Role for Exercise in Risk Factor Modification after Stroke: New Models of Task-Oriented Training...
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Transcript of Role for Exercise in Risk Factor Modification after Stroke: New Models of Task-Oriented Training...
Role for Exercise in Risk Factor Modification after Stroke:
New Models of Task-Oriented Training
Richard Macko, M.D. Baltimore Veterans Affairs Medical Center
Director, Exercise & Robotics Rehabilitation Center of Excellence
Geriatric Education Series
November 30, 2006
No disclosures
Cardiovascular Disease Risk Factor
Profiles after a Stroke Recurrent stroke in 10-14% / 1st year, 28-33% / 5 years Coronary artery disease in 30–70% Cardiovascular co-morbidities in 75% Insulin resistance in 80%
Current Health Care Model Medical management is the cornerstone of contemporary
tertiary stroke prevention.
Medical Rx not enough…..
Atherothrombotic risks remain high !
What is the role of exercise in current stroke rehabilitation care models?
Current Care - Emphasizes early rehabilitation to improve ADL function; finished <3-6 months
Persistent neurological deficits in 75% Inactivity & age-related declines propagate disability, and
worsen CVD risk by promoting insulin resistance.
No evidence-based recommendations to promote regular exercise in chronic stroke.
Percent of stroke patients with plateau in motor recovery while receiving conventional rehabilitation.
Jorgenson et al. Arch Phys Med Rehabil 1995
N=804
95% get no
better after 11 weeks with
routine care.
What may be deficient in conventional rehabilitation models ?
1. Is exercise intensity enough to improve fitness and modify stroke and cardiovascular risk profiles ?
Typical 51 minute physical therapy session < 3 minutes of low aerobic intensity exercise.
McKay Lyons et al. 2002
2. Is motor learning optimized ? 20-30 minutes practice to produce short-term cortical motor adaptations
in normal adults. Classen 1998
3.Do we exploit full time window for neuroplasticity ? Motor control can be modified by training many years post-stroke, and this
is associated with brain plasticity. Liepert 2001 Luft 2004
Multi-System Model of Neurological DisabilityTask-Oriented Exercise Interventions Target
Cardiovascular Fitness
HEALTH &FUNCTION OUTCOMES
Neuroplasticity &
Motor Learning
Skeletal Muscle
- Outline -
I. What is biologic rationale for Exercise after stroke: Peripheral Mechanisms - Cardiovascular deconditioning & muscle
abnormalities worsen disability & risk factor profiles by promoting insulin resistance.
Central Neural Mechanisms – task repetition to promote plasticity.
II. What is the evidence that exercise can improve fitness & mobility function in chronic stroke:
Mechanisms of modifying metabolism - insulin sensitivity Mediating brain plasticity in subcortical networks
How unfit are stroke patients?
We tested fitness levels & energy demands of gait in 156 patients
Mean Age 67 + 8 years Mean 3 years post-stroke Hemiparetic gait, not
wheelchair bound.
Lab Measures of Fitness & Efficiency of Gait
Peak Effort TM Exercise Test Test cardiopulmonary response to
peak exertion. V02 peak: Best measure of fitness.
Economy of Gait Purpose - estimate energy demands
of hemiparetic gait 75% of floor-walking pace Rate of V02 calculated at steady state
oxygen kinetics Macko et al. 1997
Dobrovolny et al 2003
Stroke patients havediminished fitness reserve
Low Peak Fitness Levels V02 Peak = 13.8 + 4 ml/kg/min;
50 % below sedentary controls.
Poor Economy of Gait: Mean rate V02 9.7 + 2 ml/kg/min
0
5
10
15
20
25
30 economy (ml/kg/min)
V02 peak
ControlsStroke
75%27%
*V02
A
D
L
Relationship of Peak VO2 to Thigh Lean Tissue Mass (DXA)
r=0.64, P<0.001
CT Scan of the Mid-Thigh Cross-Sectional Muscle Area in a Stroke Patient
Muscle area is 20% lower in hemiparetic thigh (N=30, P<.001).
