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Review of NASA’s Biomedical Research Program 5 Cardiovascular and Pulmonary Systems INTRODUCTION The cardiovascular (CV) system is tightly regulated, gravity dependent, and extremely adaptable. The plasticity of this system results in a rapid, but not immediate, adjustment to weightlessness that occurs within the first few days of spaceflight. However, the system is unable to reverse its adaptation to spaceflight immediately upon return to normal gravity, and this delay leads to the physiologically and operationally important limitations in CV function that have been observed with reentry into Earth’s gravitational field. In addition to postflight orthostatic intolerance, the main CV issues of potential importance for spaceflight include in-flight aerobic deconditioning, cardiac atrophy, cardiac arrhythmias, and long-term effects on crew member health of the CV adaptive changes induced by spaceflight. The major concerns with respect to the pulmonary system, and the main foci of pulmonary research, are adequate denitrogenation prior to extravehicular activities (EVAs), increased aerosol deposition in spaceflight, and changes in pulmonary perfusion. Both the CV and the pulmonary systems have been studied extensively in dedicated life science flights as well as experiments performed for Detailed Supplemental Objectives (DSOs) and in the Extended Duration Orbiter Medical Project (EDOMP) program. Nonetheless, orthostatic intolerance remains an operational problem, and fundamental questions remain about the nature, degree, and severity of spaceflight-related cardiac atrophy and arrhythmias. Differences of opinion and confusion exist concerning the incidence of arrhythmias during and following spaceflight. The Strategy report (NRC, 1998) did not identify arrhythmias as a significant concern, whereas the National Space Biomedical Research Institute (NSBRI) and the Johnson Space Center (JSC) have targeted the potential for arrhythmias as a major concern. With respect to cardiac atrophy, there was a report from the postflight workshop for the Deutsche 2 Spacelab Mission (Blomqvist, 1995) indicating significant cardiac atrophy during this two-week flight. Although one data set does not constitute clear and convincing evidence, the problem of cardiac atrophy is potentially significant enough to require follow-up and confirmation. For the pulmonary system, an excellent basic physiologic understanding has been established, but operational problems, such as prebreathing protocols and aerosol deposition, remain.
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Review of NASA’s Biomedical Research Program The Strategy report made several recommendations in the cardiovascular area. These recommendations were to determine the following: (a) adaptive responses of the cardiovascular system to spaceflight and the mechanisms underlying these adaptations, (b) immediate postflight cardiovascular responses and their mechanisms, (c) adequacy of ground-based models to replicate spaceflight-induced cardiovascular changes, (d) long-term consequences of extended spaceflight on cardiovascular health, and (e) the need for and validation of countermeasures to be applied for the cardiovascular effects of spaceflight. The major pulmonary recommendations were to determine the following: (a) effects of microgravity on aerosol deposition, including the possible effects of lunar or Martian dust particles, (b) effects of long-duration spaceflight on pulmonary and respiratory muscle function, and (c) optimal denitrogenation protocols for Space Station EVA. Technology needs identified in the Strategy report were for (a) advanced physiological data systems (e.g., heart rate, beat-to-beat blood pressure, cardiac output, gas exchange); (b) improved imaging systems (e.g., scintigraphic system for spaceflight use); (c) new exercise equipment; (d) advanced aerosol monitoring systems; and (e) improved decompression sickness monitoring equipment. The following sections summarize the findings relevant to these recommendations. NASA’S CURRENT RESEARCH PROGRAM IN CARDIOVASCULAR AND PULMONARY SYSTEMS At an FY 1999 funding level of about $4.9 million, CV studies account for approximately 14 percent of the total NASA budget for biomedical and countermeasure research funding. Additional funding comes from sources such as operations (e.g., to support the clinical evaluation of reduced prebreathe times and for integrated testing regimes), but the magnitude is unknown. The NASA