Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE. We aimed to identify mechanisms of immobility-associated VTE protection in a cross-species approach. Mass spectrometry–based proteomics revealed an antithrombotic signature in platelets of hibernating brown bears with heat shock protein 47 (HSP47) as the most substantially reduced protein. HSP47 down-regulation or ablation attenuated immune cell activation and neutrophil extracellular trap formation, contributing to thromboprotection in bears, SCI patients, and mice. This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE.

The harsh environmental conditions in space, particularly weightlessness and radiation exposure, can negatively affect cardiovascular function and structure. In the future, preventive cardiology will be crucial in enabling safe space travel. Indeed, future space missions destined to the Moon and from there to Mars will create new challenges to cardiovascular health while limiting medical management. Moreover, commercial spaceflight evolves rapidly such that older persons with cardiovascular risk factors will be exposed to space conditions. This review provides an overview on studies conducted in space and terrestrial models, particularly head-down bedrest studies. These studies showed that weightlessness elicits a fluid shift towards the head, which likely predisposes to the spaceflight-associated neuro-ocular syndrome, neck vein thrombosis, and orthostatic intolerance after return to Earth. Moreover, cardiovascular unloading produces cardiopulmonary deconditioning, which may be associated with cardiac atrophy. In addition to limiting physical performance, the mechanism further worsens orthostatic tolerance after return to Earth. Finally, space conditions may directly affect vascular health; however, the clinical relevance of these findings in terms of morbidity and mortality is unknown. Targeted preventive measures, which are referred to as countermeasures in aerospace medicine, and technologies to identify vascular risks early on will be required to maintain cardiovascular performance and health during future space missions.

The molecular mechanisms of skeletal muscle adaptation to spaceflight are as yet not fully investigated and well understood. The MUSCLE BIOPSY study analyzed pre and postflight deep calf muscle biopsies (m. soleus) obtained from five male International Space Station (ISS) astronauts. Moderate rates of myofiber atrophy were found in long-duration mission (LDM) astronauts (~180 days in space) performing routine inflight exercise as countermeasure (CM) compared to a short-duration mission (SDM) astronaut (11 days in space, little or no inflight CM) for reference control. Conventional H&E scout histology showed enlarged intramuscular connective tissue gaps between myofiber groups in LDM post vs. preflight. Immunoexpression signals of extracellular matrix (ECM) molecules, collagen 4 and 6, COL4 and 6, and perlecan were reduced while matrix-metalloproteinase, MMP2, biomarker remained unchanged in LDM post vs. preflight suggesting connective tissue remodeling. Large scale proteomics (space omics) identified two canonical protein pathways associated to muscle weakness (necroptosis, GP6 signaling/COL6) in SDM and four key pathways (Fatty acid β-oxidation, integrin-linked kinase ILK, Rho A GTPase RHO, dilated cardiomyopathy signaling) explicitly in LDM. The levels of structural ECM organization proteins COL6A1/A3, fibrillin 1, FBN1, and lumican, LUM, increased in postflight SDM vs. LDM. Proteins from tricarboxylic acid, TCA cycle, mitochondrial respiratory chain, and lipid metabolism mostly recovered in LDM vs. SDM. High levels of calcium signaling proteins, ryanodine receptor 1, RyR1, calsequestrin 1/2, CASQ1/2, annexin A2, ANXA2, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) pump, ATP2A, were signatures of SDM, and decreased levels of oxidative stress peroxiredoxin 1, PRDX1, thioredoxin-dependent peroxide reductase, PRDX3, or superoxide dismutase [Mn] 2, SOD2, signatures of LDM postflight. Results help to better understand the spatiotemporal molecular adaptation of skeletal muscle and provide a large scale database of skeletal muscle from human spaceflight for the better design of effective CM protocols in future human deep space exploration.

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

Sepsis remains a leading cause of mortality in intensive care units. Understanding the dynamics of the plasma proteome of patients with sepsis is critical for improving prognostic and therapeutic strategies. This prospective, multicentre observational cohort study included 363 patients with sepsis recruited from five university hospitals in Germany between March 2018 and April 2023. Plasma samples were collected on days 1 and 4 after sepsis diagnosis, and proteome analysis was performed using mass spectrometry. Classical statistical methods and machine learning (random forest) were employed to identify proteins associated with 30-day survival outcomes. Out of 363 patients, 224 (62%) survived, and 139 (38%) did not survive the 30-day period. Proteomic analysis revealed significant differences in 87 proteins on day 1 and 95 proteins on day 4 between survivors and non-survivors. Additionally, 63 proteins were differentially regulated between day 1 and day 4 in the two groups. The identified protein networks were primarily related to blood coagulation, immune response, and complement activation. The random forest classifier achieved an area under the receiver operating characteristic curve of 0.75 for predicting 30-day survival. The results were compared and partially validated with an external sepsis cohort. This study describes temporal changes in the plasma proteome associated with mortality in sepsis. These findings offer new insights into sepsis pathophysiology, emphasizing the innate immune system as an underexplored network, and may inform the development of targeted therapeutic strategies. European Regional Development Fund of the European Union. The State of North Rhine-Westphalia, Germany.

Background: The harsh environmental conditions during space travel, particularly weightlessness, impose a major burden on the human body including the cardiovascular system. Given its importance in adjusting the cardiovascular system to environmental challenges, the autonomic nervous system has been in the focus of scientists and clinicians involved in human space flight. This review provides an overview on human autonomic research under real and simulated space conditions with a focus on orthostatic intolerance. Methods: The authors conducted a targeted literature search using Pubmed. Results: Overall, 120 articles were identified and included in the review. Conclusions: Postflight orthostatic intolerance is commonly observed in astronauts and could pose major risks when landing on another celestial body. The phenomenon likely results from changes in volume status and adaptation of the autonomic nervous system to weightlessness. Over the years, various non-pharmacological and pharmacological countermeasures have been investigated. In addition to enabling safe human space flight, this research may have implications for patients with disorders affecting cardiovascular autonomic control on Earth.