Cardiovascular risks and hazards associated with deep space exploration

Abstract

Space flight exposes astronauts to a unique environment characterized by microgravity, ionizing radiation, and other stressors that can profoundly affect the human body. Deep-space exploration-type missions to the Moon (NASA’s Artemis and Gateway programs), Mars, and beyond will introduce prolonged exposure to health hazards, including but not limited to isolation and confinement, sleep disruption, and exposure to different types and quantities of particle radiation (i.e., high-energy and atomic number – HZE). There are also logistical implications of traveling farther from low Earth orbit (LEO), including limited access to medical help and supplies. Currently, the known effects of space travel on the cardiovascular system include dysrhythmias, altered vascular compliance, dysautonomia, and induction of a pro-inflammatory state. It is not known how these concerns, and other potentially unknown cardiovascular risks, will manifest during and/or after exploration-type missions. This manuscript comprehensively reviews the cardiovascular disease risks associated with deep space exploration.

Brojakowska et al. review the synergistic cardiovascular risks of deep-space travel, from HZE radiation to microgravity-induced remodeling. By integrating murine mechanistic data with probabilistic modeling, the authors advocate for a shift toward individualized, Earth-independent medical frameworks to safeguard astronauts on multi-year missions.

Introduction

The extraterrestrial environment harbors unique risk factors for human health, specifically cardiovascular health, including exposure to space radiation and microgravity, among other stressors, whose effects on human physiology and health remain largely unclear. However, with planned deep space missions and emerging interest in commercial spaceflight, the impact of various spaceflight stressors on short- and long-term health is increasingly important. Table 1 summarizes cardiovascular risks across the spaceflight timeline, including short-term inflight, long-term inflight, acute post-return, and long-term post-career risks. Overall, the table highlights the importance of in-mission countermeasures, post-flight rehabilitation, and long-term surveillance.

Table 1.

Comparison of short-term inflight cardiovascular risks and long-term post-career risks: short-term inflight and long-term post-career cardiovascular risks in astronauts

Category	Timing	Typical changes or events	Evidence base	Operational/clinical implications
Short-term inflight risks	During spaceflight	Altered cardiac output and stroke volume; vascular tone changes/systemic vasodilation; fluid shifts toward the head with reduced plasma volume; autonomic/baroreflex changes; early electrophysiologic changes such as ectopy/repolarization changes.	Derived mainly from inflight monitoring, ISS and Shuttle mission studies, and short-duration analog experiments	May impair mission performance, crew safety, and exercise tolerance; require in-mission countermeasures such as exercise regimen, fluid loading, and compression garments.
Long-term in-flight risks	During spaceflight	Cumulative cardiac unloading/remodeling or atrophy (countermeasure-dependent); persistent autonomic/vascular deconditioning; venous stasis or retrograde jugular flow with rare thrombosis; oxidative/inflammatory stress; possible arterial stiffness/endothelial injury; arrhythmia and QT-repolarization concerns; radiation-related vascular injury.	Derived from long-duration ISS cohorts, cardiac MRI/vascular ultrasound studies, NASA risk reports, and limited astronaut epidemiology, terrestrial and animal data.	Important for prolonged-mission monitoring; supports continued exercise countermeasures, venous thrombosis surveillance, rhythm monitoring, and radiation-risk mitigation/shielding for exploration-class missions.
“Acute” post-return risks (landing to several months after return)	Immediately upon return to several months	Orthostatic intolerance/presyncope or collapse; reduced upright arterial pressure and stroke volume; hypovolemia; altered sympathetic/baroreflex responses; functional deconditioning. Most changes improve over days to weeks, often approaching baseline by about 1 month, though some recovery can extend longer.	Based on landing-day and early postflight stand/tilt testing, hemodynamic studies, and short follow-up studies after Shuttle and ISS missions.	Highest risk window for re-entry, landing, and immediate operational tasks; requires supervised rehabilitation, fluid/salt replacement, mobility support, and compression countermeasures.
Long-term post-career risks	Months to decades after career ends	Possible accelerated vascular stiffening, myocardial remodeling/fibrosis, atherosclerotic progression, CAC increase, and late radiation-associated cardiovascular disease; however, persistent LEO-related vascular impairment has not been clearly demonstrated, and the epidemiology is mixed.	Based on longitudinal follow-up studies, event-rate studies, CAC surveillance, and radiation-risk modeling, the strongest uncertainty is for deep-space exposure.	Important for post-mission healthcare, surveillance programs, and guiding occupational health policy

This table summarizes cardiovascular alterations associated with human spaceflight, highlighting factors that were likely unknown at the time of astronaut selection. Short-term in-flight risks include hemodynamic, vascular, autonomic, and electrophysiological changes documented during spaceflight. Long-term post-career risks may involve vascular stiffening, myocardial remodeling, fibrosis, and variable reports of increased cardiovascular events.

In June 2025, a complete list of deceased US astronauts was published (public database at https://www.wa-wd.com/l_astro.asp). While direct conclusions cannot be drawn from this epidemiologic data, it suggests that acute myocardial infarction (AMI) was the second leading cause of death (after non-flight accidents) in astronauts formerly involved in the Apollo 1 through 17 Moon missions¹. A reasonable explanation for the occurrence of AMI in three middle-aged Apollo astronauts may be underlying heart disease or predisposing cardiovascular risk factors that were likely unknown at the time of their selection process.

Several important limitations affect the interpretation of the findings reported by Delp et al.¹, who noted a higher proportional mortality rate from cardiovascular disease (CVD) in Apollo lunar astronauts compared to other astronaut cohorts. The number of cause-specific deaths was small, reducing statistical power and increasing uncertainty in the results. Additionally, the analysis did not adjust for major confounding variables, such as age, sex, smoking status, use of cardiovascular medications, blood pressure, diet, and fitness levels. Without these adjustments, it is difficult to determine whether the mortality rates meaningfully differ from those expected in comparable non-astronaut cohorts. While deep space radiation has been proposed as a potential contributing factor, the specific environmental factor(s) responsible for the observed outcomes remain unidentified, and no in-flight structural CVD events have been documented. Supporting animal studies employed acute, high-dose HZE irradiation (1 Gy at 10 cGy/min)², which differs significantly from the lower-dose prolonged exposures experienced during deep space missions. These differences in dose rate and exposure duration limit the direct extrapolation of human risk. A primary challenge in translating these experimental findings into clinical or occupational risk involves significant differences in dose rate and exposure duration between laboratory models and human exposure conditions. However, these constraints are not unique to cardiovascular radiobiology. Similar challenges are successfully managed in Space Radiation Cancer Risk Assessment, where terrestrial high-dose-rate data is routinely translated to low-dose-rate cosmic environments³. In that context, the use of dose and dose-rate effectiveness factors (DDREF) and probabilistic uncertainty modeling allows for the development of operationally useful safety standards despite inherent data gaps⁴. In acknowledging these issues, we emphasize that while cardiovascular radiation data requires careful correction and contextualization, it remains a robust and necessary foundation for informing long-term health risk assessments in both terrestrial and deep-space environments. Therefore, ground-based findings in animal models should be considered preliminary and hypothesis-generating, underscoring the need for larger, well-controlled studies with space-relevant exposure models to clarify potential causal relationships.

The need to identify and better manage health issues related to space travel prompted the National Aeronautics and Space Administration (NASA) to develop the Accepted Medical Conditions List (AMCL) in 2019⁵. The AMCL serves as a framework for identifying the health vulnerabilities of astronauts before embarking on long-duration missions. However, these conditions cannot be considered in isolation because they may be exacerbated by spaceflight-specific stressors such as sleep deprivation, circadian misalignment, isolation, and altered gravity. For example, cardiovascular, neurocognitive, and metabolic conditions may worsen under chronic sleep disruption and psychosocial stress⁶, both of which are highly common in mission simulations and in-flight scenarios. Moreover, preclinical studies using animal models have demonstrated that exposure to space-relevant radiation not only accelerates atherosclerotic lesion formation but also worsens outcomes in models of metabolic syndrome and neurodegeneration, underscoring how space stressors can act synergistically with underlying medical vulnerabilities^7,8. These insights emphasize the critical need to align the AMCL with emerging evidence from clinical investigations and preclinical models, thereby enhancing the predictive capacity for health risks during future missions.

Considering that CVD remains leading cause of death on Earth and there are limited capabilities to rule out pre-existing disease, the AMCL contains CVD-related medical conditions including hypertension, atrial fibrillation or flutter, cerebrovascular stroke, angina, AMI, cardiogenic shock secondary to AMI, and sudden cardiac arrest (Fig. 1). Blue R. et al.⁹, came up with “best case” and “worst case” definitions to determine the scope of intervention and treatment that could be provided when considering current clinical capabilities for spaceflight medicine (Fig. 1; attempt to treat with good response—green, attempt to treat with response dependent on available resources—yellow; attempt to treat but most likely may end in loss of life—red). Therefore, NASA has anticipated the possibility of in-flight cardiovascular conditions and complications, which must be considered when designing and conducting ground-based analog CVD studies to provide a biological and mechanistic foundation for identifying mitigating factors and, ultimately, developing effective countermeasures. While existing longitudinal studies of low Earth orbit (LEO) astronauts provide a foundation for understanding microgravity-induced cardiovascular remodeling, these findings remain qualitatively distinct from the risks associated with deep-space transit¹⁰. The current epidemiologic record lacks data on the synergistic effects of chronic GCR exposure and multi-year isolation. Consequently, LEO-derived outcomes should be viewed as a baseline for terrestrial-adjacent spaceflight, rather than a definitive predictive model for lunar or Martian trajectories. It is also critical to highlight the limitations of these case definitions, which, given the limitations of making definitive diagnoses in space, reduce the scope of cases that may be identified and acted on.

Fig. 1. Representative examples of cardiovascular medical conditions for Cis-Lunar and Mars transit design reference mission examples.

