The effect of sarcomere length on myocardial tension development has been the subject of intense investigation. It has been demonstrated that at a given sarcomere length, peak twitch tension is below normal in pressure overload hypertrophy. The basis for reduced tension development is important to understand when considering myocardial function in hypertrophic disease. The primary goal of this project is to identify the mechanism(s) by which tension development is reduced in hypertrophy. The working hypothesis is that in hypertrophy there is reduced activation of the myofilaments during a twitch; this reduced activation is independent of calcium sensitivity, or membrane influence. To test the hypothesis, sarcomere length- and segment length-tension relations will be measured when activation is controlled in intact (tetanus) and skinned trabeculae from normal and hypertrophied rabbit hearts. Dose-response curves over a range of lengths will assess the sensitivity and contactile response to calcium in the skinned preparations. The skinning procedure will also be used to selectively destroy the sarcolemma while maintaining the function of the sarcoplasmic reticular membranes to assess the influence of these membranes on tension development in hypertrophy. Photomicrographs will be used to determine the extent of sarcomere length heterogeneity within the preparations and assess whether regional areas of deactivation occur at peak tension development in hypertrophy. A second goal of the project is to establish whether initial (resting) sarcomere length has a significant influence on peak twitch tension development in cardiac muscle. Sarcomere isometric and auxotonic twitches will be used to assess whether peak tension development at a given sarcomere length is independent of how the sarcomere length was reached, i.e., Is peak twitch tension independent of the history of contraction? The goals of the project are important when assessing the function of the hypertrophied heart since it is known that both the active and resting sarcomere length-tension relations are altered in hypertrophy.
