Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00387712
• Collaborator: (none)
• Enrollment: 99
• Location: 1
• Arms: 2
• Duration (Months): 94
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The purpose of this study is to first define whether abnormalities of skeletal muscle are related to the presence of inflammation and to poor motor performance and whether this can be modified by exercise interventions.

Condition or Disease	Intervention/Treatment	Phase
Stroke; Inflammation	Other: Velocity based treadmill training; Other: Duration based treadmill training	N/A

Detailed Description

Stroke is the leading cause of disability in the United States. Biological changes in hemiparetic skeletal muscle may further propagate the disability. The investigators report gross muscular atrophy and major shift to fast myosin heavy chain (MHC) isoform distribution in hemiparetic thigh that are related to reduced fitness and slow walking speed. The investigators also find elevated inflammatory mediators, tumor necrosis factor (TNF) and nuclear factor kappa beta (NFkB) in the paretic thigh muscle. No prior studies have systematically examined the profile of hemiparetic muscle contractile proteins and their relationship to function and fitness after stroke. Furthermore, the molecular mechanisms underlying hemiparetic skeletal muscle atrophy and contractile protein abnormalities are unknown.

The investigators have investigated treadmill aerobic exercise (T-AEX), as a task-oriented training model. This exercise model can reverse the alterations in MHC profile in hemiparetic leg muscles after stroke. This T-AEX program also improves fitness (VO2) levels, leg strength, and ambulatory performance in chronic stroke. Moreover, post hoc analyses our randomized treadmill exercise program show that specific features of the exercise prescription likely influence the nature of exercise-mediated adaptations.

Hypothesis: The investigators propose a randomized clinical study to investigate the hypothesis that in chronic stroke patients a 6 month velocity-based progressive T-AEX program is superior to duration-based progressive T-AEX for improving hemiparetic (HP) leg skeletal muscle contractile protein expression and reducing inflammatory markers to improve muscle function, fitness, and ambulation.

Specific Aims: 1) Determine whether skeletal muscle MHC isoform expression is altered and inflammatory mediators, TNF and markers of NFkB activation, present in the hemiparetic vastus lateralis muscle, compared the non-paretic leg and matched non-stroke control leg muscles, and related to muscle function, fitness, and gait performance. 2) Determine whether 6 months progressive T-AEX programs can attenuate this abnormal MHC profile and inflammatory mediators to improve muscle structure and function.

Methods: At baseline, bilateral vastus lateralis (VL) biopsies are obtained from chronically disabled, stroke participants with hemiparetic gait to examine the HP and non-P thigh skeletal muscles for alterations in MHC isoforms, key muscle contractile protein, and evidence for inflammation (TNFa) and NFkB activation. Participants are randomized to 6 months of progressive velocity-based or duration-based T-AEX training. Repeat VL muscle biopsies are obtained in the HP limb only after exercise interventions to assess whether 6-month exercise rehabilitation can restore MHC profile and attenuate activation of inflammatory pathways. Expression of the specific MHC isoforms, TNF, and NFKB marker expression (mRNA and protein) are investigated in these muscle tissues by real-time real time (RT)- polymerase chain reaction (PCR), Western Blot analysis, and immunohistochemistry. The investigators will explore relationships between T-AEX mediated changes in MHC expression and inflammatory activation in skeletal muscle after stroke to improve muscle strength, muscle performance, fitness and activity levels, activities of daily living (ADL) performance, and gait deficit severity.

Anticipated Results and Relevance: The cross-sectional baseline data will provide the first systematic study of a substantial cohort of stroke patients to define the relationship between altered structural and contractile protein expression to both muscle physiology and clinical measures of muscle performance, metabolic fitness, and rehabilitation mobility outcomes. HP VL muscle will be directly compared to the non-paretic (NP) limb muscle within-subjects and to non-stroke reference controls, in order to better understand the scope of skeletal muscle inflammatory and metabolic abnormalities in the stroke population. The intervention results will allow us to determine the specific requirements of treadmill training that are optimal and crucial to produce the exercise-mediated adaptations in hemiparetic skeletal muscle that lead to improved rehabilitation outcomes to reduce the disability of chronic stroke.