These conditions are based on confirmed and repeated medical evidence/events over the last several decades of NASA space flights that include Exploration Medical Condition List (EMCL) (Gilkey K.M. et al. 2012)^a, which was derived from the International Space Station (ISS) Integrated Medical Group (IMG) Medical Checklist (NASA/JSC-48522-E4, 2001)^b, the Flight Data File Medical Checklist (NASA/JSC-48031, 2006)^c, inflight medical incidence data in the Lifetime Surveillance of Astronaut Health (LSAH) repository, and NASA Flight Surgeon subject matter expertise. These were consolidated in the Integrated Medical Model (IMM) condition list (IMCL), which is a list of medical conditions considered to be of concern for ISS-specific spaceflights (Keenan A. et al., 2015)^d. The IMCL, along with data from the Integrated Medical Evidence Database (iMED), has been used for probabilistic risk analysis calculations (Adopted and modified from—NASA Technical Memorandum (Document ID 20190027540)⁹. Green shading signifies conditions where an attempt to treat could reasonably result in a good response; yellow—attempt to treat with response dependent on available resources; red—attempt to treat, but most likely may end in loss of life.

In contrast to reports suggesting that astronauts may have a higher long-term risk of CVD, data collected on 310 NASA astronauts and 981 non-astronaut (non-astronauts were matched to the astronauts on age, sex, and body mass index) NASA employees in the Longitudinal Study of Astronaut Health¹¹ have not consistently supported this notion. This study found that the rates of heart disease and related events were essentially the same between the two groups, even after accounting for common cardiovascular risk factors¹¹. Similarly, an analysis of cosmonauts spanning more than five decades showed that their overall and heart-related mortality rates were lower than those of the general Russian population¹². These findings emphasize that results can vary depending on the group studied, the time period, and the comparison population, highlighting the need for continued long-term monitoring of astronauts after their return to Earth with consistent methods.

Overall, the question of whether astronauts face an increased cardiovascular risk remains unresolved, as studies have yielded conflicting results. For example, Ade et al. and Ushakov et al. reported no significant increase in CVD incidence or mortality among NASA astronauts or cosmonauts compared with matched control populations^11,12. A recent systematic review by Krittanawong et al. further underscored this uncertainty, concluding that while mechanistic studies link microgravity to transient changes in cardiac and vascular function, as well as potential radiation-induced vascular injury, human epidemiologic data do not consistently demonstrate increased atherosclerotic disease or long-term cardiovascular mortality¹³. Importantly, many existing studies are limited by small sample sizes, a lack of adjustment for confounding variables such as age, smoking, and medication use, and reliance on radiation paradigms that differ from actual spaceflight exposures. Recently, Mircea et al. highlighted ongoing uncertainties regarding long-duration missions, particularly in the context of planned lunar and Martian exploration¹⁴. While current evidence remains hypothesis-generating, the feasibility of large-scale longitudinal human studies for deep space is severely constrained by mission frequency and crew size. Consequently, a more actionable path forward lies in adopting probabilistic risk-modeling frameworks, akin to those used for astronaut carcinogenesis¹⁵. By integrating high-linear energy transfer (LET) radiation data from terrestrial analogs with biologically based dose–response models, we can quantify cardiovascular risk through an inference-to-risk pipeline that accounts for deep space uncertainties where direct epidemiological observation is impossible.

Consequently, current evidence should be interpreted as hypothesis-generating rather than conclusive, underscoring the need for large-scale, longitudinal studies using realistic spaceflight exposure models. Limited musculoskeletal activity at or near zero-gravity during exploration-type space missions results in progressive alterations in the cardiovascular system, including up to a 12 ± 6.9% loss of left ventricular (LV) mass¹⁶, which reduces cardiac function. Also, there is substantial evidence on the effects of microgravity on cardiovascular physiology. Yet the combined effects of space radiation, reduced gravity, and other unique health risks remain understudied, and the degenerative risks to the cardiovascular system associated with long-duration space missions remain uncertain. All Low Earth Orbit (LEO) and Apollo human research data represent the combined effect; however, we cannot differentiate the contribution of any one spaceflight stressor. Only ground-based analogs can isolate the effects of individual stressors, although there is limited combined-stressor data from ground-based analogs for both human and animal studies.

While human data is currently limited to low-LET or terrestrial exposures, mechanistic data provides the necessary biological plausibility for the risks predicted in deep space. As illustrated in Table 2, the evidence for cardiovascular risk in spaceflight follows a tiered structure. While human epidemiologic data from the Life Span Study (LSS), clinical radiotherapy patients, and occupational exposures (Table 2) provide foundation for evidence of radiation-induced heart disease (RIHD)¹⁷, they lack the high-LET specificity of the deep space environment. Consequently, studies in murine simplified GCR simulation (simGCRsim) models serve as a critical mechanistic bridge. By identifying specific molecular drivers—most notably RNA signatures and cytokine signaling pathways—the ground-based studies move beyond broad epidemiologic correlations toward a predictive^18–23, biomarker-driven framework that addresses the specific gaps identified in the NASA Human Research Roadmap (e.g., Gaps CV-101 and CV-102).

Table 2.

Cardiovascular risk in spaceflight, cardiovascular risk in spaceflight and epidemiological evidence for radiation-induced cardiovascular risk

Level of evidence	Source/Model	Key cardiovascular observations	Role in risk assessment
Epidemiologic	Human: LSS (atomic bomb) and radiotherapy	Dose-dependent increase in ischemic heart disease and stroke (>0.5 Gy).	Establishes the primary terrestrial baseline for human risk.
Clinical	Human: ISS and Apollo Crews	Carotid-intima thickness shifts; microvascular remodeling in LEO.	Validates human physiological response in the space environment.
Mechanistic	Animal: simGCRsim Murine models	Accelerated atherosclerosis; myocardial fibrosis; reduced EF%.	Recapitulates the deep space (High-LET) hazard profile.
Molecular	Experimental: Omics and in vitro	RNA dysregulation; cytokine signaling; oxidative stress.	Identifies predictive biomarkers and early-warning signatures.
Epidemiological evidence for radiation-induced cardiovascular risk
Cohort type	Key examples	Exposure characteristics	Relevance to spaceflight
Atomic bomb survivors	Life Span Study (LSS)	Acute, high-dose-rate; mixed photon-neutron field.	Foundational for stochastic risk and dose–response modeling.
Clinical radiotherapy	Breast cancer and Hodgkin lymphoma survivors	High-dose, localized fractions; primarily photons.	Identifies specific tissue reactions (valvular disease, pericarditis).
Occupational	INWORKS, Mayak workers, Chornobyl liquidators	Chronic, low-dose-rate; protracted over years; primarily gamma/neutron.	Most relevant for modeling the cardiovascular effects of protracted GCR exposure.

This table summarizes the hierarchy of evidence characterizing the cardiovascular hazards associated with space travel and epidemiological evidence for radiation-induced cardiovascular risk, both categorized by research scale and clinical relevance.

To date, studies have identified over 30 health risks associated with space flight. NASA’s Human Research Program identifies five major hazards of human spaceflight: space radiation, isolation and confinement, distance from Earth, gravity fields, and hostile/closed environments²⁴. These categories, which often interact and compound one another’s effects, provide a unifying framework for studying the physiological and psychological challenges of extended space missions and developing countermeasures to protect astronaut health (NASA Human Research Program, “Five Hazards of Human Spaceflight”). Here, we provide a comprehensive summary of the most prominent risk factors on cardiac physiology and their known effects, including (1) distance from Earth, (2) altered gravity, (3) space radiation, (4) isolation and confinement, (5) sleep deprivation/fragmentation, and (6) food/nutrition²⁴.

Space environment-associated cardiovascular risks

Distance from Earth

Variables such as a mission’s distance from Earth play a prominent role in determining the duration of exposure to various space hazards. A recent study of lunar astronauts has shown a significantly lower risk of CVD mortality than the general US population²⁵. However, multiple socioeconomic factors, such as level of education, access to nutritious food, and health literacy, render the general US population a poor reference for comparison to astronauts. While socioeconomic risk factors (e.g., high educational attainment, superior healthcare access, and stable income) provide a baseline for the “healthy worker effect” observed in the astronaut corps, smoking status is a critical independent variable that warrants greater emphasis. To reflect the unique health profile of astronauts, NASA risk assessments—specifically the NASA Space Cancer Risk (NSCR) models—utilize non-smoker (NS) corrections when estimating both stochastic and deterministic risks. The necessity of this emphasis in cardiovascular discussion is two-fold: (a) baseline calibration —smoking is a primary driver of endothelial dysfunction, systemic inflammation, and accelerated atherosclerosis. Since the astronaut cohort consists almost exclusively of career non-smokers or long-term quitters, comparing their cardiovascular outcomes to a general population with a ~12–15% smoking prevalence can create a significant statistical “noise.” Without the NS correction, the “astronaut advantage” is artificially inflated by the absence of tobacco-induced pathology, rather than a true resilience to spaceflight stressors; (b) isolating radiation-induced vasculopathy—in terrestrial studies, the synergistic effects of tobacco and ionizing radiation on the vasculature are well-documented. By applying an NS correction, the model effectively isolates the cardiovascular risks unique to the space environment, such as galactic cosmic radiation (GCR) and microgravity-induced remodeling, from the confounding inflammatory signals associated with tobacco use.

Consequently, any comparison of astronaut cardiovascular health with that of the general population must move beyond broad socioeconomic categories. It must specifically account for the astronaut corps’ screened, non-smoking, high-fitness baseline. Failure to sufficiently weight the NS correction risks overestimates baseline resilience and may mask subtle, long-term vascular strain induced by deep-space missions.

More recently, a longitudinal study following astronauts for 30 years, enrolled in 1959–2009 with at least one completed mission, found that astronauts did not exhibit an increased risk of CVD mortality compared to a control group composed of individuals who met the astronaut selection criteria. However, the study revealed a significantly higher risk of CVD events among astronauts, including AMI, ischemic atherosclerotic stroke, and the need for revascularization procedures¹⁰. This data, although limited, raises the question of whether this potential difference in cardiovascular morbidity in astronauts following LEO and Apollo missions could be a direct result of differences in the extraterrestrial environment (e.g., type of radiation, altered gravity, isolation, and confinement), depending on the distance traveled from Earth; it highlights the need to consider the effect of spaceflight on CVD.

