Chronic stress is a recognized risk factor for atherosclerotic cardiovascular disease (CVD), yet the underlying biological mechanisms remain incompletely understood. Dysregulation of cortico-limbic brain circuits, leading to heightened systemic inflammation and accelerated progression of CVD risk factors, has been proposed as a central pathway. Prior research has primarily focused on altered connectivity between the amygdala and the prefrontal cortex (PFC); however, the contributions of additional cortical and subcortical regions have not been fully delineated.

In this study, we utilized a multimodal imaging approach, integrating brain magnetic resonance imaging (MRI) and vascular imaging, to assess both functional and structural connectivity between the amygdala and broader brain networks. Consistent with previous findings demonstrating increased inflammation, greater atherosclerotic burden, and impaired amygdala– PFC connectivity in chronically stressed individuals, we show that task-based functional and structural connectivity measures independently distinguish participants with higher versus lower atherosclerotic burden. Importantly, while limbic and prefrontal regions remain critical, our findings also highlight brain regions involved in sensorimotor and autonomic processes, including the sensorimotor cortices and cerebellum, in the stress–atherosclerosis pathway.

By expanding the scope beyond the amygdala–PFC axis, these results offer a more comprehensive framework for understanding the neural mechanisms linking chronic stress to CVD and may guide the development of novel therapeutic strategies aimed at neuroimmune modulation.

MTO has received consulting fees from WCG Clinical for unrelated work. LMS receives textbook royalties from Pearson for unrelated work. AT received consulting fees from Genentech and Tourmaline, and is supported in part by Lung Biotechnology Inc, each for unrelated work. ZAF is a founder and board member of Trained Therapeutix Discovery, which is unrelated to the current work. In the past five years, JWM has provided consultation services and/or served on advisory boards for Biohaven, Compass Pathfinder, Boehreinger Ingelheim, Clexio Biosciences, Engrail Therapeutics, FSV7, Otsuka, and Sage Therapeutics. JWM is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of KCNQ channel openers to treat depression and related conditions. JWM's disclosures are unrelated to the current work. The other authors have no competing interests to declare.

This work is supported by NHLBI P01HL131478. SA is supported by American Heart Association (AHA) Second Century Early Faculty Independence Award 10.58275/AHA.24SCEFIA1256969.pc.gr.193937. MTO is supported by National Institutes of Health K23HL151909, American Heart Association 10.58275/AHA.23SCISA1143491.pc.gr.172152, and the generosity of the Hassenfeld family, MTO.

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