REGIONAL FDG UPTAKE IN STUNNED VS HIBERNATING MYOCARDIUM

心肌“冬眠”是指慢性应激引起的左心功能障碍。 低灌注率。尽管有极少的实验证据表明 存在，严重冠心病患者的功能得到改善 血运重建。心肌“顿抑”指的是可逆性功能障碍 在严重缺血和再灌流后。在临床和实验上， 目前尚不清楚这两个实体是否不同。这项建议 介绍了两种情况下的两种典型模型。令人惊叹的将是 通过临时阻断左前降支20分钟和再灌流24小时 而冬眠将通过在周围放置一个固定的收缩来诱导 随着动物的增大，LAD限制了灌注量。宠物和适当的 示踪剂将被用来测量心肌血流的连续变化 和新陈代谢。 首先，我们假设两种模型都会导致区域功能障碍。 在没有明显坏死的情况下。我们假设局部葡萄糖 在这两种模型中，摄取相对于灌流都是增加的。然而，我们 推测葡萄糖摄取的增强标志着一种广泛的适应过程 平衡能源供应和需求的冬眠。 其次，我们假设在慢性低灌流心肌中， 心肌保持再生高能磷酸盐的能力和 糖原储藏室。使用核磁共振技术，我们已经证明了快速起搏 导致冬眠中跨壁ATP的减少，这表明 心肌适应了能量供应平衡的新水平，尽管是在 缺血阈值。我们推测，能源供应与此不同 在功能被抑制时的慢性再灌流心肌 葡萄糖摄取增加(缺血后24小时)。 第三，我们假设心肌对慢性低灌流具有适应性。 通过“下调”总能源消耗。因此，我们预计 随着冬眠的发展，地区性MVO2将受到抑制。而令人惊叹的是 与功能相关的MVO2增强，冬眠是 与氧气供应和需求相关的效率。 第四，我们将确定是否存在可测量的流量储备 在冬眠的心肌内。如果是这样的话，这将支持这样的观点 阻力血管在慢性血流减少时进行重塑。这项研究 还将允许我们在流量储备方面采取一系列措施 模式的演变。这项研究推论是流动储备 在再灌流时，心肌组织正常。如果是这样，这将与 我们对急性晕厥心肌的研究。 第五，我们提出不同于顿抑心肌，冬眠区域 将变得更加依赖碳水化合物底物的利用，例如 用于能源生产的葡萄糖。静脉注射2 脱氧葡萄糖已被证明可阻断糖酵解75%。在正常血糖下 条件下，我们将测试阻断糖酵解是否会改变核磁共振 静息或适度起搏时跨壁ATP的估计 压力。如果是真的，这些发现将表明葡萄糖新陈代谢起作用 在冬眠的适应过程中起着重要作用。并行的 实验中，我们将评估GLUT4蛋白是否转移到 冬眠心脏的质膜。令人震惊的初步数据 提示葡萄糖的主要胰岛素依赖转运体GLUT4是 而不是被上调。 最后，我们推测腺苷可能在 通过A1受体刺激改变葡萄糖摄取。宠物和菲克 将确定葡萄糖摄取量的估计值，以测试 在以下情况下，PET测量的准确性是可靠的 组织中的腺苷水平增加。

Myocardial "hibernation" refers to LV dysfunction in response to chronic hypoperfusion. Although there is minimal experimental evidence that it exists, patients with severe CAD show improved function with revascularization. Myocardial "stunning" refers to reversible dysfunction following severe ischemia and reperfusion. Clinically and experimentally, it is not clear whether the two entities are distinct. This proposal presents 2 models which typify both situations. Stunning will be induced by temporarily occluding the LAD for 20 min and reperfusing for 24 hours and hibernation will be induced by placing a fixed constrictor around the LAD which limits perfusion as the animal enlarges. PET and appropriate tracers will be used to measure serial changes in myocardial blood flow and metabolism. Firstly, we hypothesize that both models will induce regional dysfunction in the absence of significant necrosis. We postulate that regional glucose uptake is increased relative to perfusion in both models. However, we speculate that enhanced glucose uptake signals a broad adaptive process in hibernation which balances energy supply with demand. Secondly, we hypothesize that within chronically hypoperfused myocardium, myocardium retains the capacity to regenerate high energy phosphates and glycogen stores. Using NMR techniques, we have shown that rapid pacing causes a reduction in transmural ATP in hibernation, suggesting that the myocardium adapts to a new level of energy-supply balance, albeit on the threshold of ischemia. We speculate that energy supply differs from that of chronically reperfused myocardium at a time that function is depressed and glucose uptake is increased (24 hours post-ischemia). Thirdly, we postulate that the myocardium adapts to chronic hypoperfusion by "down-regulating" total energy expenditure. Therefore, we expect that regional MVO2 will be depressed as hibernation evolves. Whereas stunning is associated with enhanced MVO2 relative to function, hibernation is efficient related to O2 supply and demand. Fourthly, we will determine whether measurable flow reserve is present within hibernating myocardium. If so, this would support the notion that resistance vessels remodel during chronic reductions in flow. The study would also allow us to make serial measures in flow reserve during evolution of the model. The corollary to this study is that flow reserve in reperfused myocardium is normal. If so, this would be consistent with our studies in acutely stunned myocardium. Fifthly, we propose that unlike stunned myocardium, hibernating regions will become more dependent upon carbohydrate substrate utilization such as glucose for energy production. Administration of intravenous 2 deoxyglucose has been shown to block glycolysis by >75%. Under euglycemic conditions, we will test whether blocking glycolysis will alter NMR estimates of transmural ATP either at rest or during a modest pacing stress. If true, the findings would suggest that glucose metabolism plays an important role in the adaptive process of hibernation. In parallel experiments, we will assess whether GLUT4 protein is translocated to the plasma membrane in hibernating hearts. Preliminary data in stunning suggests that GLUT4, the major insulin-dependent transporter of glucose is not upregulated. Finally, we postulate that adenosine may play an important role in altering glucose uptake via A1 receptor stimulation. PET and Fick estimates of glucose uptake will be determined to test whether the accuracy of PET measurements are reliable under circumstances in which tissue levels of adenosine are increased.