As noted previously, NASA has anticipated the possibility of acute health concerns during missions irrespective of a crew’s pre-flight health and conditioning status. Astronauts on the ISS have their own dedicated doctor. This flight surgeon stays in regular contact with the crew and does a personal health check with each astronaut once a week²⁶. Because a round trip to Mars takes 2–3 years, astronauts won’t have complete medical care unless we develop new ways for them to run medical tests and treat illnesses by themselves in deep space. Given that many experienced astronauts fall into the middle-aged category, with an average age of 46 and a range of 33–58 years, they face an increased risk of developing cardiovascular events²⁷, which could potentially be life-threatening for the astronaut and mission-threatening for NASA. These exploration class missions will require the ability to conduct Earth-independent medical operations, due to the following: (1) communication barriers (on Mars, one-way delays can be more than 20 minutes), (2) breadth of medical capabilities necessary to support deep space exploration (given the possible shift in risk balance beyond LEO); and (3) available medical inventory due to lack of effective resupply. Indeed, perishable supplies like food and medication are not designed for a 1–3 year full mission to Mars, including a transit phase (6–9 months), a surface stay (about 12 months), and a return transit of similar duration²⁸. Additionally, the resupply missions often take longer because they occur when the planets are not in the most favorable alignment. Therefore, the focus is on the cargo modules that accompany the crew during the mission. Thus, it is essential to predict, prevent, or mitigate the development of adverse cardiovascular events that may arise during deep space missions by developing sensitive and specific Earth-independent screening strategies, noninvasive nutritional and physical therapy programs, and to be able to mobilize therapeutics relevant to the potentially unique pathophysiologies of different diseases that may present during deep space exploration.

Altered gravity

Prolonged exposure to altered gravity environments induces cardiovascular adaptations that extend beyond temporal hemodynamic shifts and have important implications for CVD development during spaceflight. Microgravity leads to cardiac atrophy, reduced stroke volume, and impaired vascular compliance, which collectively diminish reserve capacity²⁹. While these changes may be adaptive in-flight, they can predispose astronauts to arrhythmias, hypertension, and orthostatic intolerance upon re-entry³⁰.

Most of the space flight-associated CVD risks identified to date were determined after short Shuttle missions and long-duration ISS flights and include cardiac arrhythmias, compromised orthostatic cardiovascular response, and the manifestation of previously asymptomatic CVD³¹. Changes in gravity pose a significant stressor to the cardiovascular system, given the integral role of gravity in maintaining proper hemodynamic responses to postural changes. While LEO missions remain well within Earth’s gravitational field, astronauts experience apparent weightlessness because of continuous orbital free fall. It causes redistribution of volume towards the head and a reduction in intrathoracic pressure, leading to the expansion of the thorax^32,33. Furthermore, weightlessness leads to a more pronounced drop in intrathoracic pressure with changes in the central venous pressure (CVP), resulting in increased cardiac transmural pressure, left atrial diameter, and cardiac preload³⁴. The weightlessness results in a loss of hydrostatic cranial-caudal gradient, implicating alterations in venous pressure and volume relationships due to decreased intrathoracic pressure and loss of gravitational tissue compression³⁵.

Cardiac output (CO) and stroke volume (SV) in the seated position also increase relative to preflight measures and appear to vary depending on the duration of the mission (CO increased by 41–56% between 3 and 6 months on the ISS³⁶ vs. 18–26% on a 1-week ISS mission³⁷). Importantly, these changes were independent of changes in heart rate and were consistent with systemic vasodilation, despite unchanged catecholamine levels³⁶, with the exact mechanisms of vasodilation remaining unclear. It is important to note that there are several discrepancies in the effect of microgravity on CO and SV between studies^36,38–40, which have been attributed to participants’ positions during image acquisition and the overall technical challenges of performing echocardiography in free-floating conditions.

Adaptations of the cardiovascular system to changes in loading conditions have also been observed during long-duration (4–6 months) ISS missions (n = 13 astronauts), with a ~12% decrease in CO compared to preflight²⁹. Still, there was no evidence of a reduction in either LV or right ventricular (RV) cardiac mass as assessed by MRI when assessing the whole cohort, which was thought to be potentially related to exercise activities conducted on the ISS. However, there was notable interindividual variance in this LV mass response. Interestingly, left atrial (LA) volume increased post-flight, suggesting that spaceflight may have nonuniform effects on cardiac remodeling, and the implications of LA remodeling for long-term arrhythmia risk should be considered. Although a study of Space Shuttle and ISS missions that employed 24-h Holter monitors showed that there was no significant difference in ectopy before, during, or after spaceflight⁴¹, studies of LEO missions have shown that most of the symptomatic arrhythmias are related to premature ventricular or atrial contractions. Overall, there is limited evidence suggesting that the spaceflight environment increases the risk of life-threatening arrhythmias⁴²; however, several possible mechanisms by which important electrophysiologic changes could occur have been proposed, including the effect of long-term microgravity exposure on elevated low-frequency oscillations of ventricular repolarization, which are associated with the risk of repolarization instability⁴³.

Fluid shifts within an individual have additional clinical implications concerning central venous congestion, thrombosis, and orthostasis. Microgravity reduces plasma volume in the cardiovascular system, leading to temporary hemoconcentration. This plasma volume reduction, estimated at ~22%, occurs within the first week of spaceflight due to changes in venous return and fluid dynamics³³. Prior studies have shown increased internal jugular vein area and pressure with decreased flow, thus linking venous stasis induced by weightlessness to the potential increased risk of neck vein thrombosis in space^44,45. Thus, recent reports have highlighted venous thromboembolism (VTE) as an emerging, high-priority health risk during spaceflight. Spaceflight-associated venous thrombosis, particularly in the internal jugular vein, is thought to arise from a convergence of risk factors described by Virchow’s triad: venous stasis, endothelial alterations, and hypercoagulability⁴⁶. In microgravity, sustained headward fluid shifts promote venous engorgement, retrograde blood flow, and stasis, all of which may predispose astronauts to thrombus formation. Although only a limited number of cases have been documented, these events highlight the clinical significance of VTE in astronauts^47,48. Management during missions has included ultrasound-based diagnosis and anticoagulation therapy, with careful timing of drug discontinuation before re-entry to minimize the risk of hemorrhage. In response, NASA and the European Space Agency convened expert working groups that now recommend routine in-flight ultrasound surveillance of jugular venous flow, the use of evidence-based algorithms for thrombus assessment and treatment, and further research into countermeasures that balance efficacy and safety in a weightless environment⁴⁹. These efforts, along with ongoing studies exploring the links between venous stasis, neuro-ocular changes, and long-duration exposure, underscore the importance of VTE as a top health priority for future deep-space missions.

Increased fluid shifts toward the head also likely mediate spaceflight-associated neuro-ocular syndrome, as increased intracranial pressure precipitates optic disc edema, decreased visual acuity, headache, and morphological head changes^50–52. It is conceivable that changes in gravity could also lead to transient ischemia, which may affect several aspects of cardiac function and alter perfusion of the heart and other organs, as reported in in vitro studies⁵³. The transient ischemic periods may contribute to reperfusion injury during the restoration of normal blood flow, including inflammation and oxidative damage, as reported in ischemia/reperfusion animal models⁵⁴. Post-flight orthostatic intolerance observed in astronauts is thought to result from changes in volume status and autonomic adaptation to microgravity⁵⁵. Altered gravity poses a significant stressor on cardiovascular function due to volume redistribution and altered autonomic control related to vestibular signaling, amongst other mechanisms. One must consider additional contributing factors to dysautonomia, including altered chemoreceptor and baroreceptor engagement, associated with the isolation and confinement of spaceflight. A post-flight study of 14 astronauts returning from short (9–14 days) Shuttle missions noted markedly increased heart rate and vascular resistance when upright, while CO and SV were reduced compared with baseline measurements⁵⁵. Further ground-based experiments using a surrogate model of microgravity are in support of these data in showing substantial cardiac remodeling due to exposure to microgravity^56,57. Symptoms related to orthostatic intolerance, which appear to be a consequence of an adaptation to microgravity and not causatively related to other space hazards like ionizing radiation (IR)⁵⁸, could be remedied by a post-mission aerobic exercise regimen to improve cardiac conditioning and were not identified as risk factors for future CVD events.

While orthostatic symptoms have been mild to moderate after returning to Earth following space missions so far, further consideration is warranted regarding the implications of landing on other celestial bodies. Dysautonomia during longer deep-space missions is likely multifactorial; however, direct autonomic effects of space radiation in humans remain unproven. Experimental studies indicate that low- to moderate-dose charged-particle exposure can induce persistent neural, oxidative, and neuroinflammatory changes, suggesting that radiation may be one of several contributing factors to autonomic dysregulation⁵⁹. Therefore, the effects of space IR on the dynamic interplay between the autonomic nervous system and cardiovascular system need to be considered, along with the long-lasting consequences of dysautonomia. Additionally, the endothelial dysfunction and increased arterial stiffness observed in long-duration spaceflights resemble early hallmarks of atherosclerosis and heart failure⁶⁰. The risk is further compounded when these gravity-induced alterations interact with other hazards, such as space radiation, sleep disruption, and systemic inflammation, which may accelerate vascular aging and increase cardiovascular vulnerability⁶¹. Together, these observations suggest that altered gravity does not function solely as a transient physiological stressor but also as a persistent factor that may actively contribute to the development and progression of CVD during and after long-duration space flights.

