CARDIAC PRESERVATION PRIOR TO TRANSPLANTATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 成功的心脏移植取决于在获取和运输过程中充分保护供体心脏的能力。迄今为止，这已经通过将冷保存溶液注入心脏并将心脏储存在冰柜中（静态保存）来实现。 该方法具有局限性，并且已经导致了在运输期间向供体心脏提供连续的氧合溶液流的技术的发展（机器灌注保存）。 这种新的策略可能允许心肌中持续的氧化代谢，这可以支持必要的细胞过程。 然而，现有的保存溶液被设计用于静态保存，并且不太适合利用机器灌注提供的条件。 本项目将检查心肌代谢期间和之后的机器灌注保存，以确定在保存液中的底物条件，最大限度地提高氧化代谢。 另外的实验将测试储存期间代谢增加导致移植后上级功能结果的概念。 该研究项目的具体目标是： 在心脏移植机械灌注保存的小动物模型中，验证不同外源性底物影响心肌氧化代谢程度的假设。 确定灌注溶液中的最佳底物组成和底物浓度，以在机器灌注保存期间最大化氧化代谢。 在流速和心脏大小不同的大型动物（犬）模型中，检验改变灌注液底物组成对氧化代谢产生相似影响的假设。 在大型动物模型中检测机器灌注保存期间外源性底物氧化代谢速率增加对移植后心室功能以及坏死和凋亡引起的细胞损伤的影响。 从这些研究中获得的信息可能使我们能够开发出用于机器灌注保存的改进灌注溶液，从而在心脏移植中获得上级结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Successful cardiac transplantation depends on the ability to adequately protect the donor heart during procurement and transport. To date this has been accomplished by infusing a cold preservation solution into the heart and storing the heart in an ice chest (static preservation). This method has limitations and has led to the development of techniques that provide a continuous flow of oxygenated solution to the donor heart during transport (machine perfusion preservation). This new strategy may allow ongoing oxidative metabolism in the myocardium which can support essential cellular processes. However, existing preservation solutions are designed for static preservation and are not well suited to take advantage of the conditions provided by machine perfusion. This project will examine myocardial metabolism during and after machine perfusion preservation to identify substrate conditions in the preservation solution that maximize oxidative metabolism. Additional experiments will test the concept that increased metabolism during storage leads to superior functional results after transplantation. The specific aims of this research project are: To test the hypothesis that different exogenous substrates affect the degree of myocardial oxidative metabolism in a small animal model of machine perfusion preservation for heart transplantation. To determine the optimal substrate composition and substrate concentration in a perfusion solution to maximize oxidative metabolism during machine perfusion preservation. To test the hypothesis that altering perfusion solution substrate composition leads to similar effects on oxidative metabolism in a large animal (canine) model where flow rates and heart size are different. To test the effect of increased rates of oxidative metabolism of exogenous substrates during machine perfusion preservation on post-transplant ventricular function and cellular damage from necrosis and apoptosis in a large animal model. Information from these studies may enable us to develop improved perfusion solutions for use with machine perfusion preservation, leading to superior results in cardiac transplantation.