Correlation Between Invariable Blood Proteins and Heart Rate Variability in Long-Duration Space Flights

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The results are discussed taking into correlation between them. Seven Russian cosmonauts took part in the research during their missions to the International Space Station. Samples of dry blood drops were collected as part of the space experiment ''OMICs-SPK'', electrocardiogram samples were collected as part of the space experiment "Cardiovector". It was established a linear relationship between the concentrations of some proteins and spectral analysis parameters of heart rate at all stages of space flight. In the context of the physiological cardiovascular regulation, the linear correlation found between the six invariant proteins and HRV may be evidence of how and to what extent an adaptive regulation system provides flexible control over the periphery when several processes influence each other. The heart rate variability provides high adaptability, which makes it possible to quickly cope with the challenges of an aggressive and changing environment, maintain homeostatic processes and provide valuable information about the body's ability to function effectively in microgravity. Microgravity space flight heart rate variability blood proteins. Figures Figure 1 Introduction In space, the complex processes that underlie the functional changes in the regulation of the cardiovascular system - one of the most gravity-sensitive systems in the body - determine the success of adaptation to an array of space flight factors and reflect the state not only of this system, but also of the body as a whole [ 1 ]. Despite the fact that today we have considerable amount of data on the state of cardiovascular regulation in space flights, most studies only analyze individual components of the regulation process, whereas the molecular aspect remains largely unexplored [ 2 ]. Assessing the molecular interaction networks and their connection with cardiovascular regulation in cosmonauts will make it possible to predict cardiovascular events even before the mission, as well as to develop personalized countermeasures using both physiological and molecular data [ 3 – 5 ]. Obviously, it is necessary to apply various analytical approaches to the processing of existing and newly collected data from clinical, laboratory and instrumental examinations of cosmonauts. Previously, we performed a study that was first to show the differences between the variability of urine proteome parameters and several biochemical blood parameters, which reflected the peculiarities of adaptation to space flight in cosmonauts with different ratios of autonomic influences (sympathetic or parasympathetic) before and after a long-duration space mission. In particular, it was found that the main proteins which regulate the cardiovascular adaptation to space flight factors had different representations in cosmonaut urine and, same as biochemical blood parameters, they had varying trends of change in the acute re-adaptation period after landing. These results reflect the possible risk of pathological processes in cosmonauts after returning to terrestrial gravity conditions after space flight [ 3 ]. The mechanisms of blood circulation autonomic regulation reflected in the heart rate variability (HRV) parameters can serve as markers of cardiovascular adaptation due to their sensitivity to various external influences or changes in the internal environment of the body [ 6 ]. However, the available literature contains no information about the relationship between invariant proteins and HRV in long-duration space missions. Thus, in order to produce new knowledge in the field of both fundamental physiology and personalized medicine, we have conducted a study of bioinformatic techniques that are used to identify key proteins and molecular networks associated with the mechanisms of autonomic regulation of the cardiovascular system in space flight. Materials and methods The research was carried out as part of the experiments on board of the International Space Station (ISS) that were approved by the Biomedical Ethics Committee of the Institute of Biomedical Problems of the Russian Academy of Sciences and the Human Research Multilateral Review Board. Seven Russian cosmonauts took part in the research (average ± SD age: 44 ± 6 years, all male). All cosmonauts signed informed consent forms and went through full clinical examination according to approved criteria. Most of the test-subjects had previous experience in 6-month space missions. The cosmonauts stayed on board for 170–181 days. Samples of dry blood drops were collected as part of the space experiment "The assessment of human health and adaptive reserves by dry blood spots using proteomics, metabolomics and lipidomics" (code ''OMICs-SPK''), electrocardiogram samples were collected as part of the space experiment "Research on the influence of space flight factors on the spatial distribution of heart energy and the role of the right and left heart sections in the adaptation of the circulatory system to the conditions of prolonged weightlessness" (code "Cardiovector"). Capillary blood was collected as drops on special Wathman papers by puncturing the terminal phalanx of the ring finger with an automatic scarifier. The samples were collected 30 days before the launch (designation, hereinafter - background period); on day 7 of the mission; on the 3rd and 6th months of the expedition; and on days 1, 7, 14 and 26 post-missions. The samples were dried in a dark place at room temperature for 2 hours and then stored until further proteomic studies using chromatography-mass spectrometry. Sample preparation and analysis of the protein composition of the spots were carried out in a laboratory on Earth, after the samples were delivered from the ISS. The dry blood spots were cut out and placed in 1.5 ml microcentrifuge tubes. The proteins were extracted in 1 ml of 25 mM ammonium bicarbonate solution, 1% sodium deoxycholate and 5 mM TCEP (tris-(2-carboxyethyl) phosphine hydrochloride) (Thermo Scientific). The tubes were then incubated for 1 hour at a temperature of 60 ° C at 1,000 rpm (ThermoMixer, Eppendorf). The preparation of samples for mass-spectrometric analysis consisted of reduction with 0.1 M dithiothreitol in 0.1 M tris buffer (pH 8.5) containing 8 M urea at 47°C for 30 minutes; alkylation with 0.05 M iodoacetate and incubation in the dark at room temperature for 30 minutes. The proteins were then precipitated for 15 hours at -20°C with five volumes of acetone over 0.1% trifluoroacetic acid. The protein precipitate was washed first with acetone then with 96% alcohol, separating the precipitate by centrifugation at 16,000 g at 4 ° C for 10 minutes. 100 µl of 0.05 M ammonium bicarbonate buffer and 2 µl of trypsin solution with a concentration of 1 µg/µl in 50 mM acetic acid were added to the sample of the protein substrate. The mixture was incubated for 15 hours at 37°C at 750 rpm. After that, 1 µl of 10% formic acid solution was added to inactivate trypsin and precipitate deoxycholate. The samples were centrifuged at 21,000 g for 10 minutes, and the aliquot of the supernate was then transferred to a new tube for subsequent chromatography-mass spectrometric analysis. Prior to the analysis, the peptide mixtures of dry blood spots were sorted according to the total protein concentration determined via BCA Protein Assay Kit (Pierce) on the iMark Microplate Absorbance Reader from Bio-Rad. The targeted liquid-chromatography multiple-reaction-monitoring mass-spectrometry quantitative analysis (LC-MRM MS) was performed using synthetic Internal Standards (SIS) with stable-isotope labels to assay the corresponding proteins according to standard curves, as described in detail previously [ 7 ]. All samples were analyzed in duplicate with a LC-MS system consisting of an Ex-ionLC™ UHPLC system (Thermo Fisher Scientific, USA) connected to a triple quadrupole mass spectrometer SCIEX QTRAP 6500+ (SCIEX, Toronto, Ontario, Canada). The MRM parameters (Q1/Q3 masses) were adapted and optimized based on previous studies [ 7 ]. Chromatographic separation was performed on an Acquity UPLC Peptide BEH column (C18, 300 Å, 1.7 µm, 2.1 mm × 150 mm, 1/pack) (Waters, USA) with gradient elution. The mobile phase A was 0.1% formic acid in water; the mobile phase B was 0.1% formic acid in acetonitrile. The separation was performed at a flow rate of 0.4 ml/min using a 53-minute gradient from 2 to 45% of the mobile phase B. The mass-spectrometric measurements were performed using the MRM data collection method. The parameters of the electrospray ionization source (ESI) were as follows: ion sputtering voltage 4000 V, temperature 450°C, ion source gas consumption 40 l/min. The Skyline Quantitative Analysis software (version 20.2.0.343, University of Washington) was used for quantitative analysis of the LC-MRM MS raw data. To calculate peptide concentrations in the measured samples, calibration curves were plotted using the weighted linear regression method 1/(x × x). The quality of the MRM data for all selected proteins/peptides was manually checked in Skyline, including the absence of interfering peaks, good peak shape quality and the ratio of natural/SIS-peptide product ions. The ECG was recorded in the II standard lead with a sampling frequency of 1000 Hz. The ECG duration was 5 minutes. In ground-based studies, the ECG was recorded in a seated position. The complete signal was carefully edited using visual verification and manual correction of individual RR intervals and classification of QRS complexes. Abnormal complexes that were not caused by SA node depolarization were excluded from the records. The calculation and analysis of the parameters were performed using both the Russian Recommendations for HRV Analysis, and the European Society of Cardiology and North American Society of Pacing and Electrophysiology Guidelines [ 8 , 9 ]. The ICSIM-6 software (developed by the Institute for the Introduction of New Medical Technologies "Ramena" (LLC), Ryazan, Russia) was used to analyze the interval chart. TP is the full power of the spectrum. In short-term records, it is the sum of the power of the above-described wave ranges of the spectrum. HF (High Frequency) is the range of HRV spectrum within 0.15–0.40 Hz. It is formed by the rhythms with an oscillation period of 2–6 seconds and is associated with respiratory sinus arrhythmia. These oscillations reflect the modulation of vagal tone and are associated with the parasympathetic cardioinhibitory center of the medulla oblongata. LF (Low Frequency) is the range of HRV spectrum within 0.04–0.15 Hz. It is formed by the rhythms with an oscillation period of 7–25 seconds. At rest, this parameter rather reflects baroreflex activity. Spectral analysis parameters were estimated in ms 2 . The HRV spectral analysis allows to estimate the frequency and amplitude of specific rhythms present in the HRV waveform, in order to quantify various oscillations throughout the recording period. At the first stage of statistical analysis via discriminant analysis the proteins involved in the adaptation to space flight were selected from the targeted panel of 200 proteins. Then, through multidimensional scaling, we identified a stable cluster of 18 proteins that were responsible for relations among the observed variables at all times before, during and after space flight. This cluster was able to "self-unfold" numerous protein chains while maintaining its structure and stable connections within the main network. At the second stage, we conducted a dispersion analysis to verify that the proteins significantly changed at all stages of space fight. At the third stage, we found linear relationship between protein concentration and HRV spectral analysis results at all stages of space flight, the results of which will be presented below. Results We have established a linear relationship between the concentrations of the following proteins: complement C1q subcomponent subunit A (encoded by the C1QA gene), complement C1r subcomponent (encoded by the C1R gene), fibrinogen gamma chain (encoded by the FGG gene), galectin-3 (encoded by the LGALS3 gene), interstitial collagenase or matrix metalloproteinase-1 (encoded by the MMP-1 gene), pigment epithelium-derived factor (encoded by the PEDF gene) and HRV spectral analysis parameters at all stages of space flight (Table 1 ). Table 1 The relationship between invariant proteins and HRV parameters in space flight C1QA C1R FGG LGALS3 MMP-1 PEDF TP, ms 2 0.850 -0.933 -0.998 HF, ms 2 0.891 -0.854 -0.901 -0.988 0.850 LF, ms 2 0.827 0.863 -0.842 As can be seen from the table, three proteins were associated with HRV spectrum total power parameters, and either positively correlated with the low-frequency domain of the spectrum as in the case of the C1QA (complement C1q subcomponent subunit A) or negatively - LGALS3, MMP-1 (galectin-3, matrix metalloproteinase-1) correlated with the high-frequency domain of the spectrum. According to the accepted physiological interpretation of spectral indicators, the increase in wave power in the low frequency domain, as well as its decrease in the high frequency domain, reflects the baroreflex activity, as well as (indirectly) sympathetic modulating influences [ 8 ]. One of the proteins, the PEDF (pigment epithelium-derived factor), positively correlated with the high-frequency wave power, which correspondingly reflected the effect of vagal modulation on the SA node. The Complement C1r subcomponent had positive correlations with both high-frequency and low-frequency parameters. The FGG (fibrinogen gamma chain) was negatively correlated with both individual components of the spectrum (HF, ms2, LF ms2) and its total power. We assume that such statistical relationships reflect an increase in the overall variability of R-R intervals and the tension of regulatory mechanisms, which is consistent with classical studies of autonomic regulation in space flight [ 9 ]. Figure 1 shows the dynamics of changes in the above-mentioned proteins before, during and after space flight. As can be seen from Fig. 1 , all of them changed in space flight, but the dynamics of changes were not identical. On day 7 of the mission, the C1QA level continuously increased up to the 3rd month of flight. Subsequently, by the 6th month of the mission, a slight decrease in C1QA was noted, yet its level was higher than pre-flight values. On day 1 after landing, there was a significant decrease in the protein content, with an increase by day 7 and further by day 14 post-mission. By day 26 post-mission, the C1QA level returned to background values. Starting from day 7 of the mission, the C1R level increased with max values by the 3rd month of the flight and a relative decrease by the end of the mission. On day 1after landing, the C1R level almost reached the values of the 6th month in-mission. On day 7 post-mission, the C1R decreased sharply, rising in waves by day 14 and falling below background values by day 26. By the 3rd month post-flight, there was a significant decrease in the FGG level. From day 1 post-mission, the FGG level steadily increased through days 7, 14 and 26 of the recovery periods, exceeding the background pre-flight values. The LGALS3 showed a wave-like dynamics with an increase on day 7 and a relative decrease by the 3rd month in-mission. The observed LGALS3 increase started from the 6th month in-mission and and remains after landing. On day 7 in-mission, we saw a decrease in the MMR-1 content. By the 3rd month in-mission, the MMR-1 level almost equaled the background values. By the 6th month in-mission, the MMR-1 decreased. On days 7, 14 and 26 days of the recovery period, the MMR-1 levels were low compared to the background. On day 7 and the 3rd month in-mission, the PEDF level slightly decreased compared to background values. A slight increase can be seen by day 7 post-mission. Thus, all studied proteins show maximum changes by the 3rd month in-mission and day 1 after landing, which, in our opinion, corresponds to space flight adaptation and reflects of the acute recovery period. The obtained proteomic characteristics correlate with some HRV parameters, as shown in Table 1 and discussed in detail below. Discussion The HRV characterizes the state of the cardiovascular control mechanisms. The neurovisceral integration model considers the HRV dynamics as the final link of the activating and inhibitory influences of the autonomic nervous system. The HRV is an integrative characteristic of various processes present at different levels of the body (including adaptation), which reflects a dynamically maintained systemic homeostasis of blood circulation [ 10 ]. This is due to the fact that nervous and metabolic regulation mechanisms modulate the activity of the SA node and provide a complex response to the challenges for the functional state of the body and its adaptive reactions at any given time [ 11 – 14 ]. The signaling proteins that form the molecular networks of this process determine its characteristics. Recently, there has been a strong surge of interest in the field of complement research [ 15 ]. It has been shown that C1q binds to the C1r and C1s pro-enzymes to form C1, the first component of the serum complement system. Associative protein-protein interactions bind C1QA, SERPING1, C3, FGA, FGB and FGG in the cascades of complement coagulation, regulating the biological processes of fibrin degradation, cell lysis, degranulation chemotaxis and phagocytosis [ 16 ]. Also, the role of complement C1-induced activation of β-catenin signaling in arterial remodeling in hypertension has been established [ 17 ]. It has been shown that the controlling mechanisms of autonomic nervous system are closely related to complement activation in microglia/monocytes [ 18 ]. In some cases, cardiomyocyte-specific deletion of C1QBP leads to contractile dysfunction, cardiac dilation and fibrosis, which, as we assume, warrants another mechanism underlying the close relationship between proteins and HRV [ 19 ]. In cardiomyocytes, C1QBP acts as an RNA and a chaperone, modulating signal translation and mitochondrial function. The metabolome analysis also showed urea cycle disruption in heart tissues with C1QBP deficiency [ 20 ]. The C1R is a serine protease that, in combination with C1q and C1s, forms C1, the first component of the classical complement pathway [ 21 ]. Prabhu SD, 2016, discusses cellular