Space radiation

It is critical to distinguish between the radiation environments of current operations and those of future exploration. In Low Earth Orbit (LEO), the Earth’s geomagnetic field provides substantial protection, with radiation primarily consisting of trapped protons and secondary neutrons (Table 3). The radiation environment in LEO is characterized by a bimodal distribution. While the Earth’s magnetic field acts as a filter, its effectiveness is non-uniform and defined by geomagnetic cutoff rigidity. In the South Atlantic Anomaly (SAA), trapped protons dominate the flux and contribute significantly to the total mission dose. However, outside this specific region and increasingly at higher orbital latitudes, galactic cosmic rays (GCRs) comprising high-energy protons and HZE ions constitute the primary background radiation environment and remain the dominant penetrating concern. In contrast, Deep Space missions (Artemis, Mars) will expose crews to the full spectrum of galactic cosmic rays (GCR), including high-energy, high atomic number (HZE) particles such as ⁵⁶Fe and ²⁸Si (Table 3). Although many primary heavy ions are attenuated and fragmented by spacecraft shielding and body tissues before reaching cells, the resulting transported/fractionated radiation field still contains a significantly high-LET component⁶² that can induce more complex DNA damage and oxidative stress in vascular endothelium than the predominantly low-LET radiation environment in LEO⁶³. Because cardiovascular effects are classified as tissue reactions, risk models must move beyond the standard dose equivalent used for stochastic outcomes. Instead, they should utilize relative biological effectiveness (RBE) weighted doses, which more accurately reflect the relative biological effectiveness (RBE) of high-LET particles on the vascular endothelium and myocardial tissue (Table 3). Since the International Commission on Radiological Protection (ICRP) established a 0.5 Gy limit for cardiovascular effects, the RBE-weighted dose provides a more accurate metric to determine if an astronaut has crossed that biological limit during a mission. This distinction is critical because the generalized quality factor (Q), while useful for cancer risk, may not adequately capture the specific biological limits associated with radiation-induced cardiovascular disease.

Table 3.

Radiation environment and its consequences at LEO and deep space radiation environment and its consequences at LEO and deep space and the biological impact

Feature		Low Earth Orbit (LEO)		Deep space (Lunar/Mars)
Primary sources		Trapped protons (Van Allen Belts), Secondary neutrons		Galactic Cosmic Rays (GCR), Solar Particle Events (SPE)
Radiation quality		Predominantly Low-LET		High-LET (HZE ions: 56Fe, 28Si, etc.)
Geomagnetic shielding		Significant protection		None
Dose rate		∼0.5–1.0 mSv/day		∼1.5–2.5 mSv/day
Biological effect		Lower RBE; primarily oxidative stress		High RBE; complex DNA damage and persistent inflammation
Primary cardiovascular concern		Minor endothelial changes		Accelerated atherosclerosis; Myocardial fibrosis
Comparative radiation environments and biological impact
Environment	Primary sources		Radiation field characteristics		Biological effectiveness (reference)
LEO (ISS)	GCR (modulated), trapped particles (SAA)		Mixed field; dominance of trapped protons; lower secondary neutron flux.		Baseline effectiveness for stochastic/tissue effects; primarily low-LET driven.
Deep space	Unshielded GCR, SPE		Mixed field; high-energy, high-Z (HZE) ions; significant secondary neutron flux.		Enhanced effectiveness for complex DNA damage and cardiovascular remodeling.

Contrasts the distinct radiological profiles of Low Earth Orbit (LEO) and Deep Space (Lunar/Mars) missions, emphasizing the shift in biological risk as geomagnetic protection is lost. This data underscores the necessity for advanced shielding and countermeasure strategies as mission profiles move beyond the protection of the Van Allen Belts, where dose rates can more than double (reaching up to 2.5 mSv/day). Relative biological effectiveness (RBE) is not a fixed physical constant but is highly dependent on the specific biological endpoint, dose rate, and tissue type. In this context, enhanced effectiveness refers to the increased potency of high-Z and high-energy (HZE) ions inducing complex DNA damage, persistent oxidative stress, and late-term cardiovascular remodeling compared to low-LET reference radiation (e.g., ⁶⁰Co\gamma- or terrestrial X-rays). The radiation environments of LEO and deep space both represent complex, mixed-field exposures. While the International Space Station (ISS) is significantly shielded by the Earth’s magnetosphere, GCR remains a primary exposure source, albeit with a spectrum shifted toward lower energies compared to interplanetary space. Furthermore, we acknowledge that relative biological effectiveness (RBE) is not a fixed physical constant but is highly dependent on the specific biological endpoint, such as cell death, chromosomal aberration, or the induction of inflammatory signaling in the vascular endothelium. In deep space, the increased prevalence of HZE ions and secondary neutrons leads to a higher ionization density (LET), which generally correlates with a higher RBE for late-term cardiovascular and stochastic outcomes compared to the proton-dominant environment of LEO.

In LEO, such as on the ISS, the Van Allen Belt (Earth’s protective geomagnetic field) provides shielding from GCRs and solar particle events (SPEs); however, there is still exposure to high-LET IR with dose rates ~100 times higher than those on the ground⁶⁴. Extending further beyond LEO, and therefore outside the Earth’s protective magnetic field, the space IR environment introduces new stressors with changes in the type and dose-rate of IR, including exposure to HZE IR of GCRs and SPEs (Fig. 2). During future exploratory-type missions, astronauts will be exposed to higher total doses of space IR (~300–450 mGy) from GCRs, especially during Mars missions that are currently estimated to last from 30 to 36 months⁶⁵. It is suggested that due to GCR, each cell in an astronaut’s body would be traversed by a proton every 3–4 days, a helium nucleus every few weeks, and HZE nuclei (e.g., C, O, Si, Fe, etc.) every few months⁶⁶. Even though only 1% of GCR comprises ions heavier than helium, ~40% of the radiation dose-equivalent is predicted to be HZE particles, with more than 10% being from ⁵⁶Fe particles only⁶⁷. Nevertheless, neither the quantification of the biological effect nor the biological equivalents for deep-space radiation exposures, nor their associated relevance to disease risk, is well known.

Fig. 2. Space radiation environment.

The Van Allen Belt acts to protect the Earth from stronger IR from space, but is not as protective during space travel beyond this area. The ISS, which is in LEO, is situated beyond the inner Van Allen Belt but is partially protected by the Van Allen Belts. In LEO, IR is not as strong as in deep space, but its dosage is still significantly higher than what is received on Earth. Beyond the Moon and Mars, astronauts are exposed to higher doses of IRs, such as GCRs and SPEs. Please note that the illustration is a schematic representation and is not drawn to scale. ISS International Space Station, IR ionizing radiation, GCR galactic cosmic rays, SPE solar particle events, LEO low Earth orbit. Created with BioRender.com.

To contextualize NASA’s risk management strategy, a clear distinction must be made between the stochastic modeling used for carcinogenesis and the deterministic frameworks applied to cardiovascular health. As outlined in the updated 2016 Evidence report by Patel et al.⁶⁸, NASA’s radiation health program is structured around the three fundamental principles of radiation protection: Justification, Limitation, and Optimization that serve to facilitate the radiation risk exposure minimization by following the As Low As Reasonably Achievable (ALARA) principles. While the exposures inherent to deep-space exploration are justified by the high-priority scientific and exploratory objectives of the human spaceflight program, they are strictly governed by evolving regulatory limits. Historically, NASA utilized age- and sex-specific limits based on a 3% Risk of Exposure-Induced Death (REID). However, in accordance with recent recommendations from the National Academies of Sciences, Engineering, and Medicine, the agency has transitioned to a more streamlined Limitation framework. This includes a unified career effective dose limit of 600 mSv, applied regardless of age or sex, to mitigate stochastic effects such as carcinogenesis. Furthermore, NASA maintains specific dose limits for tissue reactions (deterministic effects) to protect critical organs, including the lens of the eye, the skin, and the cardiovascular and central nervous systems. Within this boundary of Limitation, the ALARA principle serves as the primary operational driver, ensuring that shielding, mission architecture, and trajectory planning are optimized to keep actual astronaut exposures as low as reasonably achievable below the 600 mSv limit. To manage the long-term health risks of deep space exploration, NASA has established a universal career effective dose limit of 600 mSv. This administrative limit is designed to ensure that the risk of exposure-induced death remains within acceptable regulatory bounds. Unlike biological thresholds associated with acute tissue reactions, this limit does not imply an absence of risk below 600 mSv, but rather an acceptable level of stochastic risk as dictated by current protection standards.

However, equally critical are the limits established to prevent tissue reactions, which are particularly concerning for deep-space missions where high-LET radiation poses a unique threat to the cardiovascular system. Unlike stochastic risks, these tissue reactions exhibit limit-like behavior; consequently, NASA maintains specific organ-dose limits to protect against degenerative changes in the heart and vasculature, such as accelerated atherosclerosis and microvascular dysfunction. Indeed, cardiovascular risks are currently managed under permissible exposure limits (PELs) based on the assumption of a dose-rate threshold⁶⁹. However, as deep space missions extend in duration, the potential for ‘stochastic-like’ cardiovascular behavior - where low-dose, high-LET radiation triggers chronic inflammatory signaling - suggests that current PELs may need to evolve toward a more integrated probabilistic model⁷⁰.

To clarify further, NASA’s career limits were based on a 3% REID at the 95% upper confidence limit, which resulted in age- and sex-dependent dose limits. However, following recent recommendations from the National Academies, NASA has implemented a unified career radiation limit of 600 mSv for all astronauts. This paradigm shift moves away from the 95% confidence interval approach in favor of a single effective dose limit. Crucially, this 600 mSv limit is anchored to the 3% REID point estimate for a 35-year-old female, thereby providing a conservative standard of care that ensures equitable protection across the entire astronaut corps. By doing so, NASA effectively “levels up” the protection for older male astronauts, who would have had much higher limits under the old REID system. This dose is calculated using NASA-specific quality factors (Q) and tissue weighting factors (W_T) designed to account for the unique biological effects of space radiation (e.g., heavy ions and solar protons) compared to terrestrial X-rays or gamma rays.

The effects of cosmic IR on the cardiovascular system during and after prolonged space flights remain largely unknown. The deep space IR environment is a confluence of GCRs and particles from SPEs. GCRs comprise a combination of protons and HZE particles with energy spectra around 1 GeV/nucleon (n)⁷¹. Primary GCRs can generate secondary particles through projectile and target fragmentation, resulting in a mixed radiation field that includes both dense high-LET tracks and lower-LET secondary components, thereby producing patterns and degrees of DNA damage that differ from those caused by predominantly low-LET ionizing radiation⁶². SPEs, in turn, primarily consist of high-energy protons, typically with energies greater than 30 MeV (range 0.1–1000 MeV) and are associated with solar eruptive activity. Since the events producing IR occur spontaneously, further consideration of methods to optimize shielding and risk mitigation in a complex environment is required.

