Interactions of Adverse Childhood Experiences, Sleep Disruption, and Mechanistic Links to Vascular Dysfunction in Emerging Adults

ABSTRACT Adverse childhood experiences (ACEs), including abuse, neglect, household and community dysfunction, represent potentially traumatic psychosocial stressors that occur during critical development periods and represent a latent risk factor for future cardiovascular disease (CVD). ACE exposure promotes cardiovascular disease risk in adulthood in a dose-dependent manner, such that adults exposed to 4 or more ACEs have a more than two-fold increased risk of ischemic heart disease and stroke compared to individuals with no ACEs. ACEs are also widespread, with 1 in 6 US adults reporting exposure to four or more ACEs. Identification of modifiable, bio-behavioral mechanisms by which ACEs promote early onset CVD risk is critical to establish effective interventions to improve cardiovascular health in the millions of individuals affected by ACEs. Our recent evidence indicates that young adults exposed to ACEs demonstrate impaired vascular endothelial function that is manifest prior to overt elevations in blood pressure or other CVD risk factors, and that is related to systemic oxidative stress. These vascular impairments were also observed alongside poor sleep, and our strong preliminary data suggests that poor sleep quality, or low sleep efficiency, may mediate the association of ACE exposure with vascular dysfunction. Therefore, we propose that disturbed sleep is a critical, modifiable bio- behavioral pathway by which ACEs promote vascular dysfunction in early life. Here, we propose the critical studies necessary to understand the causal, mechanistic role of disturbed sleep in ACEs-related endothelial dysfunction in young adults. To do so, we propose to 1) objectively quantify the degree to which lower sleep quality contribute to ACEs-related endothelial dysfunction, inflammation, and oxidative stress in young adults, and 2) manipulate sleep quality using an established behavioral sleep intervention, Cognitive Behavioral Therapy for Insomnia (CBT-I), in a cohort of young adults with moderate-to-severe ACE exposure in order to establish the causal, mechanistic role of disturbed sleep in ACEs-related vascular endothelial dysfunction. To accomplish these aims, we will use an innovative translational human approach that includes rigorous at home sleep monitoring using actigraphy and polysomnography, in vivo assessment of endothelial function via flow-mediated dilation testing, and in vitro determination of endothelial cell inflammation and oxidative stress from biopsied endothelial cells. Notably, while vascular endothelial dysfunction contributes to and is prognostic of future CVD, it is also reversable. Thus, outcomes of this study are expected to be of high impact by identifying and understanding how disturbed sleep, a key, targetable bio-behavioral mechanism, contributes to vascular endothelial dysfunction in young adults with exposure to ACEs.