Randomization to Treadmill Training Improves Physical and Metabolic Health in Association With Declines in Oxidative Stress in Stroke.

OBJECTIVE: To investigate the effect of aerobic exercise vs control (stretching/balance) on inflammatory and oxidative stress biomarkers in stroke survivors and whether these changes are associated with improvements in physical and metabolic health. DESIGN: Randomized controlled trial. SETTING: The general communities of Baltimore, Maryland, and Atlanta, Georgia. PARTICIPANTS: Two hundred forty-six older (>50 years), chronic (>6 months) survivors of stroke (N=246) with hemiparetic gait were recruited, with 51 completing pre-intervention testing and 39 completing postintervention testing. Participants were required to have completed all conventional physical therapy and be capable of walking 3 minutes on a treadmill (N=246). INTERVENTION: Participants completed 6 months of 2 times/wk stretching or balance (ST; n=19) or 3 times/wk aerobic treadmill rehabilitation (TM; n=20;). MAIN OUTCOME MEASURE(S): Peak oxygen uptake rate (V̇o2peak), 6-minute walking distance (6MWD), fasting plasma glucose, insulin, oxidative stress, and inflammatory biomarkers were assessed pre- and postintervention. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. RESULTS: Physical function and metabolic health parameters tended to improve after TM but not ST (ST vs TM: V̇o2peak: -9% vs 24%, P<.01; 6MWD: 1% vs 15%, P=.05; insulin: -1% vs -31%, P=.05; HOMA-IR: -3% vs -29%, P=.06). Plasma concentrations of nitrotyrosine, protein carbonyls, and oxidized low-density lipoprotein (oxLDL) tended to decrease from pre-intervention concentrations in response to TM compared to ST (ST vs TM: nitrotyrosine: 2% vs -28%, P=.01; protein carbonyls: -4% vs -34%, P=.08; oxLDL: -3% vs -32%, P<.01). Changes in circulating concentrations of C-reactive protein, protein carbonyls, and oxLDL were negatively associated with changes in V̇o2peak and 6MWD (r's=-0.40 to -0.76) and positively associated with fasting plasma insulin and HOMA-IR (r's=0.52-0.81, Ps<.01). CONCLUSIONS: Six months of TM tends to be associated with increased functional capacity and reduced oxidative stress in chronic stroke survivors. Our findings identify potentially modifiable systemic markers of inflammation and oxidative stress important to stroke rehabilitation and provide potential targets for novel therapeutics in future studies.

CD31+ Circulating Angiogenic Cell Number and Subtypes are Reduced in Individuals with Chronic Stroke.

BACKGROUND AND PURPOSE: Reduced number and function of CD31+ circulating angiogenic cells (CACs) may explain vascular complications associated with the chronic phase stroke. The purpose of this study was to quantify CD31+ CAC paracrine function, total number and number of various subtypes of CD31+ CACs in individuals with chronic stroke compared with controls. METHODS: Peripheral blood mononuclear cells were isolated from chronic stroke participants and controls. CD31+ cells were quantified by flow cytometry, as was co-expression of CD31 in combination with CD14, CD3, CD11b, or CD34. Immunomagnetically selected CD31+ cells were cultured, and conditioned medium was used in a capillary-like network assay. RESULTS: Significantly lower levels of CD31+ CACs were found in stroke participants compared with controls (-24%; P=0.04). Additionally, CD31+/CD14+, CD31+/CD11b+ and CD31+/CD3+ cells were significantly lower in the chronic stroke group compared with controls (-45%, P=0.02; -47%, P=0.02 and -32%, P=0.03, respectively). There was no group effect on CD31+ CAC conditioned media-mediated capillary-like network formation. CONCLUSION: CD31+ CACs and subtypes may serve as potential therapeutic targets in chronic stroke recovery.

Dietary and Serum Omega-6/Omega-3 Fatty Acids Are Associated with Physical and Metabolic Function in Stroke Survivors.