Given the complex environment of deep space, the biological effects of IR are determined by multiple factors, including dose, exposure rate, cumulative dose, LET, and endogenous cell repair mechanisms. While radiation therapy directed toward the thorax is known to be associated with increased CVD risk⁷² (such as ‘mantle irradiation’ for thoracic Hodgkin lymphoma), limited data exist on whether space IR poses significant cardiovascular risks during and after deep space missions. One study longitudinally following astronauts active between 1959 and 1969 (n = 73) until the primary outcome of death or end of the study (February 2017) found no significant associations between space IR dose and mortality, notwithstanding the statistical limitations of the small cohort⁷³. However, NASA’s Twin study demonstrated that after inhabiting the ISS for 1 year, one twin developed both genetic modifications (altered telomere length, DNA methylation of genes enriched in the somatostatin pathway) as well as markers of increased cardiovascular risk, such as carotid intima-media thickening, increased indices of inflammation, and increased ApoB/ApoA1 ratio¹⁹. Although these changes are likely not solely caused by exposure to space IR, it is important to determine whether they are mediated by mechanisms specific to space IR-associated injury. Therefore, ground-based studies using relevant IR exposure models (e.g., mixed HZE, absorbed dose, quality, dose equivalent, etc.) are essential for developing predictive excess relative risk (ERR) models and providing a biological foundation for determining mitigating factors and developing effective countermeasures.

Insights from terrestrial human data also support the potential cardiovascular risks associated with radiation exposure. Patients receiving chest radiotherapy for cancer treatment and certain occupationally exposed populations have been shown to exhibit increased rates of CVD, including coronary artery disease, heart failure, and stroke, often manifesting years after exposure. Although dose profiles differ substantially from those in spaceflights, medical exposures typically involve high localized doses. In contrast, astronauts are subject to lower-dose, chronic exposure to GCRs and SPEs, and their pathophysiological consequences share common features. These include vascular endothelial injury, inflammation, fibrosis, and acceleration of atherosclerosis, as summarized in a recent review⁷⁴. Integrating these terrestrial data with spaceflight studies strengthens the case for considering radiation as a key cardiovascular health hazard for astronauts. Although the direct extrapolation of ground-based HZE radiation analog studies may not fully translate to actual deep-space radiation exposure, in the absence of human studies, ground-based analogs allow evaluation of possible risks of deep-space radiation exposure to the human body.

To ensure the translational relevance of our findings to deep space exploration, the murine models utilize simulated Galactic Cosmic Ray (GCRsim) protocols rather than traditional terrestrial gamma or X-ray irradiation. While LEO environments are dominated by low-LET protons, our studies specifically focus on HZE ions, such as ⁵⁶Fe, ²⁸Si, and ¹⁶O-delivered at dose rates reflective of deep space transits. These ions produce dense ionization tracks that induce a bystander effect and persistent oxidative stress⁷⁵, which are not observed with LEO-representative radiation. This differentiation is critical, as it enables the identification of cardiovascular risks uniquely exacerbated by the absence of geomagnetic shielding, providing a high-fidelity surrogate for astronaut health during Artemis and Mars mission profiles.

Several ground-based studies using murine models have aimed to elucidate the role of HZE IR exposure on CVD, as summarized in Table 4. Studies using single whole body ¹⁶O IR (0.1 or 0.25 Gy; 600 MeV) in both male and female C57BL/6J mice showed a reduction in LV systolic function at 3 and 7 months post IR in male mice; interestingly, there was no significant difference in systolic function in irradiated female mice, though structural LV differences were noted (increased LV mass and dimensions) suggesting a possible effect of sex on IR-associated CVD effects. Irrespective of the effect on LV function, there was evidence of cardiac remodeling with increased expression of alpha-smooth muscle actin and immune cell infiltration (increased LV protein levels of T-cell marker CD2 seen in both sexes)^76,77.

Table 4.

Murine experiments investigating deep space and its biological impact

Category	IR type	LET	Dose	Model	Effect	Reference
Altered LV function and structure	16O	600 MeV/n	0.05, 0.1, 0.25, or 1 Gy	C57BL/6J (M)	Reduced LVEF and LVFS at 3 and 7 months post-IR. Increased ɑ-smooth muscle actin and CD2, CD68, and CD45+ cells. No significant difference in apoptosis or fibrosis.	Seawright (2019)
	16O	600 MeV/n	0.1, or 0.25 Gy	C57BL/6J (F)	No cardiac dysfunction, but noted cardiac remodeling (increased LV mass, EDV, diameter) with an increase in ɑ-smooth muscle actin and CD2+ cells.	Nemec-Bakk (2022)
	GCR 56Fe 16O	−1 Gev/n 600 MeV/n	1.5 Gy 0.05, 0.25, or 0.5 Gy 0.15, 0. 25, or 0.5 Gy	C57BL/6J (M)	GCR decreased cardiac contractility, increased PVR, and altered arterial elastance.	Bishawi (2022)
	GCR	500 MeV/n	0.5, 1 Gy	C57BL/6J (M)	Acute reduction in global LV systolic function (14, 28 days post-IR) and later at 660 days. Associated with increased expression of markers of fibrosis, inflammation, and hypertrophy. No lower IR threshold determined.	Brojakowska (2023)
	GCR	500 MeV/n	0.5, 1, 1.5 Gy	ApoE null (M)	Acute reduction in LV systolic function (14, 28 days). No lower IR threshold determined.	Brojakowska (2023)
Altered cardiac transcriptome	14Si 22Ti	260 MeV/n 1000 MeV/n	0.04, 0.08, 0.16 and 0.32 Gy 0.03, 0.065, 0.13, and 0.26 Gy	CB6F1/Hsd (F)	12 common DEGs across IR types; 5 of which are involved in circadian rhythms (Arntl, Cry2, Per2, Per3, Bhlhe41)	Garikipati (2021)
	56Fe	1 GeV/n	0.15 Gy	C57Bl/6NT (M)	Increased expression of genes involved in inflammation, free-radical scavenging, and CV development; activation of TFs TBX5, GATA4, and MEF2C involved in maintaining cardiac homeostasis	Coleman (2015)
Altered cardiac epigenome and metabolome	16O	600 MeV/n	0.1, 0.25, or 1 Gy	C57BL/6J (M)	Acute DNA hypomethylation of retrotransposon LINE-1 14 days post, followed by specific hypermethylation at day 90. At low dose exposures, transsulfuration pathways affected—noted increase in cystathionine levels.	Miousse (2019)
	56Fe	600 MeV/n	0.5 Gy	C57BL/6J (M)	Dynamic alteration in DNA methylation, repetitive element repression, and expression of methylation-related genes (Dnmt1, Dnmt3a, Uhrf1)	Koturbash (2016)
Prolonged apoptosis and inflammation	28Si	300 MeV/n	0.1, 0.25, or 0.5 Gy	CBA/CaJ  (M)	Prolonged elevation in PARP, NFΚB, and proinflammatory cytokines (IL1B, IL-6, TNFα)	Tungjai (2013)
Alterations in the peripheral vasculature	16O	600 MeV/n 1 GeV/n	0.5 Gy 0.01–0.25 Gy	Long Evan rat (M)	Increased abdominal aorta pulsed- wave velocity at 12 months post IR.	Sridharan (2020)
	56Fe	1 GeV/n	0.5, 1 Gy	Wistar rats (M)	Elevated arterial stiffness in 1 Gy IR rats. Vascular dysfunction mediated by xanthine oxidase and ROS, and diminished endothelial-generated NO in response to Ach	Soucy (2011)

This table summarizes murine studies investigating aspects of deep space high atomic number and high energy (HZE) particles IR on different aspects of cardiac function and other physiological functions.

With advancements in technology, more recent investigations have utilized simplified GCR simulation IR (simGCRsim; H 1000 MeV/n, ²⁸Si 600 MeV/n, ⁴He 250 MeV/n, ¹⁶O 350 MeV/n, ⁵⁶Fe 600 MeV/n, and H 250 MeV/n), which is delivered in small packets daily, resulting in the appropriate cumulative dose to better mimic the space IR environment. Studies from our team looking at the long-term effects of space IR exposure on LV function using echocardiography showed that in both wild-type C567BL/6J and ApoE null male mice, exposure to simGCRsim resulted in an acute decline in global LV systolic function as early as 14 days post-exposure, however, there was variation in LV functional response past 1 year of exposure where in wild-type mice there appeared to be a persistent impairment in LV function not seen in ApoE null mice^8,78. Interestingly, by 660 days, 50 cGy simGCRsim irradiated C57BL6/J wild-type (WT) mice exhibited preserved LV systolic function with altered structure (LV size and mass). Space-type radiation can increase molecular markers for cardiac fibrosis, inflammation, and hypertrophy, such as Tgfβ1, Mcp1, Mmp9, and βMhc. These increases may indicate that deep-space radiation induces cardiac remodeling, potentially leading to diastolic dysfunction. However, this remodeling may also be enhanced with natural aging processes. While there appears to be a possible genotypic difference, given the high mortality of ApoE null mice at ~550 days of life, neither study identified a lower IR limit for CVD risk. Current studies are underway to assess long-term degenerative effects using female murine models.

Additional studies comparing simGCRsim IR (6-ion radiation exposure delivered consequently within 20 min) to a single ion IR (⁵⁶Fe or ¹⁶O) on LV function showed that 1 year post simGCRsim exposure, mice exhibit reduced cardiac contractility, increased peripheral vascular resistance, and disrupted arterial elastin fiber integrity, which could lead to altered arterial elasticity and further contribute to increases in afterload⁷⁹. Exposure to single HZE IR has also been shown to cause endothelial dysfunction and increase arterial stiffness^80,81. This endothelial dysfunction is suggested to be mediated by increased xanthine oxidase activity, which promotes oxidative stress-mediated disruption in endothelial NO response and production⁸⁰.

