This program project represents a multi-disciplinary approach to the problem of myocardial hypertrophy and heart failure. Physiologic studies will be conducted in conscious chronically instrumented animals, to avoid the complicating effects of anesthesia and recent surgery on the LV contractile state and on neural control of the heart and coronary circulation. Tissues from these physiological models will be utilized for biochemical, molecular biological and pathological studies. Project #1 represents a continuation of studies on alterations in LV function and myocardial perfusion induced by LV hypertrophy and failure that have evolved in the laboratory of Dr. S. Vatner. Of particular importance are the recent studies conducted in collaboration with Drs. C. J. Homcy and D. E. Vatner of Mass. General Hospital, finding alterations in Beta-adrenergic and muscarinic receptor control of the hypertrophied and failing heart. Accordingly, a major goal of this component of the application will be to determine whether the previously observed reduction of high affinity Beta-adrenergic agonist binding sites, adenylate cyclase stimulation, and muscarinic receptors induce corresponding physiological deficits in models of LV hypertrophy and failure. Another major goal is to determine whether limitations in subendocardial perfusion or diastolic compliance are responsible for alterations in subendocardial systolic function in LV hypertrophy and failure. Concomitantly, Drs. c. Homcy, D. Vatner, B. Nadal-Ginard, G. Matsueda, and R. Graham will further examine the cellular and molecular mechanisms related to alterations in adrenergic and muscarinic receptor regulation in LV hypertrophy and failure (Project 2). The studies on limitations of myocardial perfusion will be carried out from an anatomic and pathologic viewpoint by Drs. Bishop and Anderson in Project 3. The studies on LV function will also be carried out in collaboration with Dr. I. Mirsky, who is proposing to test a novel hypothesis involving concepts of myocardial mechanics, i.e., end systolic myocardial stiffness is independent of end-systolic stress (Project 5). The changes in myocardial stiffness and compliance observed with LV hypertrophy and failure should be an important factor in the regulation of atrial natriuretic factor. This problem, i.e., to determine how stimulus-release and effector mechanisms of atrial natriuretic factor are altered in the presence of LV hypertrophy and failure, will be addressed by Drs. Graham, Homcy, and Young in Project 4.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL038070-03
Application #
3098589
Study Section
Heart, Lung, and Blood Research Review Committee A (HLBA)
Project Start
1987-06-01
Project End
1992-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
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