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Project Title:  Echocardiographic Assessment of Cardiovascular Adaptation and Countermeasures in Microgravity Reduce
Fiscal Year: FY 2008 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 08/01/2004  
End Date: 07/31/2008  
Task Last Updated: 03/12/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Thomas, James David M.D. / The Cleveland Clinic Foundation 
Address:  Cardiovascular Medicine 
9500 Euclid Ave 
Cleveland , OH 44195-0001 
Email: thomasj@ccf.org 
Phone: 216-445-6312  
Congressional District: 11 
Web:  
Organization Type: NON-PROFIT 
Organization Name: The Cleveland Clinic Foundation 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Greenberg, Neil  The Cleveland Clinic Foundation 
Kassemi, Mohammad  NASA GRC 
Freed, Alan  NASA GRC 
Popovic, Zoran  The Cleveland Clinic Foundation 
Setser, Randolph  The Cleveland Clinic Foundation 
Penn, Marc  The Cleveland Clinic Foundation 
Rodriguez, Luis  The Cleveland Clinic Foundation 
Project Information: Grant/Contract No. NCC 9-58-SMS00404 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 2996 
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-SMS00404 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-101:Determine whether long-duration weightlessness induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Risk/Gap changes per HRP Master Task List information dtd 12/28/2012 (Ed., 3/13/13)

Task Description: Among the most serious of the risks identified by NASA in the area of cardiovascular alterations are serious dysrhythmias and the development of orthostatic intolerance. Prolonged exposure to microgravity may lead to a reduction in cardiac performance, particularly during times of stress and that undiagnosed cardiovascular disease may manifest during long missions. The PI and colleagues have worked closely with NASA and NSBRI over the last six years to optimize use of ultrasound in the space program as an investigative modality, addressing fundamental cardiovascular problems in need of countermeasures development. We propose the following specific aims:

1) Extension of work to calculate two-dimensional myocardial strain, improving sensitivity for detecting preclinical alterations in cardiac function.

2) Since early cardiac disease is usually manifest initially during exercise stress, we will develop and validate the tools to apply 2D strain in graded exercise to detect myocardial dysfunction in its earliest phases, allowing both diagnostic capabilities and a means of judging exercise as a countermeasure.

3) To continue our ongoing study of the magnitude and predictors of LV mass regression following acute volume and pressure unloading as a ground-based analog for manned spaceflight. This work will continue to focus on patients undergoing aortic valve surgery, but exploit recent knowledge of the roles of cytokines and integrins involved in cardiac hypertrophy and regression as well as emerging technologies such as gene chip analysis.

4) To develop, in collaboration with OBPR Fundamental Physics scientists from Glenn, a sophisticated fluid-structure model of the left ventricle constrained by the pericardium to investigate the impact that microgravity has on unloading the heart by a removal of pericardial constraint.

This work will be closely focused on risks and critical questions identified by the Cardiovascular Alterations Team as described in the Bioastronautics Critical Path Road Map Baseline Document. If successful, this project will enhance assessment of cardiac function during long duration missions and potentially suggest cytokine promoters or signal transduction pathways that could be targeted for cardiac atrophy countermeasures. In addition, we will continue to provide the facilities of our Core laboratory for access by investigators throughout the NASA and NSBRI programs in need of assistance in acquiring or analyzing ultrasonic data.

Research Impact/Earth Benefits: Assessment of 2D strain and torsion will have an extensive application in earth-based clinical and research cardiology and might be expected to supplant Doppler methods.

The 3D fluid-structure model of the left ventricle will also have an extensive application in earth-based research cardiology allowing investigators to alter fundamental inputs for myocardial function and assess the effects on ventricular performance.

Wireless telemedicine systems for ultrasound enable transfer of ultrasound data within the hospital and remotely to workstations connected to our network.

We have continued to investigate three-dimensional ultrasound capabilities. Building on our experience with the Volumetrics system, we have begun to use much improved acquisition devices (Philips ie33 and GE Medical Vivid 7) to obtain 3D examinations in a wide variety of cardiac pathologies.

We have worked on the registration of CT and ultrasound data for improved understanding of both valvular and ventricular function. We are investigating prosthetic valve motion using both modalities to see if 3D ultrasound is able to noninvasively assess function. We are also working on the registration of 3D ultrasound data with nuclear medicine images for assessment of cardiac perfusion.

Task Progress & Bibliography Information FY2008 
Task Progress: AIM 1: NEW TECHNIQUES TO ASSESS CARDIAC FUNCTION IN SPACE

We found that early diastolic IVPGs are associated with LV contractility. These findings may explain the proposed mechanism in which potential energy stored during systole is released during diastole to provide for adequate ventricular filling, even under low filling pressures. Left ventricular(LV) untwisting starts early during the isovolumic relaxation phase and proceeds throughout the early filling phase, releasing elastic energy stored by the preceding systolic deformation. Studies in our animal model demonstrated moderately strong correlation of peak LV twisting with peak LV untwisting rate. In a multivariate analysis, peak LV untwisting rate was an independent predictor of tau and IVPG. The start of LV untwisting coincided with the beginning of relaxation and preceded suction-aided filling resulting from elastic recoil.

AIM 2: USE EXERCISE ECHO TO DETECT CARDIAC DYSFUNCTION

We have shown that the ability to augment IVPG is the best predictor of maximum exercise capacity, and that the release of ventricular torsion during the isovolumic relaxation period is closely correlated with IVPG, thereby linking systolic contraction to diastolic filling. We have also shown that the loss of IVPG during exercise is strongly linked to the loss of untwisting velocity to and to the loss of torsion. We have studied the effects of exercise on left ventricular diastolic function using strain techniques from AIM 1 and found that the longitudinal strain rate in healthy volunteers was the best predictor of the increase of untwisting velocity and IVPG.

