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”是指左心室功能障碍对慢性心肌病的反应。 灌注不足。尽管只有极少的实验证据表明 存在，严重 CAD 患者的功能有所改善 血运重建。心肌“震颤”是指可逆性功能障碍 严重缺血和再灌注后。临床和实验上， 目前尚不清楚这两个实体是否不同。这个提议 提出了代表这两种情况的 2 个模型。会诱发眩晕 暂时封闭 LAD 20 分钟并重新灌注 24 小时 并通过在其周围放置一个固定的收缩器来诱导冬眠 当动物变大时，LAD 会限制灌注。 PET及适当的 示踪剂将用于测量心肌血流量的连续变化 和新陈代谢。 首先，我们假设两种模型都会引起区域功能障碍 在没有明显坏死的情况下。我们假设区域葡萄糖 在两种模型中，摄取相对于灌注均有所增加。然而，我们 推测葡萄糖摄取增强标志着广泛的适应性过程 冬眠平衡能量供应与需求。 其次，我们假设在长期灌注不足的心肌中， 心肌保留再生高能磷酸盐的能力 糖原储存。使用核磁共振技术，我们已经证明快速起搏 导致冬眠期间跨壁 ATP 减少，表明 心肌适应新水平的能量供应平衡，尽管 缺血阈值。我们推测能源供应与此不同 功能下降时慢性再灌注的心肌 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低灌注 通过“下调”总能量消耗。因此，我们期望 随着冬眠的进展，区域 MVO2 将会降低。而令人惊叹的 与功能相关的 MVO2 增强有关，冬眠是 效率与 O2 供需有关。 第四，我们将确定是否存在可测量的流量储备 冬眠心肌内。如果是这样，这将支持以下观点： 血流慢性减少期间阻力血管重塑。研究 还允许我们在流量储备方面采取系列措施 模型的演变。这项研究的推论是流量储备 在再灌注心肌中是正常的。如果是这样，这将与 我们对急性顿抑心肌的研究。 第五，我们提出，与顿顿心肌不同，冬眠区域 将变得更加依赖于碳水化合物底物的利用，例如 葡萄糖用于产生能量。静脉注射2 脱氧葡萄糖已被证明可以阻止糖酵解>75%。血糖正常时 条件下，我们将测试阻断糖酵解是否会改变 NMR 休息时或适度起搏期间跨壁 ATP 的估计 压力。如果属实，研究结果表明葡萄糖代谢发挥着作用 在冬眠的适应过程中发挥着重要作用。并联 实验中，我们将评估 GLUT4 蛋白是否易位至 冬眠心脏中的质膜。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以下方面发挥重要作用： 通过刺激 A1 受体改变葡萄糖摄取。 PET和菲克 将确定葡萄糖摄取的估计值，以测试是否 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。