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Project Title:  The Multisystem Effect of Exercise Training/Nutritional Support During Prolonged Bed Rest Deconditioning: An Integrative Approach to Countermeasure Development for the Heart, Lungs, Muscles and Bones Reduce
Fiscal Year: FY 2010 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 04/30/2010  
Task Last Updated: 08/06/2010 
Download report in PDF pdf
Principal Investigator/Affiliation:   Levine, Benjamin D M.D. / The University of Texas Southwestern Medical Center at Dallas 
Address:  Institute for Exercise and Environmental Medicine (IEEM) 
7232 Greenville Ave, Suite 435 
Dallas , TX 75231-5129 
Email: benjaminlevine@texashealth.org 
Phone: 214-345-4619  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: The University of Texas Southwestern Medical Center at Dallas 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-CA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 6387 
Solicitation / Funding Source: 2004 NSBRI NNH04ZUU003N Human Health in Space 
Grant/Contract No.: NCC 9-58-CA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Renal:Risk of Renal Stone Formation
Human Research Program Gaps: (1) B08:Do pharmaceuticals work effectively in spaceflight to prevent renal stones?
(2) CV01:What are the in-flight alterations in cardiac structure and function?
Flight Assignment/Project Notes: NOTE: New end date is 4/30/2010, per N. Gibbins/NSBRI; previous end date was 8/31/2009 (8/09)

Task Description: 1). Original Aims: Sustained exposure to microgravity leads to adaptive changes in the cardiovascular and musculoskeletal systems that results in substantial morbidity. For example cardiovascular deconditioning may lead to orthostatic hypotension and syncope. Atrophy of skeletal muscle will diminish work capacity and may lead to muscle injury. Bone demineralization increases the risk of kidney stone formation and may reduce bone strength increasing the risk of fracture. Bone resorption may be particularly severe after long duration space flight with uncertain recovery. Despite in depth study, the optimal countermeasure for each system has not been defined. More importantly, previous work has focused predominantly on one organ system at a time, ignoring the interaction among systems, and preventing the development of a specific countermeasure for an individual astronaut that might be effective for the heart, muscles and bones. The global objective of this proposal is to test an integrated countermeasure that will be effective against cardiovascular deconditioning, skeletal muscle atrophy, and bone demineralization, and that ultimately can be applied practically abroad the International Space Station or a mission to Mars.

The original hypotheses and specific aims of the project are as follows:

Hypothesis 1: An "optimized" exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims:

Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing.

Specific Aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound).

Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

2). Key Findings: We completed all experiments on our projected N of 27 subjects last year and have used the current no-cost extension to finalize all the data analysis and write papers. The key outcomes can be summarized as follows: a) subjects who exercised had preserved cardiac structure and function - cardiac muscle mass as well as the mass/volume ratio were preserved, and both Starling and pressure-volume curves were superimposable; b) in contrast, those who were sedentary during bedrest had the expected leftward shifted of their p/v curves, similar to that observed after short duration bedrest. This shift was observed even if transmural pressure was used as the independent variable to the p/v curves; c) exercising subjects had no loss of peak work capacity or VO2max, both of which decreased by ~25% in the sedentary subjects; d) those exercising subjects who received the oral volume load were protected against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest; d) Muscle strength was preserved, as was histochemistry, mitochondrial function, and capillarity in the exercisers, while all decreased in the sedentary subjects; e) urinary calcium loss was been attenuated, especially in those volunteers given KMgCit, though exercise did not appear to have a prominent effect on markers of bone demineralization; f) DEXA scanning at the hip suggested that exercisers were protected from a small but measurable loss of bone mass during 5 weeks of bedrest.

3). Impact on objectives: None: objectives completed

4). Plan for upcoming year: The grant is completed. We will press on with getting the papers published!

