The long term goal of this research is to gain an understanding of the relationship between myocardial growth and the mechanical factors which may regulate this growth so that one can eventually gain an understanding of the events by which adaptive cardiac hypertrophy deteriorates into congestive heart failure. It has been suggested that one of the major factors regulating myocyte hypertrophy is the stress in the tissue. The objective of this proposal is to determine how different distributions and multi-axial patterns of myocardial stress and strain affect specific modes of hypertrophy during maturation of the heart. Since the exact nature of the stimulus to hypertrophy remains unknown, the applicant believes that these results will help define which mechanical factors, if any, are responsible for stimulating specific modes of hypertrophy. For example, is diastolic pressure, stress, or strain the stimulus for eccentric cardiac hypertrophy during physiologic growth? Do certain loading pattern produce organized myofibrillar arrangement, while other patterns of external loads do not? What role do cytoskeletal elements play in these specific modes of hypertrophy? Pathologic cardiac hypertrophy may be the result of specific loading conditions, and the applicant believes that these studies will form the basis for further investigations into the role of stress and strain in the transition from physiologic to pathologic hypertrophy. To answer these questions, regional myocardial mechanics will be measured in maturing rats 1-6 weeks of age. Epicardial wall strain will be measured with video acquisition of surface markers in both contracting and passive hearts. Estimates of material properties, as well as active and passive ventricular wall stresses, will be found with finite element models of the growing heart. In order to determine the direct effects of various strain and stress patterns on the myocytes, an isolated myocyte culture preparation will be used in which quiescent or beating neonatal myocytes are stretched on a deformable membrane. The applicant hypothesizes that uniform stretch on a myocyte induces myofibril and cytoskeletal proliferation which is not organized, compared to more aligned intracellular structures in response to a uniaxial stretch. Furthermore, the applicant proposes that cytoskeletal components play a key role in the growth response of the myofibrils and will test this hypothesis by disrupting certain cytoskeletal structures and documenting the growth response. Since hypertrophic growth will change the tissue stress in the absence of external loads, residual strains will be measured during remodeling. Residual stress is one factor that relates the isolated myocyte to the intact tissue since hypertrophy of the individual cell will result in alterations of residual stress when the cells are confluent in the intact tissue. The applicant anticipates that computational models will show material properties and internal stresses, including residual stresses, will change during the growth process.