AIM 3: ASSESS PREDICTORS OF MASS REGRESSION FOLLOWING UNLOADING

Cardiac atrophy may be a serious limitation in long-term space flight, and understanding its significance and genetic determinants is critical to designing appropriate countermeasures. We have shown by 3D echo that aortic valve replacement can result in up to 50% mass reduction in patients with aortic insufficiency of stenosis. We are continuing this study obtaining comprehensive echo studies pre and post-op (3, 7 days, 6, 12 months) with volumes, mass, ejection fraction, strain, torsion, and IVPG.

AIM 4: DEVELOP A 3D FLUID-STRUCTURE INTERACTION MODEL OF THE HEART

Coding has been completed on a full 3D model of the left ventricle, using realistic myocardial fiber architecture and calcium-transient-based contraction and relaxation coupled with full Navier-Stokes description of blood flow. We also constructed a novel lumped-parameter model of the cardiovascular system, based on calcium transients (instead of previous model based on fixed systolic elastance). This novel model has been published in the Ann of Bio Eng, shows more realistic hemodynamics than the previous one, and is used to as an input to the 3D fluid-structure interaction model. A second manuscript was also submitted to Biomechanics and Modeling in Mechanobiology.

Bibliography: Description: (Last Updated: 04/09/2019) 

Show Cumulative Bibliography
 
Articles in Peer-reviewed Journals Firstenberg MS, Greenberg NL, Garcia MJ, Thomas JD. "Relationship between ventricular contractility and early diastolic intraventricular pressure gradients: a diastolic link to systolic function." J Am Soc Echocardiogr. 2008 May;21(5):501-6. PMID: 17928198 , May-2008
Articles in Peer-reviewed Journals Lim P, Buakhamsri A, Popovic ZB, Greenberg NL, Patel D, Thomas JD, Grimm RA. "Longitudinal strain delay index by speckle tracking imaging: a new marker of response to cardiac resynchronization therapy." Circulation. 2008 Sep 9;118(11):1130-7. PMID: 18725491 , Sep-2008
Articles in Peer-reviewed Journals Matsumura Y, Fukuda S, Tran H, Greenberg NL, Agler DA, Wada N, Toyono M, Thomas JD, Shiota T. "Geometry of the proximal isovelocity surface area in mitral regurgitation by 3-dimensional color Doppler echocardiography: difference between functional mitral regurgitation and prolapse regurgitation." Am Heart J. 2008 Feb;155(2):231-8. PMID: 18215591 , Feb-2008
Articles in Peer-reviewed Journals Matsumura Y, Saracino G, Sugioka K, Tran H, Greenberg NL, Wada N, Toyono M, Fukuda S, Hozumi T, Thomas JD, Yoshikawa J, Yoshiyama M, Shiota T. "Determination of regurgitant orifice area with the use of a new three-dimensional flow convergence geometric assumption in functional mitral regurgitation." J Am Soc Echocardiogr. 2008 Nov;21(11):1251-6. PMID: 18992676 , Nov-2008
Articles in Peer-reviewed Journals Notomi Y, Popovic ZB, Yamada H, Wallick DW, Martin MG, Oryszak SJ, Shiota T, Greenberg NL, Thomas JD. "Ventricular untwisting: a temporal link between left ventricular relaxation and suction." Am J Physiol Heart Circ Physiol. 2008 Jan;294(1):H505-13. PMID: 18032523 , Jan-2008
Articles in Peer-reviewed Journals Lim P, Mitchell-Heggs L, Buakhamsri A, Thomas JD, Grimm RA. "Impact of left ventricular size on tissue Doppler and longitudinal strain by speckle tracking for assessing wall motion and mechanical dyssynchrony in candidates for cardiac resynchronization therapy." J Am Soc Echocardiogr. 2009 Jun;22(6):695-701. http://dx.doi.org/10.1016/j.echo.2009.04.015 ; PubMed PMID: 19501329 , Jun-2009
Articles in Peer-reviewed Journals Buakhamsri A, Popovic ZB, Lin J, Lim P, Greenberg NL, Borowski AG, Tang WH, Klein AL, Lever HM, Desai MY, Thomas JD. "Impact of left ventricular volume/mass ratio on diastolic function." Eur Heart J. 2009 May;30(10):1213-21. Epub 2009 Mar 20. http://dx.doi.org/10.1093/eurheartj/ehp084 ; PubMed PMID: 1930474 , May-2009
Articles in Peer-reviewed Journals Asada-Kamiguchi J, Tabata T, Popovic ZB, Greenberg NL, Kim YJ, Garcia MJ, Wallick DW, Mowrey KA, Zhuang S, Zhang Y, Mazgalev TN, Thomas JD, Grimm RA. "Non-invasive assessment of left ventricular relaxation during atrial fibrillation using mitral flow propagation velocity." Eur J Echocardiogr. 2009 Oct;10(7):826-32. PMID: 19692424 , Oct-2009
Articles in Peer-reviewed Journals Phillips KP, Popovic ZB, Lim P, Meulet JE, Barrett CD, Di Biase L, Agler D, Thomas JD, Grimm RA. "Opposing wall mechanics are significantly influenced by longitudinal cardiac rotation in the assessment of ventricular dyssynchrony." JACC Cardiovasc Imaging. 2009 Apr;2(4):379-86. PMID: 19580717 , Apr-2009
Articles in Peer-reviewed Journals Puwanant S, Park M, Popovic ZB, Tang WH, Farha S, George D, Sharp J, Puntawangkoon J, Loyd JE, Erzurum SC, Thomas JD. "Ventricular geometry, strain, and rotational mechanics in pulmonary hypertension." Circulation. 2010 Jan 19;121(2):259-66. PMID: 20048214 , Jan-2010
Articles in Peer-reviewed Journals Saraiva RM, Matsumura Y, Yamano T, Greenberg N, Thomas JD, Shiota T. "Relation of left atrial dysfunction to pulmonary artery hypertension in patients with aortic stenosis and left ventricular systolic dysfunction." Am J Cardiol. 2010 Aug 1;106(3):409-16. PMID: 20643255 , Aug-2010
Articles in Peer-reviewed Journals Beach JM, Mihaljevic T, Rajeswaran J, Marwick T, Edwards ST, Nowicki ER, Thomas J, Svensson LG, Griffin B, Gillinov AM, Blackstone EH. "Ventricular hypertrophy and left atrial dilatation persist and are associated with reduced survival after valve replacement for aortic stenosis." J Thorac Cardiovasc Surg. 2014 Jan;147(1):362-369.e8. Epub 2013 Jan 11. https://doi.org/10.1016/j.jtcvs.2012.12.016 ; PubMed PMID: 23312984 , Jan-2014
Project Title:  Echocardiographic Assessment of Cardiovascular Adaptation and Countermeasures in Microgravity Reduce
Fiscal Year: FY 2007 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 08/01/2004  
End Date: 07/31/2008  
Task Last Updated: 02/01/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Thomas, James David M.D. / The Cleveland Clinic Foundation 
Address:  Cardiovascular Medicine 
9500 Euclid Ave 
Cleveland , OH 44195-0001 
Email: thomasj@ccf.org 
Phone: 216-445-6312  
Congressional District: 11 
Web:  
Organization Type: NON-PROFIT 
Organization Name: The Cleveland Clinic Foundation 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Greenberg, Neil  The Cleveland Clinic Foundation 
Kassemi, Mohammad  NASA GRC 
Freed, Alan  NASA GRC 
Popovic, Zoran  The Cleveland Clinic Foundation 
Setser, Randolph  The Cleveland Clinic Foundation 
Penn, Marc  The Cleveland Clinic Foundation 
Rodriguez, Luis  The Cleveland Clinic Foundation 
Project Information: Grant/Contract No. NCC 9-58-SMS00404 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 2996 
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-SMS00404 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-101:Determine whether long-duration weightlessness induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Task Description: Among the most serious of the risks identified by NASA in the area of cardiovascular alterations are serious dysrhythmias and the development of orthostatic intolerance. Prolonged exposure to microgravity may lead to a reduction in cardiac performance, particularly during times of stress and that undiagnosed cardiovascular disease may manifest during long missions. The PI and colleagues have worked closely with NASA and NSBRI over the last six years to optimize use of ultrasound in the space program as an investigative modality, addressing fundamental cardiovascular problems in need of countermeasures development. We propose the following specific aims:

