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THE COUNCIL FOR TOBACCO RESEARCH-U.S.A., INC. 900 TIIIRn AVENUE NEW YORK. N. Y. 10022 DONALD H. FORD. PH.D. AeeocI..z: xssawnce DiescrO May 21, 1987 Memorandum To: Dr. S.C. Sommers and Staff From: D.H. Ford Re: Site visit with Dr. M. Osbakken, University of Pennsylvania, Philadelphia, May 18, 1987 Grant No. 1925R1 entitled "31P NMR Study of Cardiac Metabolism in Health and Disease". al: To determine the effect of heart overload on heart metabolism (high=energy phosphate systems) and relate changes in metabolism to the mechanical work accomplished by the heart: where a breakdown in mechanical function influences metabolism and vice versa. Results: From a combination of acute studies with dogs and cats with opened chests and piezoelectric crystals attached to the heart wall, it appears that with volume overloading, there is a decrease in the PCr/ATP ratio with increased work load. In chronically volume loaded dogs (closed chest with partial removal of ribs and insertion of a mylastic window covered by the skin), there were no obvious changes in the PCr/ATP or Pi/PCr ratios from pre-loading conditions at rest. However, when the chronic volume loaded dogs were stressed via pressure loading (treatment with norepinephrine, 1 µg/Kg/min) there was an increase in the Pi/PCr and a decrease in the PCr/ATP ratios. Thus, both acute and chronic volume loading induce metabolic changes, the interpretation of which requires additional work and information. Further, while there are bioenergetic changes with work overload, the degree is quite variable from animal to animal. Also, dog hearts were observed to be more resistent to changes in Pi/PCr ratios than cats with increasing work loads. It seems possible that animals adapted for different life styles (stalk and sprint vs. endurance running in the chase) may have cardiovascular systems which are mechanically and metabolically adapted for different forms of stress. Such changes might be related to differences in microvasculature or enzyme kinetics. As applied to man, what differences may relate to genetics, training or life style.

2 mm n: This study is progressing slowly. As noted before, Dr. Osbakken appears to be well aware of all the hazards in a study of this sort and continues to expand the parameters of information sought with additional biochemical analysis of the metabolic and mechanical functions of the heart. The facility in which she works is cramped and her time on the NMR apparatus limited by the number of investigators who must use it. Animal facilities appear excellent and the chronic dog preparations are healthy and energetic. Despite space and time difficulties, I believe she will obtain data which furthers our understanding of the relationships between mechanical and biochemical work in the heart under conditions of cardiac hypertrophy, hypertension, ischemia or during the increase in work load such as occurs in endurance running. Obtaining and correlating all the necessary information, may however, be a slow process. This program continues to be relevent to the goals of CTR and at this point merits continued support. DHF