Charlene E. Hafer-Macko

Cardiovascular Health and Fitness After Stroke

Abstract Stroke patients have profound cardiovascular and muscular deconditioning, with metabolic fitness levels that are about half those found in age-matched sedentary controls. Physical deconditioning, along with elevated energy demands of hemiparetic gait, define a detrimental combination termed diminished physiological fitness reserve that can greatly limit that can greatly limit performance of activities of daily living. The physiological features that underlie worsening metabolic fitness in the chronic phase of stroke include gross muscular atrophy, altered muscle molecular phenotype, increased intramuscular area fat, elevated tissue inflammatory markers, and diminished peripheral blood flow dynamics. Epidemiological evidence further suggests that the reduced cardiovascular fitness and secondary biological changes in muscle may propagate components of the metabolic syndrome, conferring added morbidity and mortality risk. This article reviews some of the consequences of poor fitness in chronic stroke and the potential biological underpinnings that support a rationale for more aggressive approaches to exercise therapy in this population.

Skeletal muscle changes after hemiparetic stroke and potential beneficial effects of exercise intervention strategies

Stroke is the leading cause of disability in the United States. New evidence reveals significant structural and metabolic changes in skeletal muscle after stroke. Muscle alterations include gross atrophy and shift to fast myosin heavy chain in the hemiparetic (contralateral) leg muscle; both are related to gait deficit severity. The underlying molecular mechanisms of this atrophy and muscle phenotype shift are not known. Inflammatory markers are also present in contralateral leg muscle after stroke. Individuals with stroke have a high prevalence of insulin resistance and diabetes. Skeletal muscle is a major site for insulin-glucose metabolism. Increasing evidence suggests that inflammatory pathway activation and oxidative injury could lead to wasting, altered function, and impaired insulin action in skeletal muscle. The health benefits of exercise in disabled populations have now been recognized. Aerobic exercise improves fitness, strength, and ambulatory performance in subjects with chronic stroke. Therapeutic exercise may modify or reverse skeletal muscle abnormalities.

Treadmill Aerobic Training Improves Glucose Tolerance and Indices of Insulin Sensitivity in Disabled Stroke Survivors A Preliminary Report

Background and Purpose— Insulin resistance and glucose intolerance are highly prevalent after stroke, contributing to worsening cardiovascular disease risk and a predisposition to recurrent stroke. Treadmill exercise training (T-AEX) increases aerobic capacity (Vo2 peak) in chronic stroke patients, suggesting intensity levels that may be adequate to improve glucose metabolism. We compared the effects of a progressive T-AEX intervention to an attention-matched stretching intervention (CONTROL) on glucose tolerance and indices of insulin sensitivity in stroke survivors. Methods— Participants had hemiparetic gait after remote (>6 months) ischemic stroke. They were randomized to 6-month T-AEX or a duration matched reference CONTROL program of supervised stretching exercises. Main outcome measures were glucose and insulin responses during a 3-hour oral glucose tolerance test (OGTT). Results— Forty-six subjects (T-AEX=26, CONTROL=20) completed OGTT testing before and after the interventions. T-AEX increased Vo2 peak (+15% versus −3% &Dgr;, P<0.01) compared with CONTROL. There were significant reductions in fasting insulin (−23% versus +9% &Dgr;, P<0.05) and the total integrated 3-hour insulin response (−24% versus +3% &Dgr;, P<0.01) in T-AEX compared with CONTROL. In patients with abnormal glucose tolerance at baseline, T-AEX resulted in a significant 14% decrease in 3-hour glucose response (n=12, P<0.05). Fifty-eight percent of T-AEX participants with abnormal baseline OGTT (7 of 12) improved glucose tolerance status at 2 hours compared with <10% (1 of 11) of impaired CONTROLS (P<0.05). Conclusions— These preliminary findings suggest that progressive aerobic exercise can reduce insulin resistance and prevent diabetes in hemiparetic stroke survivors. Larger clinical trials are needed to definitively establish the use of structured exercise training for stimulating metabolic improvement poststroke.

Exercise rehabilitation after stroke

SummaryStroke is a leading cause of disability that results not only in persistent neurological deficits, but also profound physical deconditioning that propagates disability and worsens cardiovascular risk. The potential for exercise-mediated adaptations to improve function, fitness, and cardiovascular health after stroke has been underestimated: it represents an emerging arena in neurotherapeutics. To define the health rationale for cardiovascular (aerobic) exercise, we first outline the impact of debilitating secondary biological changes in muscle and body composition on fitness and metabolic health after stroke. We provide an overview of evidence-based advances in exercise therapeutics, with a focus on task-oriented models that combine a progressive aerobic conditioning stimulus with motor learning to improve multiple physiological domains that determine longitudinal outcomes after stroke. Although progress in development of safe and effective exercise strategies is advancing, fundamental questions regarding dose intensity, prescription to optimize central and peripheral neuromuscular adaptations, and the public health value of exercise in secondary stroke prevention remain unanswered. Key issues steering future research in exercise neurotherapeutics are discussed within the context of initiatives to facilitate translation to community-based studies, requisite for dissemination.