Research Impact/Earth Benefits: The information obtained from these experiments will be relevant for patients after prolonged confinement to bed rest, or chronic reduction in physical activity, as well as for patients with disease processes that alter cardiac stiffness such as obesity, hypertension, heart failure or ischemic heart disease, plus normal aging and osteoporosis. Indeed, we are already using this strategy to treat patients with chronic orthostatic intolerance and the Postural Orthostatic Tachycardia Syndrome with outstanding results. Rowing and strength training have been incorporated into my standard clinical algorithm for management of these patients, all of whom have very small hearts. This work has led to the elaboration of a new name for this important clinical syndrome: "The Grinch Syndrome" (because their hearts are "two sizes too small"). The manuscript which was just published in the Journal of the American College of Cardiology regarding this therapy is attached.

Task Progress & Bibliography Information FY2010 
Task Progress: The project has been completed. A draft of a manuscript reporting the cardiovascular and work capacity outcomes has been completed. Drafts of the musculoskeletal manuscripts are being prepared and will be completed and submitted by the end of this calendar year.

Bibliography Type: Description: (Last Updated: 09/27/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Fu Q, VanGundy TB, Galbreath MM, Shibata S, Jain M, Hastings JL, Bhella PS, Levine BD. "Cardiac origins of the postural orthostatic tachycardia syndrome." J Am Coll Cardiol. 2010 Jun 22;55(25):2858-68. PMID: 20579544 , Jun-2010
Articles in Peer-reviewed Journals Otto C, Hamilton DR, Levine BD, Hare C, Sargsyan AE, Altshuler P, Dulchavsky SA. "Into thin air: extreme ultrasound on Mt Everest." Wilderness Environ Med. 2009 Fall;20(3):283-9. PMID: 19737030 , Sep-2009
Articles in Peer-reviewed Journals Shibata S, Hastings JL, Prasad A, Fu Q, Bhella P, Pacini E, Krainski F, Palmer D, Zhang R, Levine BD. "Congestive heart failure with preserved ejection fraction is associated with severely impaired dynamic Starling mechanism." J Appl Physiol. 2011 Apr;110(4):964-71. Epub 2011 Feb 10. PubMed PMID: 21310890 (Originally reported as "in press", June 2010.) , Apr-2011
Articles in Peer-reviewed Journals Shibata S, Levine BD. "Biologic aortic age derived from the arterial pressure waveform." J Appl Physiol (1985). 2011 Apr;110(4):981-7. https://doi.org/10.1152/japplphysiol.01261.2010 ; PMID: 21292839; PMCID: PMC3075135 [reported originally in August 2010 as "Hypertension. In press, June 2010"] , Apr-2011
Articles in Peer-reviewed Journals Shibata S, Perhonen M, Levine BD. "Supine cycling plus volume loading prevent cardiovascular deconditioning during bed rest." J Appl Physiol. 2010 May;108(5):1177-86. PMID: 20223994 , May-2010
Articles in Peer-reviewed Journals Wood HE, Levine BD, Babb TG. "Ventilatory responses to exercise and hypercapnia following 18 days of head-down rest." Aviat Space Environ Med. 2009 Apr;80(4):395-9. PMID: 19378912 , Apr-2009
Articles in Peer-reviewed Journals Jarvis SS, VanGundy TB, Galbreath MM, Shibata S, Okazaki K, Reelick MF, Levine BD, Fu Q. "Sex differences in the modulation of vasomotor sympathetic outflow during static handgrip exercise in healthy young humans." Am J Physiol Regul Integr Comp Physiol. 2011 Jul;301(1):R193-200. http://dx.doi.org/10.1152/ajpregu.00562.2010 ; PubMed PMID: 21508291 , Jul-2011
Articles in Peer-reviewed Journals Jeong SM, Shibata S, Levine BD, Zhang R. "Exercise plus volume loading prevents orthostatic intolerance but not reduction in cerebral blood flow velocity after bed rest." Am J Physiol Heart Circ Physiol. 2012 Jan;302(2):H489-97. Epub 2011 Nov 11. http://dx.doi.org/10.1152/ajpheart.00427.2011 ; PubMed PMID: 22081705 , Jan-2012
Articles in Peer-reviewed Journals Carrick-Ranson G, Hastings JL, Bhella PS, Shibata S, Levine BD. "The effect of exercise training on left ventricular relaxation and diastolic suction at rest and during orthostatic stress after bed rest." Exp Physiol. 2013 Feb;98(2):501-13. Epub 2012 Sep 21. http://dx.doi.org/10.1113/expphysiol.2012.067488 ; PubMed PMID: 23002243 , Feb-2013
