Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals
Reexamination Certificate
2000-01-21
2003-03-18
Chin, Christopher L. (Department: 1641)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
C435S007100, C435S007920, C435S810000, C435S967000, C435S975000, C436S071000, C436S063000, C436S536000, C436S541000, C436S161000, C436S162000, C436S173000, C436S808000, C530S412000, C530S413000, C530S417000
Reexamination Certificate
active
06534322
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the area of diagnosis of heart disease, and specifically relates to methods of diagnosis of heart failure, cardiac ischemia, or hypoxia by detecting the level, e.g., concentration, of a non-polypeptidic cardiac marker as an indicator of heart damage, particularly chronic underlying coronary artery disease, and for monitoring of therapeutic regimes designed to alleviate cardiac ischemia or hypoxia.
BACKGROUND OF THE INVENTION
Ischemic heart disease is the major form of heart failure. Heart failure affects millions of people worldwide and is the leading cause of death in the United States. The most common manifestation of cardiac ischemia is chest pain (angina pectoris) which can lead to heart attack (acute myocardial infarction or AMI) and sudden death. In addition to those who exhibit clinical symptoms of ischemic heart disease, many other individuals are at high risk of developing heart disease based on indicators such as hypertension conditions, high levels of serum cholesterol and/or family history.
Myocardial ischemic disorders occur when cardiac blood flow is restricted (ischemia) and/or when the oxygen supply to heart muscle is compromised (hypoxia) such that the heart's demand for oxygen is not met. Atherosclerosis of the coronary artery is the most common cause of ischemia-associated symptoms such as angina pectoris. Ischemia and hypoxia can be transient and reversible, but can also lead to infarction. During infarction, cardiac tissue is damaged and the heart cells become permeabilized, releasing a portion of their contents to the surrounding milieu, including cardiac enzymes and other biochemical markers. These cellular markers, such as creatine kinase (CK), lactic acid dehydrogenase (LDH) enzymatic activities and creatine kinase-MB (CKMB) and troponin (I and T) and myoglobin mass levels, are then detectable in the serum.
Current diagnostic procedures generally assess the extent of cardiac tissue damage after clinical signs have appeared. At that point, however, the disease may have progressed to an extent where AMI is imminent or has already occurred. Current methods of identifying and confirming infarction require more time than is often available in emergency situations where rapid evaluation is critical for effective patient treatment and survival. Moreover, about 25% of AMI patients display atypical symptoms and many known tests result in false negatives, resulting in the unintentional discharge of about 5% of patients who have AMI (Mair J. et al.,
Clin. Chem.
41:1266-1272, 1995; Newby L. K. et al.,
Clin. Chem.
41:1263-1265, 1995). In an emergency medical facility, electrocardiography (ECG) monitoring of suspected AMI patients is the most rapid diagnostic method for detecting AMI, although it successfully detects only about half of AMI patients (Mair et al., 1995).
Electrocardiography and currently available diagnostic blood tests are generally not effective for early detection of myocardial ischemia that precedes the damage associated with AMI because the tests detect infarction-associated tissue damage. They are not effective in early detection of chronic underlying coronary artery disease and the resulting myocardial ischemia that precedes the damage associated with AMI. Currently, the only diagnostic for chronic underlying coronary artery disease is ECG monitoring during exercise stress (e.g., treadmill exercise) is generally used to confirm the clinical symptoms of angina. Such stress testing is usually given after the patient has experienced symptoms and sought treatment (e.g., at an emergency medical facility). Although stress testing is sometimes used to screen asymptomatic patients, testing is costly, time-consuming and generally not amenable to routine screening of large numbers of patients. Furthermore, exercise stress test evaluations result in about 15% false negatives.
Diagnostics tests have been developed that use cardiac proteins to determine whether or not the source of the patient's chest pain is cardiac and if so, whether the patient has suffered a myocardial infarct or is suffering from unstable angina (see, e.g., U.S. Pat. Nos. 5,290,678, 5,604,105, and 5,710,008). These tests do not give an early warning for when myocardial infarct is forthcoming. Thus, a non-invasive, sensitive, and reliable point-of-care ‘bedside test’ is needed for the early detection of cardiac ischemia, particularly for people at risk for heart disease.
In view of the need for rapid and reliable methods for detecting cardiac ischemia in the absence of symptoms, particularly for screening those at high risk of heart disease, the present invention is an early detection assay for cardiac ischemia or hypoxia.
SUMMARY OF THE INVENTION
The present invention provides diagnostic methods for the early detection of heart disease (e.g., heart failure, cardiac ischemia, and cardiac hypoxia) in mammals, particularly humans, by monitoring serum or whole blood levels of non-polypeptidic cardiac markers, e.g., sphingosine and/or its metabolites. For instance, an early event in the course of cardiac ischemia (i.e., lack of blood supply to the heart) is an excess production by the heart. muscle of certain naturally occurring non-polypeptidic compounds, or cardiac markers, such as, but not limited to, sphingosine (SPH; D(+)-erythro-2-amino-4-trans-octadecene-1,3-diol or sphingenine), its isomers, and metabolites; ceramide (Cer, n-acylsphingosine), sphingosine-1-phosphate (S1P), sphingosylphosphorylcholine (SPC, lysosphingomyelin), and glycosphingolipids and lysophospholipids such as lysophosphatidic acid (LPA), and the metabolites of any of the foregoing. The present invention is based on the observation that SPH is increased in the serum and suggests that blood sphingolipid levels represent a new biochemical marker for cardiac ischemia.
Evidence indicates that the cardiac source of tumor necrosis factor alpha (TNF&agr;) may be responsible for the characteristic increased serum sphingolipids resulting from cardiac ischemia. Accordingly, preferred embodiments of the invention provide that serum SPH levels, or levels of other related lipids having a sphingosine backbone, be used in combination with levels of a secondary marker, e.g., serum TNF&agr;, as an index of ischemia. Of course, other non-polypeptidic cardiac markers can also be used in conjunction with a secondary marker such as TNF&agr; to calculate such an index. This dual analyte measure is referred to as Myocardial Risk Factor (MRF).
Kits according to the invention provide cost-effective and rapid tests that can be used to identify and predict, among other cardiac conditions, acute myocardial infarction (AMI) and to confirm that angina pectoris results from cardiac ischemia. In addition, the present invention can be used for simple screenings of early ischemic or hypoxic events before symptoms are presented, e.g., in persons with high risk for heart disease and for persons experiencing other forms of heart failure, including myocarditis, the cardiomyopathies, and congestive and idopathic heart failure. Moreover, the methods and compositions according to the invention can be used to monitor the effectiveness of therapeutic interventions designed to relieve the ischemia and heart failure.
Thus, in one aspect, the invention provides a method of detecting heart disease characterized by cardiac ischeria or hypoxia in a mammal comprising the steps of (a) measuring a level of a non-polypeptidic cardiac marker in the test sample from the mammal; and (b) determining if the level of the cardiac marker measured in the test sample correlates with cardiac ischemia or hypoxia.
“Ischemia” means a condition where the cardiac muscle receives insufficient blood supply, whereas “hypoxia” means a condition where the cardiac muscle receives insufficient oxygen.
The term “mammal” refers to such organisms as mice, rats, rabbits, goats, horse, sheep, cattle, cats, dogs, pigs, more preferably monkeys and apes, and most preferably humans.
In preferred embodiments, the subject
Chin Christopher L.
Medlyte Diagnostics, Inc.
Warburg Richard J.
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