Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capability and Risk for Cardiac Arrhythmias (Integrated Cardiovascular) - 10.31.18

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Science Objectives for Everyone
Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capability and Risk for Cardiac Arrhythmias (Integrated Cardiovascular) aims to quantify the extent, time course and clinical significance of cardiac atrophy (decrease in the size of the heart muscle) associated with long-duration space flight and identify the mechanisms of this atrophy and the functional consequences for crewmembers who spend extended periods of time in space.
Science Results for Everyone
Perhaps the Grinch was an extraterrestrial since the size of heart muscle decreases in space. The Integrated Cardiovascular investigation sought to measure this decrease and its effects on health, in an effort to find out how this happens and how it affects crew members functioning. Data  are being collected and analyzed in order to develope effective ways to maintain a strong heart for long-duration space missions.

The following content was provided by Benjamin D. Levine, M.D., and is maintained in a database by the ISS Program Science Office.
Experiment Details

OpNom: Integrated Cardiovascular

Principal Investigator(s)
Michael W. Bungo, M.D., University of Texas Medical School, Houston, TX, United States
Benjamin D. Levine, M.D., University of Texas Southwestern Medical Center, Dallas, TX, United States

Steven H. Platts, Ph.D., NASA Johnson Space Center, Houston, TX, United States
Smith L. Johnston, M.D., NASA Johnson Space Center, Houston, TX, United States
James D. Thomas, M.D., Cleveland Clinic Foundation, Cleveland, OH, United States
Ron M. Peshock, M.D., University of Texas Southwestern Medical Center, Dallas, TX, United States
Jeff Goldberger, M.D., Northwestern University, Chicago, IL, United States

NASA Johnson Space Center, Human Research Program, Houston, TX, United States

Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)

Sponsoring Organization
Human Exploration and Operations Mission Directorate (HEOMD)

Research Benefits
Earth Benefits, Scientific Discovery, Space Exploration

ISS Expedition Duration
April 2009 - September 2013

Expeditions Assigned

Previous Missions
Integrated Cardiovascular began operations during ISS Expedition 19/20. The investigators also have extensive previous experience with cardiovascular investigations performed on Space Shuttle and Mir.

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Experiment Description

Research Overview

  • Atrophy (decrease in size) of the heart muscle appears to develop during space flight and its ground-based analogues (bedrest) which could lead to impaired functioning of the heart and fainting upon return to gravity on the Earth, the Moon, or Mars. It also may be related to heart rhythm abnormalities that have been recorded in crewmembers on prior missions.
  • This experiment determines how much cardiac atrophy occurs during space flight and how fast it develops, whether this atrophy causes problems with the heart's pumping or electrical function, and how both the atrophy and any associated changes develop.

  • The effects of atrophy on how the heart fills, how blood pressure responds to the reintroduction of gravity (Earth, the Moon and Mars), a crewmember's ability to exercise, and the likelihood of developing unusual heart rhythms, are determined both in space on board the International Space Station and following return to Earth.
  • Results from this investigation are intended to help ensure crew health on future long-duration exploration missions, as well as assist in the development of any needed countermeasures to mitigate the effects of space flight on the cardiovascular system.

Cardiac atrophy (a decrease in the size of the heart muscle) appears to develop during space flight or its ground-based analogues leading to diastolic dysfunction (abnormal left ventricular function in the heart) and orthostatic hypotension (drop in blood pressure upon standing). Such atrophy may have been a potential mechanism for the cardiac arrhythmias (irregular heart rhythms) identified in some crewmembers after long-duration exposure to microgravity aboard the Mir Space Station. Recent studies suggest that cardiac atrophy may be progressive, without a clear plateau over at least 12 weeks of bedrest, and thus may be a significant limiting factor for extended duration space exploration missions. This experiment aims to quantify the extent, time course and clinical significance of cardiac atrophy and identify its mechanisms. The functional consequences of this atrophy are also determined for cardiac filling dynamics, orthostatic tolerance under both normal gravity (Earth) and fractional gravity (Mars and moon) conditions, exercise tolerance, and arrhythmia susceptibility both in space on board the International Space Station (ISS) and following return to Earth.

