METHOD OF USING PHYSIOLOGICAL
MARKERS TO ESTIMATE
RELATIONSHIP TO OTHER APPLICATIONS 5
This application claims the benefit of U.S. Provisional Application Ser. No. 60/331,189, filed Nov. 09, 2001, and of U.S. Provisional Application Ser. No. 60/340,857, filed Dec. 19, 2001, and of U.S. Provisional Application Ser. No. 10 60/394,245, filed Jul. 09, 2002. The entire disclosure of each of the above-identified U.S. Provisional Patent Applications is incorporated herein by reference.
BACKGROUND OF THE INVENTION 15
1. Field of the Invention
This invention relates to diagnostic tests for characterizing an individual's risk developing a disease and more particularly to tests for determining risk of developing atheroscle- 20 rotic diseases such as myocardial infarction, angina pectoris, stroke, and peripheral vascular disease.
2. Brief Description of the Prior Art
Almost 60 million Americans have one or another form of
cardiovascular disease. Approximately 7 million Americans are alive having survived a heart attack, with over one million additional Americans expected to experience heart attacks each year. Over 6 million Americans have chest pain (angina pectoris) caused by coronary heart disease, and nearly 5 mil- ^ lion have congestive heart failure. Approximately 2.5 million patients undergo angioplasty or bypass surgery procedures each year. Thus, cardiovascular disease is highly prevalent in the United States, as well as in all other industrialized nations and, despite new and improved therapies, in these countries 35 this group of disease continues to be the single most frequent cause of morbidity and mortality. As a result, identification of individuals at risk of developing cardiovascular disease is a critical strategy to more effectively prevent and/or treatment these diseases.
Several risk factors predicting cardiovascular events which can be measured from blood samples are now being used clinically, such as those relating to LDL and HDL cholesterol levels. However, many patients with arteriosclerosis do not exhibit such risk factors. Moreover, moreover, cardiovascular events occur even in many individuals who do not demonstrate such risk factors and thus are considered to be at low risk of experiencing a cardiovascular event.
Accordingly, a need has continued to exist for methods of detecting risk of a patient developing cardiovascular disease. 50
SUMMARY OF THE INVENTION
This need has now been met by the method of this invention wherein an individual's risk profile of developing a future 55 cardiovascular disorder is determined by 1) measuring levels of certain stress-evoked proteins, including heat shock proteins (HSPs), cytokines, adhesion molecules, chemokines, and the like, or titers of the antibodies targeted to them, or 2) determining the number of seropositive responses to a group 60 of pathogens that have been associated with the presence of atherosclerosis and/or clinical events related to atherosclerosis. These new tests help predict, for example, the risk of an individual developing atherosclerosic diseases such as myocardial infarction, angina pectoris, stroke, and peripheral vas- 65 cular disease (including claudication and gangrene). The basis of these new tests derive from the critical importance of
HSPs in cellular function, and the significant role which infection plays in contributing to the onset of atherosclerosis.
Consequently this invention comprises a method for characterizing an individual's risk profile of developing a future myocardial infarction, or of developing angina, or of developing claudication or gangrene, comprising obtaining a level of a marker (which could be a molecule or antibody targeted to a molecule) that conveys information as to the susceptibility or resistance to the development of atherosclerosis, comparing the level of the marker to a predetermined value, and characterizing the individual's risk profile of developing a cardiovascular condition such as myocardial infarction, or angina, or stroke, or claudication or gangrene, based upon the level of the marker in comparison to the predetermined value. The marker chosen is one that normally plays an important protective role in the responses to stress of cells of the individual, but one which could also serve as an antigen triggering autoimmune responses that could exacerbate the atherosclerosis process.
Accordingly, it is an object of the invention to provide a method for characterizing the risk profile of an individual for developing cardiovascular disease.
A further object it to provide a method for characterizing the risk profile of an individual for experiencing a clinical symptom of cardiovascular disease.
A further object is to provide a method for characterizing the risk profile of an individual as a means of predicting the possibility of a cardiovascular condition such as myocardial infarction, or angina, or stroke, or claudication or gangrene.
Further objects of the invention will be apparent from the description of the invention which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the relation between CAD prevalence and serum levels of HSP70.
FIG. 2 is a graph showing the odds ratio for CAD versus heat shock protein (HSP) 60 antibody titers.
FIG. 3 is a graph showing the relation between serum levels of HSP70 and antibodies to HSP60 with respect to CAD prevalence.
FIG. 4 is a graph showing the association between numbers of pathogens to which individuals were exposed and mean levels of CRP (mg/dl with SE).
FIG. 5 is a graph showing the MI of death-free survival curves according to pathogen burden.
FIG. 6 is a graph showing the effect of pathogen burden on endothelial dysfunction.
FIG. 7 is a graph showing the prevalence of CAD among subgroups with variation in inflammation and CMV infection.
DETAILED DESCRIPTION OF THE INVENTION
AND PREFERRED EMBODIMENTS
This invention is based on the discovery that certain substances found in the blood of an individual can serve as markers for demonstrating a potential for development of cardiovascular disease, e.g., athersclerosis, and clinical manifestations thereof, such as myocardial infarction, angina, stroke, or peripheral vascular conditions due to diminished blood supply, such as claudication or gangrene.
These markers, and their concentration, can be detected in the plasma of individuals using conventional modern analytical methods. Consequently, correlations can be established by conventional clinical studies between the plasma levels of these markers and the prevalence of various cardiovascular