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: 2332524
• 负责人: EDWARD O. MCFALLS
• 金额: $ 8.16万
• 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/2332524
• 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”是指回应慢性的LV功能障碍 灌注不良。尽管有最低的实验证据表明 存在，患有严重CAD的患者表现出改善的功能 血运重建。心肌“惊人”是指可逆的功能障碍 经过严重的缺血和再灌注。临床和实验， 目前尚不清楚这两个实体是否不同。这个建议 呈现2种典型情况的模型。令人惊叹的 通过暂时阻塞小伙子20分钟并饲养24小时 冬眠将通过在 LAD将灌注限制为动物扩大。宠物和适当 示踪剂将用于测量心肌流动的串行变化 和新陈代谢。 首先，我们假设这两个模型都会诱发区域功能障碍 在没有明显坏死的情况下。我们假设该区域葡萄糖 在这两个模型中，相对于灌注的吸收量增加。但是，我们 推测增强的葡萄糖摄取信号是一个广泛的自适应过程 冬眠可以平衡能源供应与需求。 其次，我们假设在慢性心肌心肌内， 心肌保留了再生高能磷酸盐和 糖原存储。使用NMR技术，我们已经表明了快速起搏 导致冬眠中透壁ATP的减少，表明 心肌适应新的能量供应平衡，尽管 缺血的阈值。我们推测能源供应与此不同 一段时间抑郁症的慢性重新填充心肌 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灌注不足 通过“下调”的总能源消耗。因此，我们期望 随着冬眠的发展，区域MVO2将抑郁。而令人惊叹 与功能相对于功能增强的MVO2相关，冬眠为 有效与O2供求有关。 第四，我们将确定是否存在可测量的流量储备 在冬眠心肌内。如果是这样，这将支持 慢性减少流动期间的电阻容器重塑。研究 还可以使我们能够在流量储备中采取串行措施 模型的演变。这项研究的推论是流量储备 在重复的心肌中是正常的。如果是这样，这将与 我们在急性震惊的心肌方面的研究。 第五，我们提出，与震惊的心肌，冬眠区域不同 将变得更加依赖碳水化合物底物利用率，例如 葡萄糖用于能源生产。静脉注射2 脱氧葡萄糖已显示出糖酵解量> 75％。在尤格血糖范围内 条件，我们将测试阻断糖酵解是否会改变NMR 在休息或适度的起搏时估计透壁ATP 压力。如果是真的，这些发现将表明葡萄糖代谢发挥作用 在冬眠的自适应过程中的重要作用。并联 实验，我们将评估GLUT4蛋白是否易位到 冬眠心中的质膜。令人惊叹的初步数据 表明GLUT4是葡萄糖的主要胰岛素依赖性转运蛋白的IS 没有上调。 最后，我们假设腺苷在 通过A1受体刺激改变葡萄糖摄取。宠物和给 将确定葡萄糖摄取的估计值以测试是否是否 宠物测量的准确性在情况下可靠 腺苷的组织水平增加。