Articles in Peer-reviewed Journals Morris CJ, Hastings JA, Boyd K, Krainski F, Perhonen MA, Scheer FA, Levine BD. "Day/Night variability in blood pressure: influence of posture and physical activity." Am J Hypertens. 2013 Jun;26(6):822-8. Epub 2013 Mar 27. http://dx.doi.org/10.1093/ajh/hpt026 ; PubMed PMID: 23535155 , , Jun-2013
Articles in Peer-reviewed Journals Krainski F, Hastings JL, Heinicke K, Romain N, Pacini EL, Snell PG, Wyrick P, Palmer MD, Haller RG, Levine BD. "The effect of rowing ergometry and resistive exercise on skeletal muscle structure and function during bed rest." J Appl Physiol (1985). 2014 Jun 15;116(12):1569-81. http://dx.doi.org/10.1152/japplphysiol.00803.2013 ; PubMed PMID: 24790012 , Jun-2014
Articles in Peer-reviewed Journals Jeong SM, Kim SO, DeLorey DS, Babb TG, Levine BD, Zhang R. "Lack of correlation between cerebral vasomotor reactivity and dynamic cerebral autoregulation during stepwise increases in inspired CO2 concentration." J Appl Physiol (1985). 2016 Jun 15;120(12):1434-41. http://dx.doi.org/10.1152/japplphysiol.00390.2015 ; PubMed PMID: 27103653 , Jun-2016
Articles in Peer-reviewed Journals Hardin EA, Stoller D, Lawley J, Howden EJ, Hieda M, Pawelczyk J, Jarvis S, Prisk K, Sarma S, Levine BD. "Noninvasive assessment of cardiac output: Accuracy and precision of the closed-circuit acetylene rebreathing technique for cardiac output measurement." J Am Heart Assoc. 2020 Sep;9(17):e015794. https://doi.org/10.1161/JAHA.120.015794 ; PMID: 32851906 , Sep-2020
Awards Levine BD. "Distinguished Professorship in Exercise Science, September 2009." Sep-2009
Awards Levine BD. "Vice President, American College of Sports Medicine, June 2010." Jun-2010
Project Title:  The Multisystem Effect of Exercise Training/Nutritional Support During Prolonged Bed Rest Deconditioning: An Integrative Approach to Countermeasure Development for the Heart, Lungs, Muscles and Bones Reduce
Fiscal Year: FY 2008 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 04/30/2010  
Task Last Updated: 02/09/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Levine, Benjamin D M.D. / The University of Texas Southwestern Medical Center at Dallas 
Address:  Institute for Exercise and Environmental Medicine (IEEM) 
7232 Greenville Ave, Suite 435 
Dallas , TX 75231-5129 
Email: benjaminlevine@texashealth.org 
Phone: 214-345-4619  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: The University of Texas Southwestern Medical Center at Dallas 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-CA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 6387 
Solicitation / Funding Source: 2004 NSBRI NNH04ZUU003N Human Health in Space 
Grant/Contract No.: NCC 9-58-CA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Renal:Risk of Renal Stone Formation
Human Research Program Gaps: (1) B08:Do pharmaceuticals work effectively in spaceflight to prevent renal stones?
(2) CV01:What are the in-flight alterations in cardiac structure and function?
Flight Assignment/Project Notes: NOTE: New end date is 4/30/2010, per N. Gibbins/NSBRI; previous end date was 8/31/2009 (8/09)

Task Description: 1). Original Aims: Sustained exposure to microgravity leads to adaptive changes in the cardiovascular and musculoskeletal systems that results in substantial morbidity. For example cardiovascular deconditioning may lead to orthostatic hypotension and syncope. Atrophy of skeletal muscle will diminish work capacity and may lead to muscle injury. Bone demineralization increases the risk of kidney stone formation and may reduce bone strength increasing the risk of fracture. Bone resorption may be particularly severe after long duration space flight with uncertain recovery. Despite in depth study, the optimal countermeasure for each system has not been defined. More importantly, previous work has focused predominantly on one organ system at a time, ignoring the interaction among systems, and preventing the development of a specific countermeasure for an individual astronaut that might be effective for the heart, muscles and bones. The global objective of this proposal is to test an integrated countermeasure that will be effective against cardiovascular deconditioning, skeletal muscle atrophy, and bone demineralization, and that ultimately can be applied practically abroad the International Space Station or a mission to Mars.

