However atherosclerosis is a progressive process. So it would be possible for an astronaut to develop increasing CAC (and atherosclerosis) over time. Moreover, the development of vascular calcification may be preceded by substantial non-calcified plaque, which may be most prone to rupture and cause an acute coronary syndrome. Finally, coronary atherosclerosis impairs coronary endothelial function which can then both initiate and stimulate progression of atherosclerosis; myocardial contrast echocardiography (MCE) can non-invasively quantify coronary microvascular function to complement the structural assessment by coronary computerized tomography angiography (cCTA).

Important for this project and the Request for Actions (RFA) is the potential for space radiation to accelerate atherosclerosis. Recent flight studies have suggested that non-coronary vascular beds may stiffen with reduced vascular reserve during 6 month International Space Station (ISS) missions, and ground based studies have identified the surprising capacity for coronary atherosclerosis to evolve rapidly under extreme stress. The global object of this project is to determine the effect of incremental doses of spaceflight on coronary anatomy and physiology, and to identify biomarkers that may be useful for early detection of accelerated atherosclerosis. To accomplish this objective, we propose to complete the following specific aims:

Specific Aim 1: to test the hypothesis that coronary atherosclerosis will be accelerated by 1 year of spaceflight. We will perform cCTA: a) 1 year before flight upon crew selection; b) within 4-8 weeks of flight; c) soon (within 1-2 weeks) after 1 year in space; and d) after 1 year recovery. This strategy will allow us to compare the trajectory of coronary atherosclerosis before and after prolonged spaceflight. The extent of calcified and non-calcified plaque will be quantified, and markers of plaque vulnerability will be assessed. To provide context, we will also compare these data to well matched controls from the Cooper Clinic Longitudinal Study and the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) cCTA registry. Specific Aim 2: to test the hypothesis that 1 year in space will impair coronary endothelial function and vasomotor reactivity. We will perform MCE before and after adenosine pre, in, and post-flight to quantify coronary microvascular function. Exploratory Aim 3: to test the hypothesis that a multimodality biomarker panel including blood (hs-troponin, NTproBNP, markers of oxidative stress and DNA damage) and relevant imaging (CAC, cCTA, MCE) can quantify risk of accelerated atherosclerosis before and during long duration flight.

This study will provide critically important information regarding changes in coronary structure and function during 1 year in space, and will form the knowledge base to assess cardiovascular risk from multiyear exploration class missions. If the changes in the coronary circulation are as pronounced as the peripheral circulation, specific plans for monitoring and management in space can be developed including prevention and treatment. These aims will directly address Gap Degen-7 (Are there synergistic effects from other spaceflight factors (e.g., altered gravity (µ-gravity), stress, altered immune function, altered circadian rhythms, or other) that modify space radiation-induced degenerative diseases in a clinically significant manner?) and Gap CV1 (What are the in-flight alterations in cardiac structure and function?), and CV8 (Can manifestations of sub-clinical or environmentally induced cardiovascular diseases during spaceflight be predicted?).