This is an application for a three-year Clinical Investigator Development Award. The applicant is an Assistant Professor of Medicine at the University of Vermont. The long-term scientific goal of the applicant's research is to understand the relationship between contraction mode and ventricular performance and energetics. The emphasis in this proposal is the phenomenon of shortening activation, a gradual increase in contractility which occurs as a consequence of ventricular ejection. In recent preliminary experiments the applicant has characterized shortening activation occurring in response to both systolic ejection and rapid unloading at end-systole. Shortening activation is associated with an increase in nonmechanical VO2, a measure of total calcium cycled per beat, and a decrease in mechanical VO2, a measure of energy used for crossbridge cycling. This suggests that the increase in contractility associated with shortening activation is related to increased calcium cycling. This proposal is designed to characterize the physiologic and pathophysiologic significance of shortening activation. Shortening activation will be related to nonmechanical VO2 under a variety of conditions in order to confirm its relationship to calcium cycling. Additionally, the applicant will begin to elucidate the mechanism of shortening activation with protocols which are designed to define whether the additional calcium cycled derives from an intra- or extracellular source. The applicant will work closely with his sponsor, Dr. Martin LeWinter, Professor of Medicine and Director of the Cardiology Unit, and will have available the advice and expertise of highly qualified basic scientists in the Department of Molecular Physiology and Biophysics, in order to allow him to fully exploit the strong environment in cardiac muscle physiology at the University of Vermont.
