Heterogeneity and predictors of stress reactivity in takotsubo syndrome

项目总结/摘要 Takotsubo综合征（TS）是一种日益被认识的疾病，其特征是急性、可逆性收缩期 心力衰竭是唯一影响老年女性的疾病（超过90%的病例）。虽然大多数病人都能康复 急性发作后，存活者发生长期主要脑血管事件（MACCE）和 左心室（LV）功能的慢性损伤。尽管有临床意义，重要的知识 关于这一有趣的、可能被低估的情况存在差距。虽然人们普遍认为 夸张的交感神经系统（SNS）放电是最后常见的病理生理事件 这是TS中急性收缩性心力衰竭发作的基础，但这种情况具有相当大的异质性。 首先，暴露于情绪触发被认为是TS的一个决定性诱因，但最近的登记数据显示， 相反，表明情感触发仅在1/3的情况下存在，物理触发（1/3）和没有 触发器（1/3）占剩余病例的比例。第二，病理生理途径连接 诱发TS发作的触发因素仍有待阐明。第三，不清楚为什么某些人 当暴露于情绪触发时，会产生夸大的SNS反应，迟早会影响所有人 在整个生命周期中对个体没有或有限的健康影响。最后，没有任何研究严格地 测试了触发事件和精神应激反应对长期预后的贡献， 这些病人。为了解决这些关键的证据差距，我们将在246名患者中进行一项机械临床试验。 来自RI普罗维登斯3家大型医疗中心的经验证诊断为TS的新入院患者 区参与者将接受全面的访谈，以确定TS发作附近的事件 并在出院后2周完成一系列心理社会问卷。约4 出院后两星期，他们将接受我们小组以前使用的实验室精神压力方案。 自主神经系统活动测量的基线和反应性变化（循环儿茶酚胺 和心脏迷走神经控制）、LV功能（2D斑点追踪超声心动图（2D-STE））和血流动力学 将评估参数。将在12个月后评估LV功能和MACCE。拟定研究 （a）严格评估最接近的各种情况， TS发作，B）评估定义TS（自主神经系统）的生理要素的星座 活动和LV功能），以及c）将触发类型与生理学联系起来。此外，委员会认为， 通过使用2D-STE，我们将能够捕获左心室功能的反应性和长期微妙异常， 这些病人。这将是第一项严格调查临床表现异质性的研究， 病理生理学和预后。TS中不同亚组的识别将提供依据 设计和测试适当的针对性干预措施，以改善这些患者的预后。

PROJECT SUMMARY/ABSTRACT Takotsubo syndrome (TS) is an increasingly recognized condition characterized by acute, reversible systolic heart failure which uniquely affects older women (more than 90% of cases). Although most patients recover after an acute episode, survivors have a high risk of long-term major cerebrovascular events (MACCE) and of chronic impairments of the left ventricular (LV) function. Despite its clinical relevance, important knowledge gaps exist about this interesting and perhaps underappreciated condition. While there is a general consensus that an exaggerated sympathetic nervous system (SNS) discharge is the final common pathophysiologic event that underlies the onset of acute systolic heart failure in TS, this condition has considerable heterogeneity. First, exposure to an emotional trigger was thought to be a defining precipitant of TS, but recent registry data indicate instead that emotional triggers are present only in 1/3 of cases, with physical triggers (1/3) and no triggers (1/3) accounting for the remaining cases. Second, the pathophysiological pathway linking the precipitating trigger to the onset of TS remains to be articulated. Third, it is unclear why certain individuals develop an exaggerated SNS response when exposed to emotional triggers which sooner or later affect all individuals throughout the lifespan with no or limited health consequences. Finally, no study has rigorously tested the contribution of triggering event and mental stress responsiveness to the long-term prognosis of these patients. To address these key evidence gaps we will conduct a mechanistic clinical trial among 246 newly admitted patients with a validated diagnosis of TS from 3 large medical centers in the Providence, RI area. Participants will undergo a comprehensive interview to identify the events proximal to the onset of TS and complete a battery of psychosocial questionnaires 2 weeks after hospital discharge. Approximately 4 weeks after discharge they will undergo a laboratory mental stress protocol previously utilized by our group. Baseline and reactive changes in measures of autonomic nervous system activity (circulating catecholamines and cardiac vagal control), LV function (2D speckle tracking echocardiography (2D-STE)), and hemodynamic parameters will be assessed. LV function and MACCE will be assessed 12 months later. The proposed study will address the noted evidence gaps by a) Rigorously assessing the full range of circumstances proximal to TS onset, b) Assessing the constellation of physiological elements that define TS (autonomic nervous system activity and LV function) under controlled conditions, and c) Link the type of trigger to physiology. Furthermore, by using 2D-STE we will be able to capture both reactive and long-term subtle anomalies of LV function in these patients. This will be the first study to rigorously investigate the heterogeneity in clinical presentation, physiopathology, and prognosis in TS. The identification of distinct sub-groups in TS will provide the rationale for the design and testing of properly targeted interventions to improve the prognosis of these patients.