In addition to gross effects on cardiac function, several studies have shown HZE IR induces alterations in the epigenetic profile of cardiac tissues, including dynamic alterations in DNA methylation as well as expression of methylation-related genes (Dnmt1, Dnmt3a, Uhrf1), which contribute to silencing of major satellites^82,83, a phenomenon previously demonstrated in the pathogenesis of various CVDs including ischemic disease and heart failure^84,85. Additional studies have shown HZE IR exposure contributes to prolonged inflammation, apoptosis, and alteration in pathways involved in free radical scavenging and regulation of circadian rhythms—all physiologic processes known to be involved in CVD^86–88.

Translational cardiovascular risk management

Ground-based analog studies explicitly address NASA Human Research Roadmap Gaps CV-101 and CV-102 by providing high-fidelity, sex-specific murine data to characterize the cardiovascular disease risks^20,86,89,90. By identifying specific biomarker signatures and clinical outcomes, these studies provide a biological basis for monitoring the late-onset degenerative tissue effects of deep-space, long-duration missions that current clinical data from LEO missions cannot. The identified predictive biomarkers can serve as a foundation for a direct monitoring strategy. Under conditions of mission uncertainty (e.g., a Solar Particle Event during an Artemis mission), these biomarkers could theoretically be used to quantify individual susceptibility (e.g., identify astronauts at higher genetic risk for radiation-induced damage) or inform countermeasure timing (e.g., determine the optimal window for administering radioprotectants or other mitigators) based on real-time biological signaling rather than fixed mission timelines. Moreover, animal models provide the statistical power required to establish dose-response curves that are currently censored in human astronaut cohorts. To address the lack of longitudinal human data for GCR exposure and to manage the statistical uncertainty, mathematical modelers could “align” the findings in ground analog studies (e.g., biomarkers, clinical manifestations, cardiac transcriptome data) with known permissible outcome limits (PELs) to reduce the risk uncertainty in NASA’s integrated medical model (IMM).

Risk modeling and operational mission planning

To translate the mechanistic insights and murine cardiovascular data discussed herein into mission-relevant data, NASA employs probabilistic risk-modeling frameworks that account for the lack of direct human deep-space epidemiologic data. Central to this approach is the transition from point-estimate risk assessments to a Probabilistic Risk Assessment (PRA). This methodology integrates terrestrial epidemiology (e.g., from the Life Span Study—LSS of atomic bomb survivors) with radiation quality factors (Q) derived from GCR simulation studies and animal models. The probabilistic framework incorporates the NASA Space Cancer Risk (NSCR) model and the emerging Multi-model Ensemble Risk Assessment (MERA) project, which integrates terrestrial LSS data with high-LET experimental findings^3,91. By using metrics such as the Risk of Exposure-Induced Death (REID) and accounting for uncertainty quantification, these models allow mission planners to evaluate the probability that an astronaut will exceed Permissible Exposure Limits (PELs) during long-duration lunar or Martian transits²⁴. As the NASA Human Research Program (HRP) evolves, these frameworks are increasingly incorporating non-cancer hazards - specifically radiation-induced CVD by integration of the Astro-CHARM clinical tool into NASA’s radiation risk models, which seeks to quantify global cardiovascular risk in middle-aged astronaut populations⁹².

To quantify the potential for late-occurring cardiovascular effects, NASA’s radiation risk framework—most notably the NSCR model—extrapolates from extensive terrestrial epidemiological datasets.

Our understanding of human radiation risk is heavily informed by the Life Span Study (LSS) of atomic bomb survivors¹⁷. It is important to note that the LSS epidemiological analyses utilize weighted absorbed doses, calculated as the sum of the gamma-ray dose and ten times the neutron dose, to account for the mixed-field nature of the initial radiation. While these data provide the most robust human evidence for late-term effects, translating these risks to the space environment remains a significant challenge. The LSS exposures were characterized by an acute, high-dose-rate delivery of a mixed photon-neutron field, which differs fundamentally from the chronic, low-dose-rate exposure to high-LET GCR and SPE encountered during transit to Mars. These differences in dose-rate and radiation quality necessitate the use of dose and dose-rate effectiveness factors (DDREF) and radiation quality factors (Q) to extrapolate terrestrial data to the astronaut population.

The current strategies for assessing cardiovascular radiation risk are increasingly incorporating data from large-scale occupational cohorts, most notably the Million Person Study (MPS) of U.S. radiation workers and veterans. The MPS is uniquely relevant to the astronaut corps for several reasons: (a) chronic exposure profile—unlike the acute exposure of the LSS, the MPS tracks individuals exposed to low-dose radiation over many years, which more closely mimics the cumulative exposure of long-duration spaceflight; (b) healthy worker comparability—the MPS cohort represents a “healthy worker” population, providing a more statistically reliable ground control for astronauts than the general civilian population; (c) cardiovascular precision—while radiation-induced heart disease was historically viewed as a deterministic effect with a high limit (>0.5 Gy), recent analysis of the MPS and the INWORKS study suggests a stochastic (probabilistic) component at much lower doses (0.1 Gy)^93,94. By integrating these terrestrial findings with mechanistic research, NASA can better calculate REID. This “top-down” epidemiologic approach, combined with “bottom-up” molecular biology, is essential for determining whether the observed vascular remodeling in space is a direct result of GCRs or a synergistic outcome of multiple stressors (e.g., microgravity and oxidative stress).

To quantify the cardiovascular burden of space radiation, NASA utilizes excess relative risk (ERR) models, which define the rate of disease in an exposed population compared to an unexposed population per unit of dose (ERR/Gy). As noted by Little et al.⁹⁵, meta-analyses of diverse cohorts, including the LSS and occupational groups, demonstrate a statistically significant ERR for ischemic heart disease and cerebrovascular disease even at low doses (<0.5 Gy). This suggests that circulatory risk may not follow a strict limit model but instead behaves stochastically, as in cancer. The biological basis for these risks involves complex vascular remodeling. Boerma et al. emphasize that radiation-induced heart disease (RIHD) is characterized by chronic oxidative stress, microvascular rarefaction, and inflammatory signaling⁹⁶. These mechanisms translate the physical energy of ionizing radiation into long-term physiological decline. However, as Huff et al.⁹⁷ describe, “making the leap” from Earth-based gamma-ray data to space-based GCR requires addressing the unique relative biological effectiveness (RBE) of heavy ions. This involves integrating terrestrial ERR data with radiation quality factors (Q) to account for the increased damage density of high-LET ions (e.g., ²⁸Si, ⁵⁶Fe), as well as for the synergistic effects of microgravity on vascular fluid shifts and endothelial stiffness. By utilizing this multi-tiered approach—grounded in the ERR frameworks of Little et al.⁹⁵ and the translational models of Huff et al.⁹⁷, NASA can better estimate the REID for deep-space missions, ensuring that cardiovascular protection is prioritized alongside cancer prevention.

While the studies discussed here demonstrate both acute and long-term effects of HZE IR exposure on CVD risk, they are limited by several factors, including limited frequency of IR exposure (single versus fractionated), doses, and energies, which may not reflect the space environment. Therefore, while certain pronounced effects on cardiovascular function may not be noted, it is essential to consider that the relative risks during space missions will be modified not only by a difference in rate, dose, and frequency of space IR exposure but also by simultaneous exposure to other space hazards such as altered gravity, and notably individual genetic and functional variability that is difficult to mimic using murine models.

Sleep deprivation and circadian desynchrony

Sleep is essential for normal physiological processes, mental health, and cognitive function. Therefore, sleep deprivation could modify astronauts’ adaptation to other space hazards, such as isolation and confinement, may have prolonged effects on cognition and performance, and affect cardiovascular physiology. Astronauts sleep approximately 6 h per day, with factors contributing to this relatively low sleep duration including numerous environmental (e.g., altered light–dark cycles) and psychological factors (e.g., isolation, confinement, stress) that contribute to chronic sleep deprivation^98–100. Sleep disorders are associated with increased CVD risk^101–103, with factors that mediate this effect including altered sympathovagal tone, increased oxidative stress, endothelial dysfunction, altered inflammatory and hematopoietic responses CVD^104–107.

Autonomic dysregulation arising from sleep disruption is evidenced by altered heart rate variability (HRV), plasma catecholamine levels, and reduced intracellular magnesium ion concentration, which in turn has been associated with an increased risk of cardiovascular events. HRV monitoring provides a noninvasive method to assess autonomic control of the heart. A study of the effect of long-duration (6-month) spaceflight on the ISS on HR and HRV during sleep showed a reduction in HRV (along low- and high-frequency bands) during sleep, which was movement-independent and likely reflective of small fluctuations in HR regulation, and associated with changes in the sleep patterns, oscillations in the renin–angiotensin–aldosterone system, and volume redistribution due to altered gravity¹⁰⁸.

