Cardiovascular Adaptations of Space Travel: A Systematic Review

Introduction: Space travel imposes significant gravitational and radiation stress on both cellular and systemic physiology, resulting in myriad cardiovascular changes that have not been fully characterized. Methods: We conducted a systematic review of the cellular and clinical adaptations of the cardiovascular system after exposure to real or simulated space travel in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed and Cochrane databases were searched in June 2021 for all peer-reviewed articles published since 1950 related to the following search terms entered in separate pairs: “cardiology and space” and “cardiology and astronaut.” Only cellular and clinical studies in English concerning the investigation of cardiology and space were included. Results: Eighteen studies were identified, comprising 14 clinical and 4 cellular investigations. On the genetic level, pluripotent stem cells in humans and cardiomyocytes in mice displayed increased beat irregularity, with clinical studies revealing a persistent increase in heart rate after space travel. Further cardiovascular adaptations included a higher frequency of orthostatic tachycardia but no evidence of orthostatic hypotension, after return to sea level. Hemoglobin concentration was also consistently decreased after return to Earth. No consistent change in systolic or diastolic blood pressure or any clinically significant arrhythmias were observed during or after space travel. Conclusion: Changes in oxygen carrying capacity, blood pressure, and post-flight orthostatic tachycardia may serve as reasons to further screen for pre-existing anemic and hypotensive conditions among astronauts.


Introduction
Space cardiology is a rapidly growing field concerned with the cardiovascular adaptations to microgravity conditions and space stressors.Space travel results in significant gravitational and radiation stress on both the cellular and systemic levels, resulting in myriad physiologic changes that involve multiple organ systems (e.g., altered circulatory physiology, bone demineralization, optic disc edema).
The National Aeronautics and Space Administration (NASA) has suggested that investigation of space cardiology may improve understanding of the physiological responses of cosmonauts exposed to long-term weightlessness environments [1].The challenges associated with more frequent and extended space exploration and improved understanding of their effects on the cardiovascular system may enhance screening, selection, and care of space travelers.
We conducted a systematic review of the cellular and clinical studies involving alterations of the cardiovascular system related to space stressors.By characterizing these changes, we hope to provide further context for the monitoring needed to enhance safe governmental and touristic human spaceflight.

Methods
A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1).The PubMed, MEDLINE, and Cochrane databases were searched in June 2020 for all peer-reviewed articles published since 1950 related to the following search terms entered in separate pairs: '"cardiology" and "space OR aerospace'' as well as "cardiology and astronaut."This allowed inclusion of a broad range of articles related to space travel with results concerning cardiovascular adaptations.
Only cellular and clinical studies in English concerning the study of cardiology and space were included.Cellular studies were defined as those reporting the molecular or genetic adaptations observed during or after space travel, whereas clinical studies involved the measurement of clinical changes in human subjects after microgravity.Microgravity is typically defined as any gravitational force that is less than one millionth (10 −6 ) of the gravitational force on Earth's surface.Case studies, case series, prospective and retrospective studies, and clinical trials that reported effects of space or simulated space conditions on the cardiovascular system were retrieved.Review articles, articles unavailable to the study team, letters to the editor, and clinical trial proposals were excluded.After full-text review, studies that did not reference cardiovascular changes (cellular or systemic) in response to space travel (real or simulated) were excluded.Study design, sample size, time in space, cardiovascular outcome measures, and findings were extracted and summarized from each article and corresponding levels of evidence (according to the Oxford Centre for Evidence-Based Medicine) were recorded (Table 1).Data were extracted independently by two authors to enhance impartiality, and only articles with a level of evidence II or above were included to minimize the risk of bias.

Results
The search revealed 2,098 records after duplicates were excluded.Articles were screened by title, abstract, and full text as needed to determine eligibility.After the initial screening, 106 full-text articles were assessed for final inclusion, resulting in 18 studies comprising our systematic review.Of these inclusions, 14 were clinical reports, and 4 were cellular investigations.Of the clinical studies, 11 were prospective and 3 were retrospective.The selection process of these articles and their corresponding levels of evidence, according to the Oxford Centre for Evidence-Based Medicine, were recorded.The modality of microgravity exposure (real or simulated spaceflight), as well as all essential data pertaining to the protocols and outcomes of each study, was included in the Table 1.