effectors and molecular signals regulating inflammatory and reparative responses involving components of the immune system [ 22 ]. All these data can characterize the relationship between C1 complement and HRV parameters, assuming that C1-induced activation of β-catenin signaling and activation of C1 complement in microglia are targets for its change in a long-term space flight. The relationship between FGG as a parameter of blood hemorheology and HRV was noted in the work of Velcheva I, et al. (2011). An increase in fibrinogen and other hemostasis parameters (hematocrit and plasma viscosity) was associated with a decrease in HRV [ 23 ]. Correlations between HRV decrease and changes in FGG levels confirm that fibrinogen is positively associated with the risk of acute cardiovascular events [ 24 ]. In terms of assessing the influence of long-term space flight factors on HRV, the LGALS3 participates in ventricular remodeling, inflammation and cardiofibrosis. There is evidence of the clinical significance of the LGALS3 in acute and chronic heart failure with preserved and reduced ejection fraction, for the diagnosis, prognosis and stratification of risks of fibrosis and inflammation [ 7 , 25 , 26 ]. Moreover, there is a research work that presents interest as it implements a single scuba dive as a model of micro-gravitational impact on the body. The authors found a significant increase in the levels of LGALS3, the N-terminal prohormone of brain natriuretic peptide (NT-proBNP), highly sensitive troponin-I (hs-TnI) and myoglobin; all recorded immediately after the dive [ 27 ]. While LGALS3 and myoglobin decreased to basal levels during the recovery period, the concentration of NT-proBNP and hs-TnI continued to increase. A direct increase in the blood level of vascular endothelial growth factor, detected immediately after diving, was accompanied by a significant decrease and return to the basal levels after 3 and 6 hours of diving, respectively. After a significant initial decrease, the level of endothelin-1 increased during the recovery period but did not return to the initial level [ 27 ]. Similarly, the levels of LGALS3 and ST2 independently correlated with the degree of fibrosis in the left atrium (diagnosed via MRI) [ 28 ]. Moreover, as shown previously, the level of LGALS3 correlated with a large number of cardiovascular risk factors, and could bind to the von Willebrand factor, thus participating in the modulation of thrombosis in its early phase [ 29 ]. Literature reports and the results of our study show that LGALS3 is a profibrotic biomarker that can help predict the development of cardiac dysfunction induced by space flight factors. On the other hand, LGALS3 can be considered as a regulatory protein acting at various stages of the continuum spanning both acute and chronic inflammation, and tissue fibrosis. It is possible to consider the expression level of LGALS3 as a therapeutic strategy to prevent a wide range of inflammatory and fibrotic diseases in relation to medical safety in long-term space missions. It is known that the MMP1 breaks down collagens of types I, II, III, VII and X. It was found that interleukin-1-beta-stimulated human endothelial cells secrete metalloproteinase by tumor necrosis factor-alpha. The metalloproteinase is then hydrolyzed and inactivates two main inhibitors of serine proteases (serpins): alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin [ 30 ]. We take into account that the MMP1 is obviously an antagonist of hypertrophic processes in the myocardium and intima of blood vessels [ 31 ]. On the other hand, it is noted that MMP1 causes vasoconstriction through protease-activated receptor-1 (PAR-1), which is known to mediate the release of endothelin 1 (ET-1) in endothelial cells, as well as to activate the RhoA (ROCK) kinase pathway [ 32 , 33 ]. The data from Euler G, Locquet F, et al. (2021) stands out as it has shown RNAs MMR1, MMR2, MMR3, MMR9 and MMR14 in isolated cardiomyocytes, along with the expression of the proteins MMR2, MMR9 and MMR14. Due to the fact thag MMPS inhibition promotes hypertrophic growth of cardiomyocytes in vitro, the MMPS found in a healthy heart may be important participants in suppressing ventricular hypertrophy [ 34 ]. The PEDF is known to be a secreted protein that is important for tissue homeostasis and is involved in the biological processes of antiangiogenesis and neuroprotection [ 35 ]. The PEDF is involved in endothelium-mediated fatty acid uptake under conditions of hyperlipidemia. Wang H, et al. (2019) confirmed that a decrease in PEDF expression exacerbates atherosclerosis due to significant vascular dysfunction and increased uptake by endothelial fatty acids, thereby exacerbating ectopic lipid deposition in peripheral tissues [ 36 ]. The PEDF is also associated with a proapoptotic effect, which complicates its role in cardioprotection. It may have significant cardioprotective properties mediated by key regulators depending on the cell type. Thus, Li Y, et al. (2018) indicate that the PEDF promotes mitophagy to protect hypoxic cardiomyocytes through the PEDF/PEDF-R/PA/DAG/PKC-α/ULK1/FUNDC1 pathway [ 37 ]. The PEDF is able to enhance cardiomyocyte apoptosis during hypoxia through Fas, while PEDF receptors are expressed on cardiomyocyte cell membranes. The experiments with miRNA have shown that it is the PEDF PLA2 receptor that is responsible for the induction of cardiomyocyte apoptosis along the Fas pathway [ 38 ]. It is also known that PEDF promotes the regression of immature blood vessels after injury and stimulates the maturation of the vascular microenvironment, thereby contributing to the return to tissue homeostasis after injury [ 39 ]. Conclusion It is known that HRV dynamics, being the final link of activating and inhibitory effects of the autonomic nervous system, is an integrative characteristic of adaptive processes, and its spectral characteristics reflect not only the level of systemic homeostasis during the examination period, but also the prognosis of the viability of the organism in the long term as a whole [ 10 ]. In relation to this study, the OMICs technologies, namely the mass-spectrometric analysis of the protein composition of "dry" blood spots, could become the missing information link that would unite all levels of regulation of the cardiovascular control mechanisms and would take into account personalized characteristics [ 40 ]. In the presented study, a linear relationship was established between the concentration of proteins: complement C1q subcomponent subunit A, complement C1r subcomponent, fibrinogen gamma chain, galectin-3, interstitial collagenase, pigment epithelium-derived factor, and the main spectral parameters of the heart rhythm – its total power, as well as its high- and low-frequency indicators at all stages of space flight. This comparison was conducted for the first time. In the context of the physiological cardiovascular regulation, the linear correlation found between the six invariant proteins and HRV may be evidence of how and to what extent an "integrative" adaptive regulation system provides flexible control over the periphery when several processes influence each other. While mutually constricting each other, these processes allow the entire system to spontaneously fluctuate within a range of states and flexibly respond to changes in external conditions [ 41 ]. That is why, by demonstrating complex patterns of variability, the HRV provides high adaptability [ 41 ], which makes it possible to quickly cope with the challenges of an uncertain and changing environment, maintain homeostatic processes and provide valuable information about the body's ability to function effectively in zero gravity. Declarations The research was approved by the Biomedical Ethics Committee of the Institute of Biomedical Problems of the Russian Academy of Sciences and the Human Research Multilateral Review Board (HRMRB). All cosmonauts who took part in the research signed informed consent forms and consent to publish information in line with the ethical standard. Author contributions L. Pastushkova and A. Goncharova conceived the idea and drafted the manuscript. V. Rusanov made substantial contributions to the conception or design of the work. E. Luchitskaya and D. Kashirina performed data acquisition of the Cardiovector and OMICs-SPK space experiments, they were responsible of the conducting investigations on cosmonauts. A. Nosovsky - had full access to all the data of this study and takes responsibility for the integrity of the data and the accuracy of data analysis T. Krapivnitskaya, I. Larina - revised critically the manuscript for important intellectual content. All the authors did proof reading and corrections for this manuscript and approved the version to be published. Competing interests All authors declare no competing interests. Availability of data and materials The raw data and parameter values are compiled and patented into a database, which can be accessed upon request by the copyright holder. Funding The research was carried out with the funding of the State Corporation Roscosmos and within the framework of the basic theme of the Russian Academy of Sciences by basic programs FMFR-2024-0032, FMFR-2024-0042 and partial support by FMFR-2024-0038 of the State Scientific Center of the Russian Federation - Institute of Biomedical Problems. Acknowledgments The authors would like to express gratitude and appreciation to the cosmonauts who participated in this research project. References Grigoriev, A.I. The concept of health and space medicine / A.I. Grigoriev, R.M. Bayevsky; Institute of Biomedical Problems of the Russian Academy of Sciences. – Moscow: Slovo, 2007. – 207 p. Larina, I.M. Innovative proteomic research in cardiology applied to occupational health problems in aerospace medicine / I.M. Larina, L.H. Pastushkova, Yu.I. Voronkov [et al.] // Cardiological bulletin. – 2020. – vol. 15, No. S. – pp. 10-11. Larina, I.M. 