The purpose of this study was to quantify habitual dietary and systemic omega-6 and omega-3 fatty acids and their ratios and to determine their relationship with physical and metabolic function in a cohort of chronic adult stroke survivors. Twenty-five older chronic stroke survivors (age: 63 ± 8 years; BMI: 31 ± 7 kg/m2; mean ± SD) were assessed for fitness (VO2peak), gait speed (GS), 3 m timed up and go (TUG), and six-minute walk distance (6MWD). Plasma lipid and glucose profiles were measured, and HOMA-IR calculated. Dietary (5-day food records) and serum (mass spectrometry) omega-6/omega-3 profiles were assessed. Participants were severely deconditioned (VO2peak: 19 ± 4 mL/kg/min; GS: 0.88 ± 0.28 m/s; TUG: 12.6 ± 5.9 s; 6MWD: 295 ± 121 m) and at elevated metabolic risk (HOMA-IR: 6.3 ± 4.5). The dietary intake ratio of omega-6/omega-3 fatty acids averaged 12.6 ± 7.1 and the serum concentration ratio was 1.21 ± 0.37, which were correlated (r = 0.88, p < 0.01). Higher dietary intake and serum concentrations of omega-6/omega-3 fatty acids were associated with lower 6MWD and higher HOMA-IR, while a higher serum omega-6/omega-3 concentration index was associated with lower VO2peak (p's < 0.05). These preliminary data suggest that both dietary omega-6 and omega-3 fatty acids (quantitated as their intake ratio) and the serum concentration ratio of omega-6/omega-3 may be important indices of physical dysfunction and insulin resistance in chronic stroke survivors.

Metabolomics of Aerobic Exercise in Chronic Stroke Survivors: A Pilot Study.

BACKGROUND: Understanding the metabolic response to exercise may aid in optimizing stroke management. Therefore, the purpose of this pilot study was to evaluate plasma metabolomic profiles in chronic stroke survivors following aerobic exercise training. METHODS: Participants (age: 62 ± 1 years, body mass index: 31 ± 1 kg/m2, mean ± standard error of the mean) were randomized to 6 months of treadmill exercise (N = 17) or whole-body stretching (N = 8) with preintervention and postintervention measurement of aerobic capacity (VO2peak). Linear models for microarray data expression analysis was performed to determine metabolic changes over time, and Mummichog was used for pathway enrichment analysis following analysis of plasma samples by high-performance liquid chromatography coupled to ultrahigh resolution mass spectrometry. RESULTS: VO2peak change was greater following exercise than stretching (18.9% versus -.2%; P < .01). Pathway enrichment analysis of differentially expressed metabolites results showed significant enrichment in 4 pathways following treadmill exercise, 3 of which (heparan-, chondroitin-, keratan-sulfate degradation) involved connective tissue metabolism and the fourth involve lipid signaling (linoleate metabolism). More pathways were altered in pre and post comparisons of stretching, including branched-chain amino acid, tryptophan, tyrosine, and urea cycle, which could indicate loss of lean body mass. CONCLUSIONS: These preliminary data show different metabolic changes due to treadmill training and stretching in chronic stroke survivors and suggest that in addition to improved aerobic capacity, weight-bearing activity, like walking, could protect against loss of lean body mass. Future studies are needed to examine the relationship between changes in metabolomic profiles to reductions in cardiometabolic risk after treadmill rehabilitation.

Brain-derived neurotrophic factor, epigenetics in stroke skeletal muscle, and exercise training.

OBJECTIVE: (1) To compare paretic (P) vs nonparetic (NP) skeletal muscle brain-derived neurotrophic factor (BDNF) and the effects of resistive training (RT) on systemic and skeletal muscle BDNF mRNA expression in stroke; and (2) to compare the DNA methylation profile for BDNF and BDNFAS (BDNF antisense RNA) between P and NP muscle and the effects of aerobic exercise training (AEX) on DNA methylation in stroke. METHODS: In this longitudinal investigation, participants (50-76 years) with chronic stroke underwent a fasting blood draw, a 12-week (3×/week) RT intervention (n = 16), and repeated bilateral vastus lateralis muscle tissue biopsies (n = 10) with BDNF expression determined by RT-PCR. Five stroke survivors completed 6 months of AEX (3×/week) and had bilateral muscle biopsies. DNA methylation status in gene BDNF and BDNFAS was assessed by Illumina 450k methylation array. RESULTS: P muscle had ∼45% lower BDNF mRNA expression than NP muscle (6.79 ± 1.30 vs 10.52 ± 2.06 arbitrary units [AU], p < 0.05), and P muscle exhibited differential methylation status in the DNA sequences of BDNF (3 CpG [5'-C-phosphate-G-3'] sites, p = 0.016-0.044) and BDNFAS (1 CpG site, p = 0.016) compared to NP. Plasma BDNF and muscle BDNF messenger RNA (mRNA) expression did not significantly change after RT. BDNFAS DNA methylation increased after AEX in P relative to NP muscle (p = 0.017). CONCLUSIONS: This is the first evidence that stroke hemiparesis reduces BDNF skeletal muscle expression, with our findings identifying methylation alterations on the DNA sequence of BDNF and BDNFAS gene. Preliminary results further indicate that AEX increases methylation in BDNFAS gene, which presumably could regulate the expression of BDNF.