The original hypotheses and specific aims of the project are as follows:

Hypothesis 1: An “optimized” exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims:

Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing.

Specific aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound).

Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

2). Key Findings: In the third year of the project, we accelerated the recruitment and study of our entire cohort because of exigencies of funding within our GCRC. In particular, UT Southwestern was awarded a Clinical Translational Science Award which did not fully fund our GCRC. Although many of these problems have since been solved, we were concerned that it would have been possible that the GCRC could have closed, or severely limited services for the next year. Therefore we have studied (and expended grant funds) for the majority of next years proposed subjects as well as this years. Specifically 74 subjects were screened, 23 subjects have completed all phases of the study, and 26 subjects have completed the pre-testing and bedrest component. One subject will finish with his bedrest exposure next week, and he plus a remaining 3 subjects will complete their post re-ambulation studies over the next month thus completing our proposed cohort. Data analysis will continue aggressively and we will focus on our key outcome variables to ensure that we are adequately powered for our primary analysis. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available. Although data analysis is not yet complete, all results point in the direction of supporting our hypotheses. Subjects who exercised and received the oral volume load were protected against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

3). Impact on objectives: None.

4). Plan for upcoming year: The plan for the next year will be to complete data analysis and begin paper writing. If underpowered for key outcome variables, we may need to study another 3-6 subjects, but we do not expect this to be likely.

Research Impact/Earth Benefits: The information obtained from these experiments will be relevant for patients after prolonged confinement to bed rest, or chronic reduction in physical activity, as well as for patients with disease processes that alter cardiac stiffness such as obesity, hypertension, heart failure or ischemic heart disease, plus normal aging and osteoporosis. Indeed, we are already using this strategy to treat patients with chronic orthostatic intolerance and the Postural Orthostatic Tachycardia Syndrome with outstanding results. Rowing and strength training have been incorporated into my standard clinical algorithm for management of these patients, all of whom have very small hearts. This work has led to the elaboration of a new name for this important clinical syndrome: "The Grinch Syndrome" (because their hearts are "two sizes too small").

Task Progress & Bibliography Information FY2008 
Task Progress: In the first 3 years of the project, 23 have completed all phases of the study, and all will have completed all phases of the project within the next 4 weeks. Therefore our targeted enrollment will have been achieved. As noted in the overview, this enrollment was accelerated because of financial exigencies at the UT Southwestern GCRC which have been resolved, but which forced us to spend the first quarter of next year's funds already in this year (we have asked for pre-award to account for this accelerated enrollment). We plan to perform an expeditious analysis of our primary outcome variables to ensure that we are adequately powered as predicted and that no new bedrest subjects need to be studied. One subject developed acute appendicitis after his post-bedrest invasive studies, but prior to MRI and maximal LBNP and exercise. There have been no other adverse events. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available as noted in the "main findings" section, with all results pointing in the direction of supporting our hypotheses. Most subjects who exercised and received the oral volume load have had complete protection against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