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The Role of Galectin-3 in Heart Failure-The Diagnostic, Prognostic and Therapeutic Potential-Where Do We Stand? Int J Mol Sci. 2023 Aug 23;24(17):13111. doi: 10.3390/ijms241713111. PMID: 37685918; PMCID: PMC10488150 Blanda V, Bracale UM, Di Taranto MD, Fortunato G. Galectin-3 in Cardiovascular Diseases. Int J Mol Sci. 2020 Dec 3;21(23):9232. doi: 10.3390/ijms21239232. PMID: 33287402; PMCID: PMC7731136 Žarak M, Perović A, Dobrović I, Goreta SŠ, Dumić J. Galectin-3 and Cardiovascular Biomarkers Reflect Adaptation Response to Scuba Diving. Int J Sports Med. 2020 May;41(5):285-291. doi: 10.1055/a-1062-6701. Epub 2020 Jan 23. PMID: 31975358. Merino-Merino A, Gonzalez-Bernal J, Fernandez-Zoppino D, Saez-Maleta R, Perez-Rivera JA. The Role of Galectin-3 and ST2 in Cardiology: A Short Review. Biomolecules. 2021 Aug 7;11(8):1167. doi: 10.3390/biom11081167. PMID: 34439833; PMCID: PMC8393977. Făgărășan A, Săsăran M, Gozar L, Crauciuc A, Bănescu C. The Role of Galectin-3 in Predicting Congenital Heart Disease Outcome: A Review of the Literature. Int J Mol Sci. 2023 Jun 22;24(13):10511. doi: 10.3390/ijms241310511. PMID: 37445687; PMCID: PMC10342020 Desrochers PE, Jeffrey JJ, Weiss SJ. Interstitial collagenase (matrix metalloproteinase-1) expresses serpinase activity. J Clin Invest. 1991 Jun;87(6):2258-65. doi: 10.1172/JCI115262. PMID: 1645757; PMCID: PMC296988. Euler G, Locquet F, Kociszewska J, Osygus Y, Heger J, Schreckenberg R, Schlüter KD, Kenyeres É, Szabados T, Bencsik P, Ferdinandy P, Schulz R. Matrix Metalloproteinases Repress Hypertrophic Growth in Cardiac Myocytes. Cardiovasc Drugs Ther. 2021 Apr;35(2):353-365. doi: 10.1007/s10557-020-07138-y. Epub 2021 Jan 5. PMID: 33400052; PMCID: PMC7994223. Estrada-Gutierrez G, Cappello RE, Mishra N, Romero R, Strauss JF 3rd, Walsh SW. Increased expression of matrix metalloproteinase-1 in systemic vessels of preeclamptic women: a critical mediator of vascular dysfunction. Am J Pathol. 2011 Jan;178(1):451-60. doi: 10.1016/j.ajpath.2010.11.003. Epub 2010 Dec 23. PMID: 21224082; PMCID: PMC3070570. Nugent WH, Mishra N, Strauss JF 3rd, Walsh SW. Matrix Metalloproteinase 1 Causes Vasoconstriction and Enhances Vessel Reactivity to Angiotensin II via Protease-Activated Receptor 1. Reprod Sci. 2016 Apr;23(4):542-8. doi: 10.1177/1933719115607998. Epub 2015 Oct 4. PMID: 26438597; PMCID: PMC5933188. Euler G, Locquet F, Kociszewska J, Osygus Y, Heger J, Schreckenberg R, Schlüter KD, Kenyeres É, Szabados T, Bencsik P, Ferdinandy P, Schulz R. Matrix Metalloproteinases Repress Hypertrophic Growth in Cardiac Myocytes. Cardiovasc Drugs Ther. 2021 Apr;35(2):353-365. doi: 10.1007/s10557-020-07138-y. Epub 2021 Jan 5. PMID: 33400052; PMCID: PMC7994223 Wang Y, Liu X, Quan X, Qin X, Zhou Y, Liu Z, Chao Z, Jia C, Qin H, Zhang H. Pigment epithelium-derived factor and its role in microvascular-related diseases. Biochimie. 2022 Sep;200:153-171. doi: 10.1016/j.biochi.2022.05.019. Epub 2022 Jun 2. PMID: 35661748. Wang H, Yang Y, Yang M, Li X, Tan J, Wu Y, Zhang Y, Li Y, Hu B, Deng S, Yang F, Gao S, Li H, Yang Z, Chen H, Cai W. Pigment Epithelial-Derived Factor Deficiency Accelerates Atherosclerosis Development via Promoting Endothelial Fatty Acid Uptake in Mice With Hyperlipidemia. J Am Heart Assoc. 2019 Nov 19;8(22):e013028. doi: 10.1161/JAHA.119.013028. Epub 2019 Nov 12. PMID: 31711388; PMCID: PMC6915260. Li Y, Liu Z, Zhang Y, Zhao Q, Wang X, Lu P, Zhang H, Wang Z, Dong H, Zhang Z. PEDF protects cardiomyocytes by promoting FUNDC1 mediated mitophagy via PEDF-R under hypoxic condition. Int J Mol Med. 2018 Jun;41(6):3394-3404. doi: 10.3892/ijmm.2018.3536. Epub 2018 Mar 6. PMID: 29512692; PMCID: PMC5881750. Li JK, Liang HL, Li Z, Gu CH, Yi DH, Pei JM. Pigment epithelium-derived factor promotes Fas-induced cardiomyocyte apoptosis via its receptor phospholipase A2. Life Sci. 2014 Mar 18;99(1-2):18-23. doi: 10.1016/j.lfs.2013.07.013. Epub 2013 Jul 24. PMID: 23892196. Wietecha MS, Król MJ, Michalczyk ER, Chen L, Gettins PG, DiPietro LA. Pigment epithelium-derived factor as a multifunctional regulator of wound healing. Am J Physiol Heart Circ Physiol. 2015 Sep;309(5):H812-26. doi: 10.1152/ajpheart.00153.2015. Epub 2015 Jul 10. PMID: 26163443; PMCID: PMC4591402. Pastushkova, L.H. Proteomic profile of a healthy person's urine in normal conditions and under space flight factors: abstract of the PhD thesis: 03/14/2008/ Pastushkova Lyudmila Hanifovna; [Place of thesis defence: Institute of Biomedical Problems]. –Moscow, 2015. – 45 p. Thayer, J.F. A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health / J.F. Thayer, F. Ahs, M. Fredrickson [et al.] // Neuroscience & Biobehavioral Reviews. – 2012. – Vol. 36, № 2. – P. 747-756. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 18 Sep, 2024 Read the published version in Microgravity Science and Technology → Version 1 posted Editorial decision: Revision requested 27 Jul, 2024 Reviews received at journal 16 Jul, 2024 Reviewers agreed at journal 10 Jul, 2024 Reviewers invited by journal 10 Jul, 2024 Editor assigned by journal 04 Jul, 2024 Submission checks completed at journal 04 Jul, 2024 First submitted to journal 27 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4648754","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":329003093,"identity":"6ad1e25b-c245-4382-b434-3a2f71fed681","order_by":0,"name":"Ludmila Pastushkova","email":"","orcid":"","institution":"Institute of Biomedical Problems","correspondingAuthor":false,"prefix":"","firstName":"Ludmila","middleName":"","lastName":"Pastushkova","suffix":""},{"id":329003094,"identity":"898d1c6d-17ed-4d23-ae7b-4ce322a67ec1","order_by":1,"name":"Vasily Rusanov","email":"","orcid":"","institution":"Institute of Biomedical Problems","correspondingAuthor":false,"prefix":"","firstName":"Vasily","middleName":"","lastName":"Rusanov","suffix":""},{"id":329003095,"identity":"4d52f00d-ff05-4afa-a3a8-f22331f30fad","order_by":2,"name":"Anna Goncharova","email":"","orcid":"","institution":"Institute of Biomedical Problems","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Goncharova","suffix":""},{"id":329003096,"identity":"ddc421dd-6326-4f74-9e42-ae5a0165dbae","order_by":3,"name":"Darya Kashirina","email":"","orcid":"","institution":"Institute of Biomedical Problems","correspondingAuthor":false,"prefix":"","firstName":"Darya","middleName":"","lastName":"Kashirina","suffix":""},{"id":329003097,"identity":"f5d4ec90-e19c-49d7-8d62-efaa73a16f45","order_by":4,"name":"Andrey Nosovsky","email":"","orcid":"","institution":"Institute of Biomedical Problems","correspondingAuthor":false,"prefix":"","firstName":"Andrey","middleName":"","lastName":"Nosovsky","suffix":""},{"id":329003098,"identity":"d561bdbd-7329-4ad7-83dc-2855b47ae590","order_by":5,"name":"Elena Luchitskaya","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYFAC5gYGxgYJBgYeEKcCJAAUwQ8YwVokIFrOgLQwEqWFAaKFsQ0qgg/wA5VJ/NxhUSffc/iZxM95tdH87UAtPyq24dQi2cDYJtl7RkLC4GybmWTvtuO5Mw4zNjD2nLmNU4vBAcY2aaBFEgb8DGYSvNuO5TYAtTAztuHWYg/TIt/P/k3y75xjufMJaTFggGphONtjJs3bUJO7gZAWicOMzZa9bRKSG86cKbaWOXYgdyNQy0F8fuFvbz5442dbHb98T/rGm29q6nLnnT988MGPCtxaGJgRTBZgGjgMZh3ArR5N9wcGhjpiFY+CUTAKRsEIAgCDqVb4fBZnAwAAAABJRU5ErkJggg==","orcid":"","institution":"Institute of Biomedical Problems","correspondingAuthor":true,"prefix":"","firstName":"Elena","middleName":"","lastName":"Luchitskaya","suffix":""},{"id":329003099,"identity":"818008b1-f938-413c-9d9e-9c7bb45fc773","order_by":6,"name":"Tatyana Krapivnitskaya","email":"","orcid":"","institution":"Russian Medical Academy of Continuous Professional Education","correspondingAuthor":false,"prefix":"","firstName":"Tatyana","middleName":"","lastName":"Krapivnitskaya","suffix":""},{"id":329003100,"identity":"c2ce183f-4f21-4cb4-8e51-be337dc6b719","order_by":7,"name":"Irina Larina","email":"","orcid":"","institution":"Institute of Biomedical Problems","correspondingAuthor":false,"prefix":"","firstName":"Irina","middleName":"","lastName":"Larina","suffix":""}],"badges":[],"createdAt":"2024-06-27 13:09:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4648754/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4648754/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12217-024-10139-3","type":"published","date":"2024-09-18T15:57:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61338186,"identity":"e66ac58a-47c0-4a27-84bc-b4ee41ccae72","added_by":"auto","created_at":"2024-07-29 16:05:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":116344,"visible":true,"origin":"","legend":"\u003cp\u003eDynamics of changes in the above-mentioned proteins before, in, and after space flight.