Identifying Early Intervention Targets for Reducing Cardiovascular Risk in Posttraumatic Stress

项目总结 创伤后应激障碍(PTSD)使发生心血管疾病(CVD)的风险增加25%-50%。多数 个人(50%-90%)在一生中经历过创伤事件，创伤后应激障碍是第五大常见事件 精神障碍。专家们现在呼吁加强创伤后心血管疾病的监测和创伤后应激障碍 旨在降低心血管疾病风险的治疗试验。然而，心血管疾病风险和创伤后应激障碍都是复杂的现象， 可能会以微妙的方式进行互动。因此，要使这些努力取得成功，我们必须首先确定 创伤后应激障碍影响突发心血管疾病风险的机制。此外，我们必须了解哪些是 创伤后应激障碍背后的维度激活了这些心血管疾病风险机制。这项研究将确定哪种创伤后应激障碍 维他命(S)导致内皮功能障碍，这是心血管疾病最早的可修改前体之一。只有三个 在选定的创伤暴露人群(男性退伍军人和警察)中进行的研究已经测试了 PTSD症状与血流介导的扩张(FMD)，一种内皮功能障碍的衡量标准。这么早 研究指出，内皮功能障碍是创伤后应激障碍-心血管疾病联系的潜在机制，但 创伤后应激和内皮功能障碍的概括性和缺乏细微差别的测量 这些研究限制了它们的影响。事实上，我们仍然不知道创伤后应激障碍和内皮功能障碍 在更广泛的社区中与个人相关联。了解创伤后应激障碍的哪些方面是最严重的 “心脏毒性”也是缺乏的，所以我们不知道创伤后应激的哪些维度是目标。恐惧 反应是创伤后应激障碍的核心组成部分，与心血管功能有直接的生物学相关性，而 创伤后应激障碍的焦虑症维度被认为更具辅助性。在这项研究中，我们将检查横断面 创伤后应激障碍及其潜在维度与功能和细胞的纵向关联 内皮功能障碍的测量方法(分别为FMD和循环内皮细胞衍生的微粒) 在一个社区居住的样本中，没有心血管疾病的成年男性和女性有创伤史(50%的人有目前的 创伤后应激障碍)。在主要目标1中，我们将测试创伤后应激障碍的诊断与内皮功能障碍的关系。在……里面 主要目标2，我们将检查创伤后应激障碍的哪些维度(恐惧和焦虑症的客观测量，以及 访谈评估的低阶症状维度)与内皮细胞的相关性最强 功能障碍。在第二个目标中，我们将检查这些PTSD维度如何预测内皮细胞的变化 样本中的一个子集中的功能障碍超过2年。最后，我们将探讨与应激相关的生物学作用 创伤后应激障碍的相关机制，包括自主神经失衡、炎症和氧化应激 血管内皮细胞功能障碍。这项研究将提供迄今为止生物学上最有力的证据 创伤后应激障碍对突发心血管疾病风险影响的可信机制模型。如果我们的假设得到支持，未来 将优化干预措施，以减少创伤后恐惧或创伤后应激障碍的另一个方面，以减少早期 内皮损伤和抵消CVD风险，使得创伤后的CVD监测和干预是值得的。

PROJECT SUMMARY Posttraumatic stress disorder (PTSD) increases risk of incident cardiovascular disease (CVD) by 25-50%. Most individuals (50-90%) experience a traumatic event in their lifetime, and PTSD is the fifth most common psychiatric disorder. Experts have now called for increased CVD surveillance after trauma and for PTSD treatment trials powered to reduce CVD risk. However, both CVD risk and PTSD are complex phenomena that likely interact in nuanced ways. Therefore, for such efforts to be successful, we must first identify the mechanisms by which PTSD influences incident CVD risk. Further, we must understand which of the dimensions underlying PTSD activate those CVD risk mechanisms. This study will determine which PTSD dimension(s) contribute to endothelial dysfunction, one of the earliest modifiable precursors to CVD. Only three studies in select trauma-exposed populations (male veterans and police officers) have tested the association of PTSD symptoms with flow-mediated dilation (FMD), a functional measure of endothelial dysfunction. This early work points to endothelial dysfunction as a potential mechanism of the PTSD-CVD link, but the limited generalizability and lack of nuanced measurement of both posttraumatic stress and endothelial dysfunction in those studies has limited their impact. Indeed, we still do not know whether PTSD and endothelial dysfunction are associated in individuals from the broader community. Knowledge of which aspects of PTSD are most “cardiotoxic” is also lacking, so we do not know which posttraumatic stress dimensions to target. Fear responses are a core component of PTSD with direct biological relevance to cardiovascular function, whereas the dysphoria dimension of PTSD is considered more auxiliary. In this study, we will examine cross-sectional and longitudinal associations of PTSD and its underlying dimensions with functional and, secondarily, cellular measures of endothelial dysfunction (FMD and circulating endothelial cell-derived microparticles, respectively) in a community-dwelling sample of CVD-free adult men and women with a history of trauma (50% with current PTSD). In Primary Aim 1, we will test the association of PTSD diagnosis with endothelial dysfunction. In Primary Aim 2, we will examine which PTSD dimensions (objective measures of fear and dysphoria, as well as interview-assessed lower-order symptom dimensions) are most strongly associated with endothelial dysfunction. In a Secondary Aim, we will examine how these PTSD dimensions predict change in endothelial dysfunction over 2 years in a subset of the sample. Finally, we will explore the role of stress-related biological mechanisms, including autonomic imbalance, inflammation, and oxidative stress, in the associations of PTSD dimensions with endothelial dysfunction. This study will provide the strongest evidence to date for a biologically plausible mechanistic model of PTSD’s influence on incident CVD risk. If our hypotheses are supported, future interventions will be optimized to reduce posttraumatic fear or another PTSD dimension so as to reduce early endothelial damage and offset CVD risk, making CVD surveillance and intervention after trauma worthwhile.