Cellular Adaptations
Among the four studies in this group, three focused on cellular adaptations, and one utilized an animal model (mice) for physiologic study.Two out of the four reports demonstrated that space stressors may induce arrhythmias in isolated, supported cardiac myocytes when exposed to both real and simulated spaceflight [2,5].Wnorowski et al. [3] reported an increase in beat irregularity among human induced pluripotent stem cells (hiPSC-derived cardiomyocytes) after 5.5 weeks aboard the International Space Station (ISS) that persisted • Decreases of hemoglobin and hematocrit 24 h after spaceflight • Total white blood counts were unaltered, differential subset analysis revealed significant decreases of eosinophil granulocytes and monocytes Khine [15] 29752376 2018 III Clinical 13 6 months (real) • No definite evidence of increased supraventricular arrhythmias and no identified episodes of atrial fibrillation Jirak [16] 32423045 2020 II Clinical 14 Short-term (simulated) • sST2 and GDF-15 evidenced a significant decrease 24 h after parabolic flight • suPAR showed a significant decrease 24 h after parabolic flight • Fetuin-A showed a significant increase at 1 h and 24 h after parabolic flight • H-FABP and IL-33 showed no significant differences at all time points Bimpong-Buta [17] 32903511 2020 II Clinical 12 Short-term (simulated) • SBP (−6 mm Hg) and DBP c (−2 mm Hg) reduced, cardiac output increased Mostl [18] 34122149 2021 II Clinical 24 60 days (simulated) • DBP (+8 mm Hg) and HR (+7 beats) increased Iwasaki [19] 33103234 2021 II Clinical 11 4-11 months (real) • Hgb decreased significantly after spaceflight by 9% and did not return to baseline after 30 days • HR increased (+6 beats) • The mean intracranial pressure did not change significantly RyR2, ryanodine receptor 2; HR, heart rate; MAP, mean arterial pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; Hgb, hemoglobin; RR, respiratory rate; bpm, beats per minute; sST2, suppression of tumorigenicity; GDF-15, growth differentiation factor 15; suPAR, soluble urokinase plasminogen activator receptor; H-FABP, heart-type fatty acid binding protein; IL-33, interleukin-33.*As per the Oxford Centre for Evidence-Based Medicine.

Space Cardiology
Cardiology 2023;148:434-440 DOI: 10.1159/000531466 following return to normal gravity.Respress et al. [2] found that nonsustained ventricular tachycardia events were higher and pacing-induced ventricular arrhythmias developed after extended microgravity conditions (1-2 months via hindleg unloading) in mice, which may be attributable to RyR2 phosphorylation at serine 2,814 followed by sarcoplasmic reticulum calcium leak.Similarly, two out of four studies reported alterations on the genetic level associated with exposure to real space travel.Yamanouchi et al. [4] found an increase in the frequency of chromosomal aberrations, both simple and complex, in cultured human lymphoblastic cells after concurrent exposure to 96 h of simulated microgravity and radiation compared to cells exposed only to radiation.More broadly, Wnorowski et al. [3] noted 2,635 differentially expressed genes in their hiPSC-derived cardiomyocytes after 5.5 weeks of real spaceflight.

Clinical Adaptations
Data on cardiovascular adaptations to space travel in humans concerned primarily autonomic and hemodynamic function.Most studies that measured changes in rate after actual or simulated spaceflight demonstrated an increase, some of which were substantial (increases of up to 20 beats per min in humans) [6,[8][9][10][11][12].In three investigations, heart rate variability was assessed, with two studies reporting no change in this variable during long-term (6 months) real spaceflight [7,13].
Systolic blood pressure, diastolic blood pressure (DBP), and mean blood pressure most often either did not change or decreased in studies that measured this parameter [6,[8][9][10][11]17].Only Mostl et al. [18] reported an increase in DBP (+8 mm Hg) after 60 days of strict headdown tilt bed rest (an established space analog).Blood pressure was also measured in supine, sitting, and standing positions.Orthostatic tachycardia was a frequent finding post-spaceflight, with Liu et al. [11] describing a noticeable difference in the presence of tachycardia between European (5/5) and Chinese astronauts (2/5), but no evidence of orthostatic hypotension.A recent investigation of cardiac microcirculatory changes revealed modest systolic blood pressure (6 mm Hg) and DBP (2 mm Hg) reductions in seated positions but not in supine postures immediately after parabolic flight [18].
Decreases in both hemoglobin and hematocrit were observed after spaceflight.Bimpong-Buta et al. [14] reported 14 human volunteers undergoing brief parabolic flight who experienced a return to hematologic baseline 24 h after return to sea level.White blood cell and platelet counts revealed no significant change in concentration, but both eosinophils and monocytes stayed significantly decreased after 24 h [14].Iwasaki et al. [19], however, noted a more persistent change, with 11 astronauts after 4-11 months in space, displaying a persistent 9% decrease in hemoglobin and hematocrit after 30 days upon return to Earth.
Two studies totaling 17 human subjects utilized echocardiography to quantify changes in cardiac chamber volumes, revealing distinct decreases in left ventricular end-diastolic and end-systolic volumes after real spaceflight; a transient increase (12 ± 18 mL) was also observed in left atrial volume [6,15].Notably, despite the increase in left atrial size, there was no evidence of more frequent supraventricular arrhythmias, including atrial fibrillation [15].Additionally, there was reduction of multiple biomarkers of heart failure after 24 h of parabolic flight, such as soluble suppression of tumorigenicity (sST2), growth differentiation factor 15 (GDF-15), and soluble urokinase plasminogen activator receptor (suPAR) [16].