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4648754/v1/4cf0dd8a257b716bdadd065d.png"},{"id":65103962,"identity":"329790f7-1cdc-4b56-ae24-6dc9eb777730","added_by":"auto","created_at":"2024-09-23 16:10:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":461597,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4648754/v1/d396da49-7fce-47b3-9c4d-f8c7bbd6359b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eCorrelation Between Invariable Blood Proteins and Heart Rate Variability in Long-Duration Space Flights\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn space, the complex processes that underlie the functional changes in the regulation of the cardiovascular system - one of the most gravity-sensitive systems in the body - determine the success of adaptation to an array of space flight factors and reflect the state not only of this system, but also of the body as a whole [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the fact that today we have considerable amount of data on the state of cardiovascular regulation in space flights, most studies only analyze individual components of the regulation process, whereas the molecular aspect remains largely unexplored [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAssessing the molecular interaction networks and their connection with cardiovascular regulation in cosmonauts will make it possible to predict cardiovascular events even before the mission, as well as to develop personalized countermeasures using both physiological and molecular data [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Obviously, it is necessary to apply various analytical approaches to the processing of existing and newly collected data from clinical, laboratory and instrumental examinations of cosmonauts.\u003c/p\u003e \u003cp\u003ePreviously, we performed a study that was first to show the differences between the variability of urine proteome parameters and several biochemical blood parameters, which reflected the peculiarities of adaptation to space flight in cosmonauts with different ratios of autonomic influences (sympathetic or parasympathetic) before and after a long-duration space mission. In particular, it was found that the main proteins which regulate the cardiovascular adaptation to space flight factors had different representations in cosmonaut urine and, same as biochemical blood parameters, they had varying trends of change in the acute re-adaptation period after landing. These results reflect the possible risk of pathological processes in cosmonauts after returning to terrestrial gravity conditions after space flight [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mechanisms of blood circulation autonomic regulation reflected in the heart rate variability (HRV) parameters can serve as markers of cardiovascular adaptation due to their sensitivity to various external influences or changes in the internal environment of the body [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, the available literature contains no information about the relationship between invariant proteins and HRV in long-duration space missions.\u003c/p\u003e \u003cp\u003eThus, in order to produce new knowledge in the field of both fundamental physiology and personalized medicine, we have conducted a study of bioinformatic techniques that are used to identify key proteins and molecular networks associated with the mechanisms of autonomic regulation of the cardiovascular system in space flight.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThe research was carried out as part of the experiments on board of the International Space Station (ISS) that were approved by the Biomedical Ethics Committee of the Institute of Biomedical Problems of the Russian Academy of Sciences and the Human Research Multilateral Review Board. Seven Russian cosmonauts took part in the research (average\u0026thinsp;\u0026plusmn;\u0026thinsp;SD age: 44\u0026thinsp;\u0026plusmn;\u0026thinsp;6 years, all male). All cosmonauts signed informed consent forms and went through full clinical examination according to approved criteria. Most of the test-subjects had previous experience in 6-month space missions. The cosmonauts stayed on board for 170\u0026ndash;181 days.\u003c/p\u003e \u003cp\u003eSamples of dry blood drops were collected as part of the space experiment \"The assessment of human health and adaptive reserves by dry blood spots using proteomics, metabolomics and lipidomics\" (code ''OMICs-SPK''), electrocardiogram samples were collected as part of the space experiment \"Research on the influence of space flight factors on the spatial distribution of heart energy and the role of the right and left heart sections in the adaptation of the circulatory system to the conditions of prolonged weightlessness\" (code \"Cardiovector\").\u003c/p\u003e \u003cp\u003eCapillary blood was collected as drops on special Wathman papers by puncturing the terminal phalanx of the ring finger with an automatic scarifier. The samples were collected 30 days before the launch (designation, hereinafter - background period); on day 7 of the mission; on the 3rd and 6th months of the expedition; and on days 1, 7, 14 and 26 post-missions. The samples were dried in a dark place at room temperature for 2 hours and then stored until further proteomic studies using chromatography-mass spectrometry. Sample preparation and analysis of the protein composition of the spots were carried out in a laboratory on Earth, after the samples were delivered from the ISS. The dry blood spots were cut out and placed in 1.5 ml microcentrifuge tubes. The proteins were extracted in 1 ml of 25 mM ammonium bicarbonate solution, 1% sodium deoxycholate and 5 mM TCEP (tris-(2-carboxyethyl) phosphine hydrochloride) (Thermo Scientific). The tubes were then incubated for 1 hour at a temperature of 60 \u0026deg; C at 1,000 rpm (ThermoMixer, Eppendorf). The preparation of samples for mass-spectrometric analysis consisted of reduction with 0.1 M dithiothreitol in 0.1 M tris buffer (pH 8.5) containing 8 M urea at 47\u0026deg;C for 30 minutes; alkylation with 0.05 M iodoacetate and incubation in the dark at room temperature for 30 minutes. The proteins were then precipitated for 15 hours at -20\u0026deg;C with five volumes of acetone over 0.1% trifluoroacetic acid. The protein precipitate was washed first with acetone then with 96% alcohol, separating the precipitate by centrifugation at 16,000 g at 4 \u0026deg; C for 10 minutes. 100 \u0026micro;l of 0.05 M ammonium bicarbonate buffer and 2 \u0026micro;l of trypsin solution with a concentration of 1 \u0026micro;g/\u0026micro;l in 50 mM acetic acid were added to the sample of the protein substrate. The mixture was incubated for 15 hours at 37\u0026deg;C at 750 rpm. After that, 1 \u0026micro;l of 10% formic acid solution was added to inactivate trypsin and precipitate deoxycholate. The samples were centrifuged at 21,000 g for 10 minutes, and the aliquot of the supernate was then transferred to a new tube for subsequent chromatography-mass spectrometric analysis. Prior to the analysis, the peptide mixtures of dry blood spots were sorted according to the total protein concentration determined via BCA Protein Assay Kit (Pierce) on the iMark Microplate Absorbance Reader from Bio-Rad.\u003c/p\u003e \u003cp\u003eThe targeted liquid-chromatography multiple-reaction-monitoring mass-spectrometry quantitative analysis (LC-MRM MS) was performed using synthetic Internal Standards (SIS) with stable-isotope labels to assay the corresponding proteins according to standard curves, as described in detail previously [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll samples were analyzed in duplicate with a LC-MS system consisting of an Ex-ionLC\u0026trade; UHPLC system (Thermo Fisher Scientific, USA) connected to a triple quadrupole mass spectrometer SCIEX QTRAP 6500+ (SCIEX, Toronto, Ontario, Canada). The MRM parameters (Q1/Q3 masses) were adapted and optimized based on previous studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eChromatographic separation was performed on an Acquity UPLC Peptide BEH column (C18, 300 \u0026Aring;, 1.7 \u0026micro;m, 2.1 mm \u0026times; 150 mm, 1/pack) (Waters, USA) with gradient elution. The mobile phase A was 0.1% formic acid in water; the mobile phase B was 0.1% formic acid in acetonitrile. The separation was performed at a flow rate of 0.4 ml/min using a 53-minute gradient from 2 to 45% of the mobile phase B. The mass-spectrometric measurements were performed using the MRM data collection method. The parameters of the electrospray ionization source (ESI) were as follows: ion sputtering voltage 4000 V, temperature 450\u0026deg;C, ion source gas consumption 40 l/min.\u003c/p\u003e \u003cp\u003eThe Skyline Quantitative Analysis software (version 20.2.0.343, University of Washington) was used for quantitative analysis of the LC-MRM MS raw data. To calculate peptide concentrations in the measured samples, calibration curves were plotted using the weighted linear regression method 1/(x \u0026times; x). The quality of the MRM data for all selected proteins/peptides was manually checked in Skyline, including the absence of interfering peaks, good peak shape quality and the ratio of natural/SIS-peptide product ions.