Type 2 diabetes and older age contribute to elevated plasma microparticle concentrations independent of chronic stroke.

NEW FINDINGS: What is the central question of this study? What is the effect of chronic stroke on circulating microparticle populations, accounting for potential effects of age and type 2 diabetes? What is the main finding and its importance? Elevated concentrations of CD31+ /CD42b- and CD62E+ microparticles appear to be driven by type 2 diabetes but not chronic stroke and are associated with fasting glucose and triglyceride levels. Older age results in elevations in CD62E+ and CD34+ microparticle concentrations. These microparticles have been proposed as potential targets for diagnosing, treating and identifying the clinical progression and complications of type 2 diabetes. ABSTRACT: The elevated circulating concentration of endothelial microparticles (MPs) may provide an index of the extent and nature of cellular damage in chronic stroke. The purpose of this study was to determine the circulating concentrations of CD31+ /CD42b- , CD62E+ and CD34+ MPs in chronic stroke subjects, focusing on the effects of chronic stroke by comparison with both older adults without a history of stroke but with type 2 diabetes mellitus (T2DM) and older and young healthy controls. Plasma from three groups of sedentary older (50-75 years) men and women (chronic stroke, T2DM or older healthy) as well as a group of younger (18-39 years) healthy controls was isolated from fasting blood, and CD31+ /CD42b- , CD62E+ and CD34+ MPs were quantified using flow cytometry (n = 17/group). Concentrations of CD31+ /CD42b- and CD62E+ MPs were higher in the T2DM group (P < 0.05), but not chronic stroke, compared to older and younger healthy adults. CD62E+ MP and CD34+ MP concentrations were elevated in the older compared to younger adults (P < 0.05 for both). Sub-analyses excluding chronic stroke subjects who were also diagnosed with diabetes [stroke (diabetes- )] revealed lower CD31+ /CD42b- (P < 0.05) and CD62E+ (P = 0.08) MPs in the stroke (diabetes- ) group compared to the T2DM group. CD31+ /CD42b- MP and CD62E+ MP concentrations were each associated with fasting glucose levels and CD31+ /CD42b- MPs also were associated with triglyceride levels. As MPs have been proposed as potential targets for diagnosing, treating and identifying the clinical progression of T2DM, our study provides further support for the use of CD31+ /CD42b- and CD62E+ MPs in the clinical progression of T2DM and associated vascular complications.

Validating accelerometry as a measure of physical activity and energy expenditure in chronic stroke.

BACKGROUND: Accelerometers can objectively measure steps taken per day in individuals without gait deficits, but accelerometers also have the ability to estimate frequency, intensity, and duration of physical activity. However, thresholds to distinguish varying levels of activity intensity using the Actical brand accelerometer are standardized only for the general population and may underestimate intensity in stroke. OBJECTIVE: To derive Actical activity count thresholds specific to stroke disability for use in more accurately gauging time spent at differing activity levels. METHODS: Men (n = 18) and women (n = 10) with chronic hemiparetic gait (4 ± 2 years latency, 43% Caucasian, 56% African-American, ages of 47-83 years, BMI 19-48 kg/m2) participated in the study. Actical accelerometers were placed on the non-paretic hip to obtain accelerometry counts during eight activities of varying intensity: (1) watching TV; (2) seated stretching; (3) standing stretching; (4) floor sweeping; (5) stepping in place; (6) over-ground walking; (7) lower speed treadmill walking (1.0 mph at 4% incline); and (8) higher speed treadmill walking (2.0 mph at 4% incline). Simultaneous portable monitoring (Cosmed K4b2) enabled quantification of energy cost for each activity in metabolic equivalents (METs, or oxygen consumption in multiples of resting level). Measurements were obtained for 10 min of standard rest and 5 min during each of the eight activities. RESULTS: Regression analysis yielded the following new stroke-specific Actical minimum thresholds: 125 counts per minute (cpm) for sedentary/light activity, 667 cpm for light/moderate activity, and 1546 cpm for moderate/vigorous activity. CONCLUSION: Our revised cut points better reflect activity levels after stroke and suggest significantly lower thresholds relative to those observed for the general population of healthy individuals. We conclude that the standard, commonly applied Actical thresholds are inappropriate for this unique population.