Ryan et al. APMR 2002
Changes in Paretic Leg
Skeletal Muscle Phenotype after Stroke
Myosin Heavy Chain Profile
Increased fast MHC isoforms in paretic leg quadriceps. Paretic leg = *67% Unaffected leg = 51% (*p<.001, N=15)
Fast MHC Insulin Resistance, Metabolic Syndrome
FastIIAIIX
I (Slow)
_______Rat_____
Tib Ant Soleus
Patient #1__
Paretic NP
__Patient #2___
NP Paretic
DeDeyne et al. Muscle & Nerve 2004
Components of Metabolic Syndrome
Metabolic Syndrome
3. Hypertension& Micro-Albuminuria
1. Insulin Resistance•Glucose intolerance•Hyper-insulinemia•Type 2 diabetes
2. Dyslipidemia Triglycerides HDL-C
4. Central ObesityWC-M 102cm
WC-F 88 cm
“Lipo-toxicity”
Report – NHLBI / AHA Circ 2004
Metabolic syndrome is more prevalent than T2DM and is an independent risk factor for stroke
Najarian et al Framingham Offspring Study Arch Int Med 2006
What is Metabolic Syndrome?
In non-stroke populations…..
“Central Obesity” is the classical
phenotype.
Where’s the fat?
Relative fat content 25% higher in hemiparetic thigh (N=30, P<.001).
Ryan et al. 2002
Intra-muscular area fat - Linked to Insulin Resistance
paretic non-paretic
Low Density CT Scan Mid-Thigh Intra-Muscular Area Fat
What unique body composition abnormalities
propagate insulin resistance after stroke ?
Molecular mechanisms underlying insulin resistance & muscle atrophy after stroke
TNF = atrophy & insulin resistance
Exercise lowers muscle TNF to increase muscle mass & exercise improves insulin sensitivity (CHF, elderly).
Skeletal Muscle TNF expression
0
2
4
6
8
10
P NP C
TNF
/ 36B
4 co
ncen
trat
ion
Ivey, Hafer-Macko et al 2005
Hafer-Macko Stroke 2005
Factors Related to Pathogenesis of Metabolic Syndrome
Obesity &
Lipotoxicity
Advancing age
Insulin Resistance
& Inflammation
Physical Inactivit
y
NHLBI / AHA Circ 2004
- Clinical Significance - Insulin Resistance after HP Stroke
35% Diabetic by Med Hx.
46% IGT or T2DM by Fasting or OGTT
19% Normal
IGT & T2DM predict a 2-3 fold increased risk for recurrent stroke Dutch TIA Trial – Stroke 2006
81% of HP stroke patients (N=216) have Impaired Glucose Tolerance (IGT) or T2 Diabetes Mellitus (T2DM)
Ivey, Macko et al. Cerebrovasc Dis 2006
A change in our understanding of Risk Factors
2006 Can lifestyle modification including exercise improve cardiovascular-metabolic
health ?
Can lifestyle modification reduce development of T2DM in high risk non-stroke populations?
Lifestyle Modification vs. metformin to prevent T2DM in adults at high risk: #1 Exercise & Wt loss #2 Metformin #3 placebo
AGE REDUCTION IN INCIDENCE OF T2DM Lifestyle vs. Placebo Metformin vs. Placebo
45-59 59% * 31%>60 71% * 11%
Diabetes Prevention Program shows lifestyle modification more effective than metformin to reduce progression to
T2DM in high-risk non-stroke populations.
*p<0.01 vs. placebo & metformin
The Diabetes Prevention Program NEJM 2002
Biological rationale for regular exercise after stroke:
Physical deconditioning threatens capacity of stroke patients to meet high energy demands of hemiparetic walking.
Inflammatory-metabolic abnormalities in muscle propagate disability and increase cardiovascular and stroke risk by promoting insulin resistance.