Study Design

• Study Type: Interventional
• Actual Enrollment: 99 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Velocity based treadmill training 6 month of progressive treadmill walking with treadmill speed gradually progressed to meet the training heart rate goals for moderate intensity aerobic exercise, when hemiparetic gait velocity can no longer be safely progressed, incline is added to achieve the heart rate training goals.	Other: Velocity based treadmill training; 6 month of progressive treadmill walking with a safety harness and hand rail support to prevent falls. Treadmill speed is gradually progressed to meet the training heart rate goals for moderate aerobic exercise, when hemiparetic gait velocity can no longer be progressed, incline is added to achieve heart rate training goals. Progression is also based on participant's tolerance, abilities and safety.
Experimental: Duration based treadmill training 6 month of progressive treadmill walking with duration is gradually progressed to meet the endurance goals for low aerobic intensity exercise, gait velocity and incline do not progress.	Other: Duration based treadmill training; 6 month of progressive treadmill walking with a safety harness and hand rail support to prevent falls. Treadmill duration is gradually progressed to meet the endurance goals for low aerobic intensity exercise, gait velocity and incline do not progress. Progression is based on participant's tolerance, abilities and safety.

Outcome Measures

Primary Outcome Measures

1. Cardiovascular Fitness (VO2 Peak) [Baseline to 6 month]

   Cardiovascular fitness is measured by collecting the expired gases during a progressive graded treadmill test.

2. Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a [Baseline to 6 month]

   Skeletal muscle punch biopsies are obtained from the bilateral (paretic and non-paretic) vastus lateralis thigh muscle, at baseline and after 6 month interventions. Homogenized muscle messenger ribonucleic acid (mRNA) for myosin heavy chain isoforms are analyzed by real time polymerase chain reaction as fluorescent units with normalization to an acidic ribosomal protein, a housekeeping gene.

Secondary Outcome Measures

1. 30 Foot Walk Time (Sec) [baseline to 6 month]

   Participants are instructed to walk fast as comfortable on a straight pathway on the floor demarcated by cones. They may use their usual canes, walkers, and orthotics while they walk. The walks are timed, the value is the mean of three trials with an interval rest between each trial.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Chronic stroke (>6 months after initial stroke)

• Age 40-80

• Stable neurologic deficits

• Able to walk with an assistive device

• Language skills to understand the training program safely

Exclusion Criteria:

• No anticoagulation or medical conditions that preclude exercise.

• No dementias or depression

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Maryland Health Care System, Baltimore	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Charlene Hafer-Macko, MD, VA Maryland Health Care System, Baltimore

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for more information about this study: Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise
• Click here for more information about this study: Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise
• Click here for more information about this study: Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise

Publications

• Ivey FM, Hafer-Macko CE, Macko RF. Exercise training for cardiometabolic adaptation after stroke. J Cardiopulm Rehabil Prev. 2008 Jan-Feb;28(1):2-11. doi: 10.1097/01.HCR.0000311501.57022.a8. Review.
• Ivey FM, Hafer-Macko CE, Macko RF. Task-oriented treadmill exercise training in chronic hemiparetic stroke. J Rehabil Res Dev. 2008;45(2):249-59. Review.
• Ivey FM, Ryan AS, Hafer-Macko CE, Macko RF. Improved cerebral vasomotor reactivity after exercise training in hemiparetic stroke survivors. Stroke. 2011 Jul;42(7):1994-2000. doi: 10.1161/STROKEAHA.110.607879. Epub 2011 Jun 2.
• McKenzie MJ, Yu S, Macko RF, McLenithan JC, Hafer-Macko CE. Human genome comparison of paretic and nonparetic vastus lateralis muscle in patients with hemiparetic stroke. J Rehabil Res Dev. 2008;45(2):273-81.
• Prior SJ, McKenzie MJ, Joseph LJ, Ivey FM, Macko RF, Hafer-Macko CE, Ryan AS. Reduced skeletal muscle capillarization and glucose intolerance. Microcirculation. 2009 Apr;16(3):203-12. doi: 10.1080/10739680802502423. Epub 2009 Feb 16.
• Ryan AS, Ivey FM, Prior S, Li G, Hafer-Macko C. Skeletal muscle hypertrophy and muscle myostatin reduction after resistive training in stroke survivors. Stroke. 2011 Feb;42(2):416-20. doi: 10.1161/STROKEAHA.110.602441. Epub 2010 Dec 16.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00387712
• Other Study ID Numbers: B3834-R
• First Posted: Oct 13, 2006
• Last Update Posted: Sep 14, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by VA Office of Research and Development: exercise; inflammation; motor performance; skeletal muscle; chronic stroke survivors; treadmill exercise
• Additional relevant MeSH terms: Stroke; Inflammation

Study Results

Participant Flow

Recruitment Details	Veterans with chronic hemiparetic stroke (latency > 6 months) were recruited from the Baltimore VA and University of Maryland Neurology and Primary care clinics, as well as through Institutional Review Board approved flyers and ads.
Pre-assignment Detail	Reasons for participant exclusion were not meeting eligibility criteria, screen failures (ischemia on stress test or serious lab abnormalities) new medical conditions, study time requirements, return to work, lost to follow-up, lack of transportation.