Sarcopenia and Physical Function in Middle-Aged and Older Stroke Survivors.

OBJECTIVES: To determine the prevalence of sarcopenia in stroke survivors using different methodologies, and compare a subset of the stroke group to age-, sex-, and body mass index (BMI)-matched nonstroke control counterparts. DESIGN: Cohort study. SETTING: A Veterans Affairs medical center and a university hospital. PARTICIPANTS: Mild to moderately disabled participants >6 months after onset of stroke aged 40 to 84 years (N=190, 61% men, 57% African American; mean BMI ± SEM, 29±1kg/m2). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Dual-energy x-ray absorptiometry scans to assess appendicular lean mass (ALM). Rates of sarcopenia were determined using 4 established methods: (1) ALM/height2 (ALM/ht2); (2) European Working Group on Sarcopenia in Older Persons; (3) International Working Group on Sarcopenia; and (4) ALM/BMI. RESULTS: Sarcopenia prevalence in our stroke cohort ranged between 14% and 18%. The stroke survivor subset (n=38) matched one-for-one with control counterparts for race, sex, age ±4 years and BMI ±2.5kg/m2 had higher prevalence rates compared with their nonstroke counterparts (13.2% vs 5.3%, P<.0001). ALM/ht2 was related to 6-minute walking speed (r=.28, P<.01) and peak oxygen consumption (L/min: r=.58, P<.0001) for the stroke group. CONCLUSIONS: Stroke survivors show an elevated prevalence of sarcopenia when considering age, sex, and race compared with nonstroke individuals.

Strength Training for Skeletal Muscle Endurance after Stroke.

BACKGROUND AND PURPOSE: Initial studies support the use of strength training (ST) as a safe and effective intervention after stroke. Our previous work shows that relatively aggressive, higher intensity ST translates into large effect sizes for paretic and non-paretic leg muscle volume, myostatin expression, and maximum strength post-stroke. An unanswered question pertains to how our unique ST model for stroke impacts skeletal muscle endurance (SME). Thus, we now report on ST-induced adaptation in the ability to sustain isotonic muscle contraction. METHODS: Following screening and baseline testing, hemiparetic stroke participants were randomized to either ST or an attention-matched stretch control group (SC). Those in the ST group trained each leg individually to muscle failure (20 repetition sets, 3× per week for 3 months) on each of three pneumatic resistance machines (leg press, leg extension, and leg curl). Our primary outcome measure was SME, quantified as the number of submaximal weight leg press repetitions possible at a specified cadence. The secondary measures included one-repetition maximum strength, 6-minute walk distance (6MWD), 10-meter walk speeds, and peak aerobic capacity (VO2 peak). RESULTS: ST participants (N = 14) had significantly greater SME gains compared with SC participants (N = 16) in both the paretic (178% versus 12%, P < .01) and non-paretic legs (161% versus 12%, P < .01). These gains were accompanied by group differences for 6MWD (P < .05) and VO2 peak (P < .05). CONCLUSION: Our ST regimen had a large impact on the capacity to sustain submaximal muscle contraction, a metric that may carry more practical significance for stroke than the often reported measures of maximum strength.

Increased Energy Cost of Mobility in Chronic Stroke.

