Mechanisms Underlying Takotsubo Syndrome

我们的提议验证了冠状动脉调节的区域差异导致微- 心尖部缺血区域并诱发Takotsubo综合征。我们认为， 气球样变区域的局部缺血不足以引起细胞死亡，但足以引起细胞死亡。 适应性程序的“心肌冬眠”，局限于该地区的气球，在流量减少导致 导致心脏功能下降顶端休眠的结果是恢复了 由于心尖功能降低与下心肌功能相匹配， 血液流动，解决局部缺血这种休眠的“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， 将不仅提供全面的机制分析TTS（目标1），但也将确定是否增加 心尖部的血流在TTS中发挥有益健康的作用（目的2）。在此背景下，我们建议 两个目标：具体目标1。为了确定Takotsubo综合征是否是由脑血流调节受损引起的， 心脏的心尖区域导致心肌缺血的微区域和功能的下调。 此外，我们将确定当功能下调以匹配减少的功能时，缺血是否减轻。 流这一目标将通过以下假设进行检验：假设1。对血管扩张剂的血管活性反应 心脏心尖部和基底部的冠状小动脉中的血管收缩剂不同。假设2. 在TTS的最初发展过程中，心脏的心尖是缺血的。假设3.阶段期间 TTS以心尖气球样变为特征，心脏功能和心肌血流量均下调 消除心肌缺血并产生心尖冬眠。第二个具体目标 建议确定改善心肌血流量（MBF）是否会诱导代谢和 在Takotsubo综合征期间诱导的分子变化。这将在以下假设中进行检验， 2.两种独立的机制增加血流量：假设4。增加球囊扩张区域的MBF 预防或恢复心脏、冠状动脉和代谢功能障碍。该应用程序基于专业知识 东北俄亥俄州医科大学和康奈尔大学的研究小组的技术能力， 破译Takotsubo综合征的潜在机制，并确定冠状动脉血管舒张是否 挽救了与这种综合症相关的异常。一个全面的、跨学科的方法是 嵌入实验计划，包括心肌血流量测量（超声心动图） 组织代谢和（质谱），基因表达（RNA测序，RT-PCR），蛋白质表达和 使用心肌细胞特异性缺氧命运的磷酸化（Western印迹）和心肌细胞缺氧- 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.