Mechanisms Underlying Takotsubo Syndrome

我们的建议测试了一个重要的假设，即冠脉调节的地区差异导致微血管 心脏尖部区域的缺血区，并导致Takotsubo综合征。我们假设， 气球区域的缺血不足以导致细胞死亡，但足以引起细胞死亡 “心肌冬眠”的适应性程序，限制在流量减少导致气球膨胀的区域 导致心脏功能下降。顶端冬眠的结果是比赛的恢复 心肌血流和功能之间的关系，因为降低的心尖功能与较低的心肌相匹配 血液流动，消除缺血。这种冬眠的“好处”是防止不可逆转的伤害，即， 坏死。为了确定这些假设是否正确，我们采用了多学科方法， 将不仅提供TTS(目标1)的全面机制分析，而且还将确定是否增加 心尖部的血流在TTS中起到有益健康的作用(目标2)。在此背景下，我们建议 两个目标：具体目标1.确定Takotsubo综合征是否由脑血流调节受损引起 心脏的顶端区域导致微小的心肌缺血和功能下调。 此外，我们将确定当功能下调以匹配减少的 流。这一目标将通过以下假设来检验：假设1.对血管扩张剂的血管活性反应 在心尖和心底的冠状小动脉中，血管收缩因子是不同的。假设2。 在TTS的最初发展过程中，心尖是缺血的。假设3.在 TTS的特点是心尖气球膨胀，心功能和心肌血流量下调 在心尖部消除心肌缺血并产生心尖部冬眠。第二个具体目标 建议确定改善心肌血流量(MBF)是否会导致代谢和 在Takotsubo综合征期间引起的分子变化。这将在下面的假设中进行测试，使用 增加血流量的两种独立机制：假设4.在气球区域增加MBF 预防或恢复心脏、冠状动脉和代谢功能障碍。此应用程序建立在专业知识的基础上 东北俄亥俄医科大学和康奈尔大学研究团队的技术能力 破译Takotsubo综合征的机制，并确定冠状动脉血管扩张 挽救与这种综合征相关的异常。一个综合的、跨学科的方法是 嵌入实验计划，包括测量心肌血流量(超声心动图) 组织代谢和(质谱学)、基因表达(RNA序列、RT-PCR)、蛋白质表达和 磷酸化(Western Blotting)和使用心肌细胞特异性缺氧命运的心肌细胞缺氧 映射。

Our proposal tests the overarching hypothesis that regional differences in coronary regulation cause micro- areas of ischemia in the apex of the heart and induce Takotsubo Syndrome. We posit that the level of ischemia in the ballooning area is not sufficient to produce cell death, but enough of a decrease to invoke an adaptive program of “myocardial hibernation,” confined to area of ballooning, where the decrease in flow leads to a decrease in cardiac function. The consequence of apical hibernation is a restoration of the match between myocardial blood flow and function as the reduced apical function matches the lower myocardial blood flow, resolving the ischemia. The “benefit” of this hibernation is to prevent irreversible injury, i.e., necrosis. To determine if these hypotheses are correct, we have incorporated a multidisciplinary approach that will not only provide a comprehensive mechanistic analysis of TTS (Aim 1), but will also determine if increasing blood flow in the apex of the heart exerts a salubrious effect in TTS (Aim 2). Within this context, we propose two aims: Specific Aim 1. To determine if Takotsubo Syndrome is caused by impaired flow regulation in the apical regions of the heart leading to micro-areas of myocardial ischemia and a down-regulation of function. Furthermore, we will determine if the ischemia is abated when function downregulates to match the reduced flow. This aim will be tested by the following hypotheses: Hypothesis 1. Vasoactive reactions to vasodilators and vasoconstrictors are different in coronary arterioles from the apex and base of the heart. Hypothesis 2. During the initial development of TTS, the apex of the heart is ischemic. Hypothesis 3. During the stage of TTS characterized by apical ballooning, the downregulation of both cardiac function and myocardial blood flow in the apex eliminates myocardial ischemia and produces apical hibernation. The second specific aim proposes to determine if improving myocardial blood flow (MBF) will induce recovery of metabolic and molecular changes induced during Takotsubo Syndrome. This will be tested in the following hypothesis using two independent mechanisms to increase blood flow: Hypothesis 4. Increasing MBF in the area of ballooning prevents or restores cardiac, coronary, and metabolic dysfunction. This application builds upon the expertise and technological capability of research teams at Northeast Ohio Medical University and Cornell University to decipher mechanisms underlying Takotsubo Syndrome, and to determine whether coronary vasodilation rescues the abnormalities associated with this syndrome. A comprehensive, interdisciplinary approach is imbedded in the experimental plan to include measurements of myocardial blood flow (echocardiography) tissue metabolism and (mass spectrometry), gene expression (RNA seq, RT-PCR), protein expression and phosphorylation (Western blotting) and cardiac myocyte hypoxia using cardiac myocyte specific hypoxia fate- mapping.