Bibliography Type: Description: (Last Updated: 09/27/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Shibata S, Hastings JL, Prasad A, Fu Q, Okazaki K, Palmer MD, Zhang R, Levine BD. "'Dynamic' Starling mechanism: effects of ageing and physical fitness on ventricular-arterial coupling." J Physiol. 2008 Apr 1;586(7):1951-62. PMID: 18258658 , Apr-2008
Articles in Peer-reviewed Journals Shibata S, Zhang R, Hastings J, Fu Q, Okazaki K, Iwasaki K, Levine BD. "Cascade model of ventricular-arterial coupling and arterial-cardiac baroreflex function for cardiovascular variability in humans." Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2142-51. PMID: 16766646 , Nov-2006
Articles in Peer-reviewed Journals Dorfman TA, Levine BD, Tillery T, Peshock RM, Hastings JL, Schneider SM, Macias BR, Biolo G, Hargens AR. "Cardiac atrophy in women following bedrest." J Appl Physiol. 2007 Jul;103(1):8-16. PMID: 17379748 , Jul-2007
Articles in Peer-reviewed Journals Dorfman TA, 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." J Appl Physiol. 2008 Apr;104(4):1037-44. PMID: 18239079 , Apr-2008
Articles in Peer-reviewed Journals Shibata S, Hastings JL, Prasad A, Fu Q, Bhella P, Pacini E, Krainski F, Palmer D, Zhang R, Levine BD. "Congestive heart failure with preserved ejection fraction is associated with severely impaired dynamic ventricular-arterial coupling." J Am Coll Cardiol. Submitted, July 2008. , Jul-2008
Awards Levine BD. "American College of Sports Medicine (National) Citation Award, 2007." Jul-2007
Awards Levine BD. "Association of University Cardiologists, 2008." Jul-2008
Project Title:  The Multisystem Effect of Exercise Training/Nutritional Support During Prolonged Bed Rest Deconditioning: An Integrative Approach to Countermeasure Development for the Heart, Lungs, Muscles and Bones Reduce
Fiscal Year: FY 2007 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 04/30/2010  
Task Last Updated: 02/01/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Levine, Benjamin D M.D. / The University of Texas Southwestern Medical Center at Dallas 
Address:  Institute for Exercise and Environmental Medicine (IEEM) 
7232 Greenville Ave, Suite 435 
Dallas , TX 75231-5129 
Email: benjaminlevine@texashealth.org 
Phone: 214-345-4619  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: The University of Texas Southwestern Medical Center at Dallas 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-CA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 6387 
Solicitation / Funding Source: 2004 NSBRI NNH04ZUU003N Human Health in Space 
Grant/Contract No.: NCC 9-58-CA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Renal:Risk of Renal Stone Formation
Human Research Program Gaps: (1) B08:Do pharmaceuticals work effectively in spaceflight to prevent renal stones?
(2) CV01:What are the in-flight alterations in cardiac structure and function?
Flight Assignment/Project Notes: NOTE: New end date is 4/30/2010, per N. Gibbins/NSBRI; previous end date was 8/31/2009 (8/09)

Task Description: 1). Original Aims: Sustained exposure to microgravity leads to adaptive changes in the cardiovascular and musculoskeletal systems that results in substantial morbidity. For example cardiovascular deconditioning may lead to orthostatic hypotension and syncope. Atrophy of skeletal muscle will diminish work capacity and may lead to muscle injury. Bone demineralization increases the risk of kidney stone formation and may reduce bone strength increasing the risk of fracture. Bone resorption may be particularly severe after long duration space flight with uncertain recovery. Despite in depth study, the optimal countermeasure for each system has not been defined. More importantly, previous work has focused predominantly on one organ system at a time, ignoring the interaction among systems, and preventing the development of a specific countermeasure for an individual astronaut that might be effective for the heart, muscles and bones. The global objective of this proposal is to test an integrated countermeasure that will be effective against cardiovascular deconditioning, skeletal muscle atrophy, and bone demineralization, and that ultimately can be applied practically abroad the International Space Station or a mission to Mars.

The original hypotheses and specific aims of the project are as follows:

Hypothesis 1: An “optimized” exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims:

Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing.

Specific aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound) .

Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

2). Key Findings: In the second year of the project, 19 new subjects have been screened for the study (total = 46), twelve have completed all phases of the study, a 13th subject is in the middle of bedrest, and the 14th will start next week. Nine of the completed subjects were in the exercise arm, and three subjects were in the sedentary arm. There have been no adverse events. Two subjects left the study after completing all initial evaluations -- one because she elected to join a different research study from a pharmaceutical company, and a second because of a sudden, unexpected death in the family. We already have the next subject recruited and his pre-bedrest studies are scheduled. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available. Although we will not perform a preliminary data analysis to avoid reducing statistical power, all results point in the direction of supporting our hypotheses. Subjects who exercised and received the oral volume load have had complete protection against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

3). Impact on objectives: Based on the first two years' data and performance, we have not changed any of our hypotheses, and not altered the protocol.