Skeletal Muscle Hypertrophy and Muscle Myostatin Reduction After Resistive Training in Stroke Survivors

Background and Purpose— Stroke survivors experience disproportionate muscle atrophy and other detrimental tissue composition changes on the paretic side. The purpose was to determine whether myostatin levels are higher in paretic vs nonparetic muscle and the effects of resistive training (RT) on paretic and nonparetic mid-thigh muscle composition and myostatin mRNA expression in stroke survivors. Methods— Fifteen stroke survivors (50–76 years) underwent bilateral multi-slice thigh CT scanning from the knee to the hip, bilateral vastus lateralis skeletal muscle tissue biopsies, a total body scan by dual-energy X-ray absorptiometry, and 1-repetition maximum strength test before and after a 12-week, (3 times/week) RT intervention. Results— Total body fat mass and fat-free mass did not change. Bilateral leg press and leg extension 1-repetition maximum strength increased 31% to 56% with RT (P<0.001). Paretic and nonparetic muscle area of the mid-thigh increased 13% (P<0.01) and 9% (P<0.05), respectively, after RT. Muscle attenuation of the mid-thigh increased 15% and 8% (both P<0.01) in the paretic and nonparetic thigh, respectively, representing reduced intramuscular fat. Muscle volume increased 14% (P<0.001) in the paretic thigh and 16% (P<0.05) in the nonparetic thigh after RT. Myostatin mRNA expression levels were 40% higher in the paretic than nonparetic muscle (P=0.001) at baseline and decreased 49% in the paretic muscle (P<0.005) and 27% in the nonparetic muscle (P=0.06) after RT. Conclusions— Progressive RT stimulates significant muscle hypertrophy and intramuscular fat reductions in disabled stroke survivors. The increased myostatin mRNA in the paretic thigh and reduction with RT imply an important regulatory role for myostatin after stroke.

Muscle molecular phenotype after stroke is associated with gait speed

The disability of patients after stroke is generally attributed to upper motor neuron defects, but secondary changes in paretic muscle may enhance the disability. We analyzed the molecular phenotype and metabolic profile of the paretic and nonparetic vastus lateralis (VL) and we measured the severity of gait deficit in 13 patients at least 6 months after ischemic stroke. The results showed a significant increase in the proportion of fast myosin heavy chain (MHC, 68 ± 14%) in the paretic compared to the nonparetic VL (50 ± 13%). The specific activity of citrate synthase and glyceraldehyde phosphodehydrogenase was not significantly different between the two sides. The proportion of fast MHC was inversely associated with severity of gait deficit indexed by self‐selected walking speed in the paretic leg, but not the nonparetic leg. Our findings demonstrate significant and potentially modifiable secondary biologic changes in hemiparetic muscle phenotype that may contribute to the disability of stroke. Muscle Nerve 30: 209–215, 2004

Improved Cerebral Vasomotor Reactivity After Exercise Training in Hemiparetic Stroke Survivors

Background and Purpose— Animal studies provide strong evidence that aerobic exercise training positively influences cerebral blood flow, but no human studies support the use of exercise for improving cerebral hemodynamics. This randomized study in stroke survivors assessed the effects of treadmill aerobic exercise training (TM) on cerebral blood flow parameters compared to a control intervention of nonaerobic stretching. Methods— Thirty-eight participants (19 in TM group and 19 in control group) with remote stroke (>6 months) and mild to moderate gait deficits completed middle cerebral artery blood flow velocity measurements by transcranial Doppler ultrasonography before and after a 6-month intervention period. Middle cerebral artery blood flow velocity was assessed bilaterally during normocapnia and hypercapnia (6% CO2). Cerebral vasomotor reactivity (cVMR) was calculated as percent change in middle cerebral artery blood flow velocity from normocapnia to hypercapnia (cVMR percent) and as an index correcting percent change for absolute increase in end tidal CO2 (cVMR index). Results— The TM group had significantly larger improvements than did controls for both ipsilesional and contralesional cVMR index (P⩽0.05) and contralesional cVMR percent (P⩽0.01). Statin users in the TM group (n=10) had higher baseline cVMR and lower training-induced cVMR change, indicating that cVMR change among those not using statins (n=9) primarily accounted for the between-group effects. There was a 19% increase in VO2 peak for the TM group compared to a 4% decrease in the control group (P<0.01), and peak fitness change correlated with cVMR change (r=0.55; P<0.05). Conclusions— Our data provide the first evidence to our knowledge of exercise-induced cVMR improvements in stroke survivors, implying a protective mechanism against recurrent stroke and other brain-related disorders. Statin use appears to regulate cVMR and the cVMR training response.

