This proposal is designed to test the hypothesis that long-term biochemical alterations persist in tissue which has healed after experimental ischemia injury, and that such persistent alterations co-exist with electrophysiologic abnormalities. Certain of the biochemical alterations may contribute to the mechanisms of the electrophysiologic changes. These studies are based on preliminary data demonstrating enhanced epicardial refractory period shortening during bilateral sympathetic nerve stimulation in non-scarred tissue adjacent to healed myocardial infarction, increased Beta-adrenergic receptor activity in these areas, and an increased myosin heavy chain concentration in these areas. We now proposed to extend these studies to determine detailed relationships between regional responsiveness to sympathetic nerve stimulation and catecholamine levels, regional Beta-adrenergic receptor activity, changes in myosin isoezymes and ATPase activity, regional myosin heavy content, and histologic evidence of cellular hypertrophy. Four specific projects are proposed: 1) detailed quantitative measurements and histologic studies of the distribution and size of areas of increased myosin concentration and its relationship to evidence of hypertrophy; (2) assessment of myosin isoenzymes and changes in myosin ATPase activity in non-scarred tissue adjacent to the myocardial infarction and normal remote tissue, with correlation of these findings with myosin changes in hypertrophied left ventricles; (3) measurement of myoin content, catecholamine levels, and Beta-adrenergic receptor activity in preparations having disparate epicardial refractoriness during bilateral sympathetic nerve stimulation; (4) estimation of regional Beta-adrenergic receptor activity, catecholamine levels, and myosin concentration in healed myocardial infarction preparations and in left ventricles hypertrophied from pressure overload produced by aortic banding. The experiments are designed both to described quantitative and qualitative patterns of biochemical changes in various regions of the healed myocardial infarction heart; and at the same time, to provide insight into potential mechanisms which may be responsible for the enhanced electrophysiologic responsiveness to sympathetic nerve stimulation in this experimental model.