Research Announcement (NRA) and NSBRI listings indicate a total of 29 projects in the cardiopulmonary discipline. Twenty-seven studies are performed either entirely or partially in humans. Twenty studies address CV physiology and/or orthostatic changes, two address arrhythmias, three focus on the pulmonary system, one focuses on atrophy, and three are concerned primarily with countermeasure evaluation. Table 5.1 summarizes the projects and funding. Cardiopulmonary projects are carried out at JSC, the Ames Research Center (ARC), NSBRI-funded university laboratories, and other university laboratories through extramural grants. The Environmental Physiology Laboratory at JSC supports studies on EVA, and studies on pulmonary function are supported through NRA and flight projects programs at extramural laboratories. The Medical Operations TABLE 5.1 Summary of FY 1999 Funding for Cardiovascular and Pulmonary Systems Subdisciplines NRA NSBRI Subdiscipline Total ($) No. of Projects Total ($) No. of Projects Pulmonary 596,000 3 0 0 Orthostatic intolerance 2,754,195 14 549,482 6 Cardiac atrophy 0 0 143,050 1 Cardiac arrhythmias 0 0 247,087 2 Countermeasures 662,000 3 0 0 Total 4,012,195 20 939,619 9
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Review of NASA’s Biomedical Research Program Section collects CV and pulmonary data on astronauts as part of the physical certification process and for the longitudinal study of astronaut health. Currently, major inconsistencies exist among the programs (NRA, NSBRI, operational medicine) in the perception of the relative importance of the various cardiovascular changes that may result from spaceflight. To resolve these differences, it is recommended that a “cardiovascular summit” be convened to review all existing cardiovascular data from spaceflight, ground-based studies, and animal studies. Summit attendees should include representatives from the NSBRI, NASA operational medicine, NASA intramural investigators, the Astronaut Office, and outside experts in cardiovascular medicine and physiology. The charge of the group would be to: Determine if cardiac arrhythmias are a significant concern and if monitoring is warranted; Determine if cardiac atrophy is a significant concern and should be monitored; Determine if there are pre- and in-flight predictors of orthostatic intolerance; Determine which ground-based human and animal models best reproduce the effects of spaceflight; Review the data and rationale for current countermeasures and suggest new countermeasures on the basis of the existing physiological data; Determine what level of aerobic fitness should be maintained in space; and Determine if countermeasures have been effective when used as recommended. PROGRAMMATIC BALANCE Balance of Subdiscipline Areas The present complement of CV experiments shows appropriate balance between studies of orthostatic intolerance, arrhythmias, and basic physiological mechanisms, but human studies on cardiac atrophy are lacking. The pulmonary investigations are heavily focused on denitrogenation protocols and decompression sickness. There appear to be no current studies on aerosol deposition, Martian dust effects, or respiratory muscle function as recommended in the Strategy report. Balance of Ground and Flight Investigations The CV and pulmonary programs are mainly ground based. The recent Neurolab mission had a significant payload of experiments aimed at studying CV autonomic regulation, but future missions of this sort are not currently planned. The bulk of current NRA- and NSBRI-supported investigations are ground based. The CV lab at JSC is involved in testing crews after Shuttle flights. Future flight investigations will be subject to the Integrated Testing Regimen outlined in the Countermeasure Evaluation and Validation Project Plan (NASA, 1999b). The CV tests planned include tilt tests both before and after flights and exercise tests before, during, and after flights. The Countermeasure Evaluation and Validation Project Plan also mentions continuous cardiac rhythm (Holter) monitoring in flight and upon reentry, but both of these tests are currently canceled. No method to assess orthostatic responses in flight (i.e., lower-body negative pressure) is mentioned in the Integrated Testing Regimen (ITR). In the area of EVA physiology, the use of shortened prebreathe protocols is being evaluated in a multicenter trial. The use of exercise to shorten prebreathe times and the use of argon-oxygen mixtures are under evaluation as part of the NRA program.