Insulin resistance is an epidemic after stroke, and may be modifiable by exercise training.
Treadmill aerobic exercise as a model to promote locomotor re-learning
Harris-Love et al. 2001
Harris-Love et al 2004
•50% improved inter-limb stance:swing ratio. •30% improved symmetry of insole forces. •40% less cycle-cycle variability.•Improved timing quadriceps activation.
Randomized Clinical Trial: TM Training in Chronic HP Stroke
Purpose: Determine whether 6 months TM aerobic training (T-AEX at 60% HRR) improves CV fitness, insulin-glucose response during OGTT & walking function by neuroplastic mechanisms in chronic stroke patients, compared to controls.
Reference Controls: 45 minutes supervised stretching exercises 5 minutes low aerobic intensity walking. Time-matched exposure to health professionals
Subjects:Clinical & Demographic Features
TM (25) Control (20) Males : Females 18 : 7 14 : 6 Age (yrs) 65 + 10 63 + 8 Hemisphere (R : L) 10 : 13 9 : 11 Time since stroke (M) 32 + 30 42 + 65 Assistive Device
– None 9 ( 37.5% ) 5 ( 24% )– Single point cane 9 ( 37.5% ) 12 ( 57% )
– Quad cane/walker 6 ( 25% ) 4 ( 19% )
Floor Walking Speed 1.4 + 0.7 1.5 + 0.7(range MPH) ( 0.25 - 2.7 ) ( 0.19 - 2.6)
Does T-AEX improve cardiovascular fitness and efficiency (economy) of hemiparetic gait ?
RESULTS: Effects of TM-AEX on Fitness
and Economy of Gait after Stroke
0
2
4
6
8
10
12
14
16
18
V02 Peak Economy of Gait
T-AEX (N=25)Controls (N=20)
%
V02 *
*
*P<0.02
NS
Relationship between progression in
training velocity & fitness gains
Only those that trained faster increased metabolic fitness.
Progressing training velocity predicts increased V02 peak (r=0.43, P=0.017)
Does T-AEX training improve
ambulatory function in
chronic hemiparesis ?
What is the evidence for exercise-mediated brain plasticity?
Effects of T-AEX (N=25) vs. control exercises (N=20) on 6-minute walk
Macko et al Stroke - In Press
-10
-5
0
5
10
15
20
25
30
35
40
Baseline 3 months 6 months
Testing Timepoint
% C
han
ge i
n 6
min
Walk T - AEX
R - CONTROL* †
**P<0.005
0
10
20
30
40
50
60
70
80
90
100
Baseline 3 months 6 months
R-Control
T - AEX
Effect of T-AEX on Walking Impairment Questionnaire-Distance
WIQ
Dis
tan
ce S
core
*
*† P<0.005
Evidence exercise-mediated brain plasticity fMRI Paretic Knee Movement
Fulcrum and harness minimizes ballisitic head movement.
BOLD fMRI shows similar patterns of brain activation with knee movement, as occur in walking. Luft et al. 2004
Johns Hopkins University
fMRI Paretic knee movement: Increased brain activation (post – pre) with TM training
Activity dependent brain plasticity in chronic Activity dependent brain plasticity in chronic strokestroke
TM N=14 Control N=14, Group x time, p < 0,05 Luft Neurosci Abstracts 2005
Red Nucleus Cerebellum Ipsi-lesional Cortex
Cortico-Rubro-Cerebellar Pathways
Dentate
Olivary nuclei
Spinal cord
Cortex
Red nucleus
RN fires during gait
Lesion= Hemiparesis in rodents
RN discharges during gait adaptation in higher mammals
Does T-AEX modify cardiovascular - metabolic
risk factor profiles ?
0
10
20
30
40
50
60
70
80
90
100
Baseline 3 months 6 months
R-Control
T - AEX
Effect of T-AEX on Walking Impairment Questionnaire-Distance
WIQ
Dis
tan
ce S
core
*
*† P<0.005
Evidence exercise-mediated brain plasticity fMRI Paretic Knee Movement
Fulcrum and harness minimizes ballisitic head movement.