While this study did not suggest that sleep deprivation affected cardiorespiratory fitness, it is limited by its small sample size, the lack of parameters evaluating sympathetic or parasympathetic function, and the lack of consideration of other factors, such as microgravity, that can influence the autonomic response. Therefore, the true impact of fatigue from chronic sleep deprivation and circadian dysfunction on cardiac physiology remains to be determined. Circadian rhythms are fundamental in regulating various processes, including cardiac metabolism and maintaining physiologic parameters such as blood pressure, HR, and cardiac contractility^109,110. Approximately 5–10% of genes that are expressed in the heart oscillate in a circadian fashion based on downstream regulation of targets by a ‘molecular clock’, including transcription factors such as CLOCK and BMAL1; however, the heart also has its own peripheral clock, Kruppel-like factor 15 (KLF15), whose expression oscillates under the control of BMAL1. KLF15 controls 75% of transcriptomic regulation in the heart, including genes related to fatty acid metabolism, and regulates various physiological and pathophysiological conditions such as cardiac remodeling in ischemic and nonischemic cardiomyopathy¹¹¹. Human circadian rhythms are primarily synchronized by natural variations in light exposure over a 24-h cycle; in contrast, in LEO, external to the vehicle, light–dark cycles are 90 min, and astronauts compensate for this using artificial lighting (controlled blue and red wavelengths) to facilitate 8/16-h sleep–wake cycles¹¹². Although the Martian sol (24.65 h) is close to the Earth day, its approximately 39-min longer light-dark cycle can challenge human circadian entrainment, particularly under typical indoor/habitat lighting conditions; therefore, successful adaptation is likely to require appropriately timed light exposure and carefully structured sleep–work schedules¹¹³. Experimental animal studies indicate that even minor circadian perturbations can alter molecular clock function, endocrine/metabolic regulation, behavior, and cognition^114,115. Such a mismatch can challenge entrainment and, if sustained without appropriate countermeasures, may lead to cumulative circadian misalignment¹¹⁶. Circadian dysregulation in space has been seen in various model organisms, including altered expression of circadian-associated genes in skeletal muscle¹¹⁷, liver¹¹⁸, and heart⁸⁶. Circadian misalignment has also been observed in astronauts^19,119. During a long-duration mission on the ISS, circadian misalignment was associated with sleep deficiency in astronauts (~5.4 h during misaligned sleep versus ~6.4 h of aligned sleep) and increased use of sleep aids. Notably, other studies have shown that despite the use of sleep aids (e.g., melatonin, sedative-hypnotics, or short-acting barbiturates), sleep deprivation persisted^98,120. Considering these challenges and the fundamental role of circadian rhythms in regulating several biological processes and sleep, it is critical to develop countermeasures that effectively address these hazards, which may play a multifactorial role in increasing cardiovascular risk in conjunction with other space hazards.

VO₂_max decline: mechanisms, risks, and the role of individualized training

Maximal oxygen uptake (VO₂_max) is one of the strongest predictors of cardiovascular morbidity and mortality in the general population¹²¹. Spaceflight studies have consistently demonstrated a decline in VO₂_max during and after missions¹²². To date, one ground-based study simulating a 45-day space mission (n = 14) assessed the effect of confinement and sleep restriction on exercise capacity and cardiorespiratory regulation and found that this combination of hazards did not have a significant effect on exercise capacity or regulation of muscle oxygen uptake (VO_2musc) during the mission; however, defined exercise regimens contributed to accelerated HR kinetics, which correlated with slightly increased first ventilatory thresholds, that in turn was attributed to a training effect of the exercise countermeasure during missions¹²³. However, after the mission, some crewmembers experienced a decline in cardiorespiratory function (VO_2peak and VO_2musc), suggesting that training countermeasures to maintain cardiorespiratory fitness need to be tailored to each individual. This reduction is primarily due to central cardiac adaptations, including decreased plasma volume, SV, and cardiac mass. Additionally, peripheral vascular and skeletal muscle deconditioning, including impaired endothelial function and diminished capillary density, also play a significant role. These mechanisms overlap with well-established pathways that contribute to CVD on Earth, raising concerns that the decline in VO₂_max observed in microgravity may translate into an elevated long-term cardiovascular risk for astronauts. Importantly, terrestrial evidence indicates that structured exercise interventions mitigate these risks. Both resistance and aerobic exercise training improve aerobic capacity and reduce cardiovascular morbidity and mortality in healthy individuals and patients with established CVD¹²⁴. This supports the need for effective exercise countermeasures during long-duration space missions to preserve VO₂_max and reduce long-term cardiovascular hazards.

In the microgravity environment of the ISS, biological systems are subjected to persistent weightlessness. It is important to distinguish this from an ‘absence of gravity’; indeed, gravitational pull remains significant in LEO. However, the resulting free-fall state creates the mechanical unloading and cephalad fluid shifts that drive the observed cardiovascular and musculoskeletal degradation. Decades of research on the ISS have demonstrated that in weightlessness, both bone and muscle undergo rapid atrophy, with downstream implications for cardiovascular health¹²⁵. Advanced hardware, such as the Advanced Resistive Exercise Device (ARED), T2 treadmill, and Cycle Ergometer with Vibration Isolation and Stabilization System (CEVIS), has been developed to mitigate these risks, with astronauts currently performing ~2 h of daily exercise¹²⁶ Importantly, recent studies have shown that while such regimens can preserve musculoskeletal function, up to 17% of astronauts may still experience declines in muscle performance, bone health, and cardiorespiratory fitness if current countermeasures are not optimized¹²⁷. Without exercise countermeasures, these effects would be far more severe—rapid deconditioning would accelerate bone loss, muscle wasting, and reductions in CO and vascular tone, significantly increasing the risk of orthostatic intolerance, arrhythmias, and impaired performance during mission-critical tasks such as planetary landing or extravehicular activity. Exercise, therefore, remains a cornerstone for maintaining muscle and bone mass, preserving aerobic capacity, supporting vascular function, and sustaining cardiac performance, all of which are critical for reducing CVD risk during long-duration exploration missions. Investigations such as Sprint and VO2_max highlight that high-intensity, low-volume exercise is both time-efficient and effective in preserving aerobic capacity in microgravity. Furthermore, preflight conditioning, in-flight exercise prescriptions, and individualized regimens are increasingly recognized as vital for optimizing astronaut health and performance. Lastly, since missions to the Moon or Mars may last for multiple years with significant logistical constraints, ongoing refinement of exercise hardware and protocols, along with nutritional and pharmacological countermeasures, will be necessary to maintain cardiovascular resilience and overall health during prolonged missions.

Isolation and confinement

Isolation and confinement are mission-inherent stressors of space travel that are expected to become more pronounced during deep-space missions. Although these conditions cannot be fully eliminated, their effects may be partially mitigated through operational, behavioral, environmental, and emerging digital countermeasures, including virtual-reality-based approaches^128,129. Even when isolation and confinement may not directly affect cardiovascular physiology, their effect on cognitive and psychological aspects of human health indirectly contributes to increased CVD risk. Isolation and confinement during prolonged space missions can increase the risk of developing insomnia and depression and have also, in certain astronauts, been associated with poor nutritional status marked by weight loss and nutrient deficiencies (e.g., folate)^19,130,131. Several studies have demonstrated that prolonged periods (105 vs. 14–30 days) of confinement, isolation, and stress can alter cognition and behavior^130,132, and have also identified exercise as a sustainable method to help mitigate psychophysiological deconditioning under such environments¹³³.

The effect of chronic stress induced by isolation and confinement must also be considered in the context of cardiovascular risk associated with space missions. There is increasing evidence that psychological stress contributes to CVD¹³⁴ via disturbances in inflammatory, hemostatic, and autonomic processes. Imbalances in the body’s nervous system (altered sympathetic-parasympathetic balance) and stress response pathways can trigger dangerous cardiac issues, including heart attacks, left ventricular dysfunction, and abnormal heart rhythms^135,136. While ground-based studies assessing the effect of job stress, social isolation, and loneliness have suggested moderate associations between related stress and chronic heart disease, the British Whitehall II study, which examined the effect of duration of stress on CVD risk, found that more extended periods and frequent stress exposure was associated with increased risk of developing metabolic syndrome compared to individuals with limited work-related stress exposure (e.g., four periods of stress exposure had a 2.3 times higher odds of CVD (95% 1.3–3.8))^137,138. Although there are no studies on the role of stress reduction in primary prevention of CVD, extensive studies have demonstrated benefits in secondary prevention in patients with CVD¹³⁹. Therefore, the impact of isolation and confinement during space missions on stress and psychological well-being should not be underestimated, and the development of stress management programs should help minimize this hazard’s impact on short- and long-term astronaut cardiovascular and mental health.

Limited food and resources

In addition to radiation, microgravity, isolation, sleep deprivation, and lifestyle factors such as nutrition are increasingly recognized as contributors to cardiovascular health during spaceflight. Inadequate nutritional intake during long-duration missions may worsen vascular dysfunction and accelerate cardiometabolic risks. Recent reviews of spaceflight analogs have highlighted that targeted nutritional interventions, such as optimized protein/amino acid supplementation and low-glycemic index diets, may help mitigate cardiovascular complications¹⁴⁰. Together, these findings underscore the importance of integrating nutrition as a key modifier of cardiovascular risk in space.

Considering the pathophysiologic changes astronauts exhibit due to exposure to various space environment stressors, optimal nutrition is critical in mitigating many of these issues, including fatigue, unintentional weight loss, and other detrimental metabolic derangements. Currently, astronaut diets comprise 55% carbohydrates, 30% fat, and 15% protein. The primary goals of nutrition during spaceflight include counteracting a negative energy balance, preventing nutritional deficiencies, and maintaining appropriate fluid and sodium levels. Several factors throughout spaceflight can reduce dietary intake, including altered taste and smell due to fluid redistribution, limited food variety, altered microbiome, and increased physical activity¹⁴¹.

Concerning micronutrient deficiencies, there is particular concern for copper and zinc deficiencies, as increased fecal excretion of these micronutrients has been seen post-21-day bed rest (a ground-based model for spaceflight)¹⁴². Copper deficiencies can contribute to the development of anemia, neutropenia, and neuropathy, amongst other clinical manifestations, while zinc deficiencies can impair wound healing and immune function and contribute to dysgeusia. Sodium homeostasis profoundly impacts cardiac physiology, ranging from cardiomyocyte depolarization and excitation–contraction coupling, maintenance of membrane potentials, and regulation of fluid balance and blood pressure. Most space foods have a high sodium content due to processing and preservation requirements. High sodium intake has several adverse pathophysiologic effects, including increased blood pressure, but may also drive CVD through inflammatory hematopoiesis¹⁴³. Given cephalad fluid shifts in microgravity and an increase in LV dimensions while CVP is reduced, the SOLO study was conducted to determine if altered gravity changes sodium regulation and natriuretic peptide response; 8 male astronauts were fed low (2 g/d) and/or high (5.5 g/d) sodium diets while dietary nutrient and water intake remained constant, while on Earth and the ISS. Despite similar sodium excretion and body mass, natriuretic peptide and thoracic bioimpedance were lower in space than on Earth, irrespective of the sodium diet. At the same time, aldosterone levels remained unchanged, suggesting potential differences in volume regulation¹⁴⁴.

