Cardiomyocyte death is a common feature of many forms of heart disease. Since the myocardium lacks a substantive endogenous regenerative potential, cardiomyocyte death is essentially irreversible. It has recently become apparent that exogenous myocytes can be successfully engrafted into the adult myocardium, thereby increasing the number of cells present in the heart. This procedure may be of considerable therapeutic value if engrafted cells can augment function in a diseased heart. Indeed, strategies aimed at increasing myocyte number was viewed with the highest priority by the NHLBI Special Emphasis Panel on Heart Failure Research and by this RFA. However, several rather formidable issues and obstacles must be addressed before any therapy based on myocyte engraftment can be realized. The five highly integrated Collaborative RO1s proposed herein are designed to directly address these issues. A major goal of the proposed studies is to establish the fate of donor cells following engraftment. Particular emphasis is being placed on identifying factor(s) which enhance donor cell viability (Dr. Kedes), and on determining the degree to which donor and host myocytes can interact (Field and Murry). Other studies (Field, Murry and Hauschka) will establish the relative merits of a variety of different donor cells (fetal cardiomyocytes, skeletal myoblasts, ES- and EC- derived cardiomyocytes, and smooth muscle cells). Particular emphasis will be placed on weighing the issue of donor cell availability versus the functional characteristics of their respective grafts. Functional analyses of the engrafted hearts will rely largely on highly sensitive 2D echocardiography (Kloner). These latter studies will also establish to what degree cellular engraftment has a direct versus indirect effect on cardiac function (that is, participation in contractile force generation versus a positive effect on remodeling). The assembled investigators have established track records in relatively new field of cardiac engraftment, and additionally bring a diverse spectrum of experimental expertise which collectively provides a comprehensive battery of molecular, cellular and functional experimental methods.