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.