. Both studies found little improvement in the ability to predict future arteriovascular events with novel markers over the models incorporating the basic clinical parameters and traditional laboratory risk factors. As a result, the use of such novel markers remains clinically controversial. [0009] Given the foregoing, it is clear that an important discrepancy has arisen in understanding the role of the aforementioned risk factors and biomarkers compared to the development of arteriovascular disease events. In contrast to the relative ease of recognition and clarity of treatment and prevention strategies in patients with symptomatic arteriovascular disease (i.e., exhibit symptoms such as active chest pain, claudication, transient ischemic attacks (TIAs) or mild cognitive impairment (MCI), a major problem of detection, treatment, and prevention of arteriovascular disease exists in the large, apparently healthy, population who have no symptoms, yet are at an increased risk to develop arteriovascular disease or experience major arteriovascular events. A large number of victims of the disease who are apparently healthy die or have initial acute arteriovascular events suddenly without prior symptoms. Despite the many available risk assessment approaches, a substantial gap remains in the detection of asymptomatic individuals who ultimately develop arteriovascular disease. Currently available screening and diagnostic methods are insufficient to identify asymptomatic individuals before such acute events associated with arteriovascular disease occur. Of those who experience a major arteriovascular event as many as 20% have none of the traditional risk factors. There remains an unmet need in the art to directly diagnose and predict the risk of arteriovascular disease and events, particularly in those individuals who do not exhibit symptoms or few or none of the traditional risk factors currently measured by physicians. [0010] All of the foregoing references, including Tabibiazar, are herein referred to and incorporated in their entirety. SUMMARY OF THE INVENTION [0011] The present invention relates in part to the discovery that certain biological markers, such as proteins, nucleic acids, polymorphisms, metabolites, and other analytes, as well as certain physiological conditions and states, are present in subjects with an increased risk of arteriovascular events, such as, but not limited to, acute coronary syndromes such as myocardial infarction and unstable angina, as well as other acute events associated with an arteriovascular disease, including those associated with atherosclerosis, atherothrombosis, coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease (CVD), but where such subjects do not exhibit some or all of the traditional risk factors of these diseases, or subjects who are asymptomatic for these diseases. [0012] Accordingly, the invention provides biological markers of arteriovascular events that, when used together in combinations of three or more such biomarker combinations, or "panels," can be used to assess the risk of subjects experiencing said arteriovascular events, to diagnose or identify subjects with an arteriovascular disease, to monitor the risk factors for development of an arteriovascular disease, to monitor subjects that are undergoing therapies for an arteriovascular disease, to differentially diagnose disease states associated with an arteriovascular disease from other diseases or within sub-classifications of arteriovascular diseases, to evaluate changes in the risk of arteriovascular events in subjects with an arteriovascular disease, and to select or modify therapies or interventions for use in treating subjects with an arteriovascular disease, or for use in subjects who are at risk for developing an arteriovascular disease. [0013] An aspect of the present invention provides use of a panel of biological markers, some of which are unrelated to arteriovascular disease or have not heretofore been identified as related to the risk of future arteriovascular disease or events, but are related to early biological changes that can lead to the development of arteriovascular disease or arteriovascular events, to detect and identify subjects who exhibit none of the symptoms or few or none of the traditional risk factors for arteriovascular disease, i.e., who are asymptomatic for arteriovascular disease and have only non-specific indicators of potential arteriovascular events, such as arteriovascular risk factors, or who exhibit none or few of the traditional risk factors of arteriovascular disease, yet remain at risk. [0014] Significantly, many of the individual biomarkers disclosed herein have shown little individual significance in the diagnosis of arteriovascular disease, or individually for assessing the risk of arteriovascular disease or events, but when used in combination with other disclosed biomarkers and combined with the various herein disclosed