The purpose of this study was to compare the energy cost of completing mobility-related activities in chronic stroke to the estimated energy cost found in the compendium of physical activities, a resource that estimates and classifies energy cost of various human physical activities. Men (n=18) and women (n=10) with chronic hemiparetic gait (stroke latency: 4 ± 2 years, age: 60.4 ± 1.6 years, BMI: 31.5 ± 1.1 kg/m2) participated in the study. Portable energy cost monitoring (COSMED K4b2) was performed during five mobility activities of varying intensity to determine metabolic equivalents (METs, or oxygen consumption in multiples of resting level) for each activity. The METs achieved during the five activities were compared to the following compendium MET values for: 1) floor sweeping; 2) stepping in place; 3) over-ground walking; 4) lower speed treadmill walking (1.0 mph at 4% incline); and 5) higher speed treadmill walking (2.0 mph at 4% incline). Measurements were obtained for 10 min at rest and 5 minutes during each of the five activities. The energy cost of rest was only 85% of Compendium METS, while mobility-related activities were ~1.25-1.50 fold greater when measured in stroke vs. Compendium METS for all measures (P's<0.05), except floor sweeping, which was similar between groups. These data indicate that MET levels provided in the compendium are not applicable to chronic stroke survivors as they overestimate energy expenditure at rest and underestimate energy expenditure during physical activity, indicating poor efficiency in movement, thus elevating the oxygen cost of completing general daily activities.

Higher Treadmill Training Intensity to Address Functional Aerobic Impairment after Stroke.

BACKGROUND: Peak aerobic capacity (VO2 peak) is severely worsened after disabling stroke, having serious implications for function, metabolism, and ongoing cardiovascular risk. Work from our laboratory and others has previously shown that modest improvements in VO2 peak are possible in stroke participants with aerobic exercise training. The purpose of the current investigation was to test the extent to which greater enhancements in VO2 peak after stroke are possible using a treadmill protocol with far greater emphasis on intensity progression compared with a protocol without such emphasis. METHODS: Using a randomized design, we compared stroke survivors engaged in higher intensity treadmill training (HI-TM, 80% heart rate reserve [HRR]) with those undergoing lower intensity treadmill training (LO-TM, 50% HRR). Measured outcomes were change in VO2 peak, 6-minute walk distance (6MWD), 30-ft walk times (30WT), and 48-hour step counts (48SC). LO-TM participants trained for a longer period of time per session in an effort to approximately match workload/caloric expenditure. Participants were randomized with stratification according to age and baseline walking capacity. RESULTS: HI-TM participants (n = 18) had significantly greater gains in VO2 peak (+34%) than LO-TM participants (n = 16; +5%) across the 6-month intervention period (P = .001, group × time interaction). Conversely, there was no statistical difference between groups in the changes observed for 6MWD, 30WT, or 48SC. CONCLUSIONS: HI-TM is far more effective than LO-TM for improving VO2 peak after disabling stroke. The magnitude of relative improvement for HI-TM was double compared with previous reports from our laboratory with probable clinical significance for this population.

Reduced Resting Metabolic Rate in Adults with Hemiparetic Chronic Stroke.

OBJECTIVE: Resting metabolic rate (RMR) is the component of energy expenditure that explains the largest proportion of total daily energy requirements. Since RMR is determined largely by fat-free mass and a low RMR predicts weight gain in healthy adults, identifying the role of muscle atrophy following stroke on RMR may help identify ways to mitigate the development of obesity post-stroke. METHODS: Thirty-nine stroke survivors with chronic hemiparesis (mean ± SEM: age: 61 ± 1 years, latency from stroke: 107 ± 40 months, BMI: 31 ± 3 kg/m2) underwent DXA scans for measurement of body composition, including total, paretic, and non-paretic leg lean mass and fasted, 30-min indirect calorimetry for measurement of RMR. RESULT: Predicted RMR was calculated by the Mifflin-St Jeor equation, which considers weight, height, and age for both men and women. RMR was 14% lower than predicted (1438 ± 45 vs. 1669 ± 38 kcals/24 hrs; P<0.01). Total (r=0.73, P<0.01), paretic (r=0.72, P<0.01) and non-paretic (r=0.67, P<0.01) leg lean mass predicted RMR. CONCLUSION: These data indicate that muscle atrophy post stroke may lead to a reduced RMR. This substantiates the need to attenuate the loss of lean mass after a stroke to prevent declines in RMR and possible weight gain common post-stroke.

Impact of serum nutritional status on physical function in african american and caucasian stroke survivors.