\u003c/p\u003e \u003cp\u003eThe ECG was recorded in the II standard lead with a sampling frequency of 1000 Hz. The ECG duration was 5 minutes. In ground-based studies, the ECG was recorded in a seated position.\u003c/p\u003e \u003cp\u003eThe complete signal was carefully edited using visual verification and manual correction of individual RR intervals and classification of QRS complexes. Abnormal complexes that were not caused by SA node depolarization were excluded from the records.\u003c/p\u003e \u003cp\u003eThe calculation and analysis of the parameters were performed using both the Russian Recommendations for HRV Analysis, and the European Society of Cardiology and North American Society of Pacing and Electrophysiology Guidelines [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe ICSIM-6 software (developed by the Institute for the Introduction of New Medical Technologies \"Ramena\" (LLC), Ryazan, Russia) was used to analyze the interval chart.\u003c/p\u003e \u003cp\u003eTP is the full power of the spectrum. In short-term records, it is the sum of the power of the above-described wave ranges of the spectrum.\u003c/p\u003e \u003cp\u003eHF (High Frequency) is the range of HRV spectrum within 0.15\u0026ndash;0.40 Hz. It is formed by the rhythms with an oscillation period of 2\u0026ndash;6 seconds and is associated with respiratory sinus arrhythmia. These oscillations reflect the modulation of vagal tone and are associated with the parasympathetic cardioinhibitory center of the medulla oblongata.\u003c/p\u003e \u003cp\u003eLF (Low Frequency) is the range of HRV spectrum within 0.04\u0026ndash;0.15 Hz. It is formed by the rhythms with an oscillation period of 7\u0026ndash;25 seconds. At rest, this parameter rather reflects baroreflex activity.\u003c/p\u003e \u003cp\u003eSpectral analysis parameters were estimated in ms\u003csup\u003e2\u003c/sup\u003e. The HRV spectral analysis allows to estimate the frequency and amplitude of specific rhythms present in the HRV waveform, in order to quantify various oscillations throughout the recording period.\u003c/p\u003e \u003cp\u003eAt the first stage of statistical analysis via discriminant analysis the proteins involved in the adaptation to space flight were selected from the targeted panel of 200 proteins. Then, through multidimensional scaling, we identified a stable cluster of 18 proteins that were responsible for relations among the observed variables at all times before, during and after space flight. This cluster was able to \"self-unfold\" numerous protein chains while maintaining its structure and stable connections within the main network. At the second stage, we conducted a dispersion analysis to verify that the proteins significantly changed at all stages of space fight. At the third stage, we found linear relationship between protein concentration and HRV spectral analysis results at all stages of space flight, the results of which will be presented below.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe have established a linear relationship between the concentrations of the following proteins: complement C1q subcomponent subunit A (encoded by the C1QA gene), complement C1r subcomponent (encoded by the C1R gene), fibrinogen gamma chain (encoded by the FGG gene), galectin-3 (encoded by the LGALS3 gene), interstitial collagenase or matrix metalloproteinase-1 (encoded by the MMP-1 gene), pigment epithelium-derived factor (encoded by the PEDF gene) and HRV spectral analysis parameters at all stages of space flight (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe relationship between invariant proteins and HRV parameters in space flight\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC1QA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC1R\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFGG\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLGALS3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMMP-1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePEDF\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTP, ms \u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.850\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.933\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHF, ms \u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.891\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.854\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.988\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.850\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLF, ms \u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.827\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.863\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.842\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs can be seen from the table, three proteins were associated with HRV spectrum total power parameters, and either positively correlated with the low-frequency domain of the spectrum as in the case of the C1QA (complement C1q subcomponent subunit A) or negatively - LGALS3, MMP-1 (galectin-3, matrix metalloproteinase-1) correlated with the high-frequency domain of the spectrum. According to the accepted physiological interpretation of spectral indicators, the increase in wave power in the low frequency domain, as well as its decrease in the high frequency domain, reflects the baroreflex activity, as well as (indirectly) sympathetic modulating influences [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. One of the proteins, the PEDF (pigment epithelium-derived factor), positively correlated with the high-frequency wave power, which correspondingly reflected the effect of vagal modulation on the SA node. The Complement C1r subcomponent had positive correlations with both high-frequency and low-frequency parameters. The FGG (fibrinogen gamma chain) was negatively correlated with both individual components of the spectrum (HF, ms2, LF ms2) and its total power. We assume that such statistical relationships reflect an increase in the overall variability of R-R intervals and the tension of regulatory mechanisms, which is consistent with classical studies of autonomic regulation in space flight [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the dynamics of changes in the above-mentioned proteins before, during and after space flight.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAs can be seen from Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, all of them changed in space flight, but the dynamics of changes were not identical.\u003c/p\u003e \u003cp\u003eOn day 7 of the mission, the C1QA level continuously increased up to the 3rd month of flight. Subsequently, by the 6th month of the mission, a slight decrease in C1QA was noted, yet its level was higher than pre-flight values. On day 1 after landing, there was a significant decrease in the protein content, with an increase by day 7 and further by day 14 post-mission. By day 26 post-mission, the C1QA level returned to background values.\u003c/p\u003e \u003cp\u003eStarting from day 7 of the mission, the C1R level increased with max values by the 3rd month of the flight and a relative decrease by the end of the mission. On day 1after landing, the C1R level almost reached the values of the 6th month in-mission. On day 7 post-mission, the C1R decreased sharply, rising in waves by day 14 and falling below background values by day 26.\u003c/p\u003e \u003cp\u003eBy the 3rd month post-flight, there was a significant decrease in the FGG level. From day 1 post-mission, the FGG level steadily increased through days 7, 14 and 26 of the recovery periods, exceeding the background pre-flight values.\u003c/p\u003e \u003cp\u003eThe LGALS3 showed a wave-like dynamics with an increase on day 7 and a relative decrease by the 3rd month in-mission. The observed LGALS3 increase started from the 6th month in-mission and and remains after landing.\u003c/p\u003e \u003cp\u003eOn day 7 in-mission, we saw a decrease in the MMR-1 content. By the 3rd month in-mission, the MMR-1 level almost equaled the background values. By the 6th month in-mission, the MMR-1 decreased. On days 7, 14 and 26 days of the recovery period, the MMR-1 levels were low compared to the background.\u003c/p\u003e \u003cp\u003eOn day 7 and the 3rd month in-mission, the PEDF level slightly decreased compared to background values. A slight increase can be seen by day 7 post-mission.\u003c/p\u003e \u003cp\u003eThus, all studied proteins show maximum changes by the 3rd month in-mission and day 1 after landing, which, in our opinion, corresponds to space flight adaptation and reflects of the acute recovery period. The obtained proteomic characteristics correlate with some HRV parameters, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and discussed in detail below.