Glucose intolerance has also been observed during spaceflight and bed rest studies, so low-glycemic-index foods may help mitigate spaceflight-induced insulin resistance¹⁴⁰. A study of bedrest showed that high-protein intake and branched-chain amino acid supplementation could help reduce cardiac atrophy associated with chronic unloading by reducing myocardial nitrogen loss¹⁴⁵. Nutrition can also serve as an important countermeasure against spaceflight-induced effects such as increased oxidative stress, bone loss, muscle atrophy, and microbiome dysbiosis, which can be mitigated via antioxidant-rich foods, vitamins, and branched-chain amino acid supplementation^145,146 and probiotics¹⁴⁷. Therefore, it is critical to consider the implications of nutrition as a noninvasive countermeasure in helping reduce spaceflight-induced cardiovascular risks and to develop strategies to deliver an optimal diet throughout deep space missions.

Insights into risks of multi-year Mars missions

To date, human spaceflight research has largely been limited to short-duration missions (<30 days) and current ISS expeditions (~6–12 months). Extrapolating findings from these missions to multi-year expeditions to Mars raises unique challenges that extend beyond radiation exposure. Mars-class missions will expose astronauts to an integrated set of hazards, including radiation, altered gravity, isolation, and distance from Earth, which interact with genetic predispositions and chronic deconditioning to shape long-term outcomes²⁴. To ensure astronaut health and mission success, it is essential to evaluate both the physiological and psychosocial risks associated with these unprecedented missions. As missions extend toward multi-year durations on the Martian surface, the deterministic approach to cardiovascular health is insufficient. NASA’s current architecture advocates for a probabilistic risk modeling strategy, as detailed by Patel et al.²⁴ and Huff et al.⁹⁷, which integrates environmental, mission-specific, and individual biological variables into a unified risk framework. The central metric in this architecture is REID. To refine the cardiovascular component of REID, the framework must incorporate clinical tools capable of predicting long-term outcomes in a “healthy worker” cohort. A prime example is the Astro-CHARM tool⁹², which was developed specifically to enhance cardiovascular risk prediction by combining traditional risk factors (e.g., age, blood pressure, cholesterol) with coronary artery calcium (CAC) scores and high-sensitivity C-reactive protein (hsCRP) levels. The integration of Astro-CHARM into NASA’s broader risk architecture allows for: (a) individualized risk profiles—moving beyond population averages to assess how an individual astronaut’s pre-mission vascular health (the “Astro-CHARM baseline”) interacts with cumulative GCR exposure; (b) dynamic risk assessment—as suggested by Patel et al.²⁴, probabilistic models allow for the adjustment of mission-permissible limits based on real-time health data and revised excess relative risk (ERR) estimates; (c) synergistic mitigation—by quantifying the “leap from Earth to Space,” this architecture identifies where terrestrial interventions (e.g., statins or anti-inflammatories) might be most effective in mitigating radiation-induced vascular aging. Ultimately, the future of Mars mission safety lies in this integrated, probabilistic approach. By leveraging terrestrial clinical advancements, such as Astro-CHARM, within the REID framework, we can move toward a comprehensive “Space Medicine” paradigm that accounts for the complex interplay between human biology and the harsh environment of deep space.

Psychosocial and behavioral health risks

Beyond physical hazards, long-duration exploration will significantly challenge psychological resilience and team dynamics^148,149. Small crews will need to live and work in tightly controlled environments, often facing delayed or reduced communication with Earth due to vast distances. Under these conditions, stress can limit focus, rigidify decision-making, and decrease adaptability, ultimately impairing individual performance and straining group cohesion, communication, and conflict resolution. NASA’s Behavioral Health and Performance research emphasizes that effective teamwork skills, such as conflict management, shared situational awareness, and communication under stress, are vital for sustaining mission success in space¹⁵⁰. Therefore, astronaut selection and training prioritize adaptability, resilience, and interpersonal skills, with Earth-based analogs (e.g., HERA and NEK studies) providing valuable insights into coping strategies during extended isolation.

Furthermore, the risk of anxiety, depression, cognitive decline, and interpersonal conflict increases during long-duration missions. Current countermeasures include structured sleep-wake schedules, targeted team training, journaling, care packages, and regular psychological support. However, Mars-class expeditions will necessitate more autonomous approaches, as communication delays will limit ground-based assistance. Ongoing research is evaluating digital behavioral health tools, self-monitoring technologies, and environmental interventions, such as optimized lighting, private quarters, and space-based horticulture, to reduce stress and promote morale¹⁵¹. Collectively, these strategies emphasize that behavioral health is not just an ancillary concern but a core determinant of cardiovascular and systemic resilience during multi-year missions.

Conclusions and future direction

Studies have shown that prolonged exposure to unique stressors in space can result in structural and functional changes in astronauts’ cardiovascular systems. Understanding the physiological effects of space flight is crucial for the success of future space missions and for developing mitigating factors, including preventive measures (which may require significant resources such as crew time, mass, power, volume, etc.) to protect astronaut health. The implications of multifactorial cardiac disturbances, such as changes in cardiac function due to spaceflight in combination with pre-existing risk factors, make the risk of in-flight adverse cardiac events pertinent to space missions and underscore the importance of comprehensive pre-flight health assessments. It is essential to consider the effects of stressors in deep space (e.g., microgravity, confinement and isolation, sleep deprivation, sub-optimal diet, etc.) that may interact additively or synergistically with the IR-associated effects (Fig. 3). Delineating causal effects and mechanisms is critical for a comprehensive understanding of shared biological pathways, which may be targeted to optimize responses and adaptations to multiple space environment stressors. While ground-based studies are crucial for understanding possible space hazard risks, important limitations must be carefully taken into account. Furthermore, these limitations highlight the importance of correlating ground-based findings with astronaut clinical data to better inform and standardize space medicine practice. For these reasons, it is essential that NASA develops new procedures to share de-identified clinical data with researchers to accelerate discovery and prevent spaceflight-associated pathologies.

Fig. 3. Spaceflight hazards, physiological risks, and clinical manifestations.

Spaceflight environmental hazards include space radiation, altered gravity, isolation and confinement, distance from Earth, hostile and closed environments, sleep deprivation, and nutritional deficiency. These hazards act in combination to increase physiological, psychosocial, and behavioral health risks, which may ultimately manifest as multiple pathologies, including cardiovascular disease, neurodegenerative disorders, cancer, endocrine/metabolic disorders, and autoimmune disease. Created with BioRender.com.

While all five hazards of human spaceflight impact the cardiovascular system, their temporal and pathological profiles differ significantly: (a) space radiation (GCR/SPE) represents the most persistent, long-term threat. High-LET radiation induces chronic oxidative stress and DNA damage in the endothelium, leading to accelerated atherosclerosis—a stochastic risk modeled via excess relative risk (ERR); (b) microgravity—induces immediate cephalad fluid shifts, resulting in cardiac remodeling (e.g., atrophy) and changes in vascular stiffness. This is a deterministic risk that begins within hours of orbit; (c) isolation and confinement—acts as a chronic psychological stressor, elevating cortisol and catecholamine levels, which can exacerbate underlying inflammatory pathways and blood pressure instability.

However, the most significant challenge for a Mars mission is the combined effect of these stressors. Current evidence suggests that the interplay between radiation and microgravity may be non-linear. Microgravity has been shown to alter the DNA damage response (DDR) and cellular repair mechanisms. In the presence of GCR, this may lead to higher mutation rates in angiogenic progenitor cells (BM-APCs) than would be predicted by radiation alone, adding to an endothelial “double-hit”. Fluid shifts from weightlessness can increase sheer stress and mechanical strain on the vasculature, while radiation simultaneously degrades the endothelial glycocalyx. This “double-hit” may lead to rapid progression of vascular aging, as described by Huff et al.⁹⁷. As we move toward multi-year Mars missions, our risk architecture must transition from a single-hazard approach to integrated stressor models. By using probabilistic tools such as Astro-CHARM alongside high-fidelity murine simulations of combined GCR and hindlimb unloading, we can better predict the true clinical outcome of the integrated space environment.

On December 14, 1972, Apollo 17 commander Eugene Cernan took his final steps on the moon, and one era of space exploration ended. For the Apollo moon missions and the other space programs that preceded them, the relatively short duration of space travel largely prevented any major effects on the cardiovascular system. Now, as humankind envisions far more distant and longer-duration missions into space, the cardiovascular effects of deep space flight have emerged as a unique set of issues that need to be researched, understood, and mitigated.

Author contributions

Conceptualization: D.A.G. and J.C.K.; resources: D.A.G., A.A. and J.C.K.; original draft preparation: A.B., M.B., A.E., V. J., M.K.K., A.A., J.F., J.C.K. and D.A.G; reviewing and editing: A.B., M.B., A.E., V. J., M.K.K., A.A., J.F., J.C.K., and D.A.G.; visualization; A.B., M.B., A.E., V. J., M.K.K. and D.A.G.; supervision: D.A.G.; project administration: D.A.G. and J.C.K; funding acquisition: A.A. and D.A.G. All authors have read and agreed to the published version of the manuscript.

Peer review

Peer review information

Communications Medicine thanks Amir A. Bahadori, Eric King-Giunta and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Funding

This work was supported by the National Aeronautics and Space Administration Human Research Program, grant no. 80NSSC19K1079 (formerly, 80NSSC18K0921) to D.A.G. and 25FAST-1F004 funded by the Higher Education and Science Committee of the Ministry of Education, Science, Culture and Sport of the Republic of Armenia to D.A.G. and A.A. The funders had no role in the data collection and analysis, the decision to publish, or the manuscript preparation.

Data availability

Data sharing is not applicable to this article as no new datasets were generated or analyzed during the current study. The datasets supporting the conclusions of this article are included within the article. Any secondary data analyzed in this review were obtained from the published literature as cited.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s43856-026-01728-x.