4). Plan for upcoming year: The plan for the next year will be to continue a high rate of subject recruitment. We have permission to enroll 2 patients simultaneously, and therefore expect the experiment to be completed on time and within budget.

Research Impact/Earth Benefits: The information obtained from these experiments will be relevant for patients after prolonged confinement to bed rest, or chronic reduction in physical activity, as well as for patients with disease processes that alter cardiac stiffness such as obesity, hypertension, heart failure or ischemic heart disease, plus normal aging and osteoporosis. Indeed, we are already using this strategy to treat patients with chronic orthostatic intolerance and the Postural Orthostatic Tachycardia Syndrome with outstanding results. Rowing and strength training have been incorporated into my standard clinical algorithm for management of these patients, all of whom have very small hearts. This work has led to the elaboration of a new name for this important clinical syndrome: "The Grinch Syndrome" (because their hearts are "two sizes too small").

Task Progress & Bibliography Information FY2007 
Task Progress: In the first 2 years of the project, 46 subjects have been screened for the study, twelve have completed all phases of the study, and a thirteenth subject will start bedrest next week. Nine of the completed subjects were in the exercise arm, and three subjects were in the sedentary arm. This rate exceeds that of the first year of the project and is consistent with completion of the project with the time frame proposed. There have been no adverse events. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available. Although we will not perform a preliminary data analysis to avoid reducing statistical power, all results point in the direction of supporting our hypotheses. Subjects who exercised and received the oral volume load have had complete protection against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

Bibliography Type: Description: (Last Updated: 09/27/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Dorfman TA, Levine BD, Tillery T, Peshock RM, Hastings JL, Schneider SM, Macias BR, Biolo G, Hargens AR. "Cardiac atrophy in women following bedrest." J Appl Physiol. 2007 Jul;103(1):8-16. Epub 2007 Mar 22. PMID: 17379748 , Jul-2007
Articles in Peer-reviewed Journals Shibata S, Zhang R, Hastings J, Fu Q, Okazaki K, Iwasaki K, Levine BD. "Cascade model of ventricular-arterial coupling and arterial-cardiac baroreflex function for cardiovascular variability in humans." Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2142-51. Epub 2006 Jun 9. PMID: 16766646 , Nov-2006
Project Title:  The Multisystem Effect of Exercise Training/Nutritional Support During Prolonged Bed Rest Deconditioning: An Integrative Approach to Countermeasure Development for the Heart, Lungs, Muscles and Bones Reduce
Fiscal Year: FY 2006 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 08/31/2009  
Task Last Updated: 01/08/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Levine, Benjamin D M.D. / The University of Texas Southwestern Medical Center at Dallas 
Address:  Institute for Exercise and Environmental Medicine (IEEM) 
7232 Greenville Ave, Suite 435 
Dallas , TX 75231-5129 
Email: benjaminlevine@texashealth.org 
Phone: 214-345-4619  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: The University of Texas Southwestern Medical Center at Dallas 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-CA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 6387 
Solicitation / Funding Source: NSBRI 
Grant/Contract No.: NCC 9-58-CA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Renal:Risk of Renal Stone Formation
Human Research Program Gaps: (1) B08:Do pharmaceuticals work effectively in spaceflight to prevent renal stones?
(2) CV01:What are the in-flight alterations in cardiac structure and function?
Task Description: 1). Original Aims: Sustained exposure to microgravity leads to adaptive changes in the cardiovascular and musculoskeletal systems that results in substantial morbidity. For example cardiovascular deconditioning may lead to orthostatic hypotension and syncope. Atrophy of skeletal muscle will diminish work capacity and may lead to muscle injury. Bone demineralization increases the risk of kidney stone formation and may reduce bone strength increasing the risk of fracture. Bone resorption may be particularly severe after long duration space flight with uncertain recovery. Despite in depth study, the optimal countermeasure for each system has not been defined. More importantly, previous work has focused predominantly on one organ system at a time, ignoring the interaction among systems, and preventing the development of a specific countermeasure for an individual astronaut that might be effective for the heart, muscles and bones. The global objective of this proposal is to test an integrated countermeasure that will be effective against cardiovascular deconditioning, skeletal muscle atrophy, and bone demineralization, and that ultimately can be applied practically abroad the International Space Station or a mission to Mars. The original hypotheses and specific aims of the project are as follows: Hypothesis 1: An “optimized” exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims: Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing. Specific aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound) . Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