1) Extension of work to calculate two-dimensional myocardial strain, improving sensitivity for detecting preclinical alterations in cardiac function.

2) Since early cardiac disease is usually manifest initially during exercise stress, we will develop and validate the tools to apply 2D strain in graded exercise to detect myocardial dysfunction in its earliest phases, allowing both diagnostic capabilities and a means of judging exercise as a countermeasure.

3) To continue our ongoing study of the magnitude and predictors of LV mass regression following acute volume and pressure unloading as a ground-based analog for manned spaceflight. This work will continue to focus on patients undergoing aortic valve surgery, but exploit recent knowledge of the roles of cytokines and integrins involved in cardiac hypertrophy and regression as well as emerging technologies such as gene chip analysis.

4) To develop, in collaboration with OBPR Fundamental Physics scientists from Glenn, a sophisticated fluid-structure model of the left ventricle constrained by the pericardium to investigate the impact that microgravity has on unloading the heart by a removal of pericardial constraint.

This work will be closely focused on risks and critical questions identified by the Cardiovascular Alterations Team as described in the Bioastronautics Critical Path Road Map Baseline Document. If successful, this project will enhance assessment of cardiac function during long duration missions and potentially suggest cytokine promoters or signal transduction pathways that could be targeted for cardiac atrophy countermeasures. In addition, we will continue to provide the facilities of our Core laboratory for access by investigators throughout the NASA and NSBRI programs in need of assistance in acquiring or analyzing ultrasonic data.

Research Impact/Earth Benefits: Assessment of 2D strain and torsion will have an extensive application in earth-based clinical and research cardiology and might be expected to supplant Doppler methods.

The 3D fluid-structure model of the left ventricle will also have an extensive application in earth-based research cardiology allowing investigators to alter fundamental inputs for myocardial function and assess the effects on ventricular performance.

Wireless telemedicine systems for ultrasound enable transfer of ultrasound data within the hospital and remotely to workstations connected to our network.

We have continued to investigate three-dimensional ultrasound capabilities. Building on our experience with the Volumetrics system, we have begun to use much improved acquisition devices (Philips ie33 and GE Medical Vivid 7) to obtain 3D examinations in a wide variety of cardiac pathologies.

We have worked on the registration of CT and ultrasound data for improved understanding of both valvular and ventricular function. We are investigating prosthetic valve motion using both modalities to see if 3D ultrasound is able to noninvasively assess function. We are also working on the registration of 3D ultrasound data with nuclear medicine images for assessment of cardiac perfusion.