Discussion
The ISS, where astronauts live and perform scientific experiments, continues to serve as an important site for research [20].Additionally, the 21st century has seen a recent influx of commercial spaceflight companies as well as the establishment of the US Space Force, the newest branch of the US military [21].Due to the predicted rise in space travel, improved understanding of the effect of spaceflight on humans is critical for the success of future missions and the long-term health of those who travel to space [22].To provide a summary of the effects of space travel on the cardiovascular system, this systematic review analyzes cellular and clinical studies.
Research conducted under real or simulated space environment has provided insights into possible genetic alterations associated with microgravity.Cardiac myocytes from mice have exhibited cardiac beat irregularity after a month of stimulated microgravity through hindleg unloading, as well as reduced thresholds for ventricular tachycardia [2].The implication of these studies is that persons traveling in space may experience arrythmias at a higher rate than at sea level; however, this review did not find any clinical evidence supporting this postulate.Prior study has revealed that commercial air travel below 80,000 feet seldom induces clinically significant arrhythmias, and with initial data regarding space travel showing similar findings, it is likely that the arrhythmogenic threshold of human cardiac myocytes in vivo remains higher than that which is achieved from short flights [23].Prior reports of cardiac arrhythmias during space travel have largely been anecdotal, and while it is essential to closely monitor the 438 Cardiology 2023;148:434-440 DOI: 10.1159/000531466 Sharma/Meller/Sharma/Amsterdam potential for cardiac arrhythmias among astronauts and especially in less well-conditioned laypersons, a direct causative effect of microgravity remains unclear [24].
A number of changes on the genetic level have been appreciated after prolonged space travel, resulting in an increased number of both chromosomal aberrations and variable gene expression.It has been determined that space radiation can frequently induce increased oxidative stress, endothelial cell adhesion, and cytogenetic damage, with chromosomal aberrations likely a reflection of DNA damage [25,26].With an overall heightened inflammatory state amongst astronauts [25,26], identification of more sensitive biomarkers may prove helpful in tracking real-time inflammatory changes while in space.
The clinical cardiovascular studies overall revealed mild adaptations, many of which (hemoglobin, hematocrit) were observed shortly after completion of real (1 month) or simulated (24 h) spaceflight [14,19].It is known that in space, transmural cardiac pressure is increased as the normal gravitational compressive effect on myocardium is withdrawn, resulting in increases in stroke volume and cardiac output and lower left ventricular end-diastolic volumes [27].These findings were corroborated by the studies cited in this review, which reveal that transient changes in volume were also observed in the left atrium after at least 6 months of real spaceflight [6,15].Importantly, no astronauts experienced orthostatic hypotension or intolerance following real space travel, with only orthostatic tachycardia lasting post-flight [11,28].
Changes in intravascular volume have also led to alterations in hemoglobin and hematocrit, beginning with an increase during spaceflight and a decrease after completion of spaceflight.Initially, reduced fluid intake early in flight can lead to an increase in hemoglobin concentration, which eventually returns to normal levels as voluntary hydration mitigates early loss of plasma volume [25].After returning to Earth, hemoglobin levels can decrease considerably [19].This effect appears to be a physiologic adaptation to weightlessness in which newly released blood cells are removed from circulation and selectively destroyed due to their larger size compared to mature red blood cells [29].These findings suggest that screening for anemia or underlying hemolytic conditions prior to space travel may be justified in both astronauts and space tourists [30].
This review has several limitations.Given the focus of this article, no reviews or prior articles summarizing cardiovascular adaptations in space were included, many of which may have involved pertinent findings.Also, several of the studies were performed on small cohorts, precluding generalizability of their conclusions.Additionally, not all articles were consistent in their definitions or reports of physiological changes (e.g., many differed in their follow-up times after space travel).This is particularly relevant as it is possible that some cardiovascular adaptations may develop months-years after initial exposure to microgravity and radiation.

Conclusion
This systematic review on space cardiology summarizes the available data for both cellular clinical studies, revealing the possible cardiac, autonomic, and hemodynamic changes induced by space travel.As exploration beyond Earth's atmosphere becomes more common, it is imperative to recognize how changes in cardiovascular physiology may predispose travelers to adverse adaptations.The potential for changes in oxygen carrying capacity, blood pressure, and post-flight orthostatic tachycardia are important considerations in assessing those preparing for space travel.Additionally, while experimental data revealed increased arrhythmogenic potential, no clinically significant arrhythmias were appreciated in humans during or after spaceflight.Space cardiology remains an expanding field of study, and further investigation is required to elucidate the effects of space conditions more definitively in humans.

Statement of Ethics
An ethics statement is not applicable because this study is based exclusively on published literature.

Fig.
Fig. 1.PRISMA flow diagram.A systematic review on space cardiology was conducted in accordance with the PRISMA guidelines.PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1 .
Studies concerning the cardiovascular adaptations to real and simulated space travel