SA 1.  To determine the effects of long-duration spaceflight on measures of oxidative and inflammatory stress.

H1: Levels of inflammatory and oxidative biomarkers will be higher during long duration spaceflight, compared to pre-flight levels, and remain elevated immediately following spaceflight.

SA 2.  To determine the effects of long-duration spaceflight on measures of arterial structure and function through R+3.

H1: Arterial function, assessed by flow-mediated dilation, will be impaired following long duration spaceflight through R+3.  Carotid intima-medial thickness will increase in response to long duration spaceflight and will stay increased, although at a subclinical level, throughout recovery.

SA 3.  To determine how alterations in vascular function and structure correlate with changes in circulating biomarkers of oxidative and inflammatory stress.

H1: Statistical analysis of these biomarkers and indices of atherosclerosis risk will yield a cadre of potential candidates for predictors of vascular dysfunction and atherosclerosis risk.

SA4: To monitor vascular status of astronauts for up to five years after the completion of their long-duration space flight mission (surveillance). 

Aim 1 will simulate a 6 month ISS human mission, determining the impact of simulated

weightlessness and space radiation [150 MeV protons (20 mGy), 1 GeV protons (20 mGy) and

600 MeV/n silicon (10 mGy)] on cardiac rhythm and risk for cardiac disease.

Specific Aim 2 will simulate a 3-3.5 year deep space human mission, determining the impact

of simulated weightlessness combined with components of galactic cosmic rays (60 % 1 GeV

protons, 20% 250 MeV/n helium, 10% 350 MeV/n oxygen and 10% 600 MeV/n silicon) with

total doses of 0.50 and 0.75 Gy plus appropriate controls on cardiac rhythm and risk for

cardiac disease.

Specific Aim 3 will determine the response to gamma radiation with and without simulated

weightlessness, to estimate relative biological effectiveness (RBE) for early clinically relevant

endpoints for cardiac rhythm and risk for cardiac disease. Rats will be irradiated with doses of

0.25, 0.5 Gy, 1.0 Gy and 2.0 Gy of 137Cs at Brookhaven National Laboratory alongside

experimental animals.

Focus of this research is the evaluation of the effects of the combined exposures (weightlessness plus radiation) on cardiovascular structure and function.

Specific Aims:

• Aim 1: Utilize a ground-based rodent animal model involving hindlimb suspension as a simulation of weightlessness combined with radiation exposures

• Aim 2: Evaluate potential oxidative and inflammatory biomarkers as surrogate endpoints and compare with available human data from ISS missions

• Aim 3: Evaluate effects of combined exposures on disease latency and progression

• Aim 4: Investigate effects of countermeasures for mitigation of the simulated deep space effects

• Aim 5: Validate ground analogs with flight cohorts

• Aim 1: Determine potential synergistic effects from other spaceflight stressors e.g., psychological (isolation and confinement), altered gravity (micro-gravity), stress, sleep deficiency, altered circadian rhythms, hypercapnea, altered immune, endocrine and metabolic function, or other on CVD and CNS endpoints.

• Aim 2: Quantify impact of combined spaceflight stressors on the spectrum and dose responses for late functional CNS changes related to behavioral changes or degenerative neurological disease associated with space relevant exposures.

•  

Aim 3: Quantify the impact of combined spaceflight stressors on spectrum and dose responses for late functional CVD changes related to clinically relevant endpoints associated with space relevant exposures.
 

Results of previous studies on the ISS have indicated that six months of spaceflight increase stiffness of the carotid and femoral arteries and insulin resistance in astronauts (Hughson et al., 2016; Arbeille et al., 2016). Other aspects of the cardiovascular system’s adaptation to weightlessness have been studied, including for example systolic and diastolic function, cardiac chamber size and wall thickness, risk of arrhythmia, and risk of coronary artery atherosclerosis. The health and clinical effects of these findings are currently being debated and tested in space, and it is not known, whether longer duration flights could augment them. In addition, the efficiency of the in-flight exercise countermeasures to protect the cardiovascular system against increased vascular stiffness as well as against cardiac atrophy for one year in space is not known.

The purpose of this topic is therefore to understand if there are augmented cardiovascular health risk effects of extending missions to one year on ISS and the temporal profile of cardiovascular adaptation.

The main purpose of this topic is to characterize the temporal adaptation of the cardiovascular system and all its subcomponents to spaceflight of increasing duration (ranging from two month missions, through six month missions, and up to one-year missions in low-Earth orbit) and by extrapolation to understand, if extended durations in space beyond one year will induce a higher risk for developing cardiovascular disease and thus, to what degree this will be a factor in Appendix D - 6

evaluating the health risk profiles of future long duration deep space missions, that will be around three years in duration. It is also the purpose to lay a foundation for later comparisons with study outcomes in astronauts during deep space Gateway missions for understanding effects of deep space radiation on human health.

CVD-103 Gap Aim:  
To understand whether real and actual flight induced long duration weightlessness in combination with pre-flight exposure to simulated deep space radiation levels induce more pronounced cardiovascular oxidative stress, structural and functional changes than weightlessness alone.

SANS-203 Gap Aim:

To understand whether real and actual flight induced long duration weightlessness in combination with pre-flight exposure to simulated deep space radiation levels induce more pronounced brain and ocular structural and functional changes than weightlessness alone.