Strengthening Hearts by Addressing DisruptEd Sleep (SHADES) Mechanistic Trial

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7. PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) affects nearly 1 in 2 U.S. adults, is the #1 killer of men and women, burdens disadvantaged groups, and has costs greater than any other condition. While these statistics highlight the importance of CVD prevention, current approaches have only partial effectiveness. This has created a need to identify new CVD prevention targets, their underlying mechanisms, and effective interventions. Insomnia, its candidate mechanisms, and insomnia treatment are strong candidates in this regard. Thirty years of evidence indicates that insomnia is an independent, clinically important, robust, and potentially causal and modifiable risk factor for CVD. In addition, biologically plausible mechanisms that could explain how insomnia promotes the development of CVD have been proposed, with the most strongly supported being systemic inflammation, autonomic dysfunction, and metabolic dysregulation. Our recent RCT of adults with insomnia disorder provides promising preliminary support for one such candidate mechanism. Adults randomized to cognitive-behavioral therapy for insomnia (CBT-I), versus education control, had a reduced risk of high C-reactive protein (CRP), an inflammation marker implicated in the pathophysiology of CVD and predictive of future CVD events, at follow- up. Because insomnia now receives limited attention in settings where CVD prevention occurs (e.g., primary care), there is a large cohort of patients with an unaddressed CVD risk factor (insomnia). This status quo and the strong state of the insomnia-to-CVD science create the current need for a well-powered, mechanistic trial to elucidate biological mechanisms underlying the insomnia-to-CVD relationship and CBT-I’s mechanisms of action, both of which are presently unknown. Therefore, we propose a mechanistic trial of 200 primary care patients (45% minority) with insomnia disorder and CVD risk factors but no clinical CVD. Patients will be randomized to 6 months of the SHADES (Strengthening Hearts by Addressing DisruptEd Sleep) Intervention or Active Control. The SHADES Intervention is our modernized collaborative care intervention consisting of well- established internet, telephonic, and face-to-face CBT-I. Active Control consists of sleep education/hygiene, symptom monitoring, and primary care for insomnia. Our proposal has four aims – Aim 1: determine the effect of the SHADES Intervention on our primary CVD mechanism of high-sensitivity CRP; Aim 2: determine the effect of the SHADES Intervention on our secondary CVD mechanisms of systemic inflammation, autonomic dysfunction, and metabolic dysregulation; Aim 3: examine if 6-month improvements in upstream sleep mechanisms mediate the SHADES Intervention effect on 6-month improvements in downstream CVD mechanisms; ExploratoryAim: explore the effect of the SHADES intervention on proinflammatory gene expression. The proposed trial would generate the critical support for the mechanistic rationale and conceptual framework needed to justify the next-step phase III, multi-site RCT to determine the SHADES Intervention effect on CVD clinical outcomes, endpoints of great