The goal of the proposed work is to establish methods by which the adult heart can be modified to allow appropriate cellular adaptation to imposed stress. Altered cellular adaptation will then, in turn, result in normal heart function. We will utilize two experimental models of heart adaptation to pressure overload. Previous work has shown that heart functional characteristics of young animals (21 days of age) subjected to pressure overload stress are within normal limits. In contrast, depressed heart function is exhibited by adult animals treated in an identical manner. The presence or absence of cardiac muscle cell proliferation correlates with the functional characteristics in young and adult animals, respectively. Work completed during the current grant period established a relationship between heart cyclic AMP levels and adaptive heart growth of young animals subjected to pressure overload. Furthermore, a non-invasive means for manipulating either total heart cell numbers or protein synthetic capacity was revealed by experiments dealing with the nutritional status of young rats. The proposed work will expand and amplify our previous results. We will, first, establish the relationship between heart cAMP levels and cellular responsiveness, in terms of muscle cell division and protein synthetic stimulation. Secondly, we will examine the relationship between existing heart cell numbers and heart contractile function. (Rats of the same age, but having different numbers of heart cells, will be prepared by adjusting the size of the litter soon after birth.) A final series of experiments with litter-size adjusted rats will determine the functional status of hearts responding to pressure overload while possessing graded levels of either heart muscle cells or protein synthetic capacity. These studies will establish whether the heart benefits functionally from having (a) more heart cells, (b) enhanced protein synthetic capacity, or (c) greater cell proliferative capacity at the time an imposed stress is encountered. We will have established the cAMP level response necessary to achieve the most beneficial cellular adaptive state of the heart. It should then be possible to manipulate the adult heart by pharmacological means such that the cellular adaptation in response to imposed stress will lead to normal heart function.