algorithms, traditional laboratory risk factors of arteriovascular disease, and other clinical parameters of arteriovascular disease, become significant discriminates of a subject having arteriovascular disease or a subject who is at risk for developing an arteriovascular event, from one who is not at risk for arteriovascular disease or is not at significant risk of developing arteriovascular disease or an arteriovascular event. The methods of the present invention provide an improvement over currently available methods of risk evaluation of the development of arteriovascular disease and/or arteriovascular events in a subject by measurement of the biomarkers defined herein. [0015] Accordingly, in certain embodiments an aspect of the invention is directed to a method for assessing a risk of developing an arteriovascular disease in a subject. In certain embodiments, the method allows for assessing risk with a predetermined level of predictability. In certain embodiments, the method includes, measuring a level of an effective amount of two or more ARTERIORISKMARKERS. For instance, the ARTERIORISKMARKERS may include one or more of the ARTERIORISKMARKERS 1-1023, which markers are in a sample obtained from the subject. In certain embodiments, the level of expression of five or more, ten-or more, twenty-five or more, or fifty or more ARTERIORISKMARKERS are measured. The method may further include measuring a clinically significant alteration in the level of the two or more ARTERIORISKMARKERS in the sample, for instance, where the alteration indicates an increased risk of developing an arteriovascular disease in the subject. [0016] In certain embodiments, an aspect of the subject invention is directed to a method of diagnosing or identifying a subject having an arteriovascular disease. In certain embodiments, the method allows for assessing risk with a predetermined level of predictability. In certain embodiments, the method includes measuring the level of an effective amount of two or more ARTERIORISKMARKERS that are selected from ARTERIORISKMARKERS 1-1023 in a sample from the subject. The method may further include comparing the level of the effective amount of the two or more ARTERIORISKMARKERS to a reference value. The reference value may be an index value or may be may be derived from one or more risk prediction algorithms or computed indices for the arteriovascular disease. [0017] In certain embodiments, an aspect of the subject invention is directed to a method for assessing the progression of an arteriovascular disease in a subject. In certain embodiments, the method allows for assessing the progression of an arteriovascular disease in a subject with a predetermined level of predictability. In certain embodiments, the method includes detecting the level of an effective amount of two or more ARTERIORISKMARKERS selected from ARTERIORISKMARKERS 1-1023 in a first sample from the subject at a first period of time, detecting the level of an effective amount of two or more ARTERIORISKMARKERS in a second sample from the subject at a second period of time, and comparing the level of the effective amount of the two or more ARTERIORISKMARKERS detected in the first step to the amount detected in second step, or to a reference value. In certain embodiments, the first sample is taken from the subject prior to being treated for the arteriovascular disease and/or the second sample is taken from the subject after being treated for the arteriovascular disease. Further, in certain embodiments, the reference value is derived from one or more subjects who have suffered from an arteriovascular event. [0018] In certain embodiments, an aspect of the subject invention is directed to a method for monitoring the effectiveness of treatment for an arteriovascular disease. In certain embodiments, the method allows for monitoring the effectiveness of treatment for an arteriovascular disease in a subject with a predetermined level of predictability. In certain embodiments, the method includes detecting the level of an effective amount of two or more ARTERIORISKMARKERS selected from ARTERIORISKMARKERS 1-1023 in a first sample from a subject at a first period of time; detecting the level of an effective amount of two or more ARTERIORISKMARKERS in a second sample from the subject at a second period of time; and comparing the level of the effective amount of the two or more ARTERIORISKMARKERS detected in the first step to the amount detected in the second step, or to a reference value, wherein the effectiveness of treatment is monitored by a change in the level of the effective amount of two or more ARTERIORISKMARKERS from the subject. In certain embodiments, the treatment for the arteriovascular disease to be monitored includes exercise regimens, dietary supplements, therapeutic agents, surgical intervention, and prophylactic agents. In certain embodiments, the effectiveness of treatment is additionally monitored