Chronic aortic stenosis, produced by banding the ascending thoracic aorta in puppies, is one of the best experimental models currently available for the study of pressure overload left ventricular (LV) hypertrophy, because it gradually induces severe hypertrophy; up to a doubling of LV mass. The specific goal of this proposal is to determine the extent and mechanisms by which LV hypertrophy compensates for a severe pressure overload in conscious dogs and the amount of myocardial reserve available for the performance of additionsl work. This will be accomplished by assessing LV function and myocardial perfusion in mongrel dogs (12-15 months old), with supra-coronary aortic bands placed at 8-10 weeks of age, and in sham-operated littermates. LV function will be assessed in dogs at rest, and in response to sympathetic activation, e.g., by graded infusion of catecholamines, graded levels of treadmill exercise, maximal free-ranging exercise, bilateral carotid occlusion, and by stellate ganglion stimulation. The contribution of the diastolic properties of the hypertrophied LV myocardium to the limitation of myocardial reserve will be evaluated by calculating diastolic myocardial and chamber stiffness during volume loading and sympathetic stress. The importance of impaired diatolic relaxation in LV hypertrophy and the response to administration of slow-channel calcium antagonists will also be studied. Microscopic evaluation of the LV myocardium will be performed to determine whether fibrosis or functional properties of the hypertrophied myocardium are responsible for the diminished myocardial reserve. Since banding of puppies will result in varying degrees of aortic stenosis and LV hypertrophy, the results will be analyzed according to the severity of LV hypertrophy: mild (25-50% greater than control), moderate (50-75% greater than control), severe (Greater than 75% greater than control), and severe hypertrophy with congestive heart failure. A comprehensive study of this type will extend our understanding of the mechanisms utilized by the LV to meet increased demands and determine the physiologic limitations of the hypertrophied LV to compensate for a severe chronic pressure overload.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001452-05
Application #
3081834
Study Section
Research Manpower Review Committee (MR)
Project Start
1987-12-01
Project End
1989-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115