Arm/Group Title	Velocity Based Treadmill Training	Duration Based Treadmill Training
Arm/Group Description	6-month treadmill exercise progressed on speed based on individual participant's tolerance, abilities and safety.	6-month treadmill exercise at self-selected speed progressed only on training duration.
Period Title: Overall Study
STARTED	47	52
COMPLETED	18	16
NOT COMPLETED	29	36

Baseline Characteristics

Arm/Group Title	Velocity Based Treadmill Training	Duration Based Treadmill Training	Total
Arm/Group Description	6-month treadmill exercise progressed only gait speed and then incline to achieve moderate aerobic exercise heart rate training goal.	6-month treadmill exercise at self-selected speed progressed only on training duration.	Total of all reporting groups
Overall Participants	47	52	99
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 14.9%	10 19.2%	17 17.2%
>=65 years	40 85.1%	42 80.8%	82 82.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (3)	64 (6)	63 (3)
Sex: Female, Male (Count of Participants)
Female	11 23.4%	14 26.9%	25 25.3%
Male	36 76.6%	38 73.1%	74 74.7%
Race/Ethnicity, Customized (Count of Participants)
African American	28 59.6%	32 61.5%	60 60.6%
Latino	3 6.4%	1 1.9%	4 4%
Caucasian	16 34%	19 36.5%	35 35.4%
Region of Enrollment (participants) [Number]
United States	47 100%	52 100%	99 100%

Outcome Measures

1. Primary Outcome

Title	Cardiovascular Fitness (VO2 Peak)
Description	Cardiovascular fitness is measured by collecting the expired gases during a progressive graded treadmill test.
Time Frame	Baseline to 6 month

Outcome Measure Data

Analysis Population Description

Randomized study design with Intent to treat group by time analysis of change in peak cardiovascular fitness levels between the higher-intensity treadmill training group and the lower intensity training group across baseline to 6 months post-exercise time points.

Arm/Group Title	Velocity Based Treadmill Training	Duration Based Treadmill Training
Arm/Group Description	6-month treadmill exercise progressed only gait speed and then incline to achieve moderate aerobic exercise heart rate training goal.	6-month treadmill exercise at self-selected speed progressed only on training duration.
Measure Participants	18	16
baseline	15.9 (1.7)	16.6 (1.2)
6 month	21.3 (1.6)	17.5 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Velocity Based Treadmill Training, Duration Based Treadmill Training
	Comments	Power Calculation: It was calculated that 29 subjects should be randomized to 2 groups to achieve a significant time by group interaction for peak fitness for high-velocity or low velocity duration training groups, assuming a power of 90 percent power and alpha = 0.01, two-tailed analyses. Primary analyses is a group by time analysis of variance in peak fitness levels between the higher-intensity and lower intensity training groups across baseline to 6 months post-exercise time points.
	Type of Statistical Test	Other
	Comments	Analysis of variance between groups across time is the primary analyses.
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Group (high velocity training vs. low velocity duration training) by time (baseline to post-6 months) for the primary outcome category (peak fitness) using repeated measures analysis of variance. No adjustment for multiple comparisons is needed.
	Method	ANOVA
	Comments	No other adjustments such as degrees of freedom was necessary.

2. Primary Outcome

Title	Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a
Description	Skeletal muscle punch biopsies are obtained from the bilateral (paretic and non-paretic) vastus lateralis thigh muscle, at baseline and after 6 month interventions. Homogenized muscle messenger ribonucleic acid (mRNA) for myosin heavy chain isoforms are analyzed by real time polymerase chain reaction as fluorescent units with normalization to an acidic ribosomal protein, a housekeeping gene.
Time Frame	Baseline to 6 month

Outcome Measure Data

Analysis Population Description

The difference muscle and participant number reflects those that participated and completed pre/post biopsies. Paretic thigh muscle, at baseline and after 6 month interventions, are analyzed for myosin heavy chain proportions. Values were the mean of duplicates run on polymerase chain reaction were normalized to a ribosomal protein mRNA.

