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Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00387712
First Posted: October 13, 2006
Last Update Posted: September 14, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
VA Office of Research and Development
October 12, 2006
October 13, 2006
February 21, 2017
September 14, 2017
September 14, 2017
October 2006
August 2012   (Final data collection date for primary outcome measure)
  • Cardiovascular Fitness (VO2 Peak) [ Time Frame: Baseline to 6 month ]
    Cardiovascular fitness is measured by collecting the expired gases during a progressive graded treadmill test.
  • Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a [ Time Frame: 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.
Modification of Skeletal muscle contractile protein expression.
Complete list of historical versions of study NCT00387712 on ClinicalTrials.gov Archive Site
30 Foot Walk Time (Sec) [ Time Frame: 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.
Reduction of inflammatory injury pathway markers in skeltal muscles
Not Provided
Not Provided
 
Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise
Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise
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.

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.

Interventional
Not Provided
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Stroke
  • Inflammation
  • 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.
  • 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.
  • 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.
    Intervention: Other: Velocity based treadmill training
  • 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.
    Intervention: Other: Duration based treadmill training

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
99
August 2014
August 2012   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
40 Years to 80 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00387712
B3834-R
Yes
Not Provided
Plan to Share IPD: Undecided
VA Office of Research and Development
VA Office of Research and Development
Not Provided
Principal Investigator: Charlene Hafer-Macko, MD VA Maryland Health Care System, Baltimore
VA Office of Research and Development
June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP