Geriatric Education Series November 30, 2006

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 No disclosures

Cardiovascular Disease Risk Factor Profiles after a Stroke

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Recurrent stroke in 10-14% / 1 st year, 28-33% / 5 years Coronary artery disease in 30 –70% Cardiovascular co-morbidities in 75% Insulin resistance in 80%

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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

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Persistent neurological deficits in 75%

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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.

N=804 95% get no better after 11 weeks with routine care.

Jorgenson et al. Arch Phys Med Rehabil 1995

What may be deficient in conventional rehabilitation models ?

1. Is exercise intensity enough to improve fitness and modify stroke and cardiovascular risk profiles ?

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Typical 51 minute physical therapy session < 3 minutes of low aerobic intensity exercise. McKay Lyons et al. 2002 2. Is motor learning optimized ?

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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 ?

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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 Disability Task-Oriented Exercise Interventions Target Neuroplasticity & Motor Learning HEALTH &FUNCTION OUTCOMES Cardiovascular Fitness Skeletal Muscle

- Outline -

I. What is biologic rationale for Exercise after stroke:

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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:

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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

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Mean Age 67 + 8 years

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Mean 3 years post-stroke

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Hemiparetic gait, not wheelchair bound.

Lab Measures of Fitness & Efficiency of Gait

Peak Effort TM Exercise Test

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Test cardiopulmonary response to peak exertion.

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V0 2 peak: Best measure of fitness. Economy of Gait

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Purpose - estimate energy demands of hemiparetic gait

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75% of floor-walking pace

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Rate of V0 2 calculated at steady state oxygen kinetics

Macko et al. 1997 Dobrovolny et al 2003

Stroke patients have diminished fitness reserve

Low Peak Fitness Levels

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V0 2 Peak = 13.8 + 4 ml/kg/min; 30 economy (ml/kg/min) 25

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50 % below sedentary controls. 20 Poor Economy of Gait :

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Mean rate V0 2 9.7 + 2 ml/kg/min V0 2 15 10 V02 peak

* 75% 27%

5 0 Stroke Controls A D L

Relationship of Peak VO

2

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 _______Rat_____ Tib Ant Soleus Patient #1__ Paretic NP __Patient #2___ NP Paretic Fast

IIA IIX

I (Slow) Increased fast MHC isoforms in paretic leg quadriceps. Paretic leg = *67% Unaffected leg = 51% Fast MHC

 (*p<.001, N=15)

Insulin Resistance, Metabolic Syndrome

DeDeyne et al. Muscle & Nerve 2004

Components of Metabolic Syndrome

1. Insulin Resistance

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Glucose intolerance

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Hyper-insulinemia

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Type 2 diabetes 2. Dyslipidemia

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Triglycerides

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HDL-C 3. Hypertension & Micro-Albuminuria Metabolic Syndrome

4. Central Obesity

WC-M



WC-F

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102cm 88 cm “Lipo-toxicity”

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 Report – NHLBI / AHA Circ 2004

What is Metabolic Syndrome?

Where’s the fat?

In non-stroke populations…..

“Central Obesity” is the classical phenotype.

What unique body composition abnormalities propagate insulin resistance after stroke ?

Low Density CT Scan Mid-Thigh Intra-Muscular Area Fat Relative fat content 25% higher in hemiparetic thigh (N=30, P<.001). Ryan et al. 2002 paretic non-paretic

 Intra-muscular area fat -

Linked to Insulin Resistance

Molecular mechanisms underlying insulin resistance & muscle atrophy after stroke TNF

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= atrophy & insulin resistance Exercise lowers muscle TNF

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to increase muscle mass & exercise improves insulin sensitivity (CHF, elderly).

Skeletal Muscle TNF expression

Ivey, Hafer-Macko et al 2005

4 2 0 10 8 6

P NP C Hafer-Macko Stroke 2005

Factors Related to Pathogenesis of Metabolic Syndrome

Obesity & Lipotoxicity

Insulin Resistance & Inflammation

Advancing age Physical Inactivity NHLBI / AHA Circ 2004

- Clinical Significance Insulin Resistance after HP Stroke 19% Normal 35% Diabetic by Med Hx.

81% of HP stroke patients (N=216) have Impaired Glucose Tolerance (IGT) or T2 Diabetes Mellitus (T2DM)

Ivey, Macko et al. Cerebrovasc Dis 2006

46% IGT or T2DM by Fasting or OGTT IGT & T2DM predict a 2-3 fold increased risk for recurrent stroke Dutch TIA Trial – Stroke 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?

