Mechanisms Underlying Takotsubo Syndrome

Takotsubo 综合征的潜在机制

• 批准号: 10522633
• 负责人: WILLIAM M CHILIAN
• 金额: $ 58.94万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522633
• 关键词: Abate; Agreement; Apex of the Heart; Apical; Area; Blood flow; Cardiac; Cardiac Myocytes; Cell Death; Clinical; Complex; Contrast Echocardiography; Coronary; Coronary Occlusions; Development; Down-Regulation; Drug usage; Echocardiography; Event; Gene Expression; Glucose; Heart; Hibernation; Hypoxia; Image; Impairment; Injury; Ischemia; Laboratories; Left; Left ventricular structure; Mass Spectrum Analysis; Measurement; Medical; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Microcirculation; Mind; Mitochondria; Modeling; Molecular; Myocardial; Myocardial Hibernation; Myocardial Ischemia; Myocardial dysfunction; Necrosis; Ohio; Oxygen Consumption; Patients; Phenotype; Phosphorylation; Play; Process; RNA; Reaction; Recovery; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Smooth Muscle; Stress; Stress cardiomyopathy; Syndrome; Testing; Thinking; Time; Tissues; Transgenic Model; Translations; Universities; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Ventricular; Western Blotting; acute coronary syndrome; arteriole; base; contrast enhanced computed tomography; fatty acid metabolism; heart function; heart metabolism; hemodynamics; improved; interdisciplinary approach; mortality; mouse model; multiphoton imaging; necrotic tissue; prevent; programs; protein expression; regional difference; restoration; transcriptome sequencing; two-photon

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.

我们的建议测试了一个总体假设，即冠状动脉调节的区域差异导致微 心脏尖部缺血并诱发 Takotsubo 综合征的水平。 气球状区域的缺血不足以产生细胞死亡，但足以引起细胞死亡 “心肌冬眠”的适应性程序，仅限于气球区域，其中流量减少导致 心尖冬眠的结果是心脏功能的下降。 心肌血流量和功能之间的关系，因为心尖功能的降低与下心肌的功能相匹配 血液流动，解决缺血问题 冬眠的“好处”是防止不可逆的损伤，即 为了确定这些假设是否正确，我们采用了多学科方法 不仅会提供 TTS 的全面机械分析（目标 1），还会确定是否增加 在此背景下，我们建议心尖部的血流对 TTS 产生有益的作用（目标 2）。 两个目标： 具体目标 1. 确定 Takotsubo 综合征是否是由体内流量调节受损引起的 心脏的心尖区域导致心肌缺血和功能下调的微区域。 此外，我们将确定当功能下调以匹配减少的缺血时缺血是否减轻。 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。 假设 2 冠状动脉中的血管收缩剂与心尖部和基底部不同。 在 TTS 的最初发展过程中，心尖部处于缺血状态。 假设 3。 TTS 的特点是心尖气球样变、心功能和心肌血流量的下调 在心尖部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) 是否会导致代谢和功能恢复 Takotsubo 综合征期间引起的分子变化这将在以下假设中进行测试。 增加血流量的两种独立机制：假设4.增加气球区域的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和能力 破译 Takotsubo 综合征的潜在机制，并确定冠状血管是否舒张 挽救与这种综合征相关的异常是一种综合的、跨学科的方法。 嵌入实验计划中，包括心肌血流量的测量（超声心动图） 组织代谢和（质谱）、基因表达（RNA seq、RT-PCR）、蛋白质表达和 使用心肌细胞特异性缺氧命运-磷酸化（蛋白质印迹）和心肌细胞缺氧 映射。