2). Key Findings: In the first year of the project, 27 subjects have been screened for the study, five have completed all phases of the study, and the sixth subject has just started bedrest. Three of the completed subjects were in the exercise arm, and two subjects were in the sedentary arm. There have been no adverse events, and all recruited subjects have completed all the study procedures with high quality data. We already have the next subject recruited and his pre-bedrest studies are scheduled. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available. Although we will not perform a preliminary data analysis to avoid reducing statistical power, all results point in the direction of supporting our hypotheses. Both subjects who exercised and received the oral volume load have had complete protection against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

3). Impact on objectives: Based on the first year's data and performance, we have not changed any of our hypotheses, and not altered the protocol.

4). Plan for upcoming year: The plan for the next year will be to continue a high rate of subject recruitment. Our GCRC has just been renovated, and we hope to be able to study more subjects in parallel as one short term bedrest funded by Dr. Crandall comes to a close.

Research Impact/Earth Benefits: The information obtained from these experiments will be relevant for patients after prolonged confinement to bed rest, or chronic reduction in physical activity, as well as for patients with disease processes that alter cardiac stiffness such as obesity, hypertension, heart failure or ischemic heart disease, plus normal aging and osteoporosis. Indeed, we are already using this strategy to treat patients with chronic orthostatic intolerance and the Postural Orthostatic Tachycardia Syndrome with outstanding results. Rowing and strength training have been incorporated into my standard clinical algorithm for management of these patients, all of whom have very small hearts. This work has led to the elaboration of a new name for this important clinical syndrome: "The Grinch Syndrome" (because their hearts are "two sizes too small").

Task Progress & Bibliography Information FY2006 
Task Progress: In the first year of the project, 27 subjects have been screened for the study, five have completed all phases of the study, and the sixth subject has just started bedrest. Three of the completed subjects were in the exercise arm, and two subjects were in the sedentary arm. There have been no adverse events, and all recruited subjects have completed all the study procedures with high quality data. We already have the next subject recruited and his pre-bedrest studies are scheduled. Most data have been cleaned and entered into the master experiment data base, and some preliminary results are available. Although we will not perform a preliminary data analysis to avoid reducing statistical power, all results point in the direction of supporting our hypotheses. Both subjects who exercised and received the oral volume load have had complete protection against orthostatic intolerance with maximal LBNP tolerance virtually identical to baseline levels despite 5 weeks of head down tilt bedrest. Cardiac muscle mass as well as the mass/volume ratio have been preserved, and both Starling and pressure-volume curves are superimposable. Muscle strength has been preserved, and urinary calcium loss has been attenuated, though we do not know which patients have gotten KMgCit or placebo.

Bibliography Type: Description: (Last Updated: 09/27/2021) 