Task Progress & Bibliography Information FY2007 
Task Progress: AIM 1: NEW TECHNIQUES TO ASSESS CARDIAC FUNCTION IN SPACE

We examined the clinical feasibility of quantifying regional myocardial strain with online speckle tracking echocardiography. We've studied myocardial strains in hypertrophic cardiomyopathy (HCM) patients and found that despite preserved LVEF and absence of scar, HCM patients have depressed longitudinal strain (LS) and circumferential strain, compared to healthy subjects. We utilized prototype software to evaluate LS and CS of subendocardium, midwall and subepicardium in these patient groups. Profound strain differences exist between different myocardial layers in both healthy subjects and HCM patients. We've also continued experimental work on the assessment of factors that affect strain, most important of which is myocardial ischemia. We performed validation studies of speckle tracking to detect changes induced by ischemic heart disease, both acute and chronic. AIM 2: USE EXERCISE ECHO TO DETECT CARDIAC DYSFUNCTION

We have shown that the ability to augment IVPG is the best predictor of maximum exercise capacity, and that the release of ventricular torsion during the isovolumic relaxation period is closely correlated with IVPG, thereby linking systolic contraction to diastolic filling. We have also shown that the loss of IVPG during exercise is strongly linked to the loss of untwisting velocity to and to the loss of torsion. We have studied the effects of exercise on left ventricular diastolic function using strain techniques from AIM 1 and found that the longitudinal strain rate in healthy volunteers was the best predictor of the increase of untwisting velocity and IVPG.

AIM 3: ASSESS PREDICTORS OF MASS REGRESSION FOLLOWING UNLOADING

Cardiac atrophy may be a serious limitation in long-term space flight, and understanding its significance and genetic determinants is critical to designing appropriate countermeasures. We have shown by 3D echo that aortic valve replacement can result in up to 50% mass reduction in patients with aortic insufficiency of stenosis. We are continuing this study obtaining comprehensive echo studies pre and post-op (3, 7 days, 6, 12 months) with volumes, mass, ejection fraction, strain, torsion, and IVPG.

AIM 4: DEVELOP A 3D FLUID-STRUCTURE INTERACTION MODEL OF THE HEART

Coding has been completed on a full 3D model of the left ventricle, using realistic myocardial fiber architecture and calcium-transient-based contraction and relaxation coupled with full Navier-Stokes description of blood flow. We also constructed a novel lumped-parameter model of the cardiovascular system, based on calcium transients (instead of previous model based on fixed systolic elastance). This novel model has been published in the Ann of Bio Eng, shows more realistic hemodynamics than the previous one, and is used to as an input to the 3D fluid-structure interaction model. A second manuscript was also submitted to Biomechanics and Modeling in Mechanobiology.

Bibliography: Description: (Last Updated: 04/09/2019) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Buakhamsri A, Popovic ZB, Greenberg NL, Lever HM, Thomas JD. "Hypertrophic cardiomyopathy differentially affects strains in subendocardial and subepicardial myocardial layers: the result from novel echocardiography technique." American Heart Association Scientific Sessions, Orlando, FL, November 4-7, 2007.

American Heart Association. Submitted, June 2007. , Jun-2007

Abstracts for Journals and Proceedings Goh TH, Popovic ZB, Buakhamsri A, Greenberg NL, Thomas JD. "Effects of exercise on left ventricular diastolic function depend on homogenous increase in diastolic strain rates." American Heart Association Scientific Sessions, Orlando, FL, November 4-7, 2007.

American Heart Association. Submitted, June 2007. , Jun-2007

Abstracts for Journals and Proceedings Lowe BS, Tran H, Gudat S, Agler D, Popovic ZB, Thomas JD, Grimm RA. "Quantifying regional myocardial strain by online speckle tracking echocardiography: clinical feasibility and comparison with wall motion scoring." American Society of Echocardiography Annual Scientific Sessions, Seattle, WA, June 16-20, 2007.

Journal of the American Society of Echocardiography 2007 May;20(5):584. , Jun-2007

Awards Saracino G. "Computers in Cardiology Young Investigator Finalist, September 2007." Sep-2007
Project Title:  Echocardiographic Assessment of Cardiovascular Adaptation and Countermeasures in Microgravity Reduce
Fiscal Year: FY 2006 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 08/01/2004  
End Date: 07/31/2008  
Task Last Updated: 08/21/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Thomas, James David M.D. / The Cleveland Clinic Foundation 
Address:  Cardiovascular Medicine 
9500 Euclid Ave 
Cleveland , OH 44195-0001 
Email: thomasj@ccf.org 
Phone: 216-445-6312  
Congressional District: 11 
Web:  
Organization Type: NON-PROFIT 
Organization Name: The Cleveland Clinic Foundation 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Garcia, Mario  The Cleveland Clinic Foundation 
Greenberg, Neil  The Cleveland Clinic Foundation 
Deserranno, Dimitri  Case Western Reserve University 
Kassemi, Mohammad  NASA GRC 
Freed, Alan  NASA GRC 
Rodriguez, Luis  The Cleveland Clinic Foundation 
Notomi, Yuichi  The Cleveland Clinic Foundation 
Popovic, Zoran  The Cleveland Clinic Foundation 
Setser, Randolph  The Cleveland Clinic Foundation 
Sallach, John  The Cleveland Clinic Foundation 
Penn, Marc  The Cleveland Clinic Foundation 
Project Information: Grant/Contract No. NCC 9-58-SMS00404 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 2996 
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-SMS00404 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-101:Determine whether long-duration weightlessness induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Task Description: Among the most serious of the risks identified by NASA in the area of cardiovascular alterations are serious dysrhythmias and the development of orthostatic intolerance. Prolonged exposure to microgravity may lead to a reduction in cardiac performance, particularly during times of stress and that undiagnosed cardiovascular disease may manifest during long missions. The PI and colleagues have worked closely with NASA and NSBRI over the last six years to optimize use of ultrasound in the space program as an investigative modality, addressing fundamental cardiovascular problems in need of countermeasures development. We propose the following specific aims:

1) Extension of work to calculate two-dimensional myocardial strain, improving sensitivity for detecting preclinical alterations in cardiac function.