Elevated Tumor Necrosis Factor-α in Skeletal Muscle After Stroke

Background and Purpose— Tumor necrosis factor-&agr; (TNF-&agr;), an inflammatory cytokine negligibly expressed in normal muscle, is elevated in selected metabolic conditions characterized by muscle wasting and insulin resistance. Inflammation is fundamental to stroke pathogenesis. Stroke patients have gross muscular atrophy and high prevalence of diabetes and insulin resistance. Yet, no previous studies examined TNF-&agr; expression in hemiparetic skeletal muscle. This study investigates whether TNF-&agr; mRNA levels are elevated in paretic compared with nonparetic leg muscles of chronic ischemic stroke patients and age-matched controls. Method— Total RNA extracted from bilateral vastus lateralis muscle biopsies from n=20 hemiparetic stroke patients and n=9 healthy controls was reverse transcribed to cDNA, then TNF-&agr; transcripts were amplified by real-time quantitative polymerase chain reaction. TNF-&agr; mRNA concentrations were normalized against acidic ribosomal phosphoprotein, housekeeping gene. Results— TNF-&agr; mRNA levels were 2.8-fold higher in paretic compared with control leg muscle (6.28±1.86 versus 2.28±0.67; P<0.03) and 1.6-fold higher in nonparetic leg (3.71±1.02; P<0.11) compared with controls. There was a trend for higher TNF-&agr; mRNA in paretic compared with nonparetic leg. Conclusions— Findings demonstrate increased TNF-&agr; expression in paretic leg muscle, suggesting inflammatory pathways are accelerated in stroke muscle. Further studies are under way to determine whether intramuscular TNF-&agr; contributes to atrophy and metabolic abnormalities after stroke.

Atrophy and intramuscular fat in specific muscles of the thigh: associated weakness and hyperinsulinemia in stroke survivors.

Purpose. Sarcopenia and increased fat infiltration in muscle may play a role in the functional impairment and high risk for diabetes in stroke. Our purpose was to compare muscle volume and muscle attenuation across 6 muscles of the paretic and nonparetic thigh and examine the relationships between intramuscular fat and insulin resistance and between muscle volume and strength in stroke patients. Methods. Stroke participants (70; 39 men, 31 women) aged 40 to 84 years, BMI = 16 to 45 kg/m2 underwent multiple thigh CT scans, total body scan by DXA (dual-energy X-ray absorptiometry), peak oxygen intake (VO2peak) graded treadmill test, 6-minute walk, fasting blood draws, and isokinetic strength testing. Results. Muscle volume is 24% lower and subcutaneous fat volume is 5% higher in the paretic versus nonparetic thigh. Muscle attenuation (index of amount of fat infiltration in muscle) is 17% higher in the nonparetic midthigh than the paretic. The semitendinosis/semimembranosis, biceps femoris, sartorius, vastus (medialis/lateralis), and rectus femoris have lower (between 9% and 19%) muscle areas on the paretic than the nonparetic thigh. Muscle attenuation is 15% to 25% higher on the nonparetic than the paretic side for 5 of 6 muscles. The nonparetic midthigh muscle attenuation is negatively associated with insulin. Eccentric peak torque of the nonparetic leg and paretic leg are associated with the corresponding muscle volume. Conclusions. The skeletal muscle atrophy, increased fat around and within muscle, and ensuing muscular weakness observed in chronic stroke patients relates to diabetes risk and may impair functional mobility and independence.

Exercise training for cardiometabolic adaptation after stroke.

Patients with stroke are severely deconditioned, leading to metabolic abnormalities that significantly increase risk for myocardial infarction and recurrent stroke. This review characterizes the nature of the metabolic decline, the underlying causes, and the potential for progressive aerobic exercise to address metabolic impairment following disabling stroke. Although exercise training has previously been shown to improve peak aerobic capacity and sensorimotor function after stroke, establishing safe and effective exercise programs in this population presents unique challenges stemming from neurological deficit complexities and comorbid conditions. Thus, recommendations for application to practice are provided that include proper preexercise evaluation, guidelines for symptom-limited maximal effort exercise testing, as well as evidence-based suggestions for initiation and progression of an exercise program. Implementing regular, progressive exercise therapy is critical on the basis of the devastating impact of physical inactivity on overall metabolic heath. Prevalence of impaired or diabetic glucose metabolism may be as high as 80% in chronic stroke, predicting 2- and 3-fold increased risk for recurrent stroke, respectively. Tragically, nearly one third of patients with stroke experience recurrent stroke within 5 years, and comorbid cardiovascular conditions represent the leading cause of death in this population. Recent evidence showing the positive impact of exercise training on hyperinsulinemia and glucose tolerance in survivors of stroke is presented, given the central importance of these factors to overall cardiovascular risk. On the basis of these and other findings, structured exercise programs should be considered for all survivors of stroke.