In response to the abnormal hemodynamic burden imposed by pathologic conditions such as hypertension and valvular heart disease, the heart adapts by an alteration in mass and configuration which enables the heart to maintain systemic perfusion despite the excessive circulatory load. The pattern of hypertrophic growth may be concentric, an increase in mass without a change in volume, for a pressure overload or eccentric, an increase in mass in proportion to volume, for a volume overload. Despite this initial compensatory response, the hypertrophied heart is often not able to sustain the excessive load indefinitely and congestive heart failure supervenes. The overall objectives of this proposal are to determine the extent to which ventricular dimensions and morphology are critical for the transition from compensated hypertrophy to failure and to determine whether amelioration of the inciting hemodynamic burden will reverse, once present, severe cardiac dysfunction and the associated changes in cardiac mass, morphology, and dimensions. In several rat models of genetic and experimentally-induced systemic hypertension and volume overload, basal and stressed hemodynamics and passive left ventricular pressure-volume relations will be assessed at various ages to determine the leves and duration of the hemodynamic burden that produces severe left ventricular dysfunction. These parameters of cardiac performance then will be related to morphologic determinations of myocyte size and subcellular composition to determine whether heart failure is associated with a critical imbalance between cellular components and volume. Left ventricular wall stresses will be calculated to determine whether the increasing internal load imposed by an expanded ventricular diameter may eventually exceed the initial benefit of a reduction in the fiber shortening required to maintain stroke volume and thereby eventuate in cardiac decompensation. Once cardiac failure is apparent, the inciting hemodynamic burden will be ameliorated to determine whether severe cardiac dysfunction can be reversed, once present, or whether the alterations in ventricular geometry and morphology will sustain dysfunction.