2) Since early cardiac disease is usually manifest initially during exercise stress, we will develop and validate the tools to apply 2D strain in graded exercise to detect myocardial dysfunction in its earliest phases, allowing both diagnostic capabilities and a means of judging exercise as a countermeasure.

3) To continue our ongoing study of the magnitude and predictors of LV mass regression following acute volume and pressure unloading as a ground-based analog for manned spaceflight. This work will continue to focus on patients undergoing aortic valve surgery, but exploit recent knowledge of the roles of cytokines and integrins involved in cardiac hypertrophy and regression as well as emerging technologies such as gene chip analysis.

4) To develop, in collaboration with OBPR Fundamental Physics scientists from Glenn, a sophisticated fluid-structure model of the left ventricle constrained by the pericardium to investigate the impact that microgravity has on unloading the heart by a removal of pericardial constraint.

This work will be closely focused on risks and critical questions identified by the Cardiovascular Alterations Team as described in the Bioastronautics Critical Path Road Map Baseline Document. If successful, this project will enhance assessment of cardiac function during long duration missions and potentially suggest cytokine promoters or signal transduction pathways that could be targeted for cardiac atrophy countermeasures. In addition, we will continue to provide the facilities of our Core laboratory for access by investigators throughout the NASA and NSBRI programs in need of assistance in acquiring or analyzing ultrasonic data.

Research Impact/Earth Benefits: Assessment of 2D strain and torsion will have an extensive application in earth-based clinical and research cardiology and might be expected to supplant Doppler methods.

The 3D fluid-structure model of the left ventricle will also have an extensive application in earth-based research cardiology allowing investigators to alter fundamental inputs for myocardial function and assess the effects on ventricular performance.

Wireless telemedicine systems for ultrasound enable transfer of ultrasound data within the hospital and remotely to workstations connected to our network.

We have continued to investigate three-dimensional ultrasound capabilities. To date, we have performed over 3000 patient examinations with real-time 3D echocardiography. Building on our experience with the Volumetrics system, we have begun to use much improved acquisition devices (Philips Sonos 7500, and GE Medical Vivid 7) to obtain 3D examinations in a wide variety of cardiac pathologies.

We have worked on the registration of CT and ultrasound data for improved understanding of both valvular and ventricular function. We are investigating prosthetic valve motion using both modalities to see if 3D ultrasound is able to noninvasively assess function. We are also working on the registration of 3D ultrasound data with nuclear medicine images for assessment of cardiac perfusion.

Task Progress & Bibliography Information FY2006 
Task Progress: AIM 1: NEW TECHNIQUES TO ASSESS CARDIAC FUNCTION IN SPACE

We pursue work on linear and shear strains, regional measures of ventricular mechanics, and torsion, the wringing motion of the heart that reflects shear strain. We have validated (against MRI) measurement of torsion by Doppler tissue imaging (r=0.95) [Circulation] and 2D speckle tracking (r=0.93) [JACC]. We used these techniques to document the maturation of ventricular contraction from 5.8±1·3° in infancy to 13.8±3·3° in mid-adulthood (Circulation), and to document the link between the torsion and left ventricular filling during exercise. We also started the experimental work on the assessment of factors that affect strain, most important of which is myocardial ischemia. We are currently validating the response of subendocardial vs. subepicardial strains on the effects of ischemia. We developed a model that uses sonomicrometric crystals as a gold standard of strain measurements and are currently developing, with the collaboration of industry, the software that would separately analyze subendocardial strains.

AIM 2: USE EXERCISE ECHO TO DETECT SUBCLINICAL CARDIAC DYSFUNCTION

We have shown that the ability to augment IVPG is the best predictor of maximum exercise capacity (r=0.8, AJP, published), and that the release of ventricular torsion during the isovolumic relaxation period is closely correlated (r=0.72) with IVPG, thereby linking systolic contraction to diastolic filling (AJP). We have also shown that the loss of IVPG during exercise is strongly linked to the loss of untwisting velocity to (r=0.75) and to the loss of torsion (Circulation).

AIM 3: ASSESS GENETIC PREDICTORS OF MASS REGRESSION FOLLOWING UNLOADING

Cardiac atrophy may be a serious limitation in long-term space flight, and understanding its significance and genetic determinants is critical to designing appropriate countermeasures. We have shown by 3D echo that aortic valve replacement can result in up to 50% mass reduction in patients with aortic insufficiency of stenosis. We are continuing this study obtaining comprehensive echo studies pre and post-op (3, 7 days, 6, 12 months) with volumes, mass, ejection fraction, strain, torsion, and IVPG.

AIM 4: DEVELOP A 3D FLUID-STRUCTURE INTERACTION MODEL OF THE HEART

Coding has been completed on a full 3D model of the left ventricle, using realistic myocardial fiber architecture and calcium-transient-based contraction and relaxation coupled with full Navier-Stokes description of blood flow. We also constructed a novel lumped-parameter model of the cardiovascular system, based on the calcium transients (instead of our previous model that was based on fixed systolic elastance). This novel model currently in press in Ann Biomed Eng, shows more realistic hemodynamics than the previous one, and is used to as an input to the 3D fluid-structure interaction model.

Bibliography: Description: (Last Updated: 04/09/2019) 

Show Cumulative Bibliography
 
Articles in Peer-reviewed Journals Notomi Y, Martin-Miklovic MG, Oryszak SJ, Shiota T, Deserranno D, Popovic ZB, Garcia MJ, Greenberg NL, Thomas JD. "Enhanced ventricular untwisting during exercise: a mechanistic manifestation of elastic recoil described by Doppler tissue imaging." Circulation. 2006 May 30;113(21):2524-33. PMID: 16717149 , May-2006
Articles in Peer-reviewed Journals Notomi Y, Srinath G, Shiota T, Martin-Miklovic MG, Beachler L, Howell K, Oryszak SJ, Deserranno DG, Freed AD, Greenberg NL, Younoszai A, Thomas JD. "Maturational and adaptive modulation of left ventricular torsional biomechanics: Doppler tissue imaging observation from infancy to adulthood." Circulation. 2006 May 30;113(21):2534-41. PMID: 16717154 , May-2006
Articles in Peer-reviewed Journals Popovic ZB, Richards KE, Greenberg NL, Rovner A, Drinko J, Cheng Y, Penn MS, Fukamachi K, Mal N, Levine BD, Garcia MJ, Thomas JD. "Scaling of diastolic intraventricular pressure gradients is related to filling time duration." Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H762-9. PMID: 16679403 , Aug-2006
Articles in Peer-reviewed Journals Popovic ZB, Sun JP, Yamada H, Drinko J, Mauer K, Greenberg NL, Cheng Y, Moravec CS, Penn MS, Mazgalev TN, Thomas JD. "Differences in left ventricular long-axis function from mice to humans follow allometric scaling to ventricular size." J Physiol. 2005 Oct 1;568(Pt 1):255-65. PMID: 16002448 , Oct-2005
Articles in Peer-reviewed Journals Qin JX, Jones M, Travaglini A, Song JM, Li J, White RD, Tsujino H, Greenberg NL, Zetts AD, Panza JA, Thomas JD, Shiota T. "The accuracy of left ventricular mass determined by real-time three-dimensional echocardiography in chronic animal and clinical studies: a comparison with postmortem examination and magnetic resonance imaging." J Am Soc Echocardiogr. 2005 Oct;18(10):1037-43. PMID: 16198880 , Oct-2005
Articles in Peer-reviewed Journals Rovner A, Greenberg NL, Thomas JD, Garcia MJ. "Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure." Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H2081-8. PMID: 15937093 , Nov-2005
Articles in Peer-reviewed Journals Thomas JD, Popovic ZB. "Assessment of left ventricular function by cardiac ultrasound." J Am Coll Cardiol. 2006 Nov 21;48(10):2012-25. PMID: 17112991 , Nov-2006
Project Title:  Echocardiographic Assessment of Cardiovascular Adaptation and Countermeasures in Microgravity Reduce
Fiscal Year: FY 2005 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 08/01/2004  
End Date: 07/31/2008  
Task Last Updated: 10/27/2005 
Download report in PDF pdf
Principal Investigator/Affiliation:   Thomas, James David M.D. / The Cleveland Clinic Foundation 
Address:  Cardiovascular Medicine 
9500 Euclid Ave 
Cleveland , OH 44195-0001 
Email: thomasj@ccf.org 
Phone: 216-445-6312  
Congressional District: 11 
Web:  
Organization Type: NON-PROFIT 
Organization Name: The Cleveland Clinic Foundation 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Garcia, Mario  The Cleveland Clinic Foundation 
Greenberg, Neil  The Cleveland Clinic Foundation 
Deserranno, Dimitri  Case Western Reserve University 
Kassemi, Mohammad  NASA GRC 
Freed, Alan  NASA GRC 
Notomi, Yuichi  The Cleveland Clinic Foundation 
Popovic, Zoran  The Cleveland Clinic Foundation 
Setser, Randolph  The Cleveland Clinic Foundation 
Sallach, John  The Cleveland Clinic Foundation 
Penn, Marc  The Cleveland Clinic Foundation 
Rodriguez, Luis  The Cleveland Clinic Foundation 
Project Information: Grant/Contract No. NCC 9-58-SMS00404 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 2996 
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-SMS00404 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-101:Determine whether long-duration weightlessness induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Task Description: Among the most serious of the risks identified by NASA in the area of cardiovascular alterations are serious dysrhythmias and the development of orthostatic intolerance. Prolonged exposure to microgravity may lead to a reduction in cardiac performance, particularly during times of stress and that undiagnosed cardiovascular disease may manifest during long missions. The PI and colleagues have worked closely with NASA and NSBRI over the last six years to optimize use of ultrasound in the space program as an investigative modality, addressing fundamental cardiovascular problems in need of countermeasures development. We propose the following specific aims: 1)Extension of work to calculate two-dimensional myocardial strain, improving sensitivity for detecting preclinical alterations in cardiac function. 2)Since early cardiac disease is usually manifest initially during exercise stress, we will develop and validate the tools to apply 2D strain in graded exercise to detect myocardial dysfunction in its earliest phases, allowing both diagnostic capabilities and a means of judging exercise as a countermeasure. 3)To continue our ongoing study of the magnitude and predictors of LV mass regression following acute volume and pressure unloading as a ground-based analog for manned spaceflight. This work will continue to focus on patients undergoing aortic valve surgery, but exploit recent knowledge of the roles of cytokines and integrins involved in cardiac hypertrophy and regression as well as emerging technologies such as gene chip analysis. 4)To develop, in collaboration with OBPR Fundamental Physics scientists from Glenn, a sophisticated fluid-structure model of the left ventricle constrained by the pericardium to investigate the impact that microgravity has on unloading the heart by a removal of pericardial constraint. This work will be closely focused on risks and critical questions identified by the Cardiovascular Alterations Team as described in the Bioastronautics Critical Path Road Map Baseline Document. If successful, this project will enhance assessment of cardiac function during long duration missions and potentially suggest cytokine promoters or signal transduction pathways that could be targeted for cardiac atrophy countermeasures. In addition, we will continue to provide the facilities of our Core laboratory for access by investigators throughout the NASA and NSBRI programs in need of assistance in acquiring or analyzing ultrasonic data.