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Lifestyle Modification vs. metformin to prevent T2DM in adults at high risk: #1 Exercise & Wt loss #2 Metformin #3 placebo AGE 45-59 >60 REDUCTION IN INCIDENCE OF T2DM Lifestyle vs. Placebo Metformin vs. Placebo 59% * 71% * *p<0.01 vs. placebo & metformin 31% 11% Diabetes Prevention Program shows lifestyle modification more effective than metformin to reduce progression to T2DM in high-risk non-stroke populations.

The Diabetes Prevention Program NEJM 2002

Biological rationale for regular exercise after stroke:

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Physical deconditioning threatens capacity of stroke patients to meet high energy demands of hemiparetic walking.

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Inflammatory-metabolic abnormalities in muscle propagate disability and increase cardiovascular and stroke risk by promoting insulin resistance.

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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

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50% improved inter-limb stance:swing ratio.

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30% improved symmetry of insole forces.

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40% less cycle-cycle variability.

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Improved timing quadriceps activation.

Harris-Love et al. 2001 Harris-Love et al 2004

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:

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45 minutes supervised stretching exercises 5 minutes low aerobic intensity walking.

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Time-matched exposure to health professionals

Subjects: Clinical & Demographic Features

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Males : Females

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Age (yrs)

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Hemisphere (R : L)

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Time since stroke (M)

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Assistive Device

– – –

None Single point cane Quad cane/walker TM (25) 18 : 7 65 + 10 10 : 13 32 + 30 9 ( 37.5% ) 9 ( 37.5% ) 6 ( 25% ) Control (20) 14 : 6 63 + 8 9 : 11 42 + 65 5 ( 24% ) 12 ( 57% ) 4 ( 19% )

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Floor Walking Speed (range MPH) 1.4 + 0.7

( 0.25 - 2.7 ) 1.5 + 0.7

( 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 * P<0.02

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% V02 18 16 14 12 10 8 6 4 2 0 * NS * T-AEX (N=25) Controls (N=20) V02 Peak Economy of Gait

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 40 35 30 5 0 -5 -10 25 20 15 10 T - A E X R - C O N T R O L Baseline 3 mo nths

* *

6 mo nths * † P<0.005

Testing Timepoint

Macko et al Stroke - In Press

Effect of T-AEX on Walking Impairment Questionnaire-Distance 100 90 80 70 60 50 40 30 20 10 0 R -C o ntro l T - A EX

* *† P<0.005

Baseline 3 months 6 months

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 Red Nucleus Cerebellum Ipsi-lesional Cortex Activity dependent brain plasticity in chronic stroke

TM N=14 Control N=14, Group x time, p < 0,05 Luft Neurosci Abstracts 2005

Cortico-Rubro-Cerebellar Pathways

Cortex Red nucleus Dentate Olivary nuclei Spinal cord 

RN fires during gait

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Lesion= Hemiparesis in rodents

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RN discharges during gait adaptation in higher mammals

Does T-AEX modify cardiovascular - metabolic risk factor profiles ?

Effect of T-AEX on Walking Impairment Questionnaire-Distance 100 90 80 70 60 50 40 30 20 10 0 R -C o ntro l T - A EX

* *† P<0.005

Baseline 3 months 6 months

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 Red Nucleus Cerebellum Ipsi-lesional Cortex Activity dependent brain plasticity in chronic stroke

TM N=14 Control N=14, Group x time, p < 0,05 Luft Neurosci Abstracts 2005

Cortico-Rubro-Cerebellar Pathways

Cortex Red nucleus Dentate Olivary nuclei Spinal cord 

RN fires during gait

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Lesion= Hemiparesis in rodents



RN discharges during gait adaptation in higher mammals

Does T-AEX modify cardiovascular - metabolic risk factor profiles ?

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)

200 150 100

Effects of TM training on glucose response (OGTT)

ALL

200

IGT only *

Baseline Post Intervention 150 Baseline Post Intervention 100 50 0 30 60 90 Time (minutes) 120 150 180 TM training does not alter glucose response across entire TM group .

50 0 30 150 180 60 90 Time (minutes) 120 TM- reduces glucose area 14%

*P<0.05 for patients with baseline impaired glucose tolerance TM (N=12)

Potential Mechanism for Improved insulin sensitivity

Leg muscle Myosin Heavy Chain electrophoresis 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

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.

NEWS

October 23-24, 2006 National Academy Science

Adequacy of Evidence for Physical Activity Guidelines Development

October 26, 2006 DHSS – plans to develop: Evidence-based guidelines for Physical Activity for all Americans, including aging and disability conditions.

Thanks to Collaborators

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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 John Sorkin, MD, PhD Marianne Shaghnessy, CRNP, PhD Leslie I Katzel, MD, PhD Steven Kittner, MD M.PH

Susan Kopunek, RN Barbara Resnick, RN, PhD Shawnna Patterson, MD, PhD

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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.