LEFT HEART FUNCTION AND INTRACELLULAR CALCIUM AND SODIUM

Knowledge of the fundamental laws which govern the dynamics of ventricular contraction is of primary importance for advancing understanding of heart function in health and disease. Ventricular pump function is now commonly characterized in terms of various indices derived from analysis of pressure-volume loops measured under different loading conditions such as the end-systolic pressure-volume relationship or preload recruitable stroke work. Such approaches are, in the end, unrelated to basic principles of muscle mechanics. On the other hand, it is unknown whether many of the fundamental concepts of cardiac muscle contraction derived from observations made in isolated superfused muscle preparations pertain to the more physiologic conditions of intact muscles in the wall of the ventricle. Thus, there are a number of major conceptual and experimental gaps between how we think about muscle mechanics and how we think about ventricular mechanics. It is the long term objective of this research project to bridge many of these gaps by testing whether certain fundamental observations made in muscle pertain to the intact heart and testing the feasibility of a new theory of ventricular dynamics that is based upon those observations and a biochemical scheme relating calcium transients to ventricular performance over a broad range of loading condiitons and inotropic states. Studies will be performed in isolated cross perfused canine hearts in which aequorin has been macroinjected into epicardial cells. This combination of techniques will be used to study the load dependence of the calcium transient over a broad range of loading conditions as well as to test whether the load dependence of the ventricular pressure waveform can be accounted for the calcium transient and the new theory mentioned above. The validity of several of the assumptions of the theory will be tested in Langendorf rat hearts exposed to ryanodine which will permit study of the calcium and load dependence of tetanic ventricular pressure generation. One group of studies will test a new hypothesis relating to the impact of ventricular stretch on intracellular sodium and its possible links to load dependent changes in intracellular calcium. Finally, studies will be performed in cardiomyopathic hearts in which the damage to the heart is ischemic in nature, a model believed to be relevant to several forms of human heart disease. When interpreted within the framework of the new theories it is hypothesized that the results will provide new insights into mechanisms of contractile dysfunction in this form of cardiomyopathy.