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe HRV characterizes the state of the cardiovascular control mechanisms. The neurovisceral integration model considers the HRV dynamics as the final link of the activating and inhibitory influences of the autonomic nervous system. The HRV is an integrative characteristic of various processes present at different levels of the body (including adaptation), which reflects a dynamically maintained systemic homeostasis of blood circulation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This is due to the fact that nervous and metabolic regulation mechanisms modulate the activity of the SA node and provide a complex response to the challenges for the functional state of the body and its adaptive reactions at any given time [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The signaling proteins that form the molecular networks of this process determine its characteristics.\u003c/p\u003e \u003cp\u003eRecently, there has been a strong surge of interest in the field of complement research [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. It has been shown that C1q binds to the C1r and C1s pro-enzymes to form C1, the first component of the serum complement system. Associative protein-protein interactions bind C1QA, SERPING1, C3, FGA, FGB and FGG in the cascades of complement coagulation, regulating the biological processes of fibrin degradation, cell lysis, degranulation chemotaxis and phagocytosis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlso, the role of complement C1-induced activation of β-catenin signaling in arterial remodeling in hypertension has been established [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt has been shown that the controlling mechanisms of autonomic nervous system are closely related to complement activation in microglia/monocytes [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In some cases, cardiomyocyte-specific deletion of C1QBP leads to contractile dysfunction, cardiac dilation and fibrosis, which, as we assume, warrants another mechanism underlying the close relationship between proteins and HRV [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In cardiomyocytes, C1QBP acts as an RNA and a chaperone, modulating signal translation and mitochondrial function. The metabolome analysis also showed urea cycle disruption in heart tissues with C1QBP deficiency [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe C1R is a serine protease that, in combination with C1q and C1s, forms C1, the first component of the classical complement pathway [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Prabhu SD, 2016, discusses cellular effectors and molecular signals regulating inflammatory and reparative responses involving components of the immune system [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll these data can characterize the relationship between C1 complement and HRV parameters, assuming that C1-induced activation of β-catenin signaling and activation of C1 complement in microglia are targets for its change in a long-term space flight.\u003c/p\u003e \u003cp\u003eThe relationship between FGG as a parameter of blood hemorheology and HRV was noted in the work of Velcheva I, et al. (2011). An increase in fibrinogen and other hemostasis parameters (hematocrit and plasma viscosity) was associated with a decrease in HRV [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Correlations between HRV decrease and changes in FGG levels confirm that fibrinogen is positively associated with the risk of acute cardiovascular events [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn terms of assessing the influence of long-term space flight factors on HRV, the LGALS3 participates in ventricular remodeling, inflammation and cardiofibrosis. There is evidence of the clinical significance of the LGALS3 in acute and chronic heart failure with preserved and reduced ejection fraction, for the diagnosis, prognosis and stratification of risks of fibrosis and inflammation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoreover, there is a research work that presents interest as it implements a single scuba dive as a model of micro-gravitational impact on the body. The authors found a significant increase in the levels of LGALS3, the N-terminal prohormone of brain natriuretic peptide (NT-proBNP), highly sensitive troponin-I (hs-TnI) and myoglobin; all recorded immediately after the dive [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. While LGALS3 and myoglobin decreased to basal levels during the recovery period, the concentration of NT-proBNP and hs-TnI continued to increase. A direct increase in the blood level of vascular endothelial growth factor, detected immediately after diving, was accompanied by a significant decrease and return to the basal levels after 3 and 6 hours of diving, respectively. After a significant initial decrease, the level of endothelin-1 increased during the recovery period but did not return to the initial level [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSimilarly, the levels of LGALS3 and ST2 independently correlated with the degree of fibrosis in the left atrium (diagnosed via MRI) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Moreover, as shown previously, the level of LGALS3 correlated with a large number of cardiovascular risk factors, and could bind to the von Willebrand factor, thus participating in the modulation of thrombosis in its early phase [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLiterature reports and the results of our study show that LGALS3 is a profibrotic biomarker that can help predict the development of cardiac dysfunction induced by space flight factors. On the other hand, LGALS3 can be considered as a regulatory protein acting at various stages of the continuum spanning both acute and chronic inflammation, and tissue fibrosis. It is possible to consider the expression level of LGALS3 as a therapeutic strategy to prevent a wide range of inflammatory and fibrotic diseases in relation to medical safety in long-term space missions.\u003c/p\u003e \u003cp\u003eIt is known that the \u003cem\u003eMMP1\u003c/em\u003e breaks down collagens of types I, II, III, VII and X. It was found that interleukin-1-beta-stimulated human endothelial cells secrete metalloproteinase by tumor necrosis factor-alpha. The metalloproteinase is then hydrolyzed and inactivates two main inhibitors of serine proteases (serpins): alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. We take into account that the MMP1 is obviously an antagonist of hypertrophic processes in the myocardium and intima of blood vessels [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. On the other hand, it is noted that MMP1 causes vasoconstriction through protease-activated receptor-1 (PAR-1), which is known to mediate the release of endothelin 1 (ET-1) in endothelial cells, as well as to activate the RhoA (ROCK) kinase pathway [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe data from Euler G, Locquet F, et al. (2021) stands out as it has shown RNAs MMR1, MMR2, MMR3, MMR9 and MMR14 in isolated cardiomyocytes, along with the expression of the proteins MMR2, MMR9 and MMR14. Due to the fact thag MMPS inhibition promotes hypertrophic growth of cardiomyocytes in vitro, the MMPS found in a healthy heart may be important participants in suppressing ventricular hypertrophy [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe PEDF is known to be a secreted protein that is important for tissue homeostasis and is involved in the biological processes of antiangiogenesis and neuroprotection [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The PEDF is involved in endothelium-mediated fatty acid uptake under conditions of hyperlipidemia. Wang H, et al. (2019) confirmed that a decrease in PEDF expression exacerbates atherosclerosis due to significant vascular dysfunction and increased uptake by endothelial fatty acids, thereby exacerbating ectopic lipid deposition in peripheral tissues [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The PEDF is also associated with a proapoptotic effect, which complicates its role in cardioprotection. It may have significant cardioprotective properties mediated by key regulators depending on the cell type. Thus, Li Y, et al. (2018) indicate that the PEDF promotes mitophagy to protect hypoxic cardiomyocytes through the PEDF/PEDF-R/PA/DAG/PKC-α/ULK1/FUNDC1 pathway [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The PEDF is able to enhance cardiomyocyte apoptosis during hypoxia through Fas, while PEDF receptors are expressed on cardiomyocyte cell membranes. The experiments with miRNA have shown that it is the PEDF PLA2 receptor that is responsible for the induction of cardiomyocyte apoptosis along the Fas pathway [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. It is also known that PEDF promotes the regression of immature blood vessels after injury and stimulates the maturation of the vascular microenvironment, thereby contributing to the return to tissue homeostasis after injury [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIt is known that HRV dynamics, being the final link of activating and inhibitory effects of the autonomic nervous system, is an integrative characteristic of adaptive processes, and its spectral characteristics reflect not only the level of systemic homeostasis during the examination period, but also the prognosis of the viability of the organism in the long term as a whole [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In relation to this study, the OMICs technologies, namely