Arm/Group Title	Velocity Based Treadmill Training	Duration Based Treadmill Training
Arm/Group Description	6-month treadmill exercise progressed only gait speed and then incline to achieve moderate aerobic exercise heart rate training goal.	6-month treadmill exercise at self-selected speed progressed only on training duration.
Measure Participants	7	6
Baseline	3.35 (0.87)	3.64 (0.74)
6 months	4.40 (0.71)	5.44 (0.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Velocity Based Treadmill Training, Duration Based Treadmill Training
	Comments	Power Calculation: It was calculated that 22 participants should be randomized to 2 groups to achieve a significant time by group interaction for myosin heavy chain isoforms for high-velocity or low velocity duration training groups, assuming a power of 90 percent power and alpha = 0.01, two-tailed analyses.
	Type of Statistical Test	Other
	Comments	Primary analyses is a group by time analysis of variance in myosin heavy chain levels levels between the higher-intensity and lower intensity training groups across baseline to 6 months post-exercise time points.
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	30 Foot Walk Time (Sec)
Description	Participants are instructed to walk fast as comfortable on a straight pathway on the floor demarcated by cones. They may use their usual canes, walkers, and orthotics while they walk. The walks are timed, the value is the mean of three trials with an interval rest between each trial.
Time Frame	baseline to 6 month

Outcome Measure Data

Analysis Population Description

Randomized study design with intent to treat group by time analysis of change in floor walking time between the higher-intensity treadmill training group and the lower intensity training group across baseline to 6 months post-exercise time points.

Arm/Group Title	Velocity Based Treadmill Training	Duration Based Treadmill Training
Arm/Group Description	6-month treadmill exercise progressed only gait speed and then incline to achieve moderate aerobic exercise heart rate training goal.	6-month treadmill exercise at self-selected speed progressed only on training duration.
Measure Participants	18	16
baseline	15.4 (2.1)	17.2 (2.2)
6 month	13.8 (2.1)	15.9 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Velocity Based Treadmill Training, Duration Based Treadmill Training
	Comments	Primary analyses is a group by time analysis of variance in 30 foot walk time (sec) between the higher-intensity and lower intensity training groups across baseline to 6 months post-exercise time points.
	Type of Statistical Test	Other
	Comments	Analysis of variance between groups across time is the primary analyses.
Statistical Test of Hypothesis	p-Value	0.81
	Comments	Group (high velocity training vs. low velocity duration training) by time (baseline to post-6 months) for the secondary outcome category (30 ft walk time - fastest comfortable gait) using repeated measures analysis of variance.
	Method	ANOVA
	Comments	No other adjustments such as degrees of freedom was necessary.

Adverse Events

Time Frame	Adverse event data was collected from time of consent signing to completion of the final post test (consent process, screening, baseline testing, 6 month intervention, and post testing. This represents about 7 to 8 months of participant study involvement.
Adverse Event Reporting Description	Adverse and serious adverse event are the definition are similar to those used in clinical trials.gov.
Arm/Group Title	Velocity Based Treadmill Training		Duration Based Treadmill Training
Arm/Group Description	6-month treadmill exercise progressed only gait speed and then incline to achieve moderate aerobic exercise heart rate training goal.		6-month treadmill exercise at self-selected speed progressed only on training duration.
All Cause Mortality
	Velocity Based Treadmill Training		Duration Based Treadmill Training
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/52 (0%)
Serious Adverse Events
	Velocity Based Treadmill Training		Duration Based Treadmill Training
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/47 (2.1%)		2/52 (3.8%)
Infections and infestations
UTI	0/47 (0%)	0	1/52 (1.9%)	1
Nervous system disorders
recurrent stroke	0/47 (0%)	0	1/52 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
pneumonia	1/47 (2.1%)	1	0/52 (0%)	0
Other (Not Including Serious) Adverse Events
	Velocity Based Treadmill Training		Duration Based Treadmill Training
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/47 (17%)		9/52 (17.3%)
Cardiac disorders
Abnormal cardiac screening treadmill test	2/47 (4.3%)	2	3/52 (5.8%)	3
Metabolism and nutrition disorders
Screening lab abnormality	3/47 (6.4%)	3	2/52 (3.8%)	2
Musculoskeletal and connective tissue disorders
abnormal screening imaging	3/47 (6.4%)	3	4/52 (7.7%)	4

Limitations/Caveats

Limitations of the study, such as early termination, led to smaller numbers of participants analyzed and technical problems with measurement and participant inability to attend testing or complete testing led to unreliable and missing data.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.