Heterogeneity and predictors of stress reactivity in takotsubo syndrome

项目摘要/摘要 Takotsubo综合征(TS)是一种日益公认的疾病，其特征是急性、可逆的收缩 唯一影响老年妇女的心力衰竭(90%以上)。尽管大多数患者都康复了 在急性发作后，幸存者发生长期重大脑血管事件(MACCE)和 慢性左心室(LV)功能受损。尽管它与临床相关，但重要的知识 关于这一有趣的、或许还未得到充分认识的状况，人们存在分歧。虽然有一个普遍的共识 过度的交感神经系统(SNS)放电是最终常见的病理生理事件 这是TS患者发生急性收缩性心力衰竭的基础，这种情况具有相当大的异质性。 首先，暴露于情绪触发因素被认为是TS的决定性诱因，但最近的注册数据 相反，表明情感触发只出现在三分之一的情况下，有物理触发(1/3)，没有 触发(1/3)占其余案例。第二，连接细胞的病理生理途径 TS发病的诱因尚待阐明。第三，目前还不清楚为什么某些人 当暴露在早晚会影响到所有人的情绪触发因素时，会产生夸张的SNS反应 在整个生命周期内不会对健康造成任何或有限影响的个人。最后，没有一项研究严格地 检验触发事件和心理应激反应对脑出血患者远期预后的影响 这些病人。为了解决这些关键证据差距，我们将在246名患者中进行一项机械性临床试验。 来自普罗维登斯的3个大型医疗中心的确诊为TS的新入院患者 区域。参与者将接受全面的访谈，以确定TS发病附近的事件 并在出院2周后完成一组心理社会调查问卷。大约4 出院几周后，他们将接受我们小组以前使用的实验室精神应激方案。 自主神经系统活动(循环儿茶酚胺)测量的基线和反应性变化 和心脏迷走神经控制)、左心功能(2D斑点追踪超声心动图(2D-STE))和血流动力学 将对参数进行评估。12个月后进行左心室功能和MACCE评估。建议进行的研究 将通过a)严格评估接近的所有情况来解决注意到的证据差距 TS发病，b)评估定义TS(自主神经系统)的生理要素星座 活动和左心室功能)在受控条件下，以及c)触发类型与生理联系。此外， 通过使用2D-STE，我们将能够捕捉到LV功能的反应性和长期的细微异常 这些病人。这将是第一个严格研究临床表现异质性的研究， TS的病理生理和预后。在TS中识别不同的子组将提供理论基础 用于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.