Multimodal profiling of stress-induced immune reprogramming in cardiovascular patients

总结 慢性心理社会压力是人类经历的一个普遍组成部分， 心血管疾病（CVD）风险与吸烟或心脏代谢疾病（CMD）相当。而 长期以来，人们一直认为“心脑联系”是压力对大脑产生有害影响的机制。 心血管系统在很大程度上还未被研究。在上一个资助周期中，我们使用了最先进的 工具，包括正电子发射断层扫描和磁共振（PET/MR）成像，以获得 对严重的，急性心理社会压力和改变的神经，免疫， 创伤后应激障碍（PTSD）患者的心血管功能与低CVD风险。过程中 在第一个计划项目中，我们具有里程碑意义的发现揭示了与压力相关的神经免疫心血管疾病。 axis，它现在已经被其他几个团体验证，并被证明是一个普遍的促进者， 心血管疾病正如我们的初步数据所示，我们还观察到压力之间的密切联系- 相关神经活动（SNA）和几个CMD成分，我们表明遗传学和生活方式 因素可以调节应激和CVD之间的关系。然而，关键的知识差距依然存在。我们 需要更好地了解神经网络中压力诱导的破坏如何导致免疫系统 失调、CMD和动脉粥样硬化。遗传和生活方式因素影响的机制 神经-免疫-心血管轴也没有被很好地理解。此外，这些过程必须 研究对象是心血管疾病风险较高的人群， 最重要的是了解如何最好地调节这一系统，以改善心血管健康。的 项目4的总体假设是，在中至高CVD风险的受试者中：SNA升高 （特别是包括杏仁核和腹内侧前额叶皮层（vmPFC）的活动）与 CMD，增强免疫系统活性，最终，CVD表现。我们假设这 与压力相关的神经免疫心血管轴受遗传特征和健康行为的调节， 与压力敏感性有关在本项目的第一个目标中，我们将集中于表征应力- 在遗传和神经系统疾病的背景下， 健康行为。第二个目标是描述应激诱导的免疫失调， CVD。总之，这项研究将提供关键的见解之间的联系，压力引起的， 脑回路的改变，免疫失调，以及它们对大脑的下游有害后果。 心血管系统在中度至高风险的CVD患者。通过探索这些因素之间的相互作用， 过程和其他重要的心血管疾病风险因素，如心脏代谢，遗传和生活方式因素，我们将 能够揭示新的策略，以减轻压力对心血管系统的负面影响。

SUMMARY Chronic psychosocial stress is a pervasive component of the human experience, carrying an attributable cardiovascular disease (CVD) risk that is on par with smoking or cardiometabolic disease (CMD). While a “heart-brain connection” has long been postulated, the mechanisms underlying stress’s deleterious effects on the cardiovascular system are largely under-investigated. In the previous grant cycle, we used cutting-edge tools, including combined positron emission tomography and magnetic resonance (PET/MR) imaging, to gain critical insights on the links between severe, acute psychosocial stress and altered neural, immune, and cardiovascular functions in post-traumatic stress disorder (PTSD) patients with low CVD risk. In the course of this first Program Project, our landmark findings uncovered a stress-associated neuro-immune-cardiovascular axis, which has now been validated by several other groups and proven to be a pervasive promoter of cardiovascular diseases. As shown by our preliminary data, we also observed strong links between stress- associated neural activity (SNA) and several CMD components, and we showed that genetics and lifestyle factors can modulate the relationship between stress and CVD. However, critical knowledge gaps remain. We need a better understanding of how stress-induced disruptions in neural networks lead to immune system dysregulation, CMD and atherosclerosis. The mechanisms by which genetic and lifestyle factors impact the neuro-immune-cardiovascular axis are also not well understood. Moreover, these processes need to be studied in individuals at higher risk for cardiovascular disease, the same population that would stand to gain the most from insights on how best to modulate this system to improve cardiovascular health. The overarching hypothesis of Project 4 is that, in subjects with moderate-to-high risk for CVD: heightened SNA (notably including the activity of the the amygdala and ventromedial prefrontal cortex (vmPFC)) associates with CMD, heightened immune system activity, and, ultimately, CVD manifestations. We hypothesize that this stress-related neuro-immune-cardiovascular axis is modulated by genetic traits and health behaviors that are known to associate with stress sensitivity. In the first aim of this Project, we will focus on characterizing stress- related alterations in neurological networks that associate with CVD and CMD, in the context of genetic and health behaviors. The second aim will characterize the stress-induced immune dysregulations that mediate CVD. In summary, this study will provide critical insights into the connections between stress-induced alterations in brain circuitry, immune dysregulations, and their downstream deleterious consequences on the cardiovascular system in patients at moderate-to-high risk for CVD. By exploring the interactions among these processes and other important CVD risk factors, such as cardiometabolic, genetic, and lifestyle factors, we will be able to shed light on novel strategies to mitigate stress’s negative effects on the cardiovascular system.