Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – Transgenic nonhuman animal
Reexamination Certificate
1996-03-29
2001-12-25
Martin, Jill D. (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
Transgenic nonhuman animal
C800S009000, C800S013000, C800S014000, C800S017000, C800S021000, C800S025000, C435S455000, C435S320100, C424S009200
Reexamination Certificate
active
06333447
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to transgenic models of heart failure and, more particularly, to transgenic animals and methods for testing the usefulness of chemical compounds in the treatment of heart failure.
BACKGROUND OF THE INVENTION
Heart failure is one of the leading causes of morbidity and mortality in the United States. Heart failure can result from any condition that reduces the ability of the heart to pump blood. Most frequently, heart failure is caused by decreased contractility of the myocardium, resulting from reduced coronary blood flow. Many other factors may result in heart failure, including damage to the heart valves, vitamin deficiency, and primary cardiac muscle disease. [A. C. Guyton (1982)
Human Physiology and Mechanisms of Disease,
Third Edition, W. B. Saunders Co., Philadelphia, Pa., p. 205]. Heart failure is commonly manifested in association with myocardial infarction. [
Manual of Medical Therapeutics
(1989) Twenty-Sixth Edition, Little, Brown & Co., Boston (W. C. Dunagan and M. L. Ridner, eds.), pp. 106-09].
The precise physiological mechanisms of heart failure are not entirely understood. However, heart failure is generally believed to involve disorders in several cardiac autonomic properties, including sympathetic, parasympathetic, and baroreceptor responses. [K. Kiuchi et al. (1993) J. Clin. Invest. 91:907].
The sympathetic division of the autonomic nervous system plays a key role in cardiac function. Adrenergic impulses of the sympathetic system stimulate &bgr;-adrenergic receptors disposed in various regions of the heart. These regions include the sinoatrial node, the atrioventricular node, and the ventricles, which result in increased heart rate, increased automaticity and conduction velocity, and increased ventricular contractility, respectively. [Goodman and Gilman's
The Pharmacological Basis of Therapeutics
(1990) Eighth Edition, Pergamon Press, Inc. (Alfred Goodman Gilman et al., eds.), pp. 88-90]. Though the heart contains both &bgr;
1
- and &bgr;
2
-adrenergic receptors, the &bgr;
1
-adrenergic receptors are more important for physiological responses.
The effect, if any, of elevated catecholamine levels on the density of &bgr;-adrenergic receptors has not been definitively elucidated. To illustrate, studies involving experimental animals with heart failure have shown an increase in &bgr;-adrenergic receptor density, no change in density, or a decrease in density. [K. Kiuchi et al. (1993) J. Clin. Invest. 91:907; see also D. E. Vatner et al. (1989)
J. Clin. Invest.
84:1741]. Studies involving failing human hearts have been reported to contain fewer &bgr;-adrenergic receptors in the left ventricle [see, e.g., M. R. Bristow et al. (1982)
N Eng. J Med.
307:205], and the receptors that are present bind catecholamine agonists with a reduced affinity. Thus, the failing heart shows a reduced responsiveness to catecholamines (i.e., catecholamine desensitization).
Whether activation of myocardial &bgr;-adrenergic receptors is beneficial or deleterious over the long term, particularly in the pathogenesis of human heart failure, remains enigmatic. Although it seems clear that the acute role of &bgr;-adrenergic receptor-activation over a time frame of seconds to hours evolved as an evolutionary advantage for predators and prey alike (i.e., the fight or flight response), a major clinical puzzle revolves around whether a persistent enhancement of sympathetic drive to the heart, as can occur following major insults such as myocardial infarction or cardiac failure, might paradoxically lead to gradual deterioration of healthy cardiocytes and thereby to global organ dysfunction.
Generally speaking, heart failure in humans begins with reduced myocardial contractility, which leads to reduced cardiac output. In turn, the reduced cardiac output triggers increased sympathetic discharge (ie., norepinephrine, also referred to as noradrenaline and levarterenol), leading to the chronic elevation of circulating catecholamine levels characteristic of heart failure. [W. F. Ganong (1987)
Review of Medical Physiology,
Thirteenth Edition, Appleton & Lange, CN, pp. 534-535]. Heart failure is also characterized by hypertrophy of the ventricles, manifested in part by an increase in the myocyte cross-sectional area. In addition to the presence of myocardial hypertrophy, the failing heart shows excess collagen deposition. [R. A. Kloner and V. J. Dzau (1990) Heart Failure, Chapter 23 in
The Guide to Cardiology,
Second Edition, R. A. Kloner (ed.) Le Jacq Communications, p. 359].
A. The Treatment Of Heart Failure
Modalities for treating heart failure can be divided into (i) non-pharmacological treatment and (ii) pharmacological treatment. Non-pharmacological treatment is primarily used as an adjunct to pharmacological treatment. One means of non-pharmacological treatment involves reducing the sodium in one's diet. In addition, non-pharmacological treatment also entails the elimination of certain precipitating drugs, including negative inotropic agents (e.g., certain calcium channel blockers and antiarrhytmic drugs like disopyramide), cardiotoxins (e.g., amphetamines) and plasma volume expanders (e.g., nonsteroidal antiinflammatory agents and glucocorticoids).
Treatment with pharmacological agents represents the primary mechanism for reducing or eliminating the manifestations of heart failure. Diuretics constitute the first line of treatment for mild-to-moderate heart failure. Unfortunately, many of the commonly used diuretics (e.g., the thiazides) have numerous adverse effects. For example, certain diuretics may increase serum cholesterol and triglycerides. Moreover, diuretics are generally ineffective for patients suffering from severe heart failure.
If diuretics are ineffective, vasodilatory agents may be used; the angiotensin converting (ACE) inhibitors (e.g., enalopril and lisinopril) not only provide symptomatic relief, they also have been reported to decrease mortality. [L. Y. Young et al. (1989)
Handbook of Applied Therapeutics,
Applied Therapeutics, Inc., Vancouver, Wash., pp. 7.1-7.12 and 9.1-9.10]. Again, however, the ACE inhibitors are associated with adverse effects that result in their being contraindicated in patients with certain disease states (e.g., renal artery stenosis).
Similarly, an inotropic agent, ie., a drug that improves cardiac output by increasing the force of myocardial muscle contraction, may also be indicated if the diuretics do not result in adequate relief. The inotropic agent most commonly used by ambulatory patients is digitalis. However, it is associated with a panoply of adverse reactions, including gastrointestinal problems and central nervous system disfunction.
B. The Study Of Heart Failure And The Design Of Rational Drug Treatments
The currently used pharmacological agents have severe shortcomings in particular patient populations. The availability of new safe and effective agents would undoubtedly benefit patients who either cannot use the pharmacological modalities presently available, or who do not receive adequate relief from those modalities.
Different methods of designing drugs are presently being used. Regardless of the methodology utilized, the development of new pharmacological agents generally entails a great deal of time, effort, and expense. Unfortunately, many chemically different entities must often be screened before an effective agent is found (if one is found at all) for a particular ailment. Obviously, it would not be possible to test a large number of chemical entities on human hearts that exhibit signs of heart failure; not only would it be unfeasible to gather enough subjects to perform the experiments, it would not be safe to test such agents in humans.
What is needed is a model of heart failure that may be used for the testing of chemical compounds in the treatment of heart failure. The model must not require the use of human hearts, and it must be easy and relatively inexpensive t
Homcy Charles C.
Ishikawa Yoshihiro
Vatner Stephen F.
Wagner Thomas
Martin Jill D.
Medlen & Carroll LLP
The General Hospital Corporation
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