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Review of NASA’s Biomedical Research Program The current cardiovascular program is mainly ground based and thus is consistent with the Strategy report recommendation to do precursor ground-based studies. Future investigations to address the effects of spaceflight on the cardiovascular system will require human flight studies, as also recommended in the Strategy report. Emphasis Given to Fundamental Mechanisms Studies on basic physiological mechanisms receive appropriate priority. Several ongoing studies address the CV effects of spaceflight. These include NSBRI studies of embryonic development, micro-vasculature and tissue perfusion, molecular and cellular mechanisms of cardiac atrophy, and changes in gene expression. Since CV adaptations to spaceflight may depend heavily on integrated responses in the intact organism, understanding of this system is likely to be derived largely from physiological studies on intact animals or humans. The in vitro molecular and cellular studies under way should provide insight into the adaptations of the integrated CV system to spaceflight. The current balance of molecular and cellular studies versus physiological studies appears consistent with the Strategy report. Utilization and Validation of Animal Models There are several animal models under study, and a considerable volume of data is available from these model systems. As mentioned previously, there is a need to synthesize these data and develop a consensus as to which animal models best simulate different aspects of CV adaptation to microgravity in man. Various aspects of CV adaptation, such as atrophy, orthostatic hypotension, and arrhythmias, will likely require the use of different animal models to allow optimization of ground-based studies. The current research program supports studies in rodents of cardiac atrophy, and the NSBRI also has a project on rodent studies of CV deconditioning. The project descriptions mention no specific plans for validating these models. Plans for validating animal models are not evident and should be addressed by the Cardiovascular Summit. DEVELOPMENT AND VALIDATION OF COUNTERMEASURES A number of countermeasures against orthostatic intolerance either were previously utilized and abandoned (or inconsistently applied), are currently being utilized, or have been proposed but not yet tested. Few, if any, countermeasures have been proposed to protect against arrhythmias or cardiac atrophy. Further documentation is needed of the extent to which arrhythmias and atrophy actually constitute a problem before a decision is made to proceed with countermeasure development for these indications. The Countermeasure Evaluation and Validation Project Plan should be utilized to evaluate countermeasures that are currently being deployed as well as those proposed but not yet used. As new information becomes available, consideration should be given to reevaluating selected countermeasures that have been previously abandoned to ensure that potentially useful approaches have not been discarded prematurely. A partial list of countermeasures that have been proposed, (and in some cases are currently used but not adequately validated) includes the following: clothing (e.g., G-suit, elasticized (Penguin) suit, and liquid cooling garments); lower body negative pressure (LBNP) either alone or coupled with exercise; isotonic saline; supine reentry seat; pre-reentry maximal physical effort; resistive exercise; medications such as mineralocorticoid (Fluorinef) or adrenergic agents;
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Review of NASA’s Biomedical Research Program nutrients; periodic carotid baroreceptor negative pressure; continuous artificial gravity; and intermittent artificial gravity. NASA initially supported a number of studies aimed at documenting CV adaptations to spaceflight. These studies have matured into experiments designed to understand the pathophysiology of the observed adaptations. The results of these mechanistic studies are beginning to suggest possible countermeasures based on confirmed physiological mechanisms. The Neurolab mission included detailed measurements of autonomic nervous system function in space that should demonstrate whether cardiovascular autonomic nervous system function is impaired in space. The results will help direct the efforts for countermeasure studies. Of the active projects on the NRA and NSBRI lists, only three evaluate countermeasures. A multicenter trial of shortened prebreathe protocols has been undertaken to allow for shorter prebreath times on the International Space Station (ISS), but this is not supported by either the NRA process or the NSBRI. Exercise is also being studied as a way to reduce prebreathing requirements. In the NSBRI, none of the CV studies appears to be a countermeasure evaluation. The current fluid loading countermeasure appears not to be receiving ongoing evaluation, as evidenced by the cancellation of tilt testing after short-duration missions. Only one new CV countermeasure (midodrine, an alpha-adrenergic agonist for orthostatic hypotension) is mentioned in the Countermeasure Evaluation and Validation