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.