Research Impact/Earth Benefits: • Assessment of 2D strain and torsion will have an extensive application in earth-based clinical and research cardiology and might be expected to supplant Doppler methods. The 3D fluid-structure model of the left ventricle will also have an extensive application in earth-based research cardiology allowing investigators to alter fundamental inputs for myocardial function and assess the effects on ventricular performance. Wireless telemedicine systems for ultrasound enable transfer of ultrasound data within the hospital and remotely to workstations connected to our network. We have continued to investigate three-dimensional ultrasound capabilities. To date, we have performed over 3000 patient examinations with real-time 3D echocardiography. Building on our experience with the Volumetrics system, we have begun to use much improved acquisition devices (Philips Sonos 7500, and GE Medical Vivid 7) to obtain 3D examinations in a wide variety of cardiac pathologies. We have worked on the registration of CT and ultrasound data for improved understanding of both valvular and ventricular function. We are investigating prosthetic valve motion using both modalities to see if 3D ultrasound is able to noninvasively assess function. We are also working on the registration of 3D ultrasound data with nuclear medicine images for assessment of cardiac perfusion.

Task Progress & Bibliography Information FY2005 
Task Progress: AIM 1: NEW TECHNIQUES TO ASSESS CARDIAC FUNCTION IN SPACE Strain is the best measure of regional ventricular contraction. We recently published normal age-corrected values for tissue velocity, displacement, strain, and strain rate and have begun work on a novel method to quantify 2D strain from B-mode ultrasound. We have previously validated measurement of intraventricular pressure gradients (IVPG) from color Doppler M-mode echos, and recently used them to document improvement in cardiac suction (1.5 ± 0.2 to 2.6 ± 0.3 mmHg, p<0.001) following septal ablation in hypertrophic cardiomyopathy. Torsion, the wringing motion of the heart, stores energy in systole and releases it in diastole to assist in the low-pressure filling of the heart. We have validated (against MRI) measurement of torsion by Doppler tissue imaging (r=0.95) [published in Circulation] and 2D speckle tracking (r=0.93) [published in JACC] and used it to document the complex maturation of ventricular contraction from 5.8±1·3° in infancy to 13.8±3·3° in mid-adulthood (Lancet, submitted). AIM 2: USE EXERCISE ECHO TO DETECT SUBCLINICAL CARDIAC DYSFUNCTION We have shown that the ability to augment IVPG is the best predictor of maximum exercise capacity (r=0.8, AJP, in press), and that the release of ventricular torsion during the isovolumic relaxation period is closely correlated (r=0.72) with IVPG, thereby linking systolic contraction to diastolic filling (AJP, submitted). AIM 3: ASSESS GENETIC PREDICTORS OF MASS REGRESSION FOLLOWING UNLOADING Cardiac atrophy may be a serious limitation in long-term space flight, and understanding its significance and genetic determinants is critical to designing appropriate countermeasures. We have shown by 3D echo that aortic valve replacement can result in up to 50% mass reduction in patients with aortic insufficiency of stenosis. We are continuing this study obtaining comprehensive echo studies pre and post-op (3, 7 days, 6, 12 months) with volumes, mass, ejection fraction, strain, torsion, and IVPG. In addition intraoperative myocardial biopsies will be obtained pre-pump and just before closing chest and analyzed with gene chips targeting apoptosis, inflammatory cytokines and receptors, NFKB signaling pathway, and modulators of the extracellular matrix, verified with real-time PCR. AIM 4: DEVELOP A 3D FLUID-STRUCTURE INTERACTION MODEL OF THE HEART Coding has been completed on a full 3D model of the left ventricle, using realistic myocardial fiber architecture and calcium-transient-based contraction and relaxation coupled with full Navier-Stokes description of blood flow. Although computationally intensive (~1 week on 8-CPU supercomputer), it will be unique in its ability to assess the impact on LV function and IVPG of 1) generalized atrophy; 2) localized infarction; 3) dyssynchrony; 4) hypertension. A less computationally intensive 2D model has demonstrated the relationship between IVPG,

Bibliography: Description: (Last Updated: 04/09/2019) 