Project Plan. This countermeasure does not appear to be part of an NRA or NSBRI project. Another countermeasure aimed at increasing blood volume (erythropoietin) did not receive NRA funding. Few of the current cardiovascular studies evaluate current countermeasures or propose new ones. The appropriate testing regimens and candidate countermeasures should be a focus of the Cardiovascular Summit. The development of the Countermeasure Evaluation and Validation Project Plan and Integrated Testing Regimens addresses the Strategy report recommendation to validate new countermeasures. EPIDEMIOLOGY AND MONITORING Although considerable information has been gathered on CV function of crew members prior to, during, and following spaceflight, no formal program appears to be in place to monitor and review these data. Thus, these data have apparently not been synthesized into a comprehensive document available for scientific review. In addition, the most significant pathophysiologic changes noted thus far (orthostatic hypotension, cardiac arrhythmias, cardiac atrophy) have been studied to differing degrees in biomedical research flights but are not routinely evaluated using state-of-the-art techniques. It should be noted that although there are significant differences of opinion concerning the incidence of arrhythmias induced by spaceflight, no plans exist for routine cardiac rhythm monitoring. Some of the measurements under evaluation have great potential to assess cardiac arrhythmias and could be applied in a systematic way prior to, during, and after spaceflight. Measurement of cardiac mass by magnetic resonance imaging (MRI) is likely to give an accurate assessment of this potential issue, and consideration should be given to evaluating this methodology in comparison to echocardiographic methods currently in use. If MRI proves a more accurate means to detect loss of cardiac mass, it could be used pre- and postflight to determine the presence and tempo of resolution of this abnormality. Integrated testing regimes have been outlined to make certain routine measurements on all flights. The rationale for the tests included in these regimens is not documented and should be made explicit. A formal program should be in place for ongoing assessment of data collected on current or future spaceflights.
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Review of NASA’s Biomedical Research Program The current monitoring program contains the following elements. Orthostatic Intolerance For short-term flights (<30 days) the operational tilt test is used only for first-time flyers or those with demonstrated functional orthostatic impairment. Functional orthostatic impairment is not defined in the Astronaut Medical Evaluation Requirements Document (AMERD; NASA, 1998a). For longer flights, the operational tilt test is mandatory. No in-flight assessment of orthostatic function is planned, so there will be no monitoring of orthostatic function prior to reentry. Reentry monitoring was planned for flights on the ISS but was canceled. It is recommended that in-flight monitoring (e.g., using LBNP) be added to assess orthostatic intolerance before reentry. Reentry monitoring would allow for orthostatic responses to be measured at the most operationally important time. Cardiac Atrophy Echocardiographic measurements will be taken during the operational tilt test. The AMERD does not mention if changes in cardiac mass will be monitored using this technology. In addition, no MRI measurements of cardiac mass are planned. No program for monitoring cardiac atrophy exists in humans in the current program and the Cardiovascular Summit should address whether one is needed. Arrhythmias Plans for cardiac rhythm monitoring on ISS missions were canceled. In flight, the electrocardiogram (EKG) will be monitored during EVA, and a 12-lead EKG will be assessed every 60 days. Every 30 days in flight, a physical assessment and submaximal exercise test of aerobic capacity will be conducted. How the results of these tests will be analyzed and used is not outlined in current documents, nor is the underlying rationale for the testing protocol. The AMERD lists a submaximal exercise test to be performed every 30 days in flight. The rationale for this testing is not presented. Whether the crew needs to maintain a level of aerobic fitness is not explicitly stated. Pulmonary Pulmonary spirometric and peak flow measurements are planned for every 30 days in flight. An in-suit Doppler system has been developed for intravascular bubble monitoring during EVA, as recommended in the Strategy report. A system for aerosol generation and monitoring, recommended in the Strategy report, is not mentioned in the NRA or NSBRI programs. The epidemiology and monitoring results are not integrated with the research program. It is recommended that a mechanism be developed to bring together representatives from the NSBRI, NASA operational medicine, NASA intramural investigators, and outside experts in cardiovascular medicine and physiology on an ongoing basis to review new data to assist in refining testing regimens and countermeasures. In the future, this might be a role for the integrated product teams (IPTs).