The Integrated Cardiovascular experiment investigates the magnitude of left and right ventricular atrophy associated with long-duration space flight (using magnetic resonance imaging or MRI), relates this type of atrophy to measures of physical activity and cardiac work inflight, and determines the time course and pattern of the progression of cardiac atrophy inflight using cardiac ultrasound. This investigation also determines the functional importance of cardiac atrophy for cardiac diastolic function and the regulation of stroke volume (volume of blood pumped by the heart in one contraction) during gravitational transitions, as well as identifies changes in ventricular conduction, depolarization and repolarization during and after long-duration space flight, and relates these factors to changes in heart mass and morphology (shape and form).

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Space Applications
Once the magnitude, time course, and inciting factors for cardiac atrophy are determined, effective countermeasures currently being developed by the investigators in parallel ground-based experiments may be applied, focused on normalizing cardiac work and volume during long-duration space flight. Upon completion of these experiments, a number of important risks for long-duration space flight, such as cardiac function and arrhythmia risk, may either be deemed manageable by current preventive measures, or clearly defined for future countermeasure research.

Earth Applications
The information obtained from these space flight experiments has relevance for patients after prolonged confinement to bedrest, or chronic reduction in physical activity, as well as for patients with disease processes that alter cardiac stiffness such as congestive heart failure, ischemic heart disease, and normal ageing.

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Operational Requirements and Protocols

A total of twelve subjects are required for this investigation. Additionally, data will be collected before, during and after the yearlong mission of the US crewmember launching on 42S.  Inflight scanning sessions are planned on flight day 14 (FD14) ± 4 days, FD30 ±5 days, FD75 ±5 days, FD135 ±5 days, and Return minus (R-) 15 -4/+15 days.  For a mission duration of one year, additional scans on FD195, 255 and 315 (all ±5 days) are also planned. Ambulatory blood pressure, Holter and activity monitoring is required within one week (preferably three days) of each session. The total number of sessions required depends on the length of the mission. Both an operator and a subject are required for the ultrasound scans along with real-time video downlink to enable remote guidance by ground experts.

Inflight, resting echocardiograms using the HRF Ultrasound are performed on FD14, FD30, FD135, and return minus 15 days (R-15) using real-time remote guidance (for a one-year mission duration, resting echos are also performed on FD195 and FD255). On FD75 (and FD315 for a one-year mission), an exercise echocardiogram session is performed with measurements taken before and after exercise. Both the resting and exercise sessions are preceded or followed by 24 hours of ambulatory blood pressure and 48 hours of Holter and activity monitoring. For these sessions, subjects apply electrodes and then don the HRF Holter Monitor 2, ESA Cardiopres, and two Actiwatch Spectrums (one at the waist and one at the ankle). After removal, the data from the experiment hardware is downloaded to the HRF PC and downlinked to the ground. Inflight exercise and medication logs are obtained through data sharing.

On the ground, resting echocardiograms are obtained between launch minus 21 days (L-21) and L-7, and again at return plus 7 days (R+7). An exercise echocardiogram is performed between L-75 and L-60 and again at R+4 and R+14. Preflight, ambulatory blood pressure (for 24 hours), Holter and activity monitoring (for 48 hours) are conducted between L-75 and L-60, and again between L-21 and L-7. The session is repeated upon crew return to Earth (R+0).

Cardiac MRI (with Magnetic Resonance Spectroscopy and gadolinium delayed enhancement) is obtained between L-75 and L-60. Postflight MRIs occur in the R+3 to R+6 timeframe, and between R+22 and R+30. Graded tilt tests with echocardiograms are performed between L-75 and L-60, and again on R+0. Exercise and medication logs are obtained both before and after flight, preferably via data sharing.

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Decadal Survey Recommendations

Animal and Human Biology AH10
Animal and Human Biology AH11

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Results/More Information

Inflight operations with subjects on approximately six-month missions is complete. Data analysis is on-going; two “poster” presentations of preliminary results were presented at the IAA Symposium in Houston, Texas in April of 2011 and three at the American Heart Association Meetings in Dallas, TX in Nov. 2013.  These are referenced in the conference proceedings.