Show Cumulative Bibliography
 
Articles in Peer-reviewed Journals 401. Qin JX, Shiota T, Tsujino H, Saracino G, White RD, Greenberg NL, Kwan J, Popovic ZB, Agler DA, Stewart WJ, Thomas JD "Mitral annular motion as a surrogate for left ventricular ejection fraction: real-time three-dimensional echocardiography and magnetic resonance imaging studies" N/A , Jan-2004
Articles in Peer-reviewed Journals Notomi Y, et al "Enhanced Ventricular Untwisting During Exercise: A Mechanistic Manifestation of Elastic Recoil Described by Doppler Tissue Imaging" N/A , Jan-2004
Articles in Peer-reviewed Journals Notomi Y, et al "Ventricular Torsional Mechanics in Patients Receiving Cardiac Resynchronization Therapy" N/A , Jan-2004
Articles in Peer-reviewed Journals Notomi Y, et al. "Maturational and Adaptive Modulation of Left Ventricular Torsional Biomechanics: Doppler Tissue Imaging Observation From Infancy to Adulthood" N/A , Jan-2004
Articles in Peer-reviewed Journals Notomi Y, et al. "Ventricular Untwisting: A Mechanistic Determinant of Active Relaxation and Suction" N/A , Jan-2004
Articles in Peer-reviewed Journals Rovner A, Greenberg NL, Thomas JD, Garcia MJ "Relationship of Diastolic Intraventricular Pressure Gradients and Aerobic Capacity in Patients With Heart Failure" N/A , Jan-2005
Articles in Peer-reviewed Journals Notomi Y, Lysyansky P, Setser RM, Shiota T, Popovic ZB, Martin-Miklovic MG, Weaver JA, Oryszak SJ, Greenberg NL, White RD, Thomas JD "Measurement of Ventricular Torsion by Two-Dimensional Ultrasound Speckle Tracking Imaging" N/A , Jun-2005
Articles in Peer-reviewed Journals Notomi Y, Setser RM, Shiota T, Martin-Miklovic MG, Weaver JA, Popovic ZB, Yamada H, Greenberg NL, White RD, Thomas JD "Assessment of Left Ventricular Torsional Deformation by Doppler Tissue Imaging: Validation Study With Tagged Magnetic Resonance Imaging" N/A , Jan-2005
Articles in Peer-reviewed Journals Qin JX, Shiota T, Asher CR, Smedira NG, Shin JH, Agler DA, Nash PJ, Greenberg NL, Lever HM, Lytle BW, Thomas JD "Usefulness of real-time three-dimensional echocardiography for evaluation of myectomy in patients with hypertrophic cardiomyopathy" N/A , Jan-2004
Articles in Peer-reviewed Journals Sun JP, Popovic ZB, Greenberg NL, Xu X, Asher CR, Stewart WJ, Thomas JD "Noninvasive Quantification of Regional Myocardial Function Using Doppler-Derived Velocity, Displacement, Strain Rate, and Strain in Healthy Subjects: Effects of Aging." N/A , Jan-2004
Articles in Peer-reviewed Journals Tsujino H, Jones M, Qin JX, Sitges M, Cardon LA, Morehead AL, Zetts AD, Bauer F, Kim YJ, Hang XH, Greenberg NL, Thomas JD, Shiota T "Combination of pulsed-wave Doppler and real-time three-dimensional color Doppler echocardiography for quantifying the stroke volume in the left ventricular outflow tract" N/A , Jan-2004
Project Title:  Echocardiographic Assessment of Cardiovascular Adaptation and Countermeasures in Microgravity Reduce
Fiscal Year: FY 2004 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 08/01/2004  
End Date: 07/31/2008  
Task Last Updated: 03/31/2006 
Download report in PDF pdf
Principal Investigator/Affiliation:   Thomas, James David M.D. / The Cleveland Clinic Foundation 
Address:  Cardiovascular Medicine 
9500 Euclid Ave 
Cleveland , OH 44195-0001 
Email: thomasj@ccf.org 
Phone: 216-445-6312  
Congressional District: 11 
Web:  
Organization Type: NON-PROFIT 
Organization Name: The Cleveland Clinic Foundation 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-SMS00404 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Unique ID: 2996 
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-SMS00404 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-101:Determine whether long-duration weightlessness induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Task Description: Among the most serious of the risks identified by NASA in the area of cardiovascular alterations are serious dysrhythmias and the development of orthostatic intolerance. Prolonged exposure to microgravity may lead to a reduction in cardiac performance, particularly during times of stress and that undiagnosed cardiovascular disease may manifest during long missions. The PI and colleagues have worked closely with NASA and NSBRI over the last six years to optimize use of ultrasound in the space program as an investigative modality, addressing fundamental cardiovascular problems in need of countermeasures development. We propose the following specific aims: 1)Extension of work to calculate two-dimensional myocardial strain, improving sensitivity for detecting preclinical alterations in cardiac function. 2)Since early cardiac disease is usually manifest initially during exercise stress, we will develop and validate the tools to apply 2D strain in graded exercise to detect myocardial dysfunction in its earliest phases, allowing both diagnostic capabilities and a means of judging exercise as a countermeasure. 3)To continue our ongoing study of the magnitude and predictors of LV mass regression following acute volume and pressure unloading as a ground-based analog for manned spaceflight. This work will continue to focus on patients undergoing aortic valve surgery, but exploit recent knowledge of the roles of cytokines and integrins involved in cardiac hypertrophy and regression as well as emerging technologies such as gene chip analysis. 4)To develop, in collaboration with OBPR Fundamental Physics scientists from Glenn, a sophisticated fluid-structure model of the left ventricle constrained by the pericardium to investigate the impact that microgravity has on unloading the heart by a removal of pericardial constraint. This work will be closely focused on risks and critical questions identified by the Cardiovascular Alterations Team as described in the Bioastronautics Critical Path Road Map Baseline Document. If successful, this project will enhance assessment of cardiac function during long duration missions and potentially suggest cytokine promoters or signal transduction pathways that could be targeted for cardiac atrophy countermeasures. In addition, we will continue to provide the facilities of our Core laboratory for access by investigators throughout the NASA and NSBRI programs in need of assistance in acquiring or analyzing ultrasonic data.

Research Impact/Earth Benefits: • Novice sonographers can be “coached” through an echocardiogram after only 4 hours of training • Ultrasound images successfully acquired with the ISS ultrasound unit and relayed to ground • Wavelet packet compression can be applied to 3D ultrasound at ratios > 100:1 • Digital echo storage and retrieval accomplished at CCF, >200 studies/day, 10 GB/day • Implementation of standalone software for intraventricular pressure gradient measurement • IVPG predictive of exercise capacity • Cardiac strain capable of characterizing LV function better than ejection fraction

Task Progress & Bibliography Information FY2004 
Task Progress: No progress report this period.

Bibliography: Description: (Last Updated: 04/09/2019) 

Show Cumulative Bibliography
 
 None in FY 2004