the mass-spectrometric analysis of the protein composition of \"dry\" blood spots, could become the missing information link that would unite all levels of regulation of the cardiovascular control mechanisms and would take into account personalized characteristics [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the presented study, a linear relationship was established between the concentration of proteins: complement C1q subcomponent subunit A, complement C1r subcomponent, fibrinogen gamma chain, galectin-3, interstitial collagenase, pigment epithelium-derived factor, and the main spectral parameters of the heart rhythm \u0026ndash; its total power, as well as its high- and low-frequency indicators at all stages of space flight. This comparison was conducted for the first time. In the context of the physiological cardiovascular regulation, the linear correlation found between the six invariant proteins and HRV may be evidence of how and to what extent an \"integrative\" adaptive regulation system provides flexible control over the periphery when several processes influence each other. While mutually constricting each other, these processes allow the entire system to spontaneously fluctuate within a range of states and flexibly respond to changes in external conditions [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. That is why, by demonstrating complex patterns of variability, the HRV provides high adaptability [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], which makes it possible to quickly cope with the challenges of an uncertain and changing environment, maintain homeostatic processes and provide valuable information about the body's ability to function effectively in zero gravity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe research was approved by the Biomedical Ethics Committee of the Institute of Biomedical Problems of the Russian Academy of Sciences and the Human Research Multilateral Review Board (HRMRB). All cosmonauts who took part in the research signed informed consent forms and consent to publish information in line with the ethical standard.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL. Pastushkova and A. Goncharova conceived the idea and drafted the manuscript.\u003c/p\u003e\n\u003cp\u003eV. Rusanov made substantial contributions to the conception or design of the work.\u003c/p\u003e\n\u003cp\u003eE. Luchitskaya and D. Kashirina performed data acquisition of the Cardiovector and OMICs-SPK space experiments, they were responsible of the conducting investigations on cosmonauts.\u003c/p\u003e\n\u003cp\u003eA. Nosovsky - had full access to all the data of this study and takes responsibility for the integrity of the data and the accuracy of data analysis\u003c/p\u003e\n\u003cp\u003eT. Krapivnitskaya, I. Larina - revised critically the manuscript for important intellectual content. All the authors did proof reading and corrections for this manuscript and approved the version to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw data and parameter values are compiled and patented into a database, which can be accessed upon request by the copyright holder.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research was carried out with the funding of the State Corporation Roscosmos and within the framework of the basic theme of the Russian Academy of Sciences by basic programs FMFR-2024-0032,\u0026nbsp;FMFR-2024-0042 and partial support\u0026nbsp;by\u0026nbsp;FMFR-2024-0038\u0026nbsp;of the State Scientific Center of the Russian Federation - Institute of Biomedical Problems.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express gratitude and appreciation to the cosmonauts who participated in this research project.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGrigoriev, A.I. The concept of health and space medicine / A.I. Grigoriev, R.M. Bayevsky; Institute of Biomedical Problems of the Russian Academy of Sciences. \u0026ndash; Moscow: Slovo, 2007. \u0026ndash; 207 p.\u003c/li\u003e\n\u003cli\u003eLarina, I.M. Innovative proteomic research in cardiology applied to occupational health problems in aerospace medicine / I.M. Larina, L.H. Pastushkova, Yu.I. Voronkov [et al.] // Cardiological bulletin. \u0026ndash; 2020. \u0026ndash; vol. 15, No. S. \u0026ndash; pp. 10-11.\u003c/li\u003e\n\u003cli\u003eLarina, I.M. Proteomic research of human liquids from the Russian Segment of the International Space Station taken before and after orbital flights. A decade of research experience: monograph / I.M. Larina, L.H. Pastushkova, A.G. Goncharova. \u0026ndash; Moscow: IBMP RAS, 2021. \u0026ndash; 83 p.\u003c/li\u003e\n\u003cli\u003eRea, G. 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Proteomic profile of a healthy person\u0026apos;s urine in normal conditions and under space flight factors: abstract of the PhD thesis: 03/14/2008/ Pastushkova Lyudmila Hanifovna; [Place of thesis defence: Institute of Biomedical Problems]. \u0026ndash;Moscow, 2015. \u0026ndash; 45 p.\u003c/li\u003e\n\u003cli\u003eThayer, J.F. A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health / J.F. Thayer, F. Ahs, M. Fredrickson [et al.] // Neuroscience \u0026amp; Biobehavioral Reviews. \u0026ndash; 2012. \u0026ndash; Vol. 36, № 2. \u0026ndash; P. 747-756. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"microgravity-science-and-technology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mgst","sideBox":"Learn more about [Microgravity Science and Technology](http://link.springer.com/journal/12215)","snPcode":"12217","submissionUrl":"https://submission.nature.com/new-submission/12217/3","title":"Microgravity Science and Technology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Microgravity, space flight, heart rate variability, blood proteins.","lastPublishedDoi":"10.21203/rs.3.rs-4648754/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4648754/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe article analyzes how long-duration space missions effect on the heart rate variability parameters and invariable blood proteins. The results are discussed taking into correlation between them. Seven Russian cosmonauts took part in the research during their missions to the International Space Station.\u003c/p\u003e \u003cp\u003eSamples of dry blood drops were collected as part of the space experiment ''OMICs-SPK'', electrocardiogram samples were collected as part of the space experiment \"Cardiovector\".\u003c/p\u003e \u003cp\u003eIt was established a linear relationship between the concentrations of some proteins and spectral analysis parameters of heart rate at all stages of space flight. In the context of the physiological cardiovascular regulation, the linear correlation found between the six invariant proteins and HRV may be evidence of how and to what extent an adaptive regulation system provides flexible control over the periphery when several processes influence each other.\u003c/p\u003e \u003cp\u003eThe heart rate variability provides high adaptability, which makes it possible to quickly cope with the challenges of an aggressive and changing environment, maintain homeostatic processes and provide valuable information about the body's ability to function effectively in microgravity.\u003c/p\u003e","manuscriptTitle":"Correlation Between Invariable Blood Proteins and Heart Rate Variability in Long-Duration Space Flights","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-29 16:05:10","doi":"10.21203/rs.3.rs-4648754/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-27T16:09:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-16T05:11:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218340420193366790595093763858696160575","date":"2024-07-10T12:24:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-10T08:49:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-05T02:01:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-05T02:01:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Microgravity Science and Technology","date":"2024-06-27T13:08:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"microgravity-science-and-technology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mgst","sideBox":"Learn more about [Microgravity Science and Technology](http://link.springer.com/journal/12215)","snPcode":"12217","submissionUrl":"https://submission.nature.com/new-submission/12217/3","title":"Microgravity Science and Technology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6f7b2af7-c4b3-4561-9089-6cf509ba32f7","owner":[],"postedDate":"July 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-23T16:01:07+00:00","versionOfRecord":{"articleIdentity":"rs-4648754","link":"https://doi.org/10.1007/s12217-024-10139-3","journal":{"identity":"microgravity-science-and-technology","isVorOnly":false,"title":"Microgravity Science and Technology"},"publishedOn":"2024-09-18 15:57:21","publishedOnDateReadable":"September 18th, 2024"},"versionCreatedAt":"2024-07-29 16:05:10","video":"","vorDoi":"10.1007/s12217-024-10139-3","vorDoiUrl":"https://doi.org/10.1007/s12217-024-10139-3","workflowStages":[]},"version":"v1","identity":"rs-4648754","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4648754","identity":"rs-4648754","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}