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Results Publications

    Khine HW, Steding-Ehrenborg K, Hastings JL, Kowal J, Daniels JD, Page RL, Goldberger JJ, Ng J, Adams-Huet B, Bungo MW, Levine BD.  Effects of Prolonged Spaceflight on Atrial Size, Atrial Electrophysiology, and Risk of Atrial Fibrillation. Circulation - Arrhythmia and Electrophysiology. 2018 May; 11(5): e005959. DOI: 10.1161/CIRCEP.117.005959. PMID: 29752376.

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Ground Based Results Publications

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ISS Patents

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Related Publications

    Fu Q, Witkowski S, Okazaki K, Levine BD.  Effects of Gender and Hypovolemia on Sympathetic Neural Responses to Orthostatic Stress. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. 2005; 289(1): R109-R116. DOI: 10.1152/ajpregu.00013.2005.

    Fu Q, Levine BD, Pawelczyk JA, Ertl AC, Diedrich A, Cox JF, Zuckerman JH, Ray CA, Smith ML, Iwase S, Saito M, Sugiyama Y, Mano T, Zhang R, Iwasaki K, Lane LD, Buckey, Jr. JC, Cooke WH, Robertson RM, Baisch FJ, Blomqvist CG, Eckberg DL, Robertson D, Biaggioni I.  Cardiovascular and sympathetic neural responses to handgrip and cold pressor stimuli in humans before, during and after spaceflight. Journal of Physiology. 2002 08/30/2002; 544.2(2): 653-664. DOI: 10.1113/jphysiol.2002.025098.

    Iwasaki K, Levine BD, Zhang R, Zuckerman JH, Pawelczyk JA, Diedrich A, Ertl AC, Cox JF, Cooke WH, Giller CA, Ray CA, Lane LD, Buckey, Jr. JC, Baisch FJ, Eckberg DL, Robertson D, Biaggioni I, Blomqvist CG.  Human cerebral autoregulation before, during, and after spaceflight. Journal of Physiology. 2007 March; 579(3): 799-810. DOI: 10.1113/jphysiol.2006.119636.

    Arbab-Zadeh A, Dijk E, Prasad A, Fu Q, Torres P, Zhang R, Thomas JD, Palmer DM, Levine BD.  Effect of Aging and Physical Activity on Left Ventricular Compliance. Circulation. 2004; 110(13): 1799-1805. DOI: 10.1161/01.CIR.0000142863.71285.74.

    Bleeker MW, De Groot P, Pawelczyk JA, Hopman M, Levine BD.  Effects of 18 days of bed rest on leg and arm venous properties. Journal of Applied Physiology. 2004; 96(3): 840-847. DOI: 10.1152/japplphysiol.00835.2003.

    Ertl AC, Diedrich A, Biaggioni I, Levine BD, Robertson RM, Cox JF, Zuckerman JH, Pawelczyk JA, Ray CA, Buckey, Jr. JC, Lane LD, Shiavi R, Gaffney FA, Costa F, Holt C, Blomqvist CG, Eckberg DL, Baisch FJ, Robertson D.  Human muscle sympathetic nerve activity and plasma noradrenaline kinetics in space. Journal of Physiology. 2002; 538: 321-329. DOI: 10.1113/jphysiol.2001.012576.

    Lathers CM, Schraeder PL, Bungo MW.  The Mystery of Sudden Death: Mechanisms for Risk. Epilepsy and Behavior. 2008 Jan; 12(1): 3-24. DOI: 10.1016/j.yebeh.2007.09.016. PMID: 18086454.

    Cooke WH, Ames IV JE, Crossman AA, Cox JF, Kuusela TA, Tahvanainen KU, Moon LB, Drescher J, Levine BD, Blomqvist CG, Baisch FJ, Eckberg DL, Mano T.  Nine months in space: The effects on human autonomic cardiovascular regulation. Journal of Applied Physiology. 2000; 89: 1039-1045. PMID: 10956348.