by detecting changes in body mass index (BMI), total cholesterol levels, LDL levels, HDL levels, systolic and/or diastolic blood pressure, or combinations thereof. Further, the reference value is derived from one or more subjects who show an improvement in arteriovascular risk factors as a result of one or more treatments for arteriovascular disease. [0019] In certain embodiments, an aspect of the subject invention is directed to a method for selecting a treatment regimen for a subject diagnosed with or at risk for an arteriovascular disease. In certain embodiments, the method allows for selecting a treatment regimen for a subject diagnosed with or at risk for an arteriovascular disease with a predetermined level of predictability. In certain embodiments, the method includes detecting the level of an effective amount of two or more ARTERIORISKMARKERS selected from ARTERIORISKMARKERS 1-1023 in a first sample from the subject at a first period of time, optionally detecting the level of an effective amount of two or more ARTERIORISKMARKERS in a second sample from the subject at a second period of time and comparing the level of the effective amount of the two or more ARTERIORISKMARKERS detected in the first step to a reference value, or optionally to an amount detected in the second step. In certain embodiments, the reference value is derived from one or more subjects who show an improvement in arteriovascular disease risk factors as a result of one or more treatments for the arteriovascular disease. For instance, the improvement may be monitored by an imaging modality, by detecting a reduction in body mass index (BMI), a reduction in total cholesterol levels, a reduction in LDL levels, an increase in HDL levels, a reduction in systolic and/or diastolic blood pressure, or combinations thereof. In certain embodiments, the imaging modality may include one or more of: computed tomography (CT), optical coherence tomography (OCT), intravascular ultrasonography (IVUS), high-resolution IVUS, elastography (palpography), angioscopy, electron beam computed tomography (EBCT), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), immunoscintigraphy, and invasive angiography. [0020] In certain embodiments, an aspect of the subject invention is directed to a method for treating one or more subjects at risk for developing an arteriovascular disease. In certain embodiments, the method includes, detecting the presence of increased levels of at least two different ARTERIORISKMARKERS that are present in a sample from the one or more subjects; and treating the one or more subjects. For instance, the one or more subjects may be treated with one or more arteriovascular disease-modulating drugs until altered levels of the at least two different ARTERIORISKMARKERS return to a baseline value measured in one or more subjects at low risk for developing the arteriovascular disease, or a baseline value measured in one or more subjects who show improvements in arteriovascular risk markers as a result of treatment with one or more arteriovascular disease-modulating drugs. In certain embodiments, the arteriovascular disease-modulating drug comprises .beta.-blockers, angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium channel blockers, angiotensin II receptor blockers, antiplatelet agents, anti-coagulant agents, sulfonylureas, biguanides, insulin, thiazolidinediones, nitrates, non-steroidal anti-inflammatory agents, statins, cilostazol, pentoxifylline, buflomedil, naftidrofuryl, and combinations thereof. Additionally, the improvements in arteriovascular risk markers may be as a result of treatment with the one or more arteriovascular disease-modulating drugs and may include a reduction in body mass index (BMI), a reduction in total cholesterol levels, a reduction in LDL levels, an increase in HDL levels, a reduction in systolic and/or diastolic blood pressure, or combinations thereof. Continue reading... Full patent description for Markers associated with arteriovascular events and methods of use thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Markers associated with arteriovascular events and methods of use thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Markers associated with arteriovascular events and methods of use thereof or other areas of interest. ### Previous Patent Application: Method for determining the presence of a chemical compound which is homogeneously distributed in a medium by means of cross-correlating a measuring spectrum with reference spectra Next Patent Application: Metal indicator Industry Class: Chemistry: analytical and immunological testing ### FreshPatents.com Support Thank you for viewing the Markers associated with arteriovascular events and methods of use thereof patent info. IP-related news and info Results in 0.8424 seconds Other interesting Feshpatents.com categories: Computers: Graphics , I/O , Processors , Dyn. Storage , Static Storage , Printers |
||
