Treatment of hibernating myocardium with a GLP-1 peptide

Abstract

Hibernating myocardium is characterized by viable myocardium with impaired function due to localized reduced perfusion. Hibernating myocytes retain cellular integrity, but cannot sustain high-energy requirements of contraction. High plasma levels of catecholamines, such as norepinepherine, are believed to be predictive of mortality from hibernating myocardium. Likewise, high levels of catecholamines lead to cardiomyopathy in patients with diabetes. GLP-1 reduces plasma norepinepherine levels, and it thus is useful in a method of treating hibernating myocardium or diabetic cardiomyopathy.

Description

[0001] This application claims priority to U.S. Application Ser. No. 60 / 241,834, filed Oct. 20, 2000, No. 60 / 60 / 242,139, filed Oct. 23, 2000, and No. 60 / 245,234, filed Nov. 3, 2000, all of which are hereby incorporated by reference.BACKGROUND OF THE INVENTION [0002] Heart failure continues to be a major health problem. Approximately four million persons in the U.S. population have heart failure. With a steadily aging population, four hundred thousand individuals experience new onset heart failure each year, with a five year mortality rate approaching fifty percent. [0003] Rather than a single pathological entity, “heart failure” defines a clinical syndrome with many different etiologies that reflects a fundamental abnormality in effective mechanical performance of the heart, such that the heart is unable to meet the demands of the body. There are various forms of heart failure, including “forward” and “backward” heart failure. Backward failure, synonymous with congestive heart failu...

AI Technical Summary

Benefits of technology

[0012] Administration of GLP-1 has been found unexpectedly to suppress plasma blood levels of norepinepherine. By analogy to congestive heart failure, reduction in plasma norepinepherine levels will be expected to ease the ischemic stress to hibernating myocardium, thereby improving the clinical outcome. Accordingly, administration of GLP-1 will be useful in a method to treat hibernating myocardium, either alone or in conjunction with existing treatment regimes. Likewise, GLP-1 will be useful in reducing norepinepherine levels in the heart and / or plasma that are associated with the development of diabetic cardiomyopathy.

[0013] GLP-1 reduces plasma norepinepherine levels in a method of treating hibernating myocardium or diabetic cardiomyopathy. Thus, a method for treating hibernating myocardium or diabetic cardiomyopathy comprises administering a therapeutically effective amount of a GLP-1 molecule to said patient. A GLP-1 molecule also may be administered in therapeutically effective amount to a patient suffering from congestive heart failure or ischemic cardiomyopathy, particularly one who also has hibernating myocardium. A therapeutically effective amount of a GLP-1 molecule reduces the plasma and / or heart norepinepherine level. A GLP-1 molecule preferably is delivered intravenously or subcutaneously. The former is preferred for acute treatment with a GLP-1 molecule, while the latter is preferred in chronic treatment regimens.

Problems solved by technology

Heart failure continues to be a major health problem.

Backward failure, synonymous with congestive heart failure, is due to increase in venous pressure (i.e., increase in pressure in the veins that return blood to the heart) resulting from the inability of the heart to discharge its contents normally, leading to pulmonary and systemic congestion.

By contrast, forward failure is caused by an inability of the heart to maintain normal tissue perfusion, resulting in fatigue, weakness, loss of weight, and impairment of cerebral function.

The degree of ischemia is not sufficient to produce necrosis (infarction), but it locally restricts myocardial oxygenation and fuel supply, such that a part of the myocardium becomes hypoactive or dormant.

Eventually, the damage may become irreversible and may lead to heart failure when the extent of myocardial dysfunction is great enough to compromise cardiac performance and reduce the cardiac output; that is, ischemic cardiomyopathy may be the ultimate result of hibernating myocardium, if it is not treated appropriately.

The inconvenience of surgery and the incidence of morbidity or restenosis associated with these techniques underscores the need for supplemental or alternative pharmacological intervention.

While these drugs improved hemodynamics over the short term, recent studies have found a discrepancy between improved hemodynamics and clinical outcome.

Like congestive heart failure, there is evidence that administration of inotropic agents may worsen ischemia associated with hibernating myocardium.

By analogy to congestive heart failure, it has also been suggested that high plasma levels of catecholamines, like norepinepherine, are deleterious to clinical outcome of hibernating myocardium, because of their inotropic properties.

The exact etiology of this disease remains controversial, in part because many myocardial abnormalities are associated with diabetes.

Presently, very few compounds provide these characteristics.

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