    Dorfman T, Rosen BD, Perhonen MA, Tillery T, McColl R, Peshock RM, Levine BD.  Diastolic Suction is Impaired by Bed Rest: MRI Tagging Studies of Diastolic Untwisting. Journal of Applied Physiology. 2008; 104(4): 1037-1044. DOI: 10.1152/japplphysiol.00858.2006.

    Perhonen MA, Franco F, Lane LD, Buckey, Jr. JC, Blomqvist CG, Zerwekh JE, Peshock RM, Weatherall PT, Levine BD.  Cardiac atrophy after bed rest and spaceflight. Journal of Applied Physiology. 2001; 91: 645-653.

    Perhonen MA, Zuckerman JH, Levine BD.  Deterioration of left ventricular chamber performance after bed rest: "Cardiovascular deconditioning" or hypovolemia?. Circulation. 2001; 103: 1851-1857. DOI: 10.1161/01.CIR.103.14.1851.

    Dorfman T, Levine BD, Tillery T, Peshock RM, Hastings JL, Schneider SM, Macias BR, Biolo G, Hargens AR.  Cardiac atrophy in women following bed rest. Journal of Applied Physiology. 2007; 103(1): 8-16. DOI: 10.1152/japplphysiol.01162.2006.

    Levine BD, Pawelczyk JA, Ertl AC, Cox JF, Zuckerman JH, Diedrich A, Biaggioni I, Ray CA, Smith ML, Iwase S, Saito M, Sugiyama Y, Mano T, Zhang R, Iwasaki K, Lane LD, Buckey, Jr. JC, Cooke WH, Baisch FJ, Robertson D, Eckberg DL, Blomqvist CG.  Human muscle sympathetic neural and haemodynamic responses to tilt following spaceflight. Journal of Physiology. 2002 January; 538(1): 331-340. DOI: 10.1113/jphysiol.2001.012575.

    Pawelczyk JA, Zuckerman JH, Blomqvist CG, Levine BD.  Regulation of muscle sympathetic nerve activity after bed rest deconditioning. American Journal of Physiology: Heart and Circulatory Physiology. 2001; 280(5): 2230-2239.

    Martin DS, South DA, Wood ML, Bungo MW, Meck JV.  Comparison of Echocardiographic Changes After Short- and Long-Duration Spaceflight. Aviation, Space, and Environmental Medicine. 2002; 73(6): 532-536. PMID: 12056667.

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Related Websites
Institute for Exercise and Environmental Medicine
ISS Medical Project

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NASA Image: ISS030E155942 - NASA astronaut Dan Burbank, Expedition 30 commander, prepares to use the Ultrasound 2 for an  Integrated Cardiovascular (ICV) Resting Echo Scan on a crew member (out of frame) at the Human Research Facility (HRF) rack in the Columbus laboratory of the International Space Station.

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image Catherine (Cady) Coleman is performing a remotely guided echocardiogram on a test subject utilizing the Integrated Cardiovascular protocols, while Betty Chen, a training coordinator observes.
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image NASA Image: ISS026-E-015923 - NASA astronaut Catherine (Cady) Coleman, Expedition 26 flight engineer, performs tasks in the Kibo laboratory of the International Space Station while participating in the ambulatory monitoring portion of the Integrated Cardiovascular research experiment.
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image NASA Image: ISS020E040433 - Nicole Stott performs routine tasks aboard the ISS while ECG (using the HRF Holter Monitor 2) and continuous blood pressure data (using the ESA Cardiopres) are recorded for the Integrated Cardiovascular experiment.
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image NASA Image: ISS028E036071 - Astronaut Satoshi Furukawa prepares for an in-flight echocardiogram for the Integrated Cardiovascular experiment using the Ultrasound 2.
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NASA Image: ISS028E036079 - Astronaut Mike Fossum uses the Ultrasound 2 to scan the heart of crewmate Satoshi Furukawa for the Integrated Cardiovascular experiment.

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image Computer generated diagram of the Integrated Cardiovascular investigation onboard the ISS. Image courtesy of the Johnson Space Center, Human Research Program.
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