The long-range objective of this research is to determine the biochemical and physiological mechanisms underlying the efficacy and biocompatibility of fluorochemical emulsions. This work is concerned with establishing the efficacy of fluorochemical emulsions as O2 delivery agents for clinical and investigational uses involving heart and other organ perfusion, reperfusion, and preservation. The proposed research is a continuation of studies on hypothermic heart preservation using APE-LM, a novel fluorochemical emulsion composed of perfluoroperhydrophenanthrene in egg yolk phospholipid. The APE-LM emulsion exerts a specific cardioprotective effect in preserving mammalian (rat and rabbit) hearts for periods up to at least 12-24 h with 100% recovery of physiologic function.
The Specific Aims of the proposed work are: (a) to determine the mechanisms that maintain myocardial integrity and provide for improved recovery of cardiac function after extended hypothermic heart preservation times using APE-LM, and (b) to achieve complete recovery of cardiac function and long-term survival of sheep following orthotopic transplantation of hearts preserved with medium containing APE-LM. During the proposed grant period, the mechanisms responsible for substrate preferences and consequent effects on energy production in hypothermic quiescent hearts will be investigated. The role of preservation medium O2 content and delivery in determining myocardial substrate use patterns during preservation will be studied. Orthotopic transplants of sheep hearts will be done to quantify cardiac function and regional myocardial blood flow after transplant (0 hours to 30 days), and to determine long-term survival of sheep that receive transplants of APE-LM-preserved hearts. Genetically-identical sheep will be used for donor and recipient pairs which will allow us to quantify cardiac function and determine the adequacy of APE-LM preservation without the complications of immunosuppressants or rejection. This research will yield fundamental information on: (a) the interaction of fluorochemical emulsions with biological systems, which has application in the areas of red cell substitutes and lipid-encapsulated substances in general, and (b) mechanisms responsible for maintaining cardiac integrity during hypothermic preservation and strategies to improve cardiac recovery after short- and long-term preservation and reperfusion. The efficacy and safety of fluorochemical emulsions for heart preservation and for in vivo transfusion uses are health-related goals of this project.
|Segel, Leigh D; vonHaag, Derek W; Zhang, Jie et al. (2002) Selective overexpression of inflammatory molecules in hearts from brain-dead rats. J Heart Lung Transplant 21:804-11|
|Segel, L D; Follette, D M; Baker, J M et al. (1998) Recovery of sheep hearts after perfusion preservation or static storage with crystalloid media. J Heart Lung Transplant 17:211-21|
|Segel, L D; Follette, D M (1998) Cardiac function and glycogen content after twenty-four-hour preservation with various metabolic substrates. J Heart Lung Transplant 17:299-305|
|Segel, L D; Follette, D M; Castellanos, L M et al. (1997) Steroid pretreatment improves graft recovery in a sheep orthotopic heart transplantation model. J Heart Lung Transplant 16:371-80|
|Smolens, I A; Follette, D M; Berkoff, H A et al. (1995) Incomplete recovery of working heart function after twenty-four-hour preservation with a modified University of Wisconsin solution. J Heart Lung Transplant 14:906-15|
|Segel, L D; Follette, D M; Iguidbashian, J P et al. (1994) Posttransplantation function of hearts preserved with fluorochemical emulsion. J Heart Lung Transplant 13:669-80|
|Segel, L D; Follette, D M (1993) Long-term heart preservation by intermittent perfusion with crystalloid medium. J Thorac Cardiovasc Surg 106:811-22|
|Segel, L D; Follette, D M; Contino, J P et al. (1993) Importance of substrate enhancement for long-term heart preservation. J Heart Lung Transplant 12:613-23|
|Segel, L D; Minten, J M; Schweighardt, F K (1992) Fluorochemical emulsion APE-LM substantially improves cardiac preservation. Am J Physiol 263:H730-9|
|Minten, J; Segel, L D; Van Belle, H et al. (1991) Differences in high-energy phosphate catabolism between the rat and the dog in a heart preservation model. J Heart Lung Transplant 10:71-8|
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