ENERGY RESERVE IN THE FAILING MYOCARDIUM

衰竭的心脏是能量匮乏的假设既存在已久，也有争议。现在有令人信服的证据表明，在严重心力衰竭的人类心肌和动物模型中，[ATP]比正常心肌低25%，而在严重心力衰竭的动物模型中，[ATP]比正常心肌低约25%。我们提出的证据表明，减少是由于嘌呤池的损失。基于核磁共振光谱和化学分析的结果，我们和其他人已经表明，组织中磷酸肌酸（PCr）和肌酸的含量以及CK反应的容量（Vmax）也较低。这些观察结果增加了我们对心脏能量学（PCr）和肌酸两个重要方面的理解，CK反应的能力（Vmax）也较低。这些观察结果增加了我们对心脏能量学的两个重要方面的理解：ATP合成动力学和ATP利用热力学，即ATP消耗反应的化学驱动力。我们观察到衰竭心脏的肌酸和嘌呤池较低，这对理解衰竭心脏的能量学具有重要意义。因为这些底物的浓度较低，它们所支持的反应的速度必然较低。然而，肌肉收缩的atp酶的驱动力可能不会受到损害。这一新信息导致了以下假设：衰竭心肌中肌酸的损失是一种重要的代偿机制，保留了atp酶反应的驱动力。在衰竭的心脏中肌酸运输或嘌呤合成的调节机制尚不清楚。因此，提出的研究计划的主要目标是确定肌酸和嘌呤池在衰竭心脏中耗尽的机制。一个密切相关的目标是操纵正常心脏和衰竭心脏（由于大鼠主动脉带带延长）的ATP/ADP和PCr/肌酸比值，以及由于特定CK同工酶基因缺失导致的低CK Vmax心脏，以确定衰竭心脏不再能够支持正常收缩性能和收缩储备的能量状态。

The hypothesis that the failing heart is energy starved is both long- standing and controversial. There is now convincing evidence from both failed human myocardium and animal models of severe heart failure that the [ATP] is as much as 25% lower than in normal myocardium and animal models of severe heart failure that the [ATP] is as much as approximately 25% lower than in normal myocardium. We present evidence showing that the decrease is due to a loss of the purine pool. Based on results using NMR spectroscopy and chemical assay, we and others have shown that the tissue contents of phosphocreatine (PCr) and creatine and the capacity of the CK reaction (Vmax) are also lower. These observations increase our understanding of two important aspects of cardiac energetics (PCr) and creatine and the capacity of the CK reaction (Vmax) are also lower. These observations increase our understanding of two important aspects of cardiac energetics: the kinetics of ATP synthesis and the thermodynamics of ATP utilization, i.e. the chemical driving force for the ATP-consuming reactions. Our observations that the creatine and purine pools are lower in the failing heart have important implications for understanding the energetics of the failing heart. Because the concentrations of these substrates are lower, the velocities of the reactions they support must be lower. However, the driving force for ATPases of muscle contraction may not be compromised. This new information leads to the following hypothesis: that the loss of creatine in the failing myocardium is an important compensatory mechanism preserving the driving force of the ATPase reactions. Little is known about the regulation of either creatine transport or de novo purine synthesis in the failing heart. Accordingly, the primary goal of the proposed research plan is to define the mechanisms whereby creatine and purine pools are depleted in the failing heart. A closely related goal is to manipulate the ATP/ADP and PCr/creatine ratios in normal and failing hearts (due to prolonged aortic banding in the rat), and in hearts with low CK Vmax caused by gene deletions of specific CK isozymes, to define the energetic state of the failing heart no longer capable of supporting normal contractile performance and contractile reserve.