REGIONAL FDG UPTAKE IN STUNNED VS HIBERNATING MYOCARDIUM

顿挫心肌与冬眠心肌的区域 FDG 摄取

• 批准号: 2655257
• 负责人: EDWARD O. MCFALLS
• 金额: $ 8.47万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2655257
• 关键词: adenosine triphosphate; bioenergetics; creatine phosphate; disease /disorder model; glucose metabolism; glucose transport; glycogen; heart circulation; heart function; heart imaging /visualization /scanning; heart metabolism; high energy compound; high performance liquid chromatography; myocardial ischemia /hypoxia; nuclear magnetic resonance spectroscopy; oxygen consumption; positron emission tomography; radiotracer; reperfusion; spectrometry; swine; vasodilation

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.

心肌“冬眠”是指响应于慢性炎症的LV功能障碍。 低灌注尽管有最少的实验证据表明， 存在，严重CAD患者显示功能改善， 血运重建心肌“顿抑”是指可逆性功能障碍 严重缺血和再灌注。临床和实验上， 不清楚这两个实体是否不同。这项建议 提出了两种模式，代表这两种情况。惊艳将被诱导 暂时阻断左前降支20分钟，再灌注24小时 冬眠将通过在周围放置一个固定的收缩器来诱导， 随着动物增大，限制灌注的LAD。PET和适当的 示踪剂将用于测量心肌血流的连续变化 和新陈代谢。 首先，我们假设这两种模型都会引起局部功能障碍 没有明显的坏死我们假设局部葡萄糖 在两种模型中，摄取相对于灌注增加。但我们 推测增强的葡萄糖摄取信号是一个广泛的适应过程， 冬眠平衡能量供给和需求。 其次，我们假设在慢性低灌注心肌中， 心肌保留再生高能磷酸盐的能力， 糖原储存。利用核磁共振技术，我们已经证明， 导致冬眠时透壁ATP的减少，这表明 心肌适应一个新的水平的能量供应平衡，尽管在 缺血阈值我们推测能源供应与此不同 慢性再灌注心肌的功能受到抑制 并且葡萄糖摄取增加（缺血后24小时）。 第三，我们假设心肌适应慢性低灌注 通过“下调”总能量消耗。因此，我们预计， 区域MVO2将随着冬眠的发展而降低。虽然令人惊叹 与增强的MVO2功能相关，休眠是 这与O2的供应和需求有关。 第四，我们将确定是否存在可测量的流量储备 在冬眠的心肌中。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期间重塑。研究 也将使我们能够在流动储备中进行系列测量， 模型的演变。这项研究的推论是， 再灌注心肌中是正常的。如果是这样的话，这将与 我们对急性心肌顿抑的研究 第五，我们提出，与顿抑心肌不同， 将变得更加依赖于碳水化合物底物的利用， 葡萄糖用于能量生产。静脉给药2 脱氧葡萄糖已显示阻断糖酵解> 75%。血糖正常 条件下，我们将测试阻断糖酵解是否会改变NMR 静息或适度起搏时的透壁ATP估计值 应力如果这是真的，研究结果将表明葡萄糖代谢起着重要作用。 在冬眠的适应过程中起着重要的作用。并行 实验中，我们将评估GLUT4蛋白是否易位到 冬眠心脏的质膜初步数据令人震惊 表明GLUT4，主要的胰岛素依赖性葡萄糖转运蛋白， 没有上调。 最后，我们假设腺苷可能在 通过A1受体刺激改变葡萄糖摄取。PET和Fick 将确定葡萄糖摄取的估计值，以测试 PET测量的准确性在以下情况下是可靠的： 腺苷的组织水平增加。