This research will attempt to restore energetic and hemodynamic efficiency to reperfused myocardium by changing the mechanical characteristics of segmental contraction. Following various periods of complete or partial coronary artery occlusion, reperfused myocardium was found to have markedly depressed efficiency. Contraction efficiency (segment work/ myocardial oxygen consumption- MVO2) was reduced primarily because segment work was markedly depressed even as MVO2 remained normal. It is proposed that, even in the absence of a persistent metabolic lesion, mechanical uncoupling between local force development and segment shortening is responsible for depressed work and efficiency. It is also proposed that such local inefficiency directly and quantitatively causes global left ventricular energy loss, since segment shortening of post-ischemic myocardium continues well into ventricular diastole. Finally, it is proposed that efficiency will be improved by agents that improve contraction and relaxation dynamics, particularly by stimulating the re-uptake of myofibrillar calcium. Experiments will be performed and a mathematical model will be constructed to test these hypotheses. In open-chest anesthetized dogs, segment length and force will be measured in two myocardial regions. Regional and global LV work will be calculated on-line by integration of the length-force and flow-pressure loops during systole. Local and global coronary blood flow will be measured, and regional O2 saturations as well as coronary sinus oximetry will be used to calculate regional and global MVO2 respectively. Various models of ischemia and reperfusion will be produced by ligation/release of the LAD coronary artery. The effectiveness of several drugs and interventions on five markers of mechanical dysfunction and efficiency will be tested. A mathematical model of regionally impaired ventricular contraction will consist of normal and impaired regions. Each region will have a prescribed dynamic pressure-volume relationship and will be permitted to interact with each other, the arterial load, and a filling reservoir. The model will be used to test the effect of each of the mechanical markers, and their quantitative role in determining local and global efficiency. Information obtained from this study will provide a quantitative understanding of factors controlling oxygen cost of local contraction, and may lead to management of coronary insufficiency by treatment aimed at increasing efficiency.
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