BOLD fMRI shows similar patterns of brain activation with knee movement, as occur in walking. Luft et al. 2004
Johns Hopkins University
fMRI Paretic knee movement: Increased brain activation (post – pre) with TM training
Activity dependent brain plasticity in chronic Activity dependent brain plasticity in chronic strokestroke
TM N=14 Control N=14, Group x time, p < 0,05 Luft Neurosci Abstracts 2005
Red Nucleus Cerebellum Ipsi-lesional Cortex
Cortico-Rubro-Cerebellar Pathways
Dentate
Olivary nuclei
Spinal cord
Cortex
Red nucleus
RN fires during gait
Lesion= Hemiparesis in rodents
RN discharges during gait adaptation in higher mammals
Does T-AEX modify cardiovascular - metabolic
risk factor profiles ?
0
100
200
300
400
500
600
700
800
900
1000
0 30 60 90 120 150 180Time (minutes)
Baseline
Post Intervention*
Baseline and Post-Intervention Mean Insulin Curves (T-AEX group)
T-AEX reduces insulin
area 25%
*P<0.01 ANOVA
TM (N=25) vs. Controls (N=20)
Effects of TM training on glucose response (OGTT)
50
100
150
200
0 30 60 90 120 150 180
Time (minutes)
Glu
co
se (m
g/d
l)
Baseline
Post Intervention
TM training does not alter glucose response across entire TM group .
TM- reduces glucose area 14%
*P<0.05 for patients with baseline impaired glucose tolerance TM (N=12)
50
100
150
200
0 30 60 90 120 150 180
Time (minutes)
Glu
co
se (m
g/d
l)
Baseline
Post Intervention
ALL IGT only
*
Control Participant Treadmill Participant
Pre- post-
P NP C NP P TM
Restoration of slow myosin heavy chain (MHC)
More sensitive to action of insulin
Potential Mechanism forImproved insulin sensitivity
Leg muscle Myosin Heavy Chain electrophoresis
SUMMARY: TM Training in Chronic Stroke
1. Improves fitness
2. Improves insulin & glucose metabolism
3. Improves walking function
4. Locomotor gains linked to brain plasticity in cortical – subcortical networks.
Public Health Implications: I. Exercise can improve mobility function even years
after stroke.
II. Brain plasticity in subcortical rubro-cerebellar networks may underlie functional motor benefits.
III. Cardiovascular fitness & metabolic health are modifiable risk factors improved by exercise.
Larger studies needed to determine whether exercise can prevent recurrent stroke and progression to
diabetes.
October 23-24, 2006
National Academy Science Adequacy of Evidence for Adequacy of Evidence for
Physical Activity Guidelines Physical Activity Guidelines DevelopmentDevelopment
October 26, 2006
DHSS – plans to develop: Evidence-based guidelines for Physical Activity for all Americans, including aging and disability conditions.
NEWS
Thanks to Collaborators
Baltimore VA Gerontology/Neurology/Nursing & University Maryland : Andrew P. Goldberg, MD Kathleen Michael, PhD, RN Alice Ryan, PhD Charlene Hafer-Macko, MD Fred Ivey, PhD Marianne Shaghnessy, CRNP, PhD John Sorkin, MD, PhD Leslie I Katzel, MD, PhD Steven Kittner, MD M.PH Susan Kopunek, RN Barbara Resnick, RN, PhD Shawnna Patterson, MD, PhD
University of Maryland Physical Therapy & Rehabilitation Science: Larry Forrester, Ph.D. Jill Whitall, Ph.D. Mary Rodgers, Ph.D. ,P.T. Sandra McCombe-Waller, Ph.D., PT
Tubingen, Germany: Andi Luft, M.D.Johns Hopkins: D. Hanley, M.D.