Soluble CD40L (CD 154) as a prognostic marker of atherosclerotic diseases

Abstract

This invention involves the new use of a diagnostic test to determine the risk of atherosclerotic diseases such as myocardial infarction and stroke, particularly among individuals with no signs or symptoms of current disease and among nonsmokers. Further, this invention involves the new use of a diagnostic test to assist physicians in determining which individuals at risk will preferentially benefit from certain treatments designed either to prevent first or recurrent myocardial infarctions and strokes, or to treat acute and chronic cardiovascular disorders. Methods for treatment are also described.

Description

RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. §119(e) from U.S. Provisional Application Ser. No. 60 / 338,841, filed Nov. 5, 2001, and entitled: SOLUBLE CD40L(CD154) AS A PROGNOSTIC MARKER OF ATHEROSCLEROTIC DISEASES incorporated herein in its entirety by reference.GOVERNMENT SUPPORT [0002] The work leading to the present invention was funded in part by grant numbers HL-34636, HL-56985, HL-58755, HL-63293 from the National Heart, Lung and Blood Institute. Accordingly, the United States Government may have certain rights to this invention.FIELD OF THE INVENTION [0003] This invention describes the new use of a diagnostic test to determine the risk of cardiovascular disorders, such as myocardial infarction and stroke, particularly among individuals with no signs or symptoms of current disease and among nonsmokers. Further, this invention describes the new use of a diagnostic test to assist physicians in determining which individuals at risk will preferentia...

AI Technical Summary

Benefits of technology

[0027] In another aspect of the invention, a method for treating a subject to reduce the risk of a cardiovascular disorder, is provided. The method involves selecting and administering to a subject who is known to have an above-normal level of sCD40L an agent for reducing the risk of the cardiovascular disorder. The agent can be an anti-inflammatory agent (including aspirin and nonaspirin anti-inflammatory agents), an antithrombotic agent, an anti-platelet agent, a fibrinolytic agent, a lipid reducing agent, a direct thrombin inhibitor, a glycoprotein IIb / IIIa receptor inhibitor, an agent that binds to cellular adhesion molecules and inhibits the ability of white blood cells to attach to such molecules, a calcium channel blocker, a beta-adrenergic receptor blocker, a cyclooxygenase-2 inhibitor, an angiotensin system inhibitor, and / or combinations thereof. The agent is administered in an amount effective to lower the risk of the subject developing a future cardiovascular disorder. The preferred subjects are apparently healthy subjects otherwise free of current need for treatment with any one or combination of the foregoing agents. In further important embodiments, the subject treated is a nonhyperlipidemic subject. In another embodiment, the subjects are not at an elevated risk of an adverse cardiovascular event (e.g., subjects with no family history of such events, subjects who are nonsmokers, subjects who are nonhyperlipidemic subjects with normal levels of systemic inflammatory markers), other than having an elevated level of sCD40L.

[0029] The invention also involves a method for treating subjects with a lipid reducing agent, to prevent cardiovascular disorders. Such an agent is administered to a subject selected on the basis of having an above-normal level of sCD40L. The agent is administered in an amount effective to lower the risk of the subject developing a future cardiovascular disorder. In one embodiment, the subject already has had a cardiovascular event, such as a heart attack or an angioplasty. In this embodiment, the lipid reducing agent can limit further injury or help prevent restenosis, post-myocardial infarction or post-angioplasty injury. In another important embodiment, the subjects are apparently healthy subjects otherwise free of current need for lipid reducing agent treatment. In important embodiments, the subjects are not an elevated risk of an adverse cardiovascular event, other than having elevated levels of sCD40L. In further important embodiments, the subject treated is a nonhyperlipidemic subject. In any of the foregoing embodiments, the lipid reducing agent may be, but is not limited to, gemfibrozil, cholystyramine, colestipol, nicotinic acid, probucol lovastatin, fluvastatin, simvastatin, atorvastatin, pravastatin, or cerivastatin. In preferred embodiments, the lipid reducing agent is pravastatin.

[0030] The invention also involves a method for treating subjects with an agent that binds to a cellular adhesion molecule and that inhibits the ability of white blood cells to attach to such molecules, to prevent cardiovascular disorders. Such an agent is administered to a subject selected on the basis of having an above-normal level of sCD40L. The agent is administered in an amount effective to lower the risk of the subject developing a future cardiovascular disorder. In one embodiment, the subject already has had a cardiovascular event, such as a heart attack or an angioplasty. In this embodiment, the agent that binds to a cellular adhesion molecule and that inhibits the ability of white blood cells to attach to such molecules, may limit further injury or help prevent restenosis, post-myocardial infarction or post-angioplasty injury. In another important embodiment, the subjects are apparently healthy subjects otherwise free of current need for treatment with an agent that binds to a cellular adhesion molecule and that inhibits the ability of white blood cells to attach to such molecules. In important embodiments the subjects are not an elevated risk of an adverse cardiovascular event, other than having elevated levels of sCD40L. In further important embodiments, the subject treated is a nonhyperlipidemic subject.

[0038] According to another aspect of the invention, a method for reducing sCD40L levels in a subject to lower the risk of an adverse cardiovascular disorder is provided. The method involves selecting and administering to a subject having elevated levels of sCD40L an agent that reduces sCD40L levels in an amount effective to reduce the sCD40L levels in the subject. In one embodiment, the agent is a lipid reducing agent. The preferred subject is an apparently healthy subject. In some embodiments, the subject is not otherwise at an elevated risk of having an adverse cardiovascular event. In certain embodiments, the subject has elevated C-Reactive Protein (CRP) levels. In some embodiments of this aspect of the invention, the subject is otherwise free of indications calling for treatment with a lipid reducing agent.

Problems solved by technology

For example, elevated levels of sCD40L in apparently healthy, nonsmokers are predictive of an increased risk of myocardial infarction.

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