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Review of NASA’s Biomedical Research Program SUPPORT OF ADVANCED TECHNOLOGIES Progress is being made to obtain sophisticated cardiac rhythm information prior to, during, and after spaceflight. One NSBRI program is developing CV system identification technology for measuring changes in autonomic nervous function. This work addresses the Strategy report recommendations to provide accurate measurements of heart rate and blood pressure. Two NRA projects involve exercise devices, and an in-suit bubble detection system is being used for intravascular bubble detection. Both of these efforts respond to recommendations in the Strategy report. Other Strategy report equipment recommendations (automatic physiological recording devices, cardiac output devices, gas analyzers for pulmonary measurements, scintigraphic imaging systems, aerosol-monitoring equipment) are not being addressed. SUMMARY Important questions, such as whether cardiac arrhythmias (or a propensity to develop arrhythmias) are stimulated by exposure to spaceflight and whether cardiac atrophy is significant and reversible, have not yet been answered. Mechanisms responsible for orthostatic intolerance, arrhythmias, and cardiac atrophy remain to be elucidated. Countermeasure development has thus far been focused on the well-documented problem of orthostatic intolerance, but no new validated countermeasures exist as yet to prevent this important operational problem. If arrhythmias and/or atrophy are determined to be important barriers to the health and well-being of crew members, then countermeasures will have to be developed to counteract them. Most pulmonary studies are focused on the important issue of decompression sickness. Two key projects in this area (the clinical trial of reduced prebreathe protocols and in-suit Doppler monitoring) are not supported through either the NRA or the NSBRI programs, but are supported through operational funds. Other efforts recommended in the Strategy report (aerosol deposition, Martian dust effects, respiratory muscle function) are not currently in progress. The development of the countermeasure evaluation plan and integrated testing regimens addresses important areas outlined in the Strategy report. BIBLIOGRAPHY Blomqvist, C.G., L.D. Lane, S.J. Wright, G.M. Meny, B.D. Levine, J.C. Buckey, R.M. Peashock, P. Weatherall, J. Stray-Gundersen, F.A. Gaffney, D.E. Watenpaugh, Ph.R.M. Arbeille, and F. Baisch. 1995. Cardiovascular regulation at microgravity. Pp. 688-690 in Proceedings of the Nordeney Symposium on Scientific Results of the German D-2 Spacelab Mission. P.R. Sahm, M.H. Keller, and B. Schieve, eds. Bonn and Köln, Germany: WPF and Deutsche Agentur für Raumfahrtangelegenheiten (DARA) and Deutsche Forschungsanstalt für Luft- und Raumfahrt. National Aeronautics and Space Administration (NASA). 1997. Task Force Report on Countermeasures: Final Report. Washington, D.C.: NASA. NASA. 1998a. Astronaut Medical Evaluation Requirements Document (AMERD), JSC 24834, Rev. A. Houston, Tex.: NASA. NASA. 1998b. Life Sciences Program Tasks and Bibliography for FY 1998. Washington, D.C.: NASA. NASA. 1999a. Critical Path Research Plan Presentation (including EDOMP results presented at that time). Committee on Space Biology and Medicine meeting, March 3-5, 1999. Houston, Tex.: NASA. NASA. 1999b. Countermeasure Evaluation and Validation Project Plan. June 16, 1999. Houston, Tex.: NASA. NASA and Universities Space Research Association (USRA). 1999. Proceedings of the First Biennial Biomedical Investigators’ Workshop, January 11-13, 1999, League City, Texas. Houston, Tex.: NASA and USRA. National Research Council (NRC), Space Studies Board. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. Washington, D.C.: National Academy Press. National Space Biomedical Research Institute (NSBRI). 1999. Proceedings of the Artificial Gravity Workshop, January 14–15, 1999, League City, Texas. Houston, Tex.: NSBRI.
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