Show Cumulative Bibliography Listing
 
Awards Levine BD. "ACSM John Sutton Clinical Lecture, Michael J. Joyner Teaching Award, Royal Danish Academy of Cardiovascular Sciences, June 2006." Jun-2006
Project Title:  The Multisystem Effect of Exercise Training/Nutritional Support During Prolonged Bed Rest Deconditioning: An Integrative Approach to Countermeasure Development for the Heart, Lungs, Muscles and Bones Reduce
Fiscal Year: FY 2005 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 09/01/2005  
End Date: 08/31/2009  
Task Last Updated: 12/29/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Levine, Benjamin D M.D. / The University of Texas Southwestern Medical Center at Dallas 
Address:  Institute for Exercise and Environmental Medicine (IEEM) 
7232 Greenville Ave, Suite 435 
Dallas , TX 75231-5129 
Email: benjaminlevine@texashealth.org 
Phone: 214-345-4619  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: The University of Texas Southwestern Medical Center at Dallas 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-CA00701 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 6387 
Solicitation / Funding Source: 2004 NSBRI NNH04ZUU003N Human Health in Space 
Grant/Contract No.: NCC 9-58-CA00701 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Arrhythmia:Risk of Cardiac Rhythm Problems
(2) Renal:Risk of Renal Stone Formation
Human Research Program Gaps: (1) B08:Do pharmaceuticals work effectively in spaceflight to prevent renal stones?
(2) CV01:What are the in-flight alterations in cardiac structure and function?
Task Description: 1). Original Aims: Sustained exposure to microgravity leads to adaptive changes in the cardiovascular and musculoskeletal systems that results in substantial morbidity. For example cardiovascular deconditioning may lead to orthostatic hypotension and syncope. Atrophy of skeletal muscle will diminish work capacity and may lead to muscle injury. Bone demineralization increases the risk of kidney stone formation and may reduce bone strength increasing the risk of fracture. Bone resorption may be particularly severe after long duration space flight with uncertain recovery. Despite in depth study, the optimal countermeasure for each system has not been defined. More importantly, previous work has focused predominantly on one organ system at a time, ignoring the interaction among systems, and preventing the development of a specific countermeasure for an individual astronaut that might be effective for the heart, muscles and bones. The global objective of this proposal is to test an integrated countermeasure that will be effective against cardiovascular deconditioning, skeletal muscle atrophy, and bone demineralization, and that ultimately can be applied practically abroad the International Space Station or a mission to Mars.

The original hypotheses and specific aims of the project are as follows:

Hypothesis 1: An “optimized” exercise training program combining dynamic plus intermittent resistance exercise can prevent the cardiovascular atrophy and deconditioning associated with prolonged bed rest.

Hypothesis 2: This dynamic plus resistance exercise training program, when combined with potassium-magnesium-citrate supplementation will attenuate the increased risk for stone formation, and diminish bed rest-induced bone loss to a greater extent than the effect of exercise training or supplementation alone.

Hypothesis 3: This dynamic plus resistance exercise training program during bed rest will also attenuate structural and functional alternations in skeletal muscle induced by prolonged bed rest, thereby preserving strength and endurance.

To test these hypotheses, we proposed to accomplish the following specific aims:

Specific Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy for orthostatic tolerance after prolonged bed rest will be determined from a novel combination of classical, invasive cardiovascular physiology to measure the static component of diastole (Frank-Starling and LV pressure/volume curves), in conjunction with innovative, non-invasive imaging techniques to measure the dynamic component of diastole. A novel oral volume loading strategy will also be applied just prior to orthostatic tolerance testing.

Specific aim 2: To assess the effect of exercise training combined with supplementation with potassium magnesium citrate (KMgCit) in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These specific aims will be accomplished by precise metabolic control and evaluation, plus non-invasive evaluation of bone structure and function (bone quality by ultrasound).

Specific Aim 3: To demonstrate the effectiveness of dynamic and resistance exercise training in attenuating the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. This aim will include measures of whole muscle size and function (magnetic resonance imaging/spectroscopy), functional exercise testing (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (muscle fiber type and morphometry, and capillary density).

Research Impact/Earth Benefits: The information obtained from these experiments will be relevant for patients after prolonged confinement to bed rest, or chronic reduction in physical activity, as well as for patients with disease processes that alter cardiac stiffness such as obesity, hypertension, heart failure or ischemic heart disease, plus normal aging and osteoporosis. Indeed, we are already using this strategy to treat patients with chronic orthostatic intolerance and the Postural Orthostatic Tachycardia Syndrome with outstanding results. Rowing and strength training have been incorporated into my standard clinical algorithm for management of these patients, all of whom have very small hearts. This work has led to the elaboration of a new name for this important clinical syndrome: "The Grinch Syndrome" (because their hearts are "two sizes too small").

Task Progress & Bibliography Information FY2005 
Task Progress: New project for FY2005.

[Ed. note: FY2005 record added to Task Book December 2009 when discovered it missing]

Bibliography Type: Description: (Last Updated: 09/27/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2005