At the present time a major obstacle to clinical heart transplantation programs is a shortage of donor organs. This obstacle arises primarily from our inability to preserve the function of the isolated organ for longer than 3-4 hours after harvest from the donor. The result of inadequate preservation is a damaged organ that does not function adequately once transplanted into a recipient. The long-range goal of the proposed studies is to overcome this obstacle by development of improved long-term myocardial preservation techniques. To accomplish this goal the mechanisms of injury underlying failure of current procedures must be identified and strategies for circumventing them discovered. Our preliminary results suggest the following hypothesis: that the decreased contractile function observed in hearts preserved for 24 hours is directly related to injury sustained by the microcirculation during the preservation period. The result of the injury to the microcirculation is loss of functional vessels and ischemia. The general strategy of the proposed studies is to examine the relationship between parameters of flow during and after the preservation period as they relate to contractile function, with an emphasis on identifying the mechanism of injury to the microcirculation. Rabbit hearts will be used in the studies. Initially, they will be preserved by continuous perfusion with a cardioplegia solution at low pressure and temperature. Reperfusion will occur in vitro and in vivo, the latter making use of a heterotopic transplant model. Contractile function, coronary flow, microvascular function (percentage of flowing capillaries, permeability and density), and ultrastructural alterations will be measured. Specific questions and goals include: Are coronary flow rate and microcirculatory function, in terms of the percentage of vessels supporting flow, related? Preliminary evidence indicates that the answer to this question is yes. Is contractile function upon reperfusion related to microcirculatory function during the preservation period? Are the alterations of microcirculatory function reversible with reperfusion? Are vessels permanently lost as a result of the long-term preservation procedure? The site of block within the vascular tree will be localized and the injury, in terms of ultrastructural abnormalities, will be characterized. The mechanisms of injury which might underlie the alteration of microcirculatory function will be examined. Possible mechanisms include: 1) a mechanical problem of inadequate pressure, and 2) vascular damage due to lack of blood constituents in the perfusate. These studies will provide new information for the development of long-term preservation techniques. If the studies are successful, the information could lead to alleviation of the donor shortage problem.
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