Background. The purpose of this study is to compare serum nutritional profiles in chronic stroke survivors to a representative sample of US Adults (NHANESIII) and determine whether these serum markers differed by race and impact physical function in stroke. Methods. Fasting serum samples were collected for analysis of lipids, uric acid, and albumin in 145 African American (AA) and 111 Caucasian (C) stroke survivors (age: 60 ± 1 years [mean ± SEM]). A six-minute walk was performed in a subset of stroke survivors (N = 134). Results. Triglycerides were higher and HDL-cholesterol and albumin lower in C than AA women stroke survivors (Ps < 0.05). Uric acid was lower in C than AA stroke survivors (P < 0.05). Compared to NHANESIII, HDL-cholesterol, albumin, and hemoglobin generally were lower (Ps < 0.05) and lipids were more favorable in stroke (Ps < 0.01). Uric acid was related to six-minute walk performance among a subset of stroke survivors (P < 0.05). Conclusion. In stroke, racial differences exist with regard to serum nutritional risk, but these differences are similar to that observed in the general population. Regardless of race, nutritional risk appears elevated above that of the general population with regard to many of the serum markers. As a modifiable biomarker, uric acid should be monitored closely as it may provide insight into the functional risk of stroke survivors.

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/m(2) underwent multiple thigh CT scans, total body scan by DXA (dual-energy X-ray absorptiometry), peak oxygen intake (VO(2peak)) 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.

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.

Impaired leg vasodilatory function after stroke: adaptations with treadmill exercise training.

BACKGROUND AND PURPOSE: Resting and reactive hyperemic leg blood flows are significantly reduced in the paretic compared with the nonparetic limb after disabling stroke. Our objective was to compare the effects of regular treadmill exercise (TM) with an active control regimen of supervised stretching (CONTROL) on peripheral hemodynamic function. METHODS: This intervention study used a randomized, controlled design, in which participants were randomized with stratification according to age and baseline walking capacity to ensure approximate balance between the 2 groups. Fifty-three chronic, ischemic stroke participants (29 TM and 24 CONTROL) with mild to moderate hemiparetic gait completed bilateral measurements of lower leg resting and reactive hyperemic blood flow using venous occlusion strain gauge plethysmography before and after the 6-month intervention period. Participants also underwent testing to track changes in peak aerobic fitness across time. RESULTS: Resting and reactive hyperemic blood flows were significantly reduced in the paretic compared with the nonparetic limb at baseline before any intervention (-28% and -34%, respectively, P<0.01). TM increased both resting and reactive hyperemic blood flow in the paretic limb by 25% compared with decreases in CONTROL (P<0.001, between groups). Similarly, nonparetic leg blood flow was significantly improved with TM compared with controls (P<0.001). Peak aerobic fitness improved by 18% in TM and decreased by 4% in CONTROL (P<0.01, between groups), and there was a significant relationship between blood flow change and peak fitness change for the group as a whole (r=.30, P<0.05). CONCLUSIONS: Peripheral hemodynamic function improves with regular aerobic exercise training after disabling stroke.

Plasma adiponectin levels are associated with insulin sensitivity in stroke survivors.

OBJECTIVE: Adiponectin is an anti-inflammatory and insulin-sensitizing adipokine produced by adipose tissue. The purpose of this study was to determine the relationships between adiponectin and glucose metabolism in stroke survivors and to compare adiponectin levels between patients with stroke and nonstroke control subjects similar in age, sex, and body mass index. METHODS: In all, 52 stroke survivors (35 men, 17 women) and 33 nonstroke control subjects (22 men, 11 women) had plasma adiponectin levels measured by RIA, an oral glucose tolerance test, and a peak oxygen consumption-graded treadmill test. Insulin resistance (IR) and insulin sensitivity were assessed using the homeostasis model assessment for IR (HOMA-IR) and insulin sensitivity index (ISI(M)). RESULTS: Adiponectin levels were positively associated with age (r = 0.32, P < .05) and negatively associated with glucose homeostasis (fasting glucose: r = -0.42; insulin: r = -0.36; Glucose at (120 min): r = -0.39; HOMA-IR: r = -0.45; and ISI(M): r = 0.44, all P < .01) in stroke survivors. Adiponectin levels were significantly different among normal glucose-tolerant, impaired glucose-tolerant, and diabetic patients with stroke (11.1 +/- 0.99 v 9.56 +/- 0.99 v 5.75 +/- 1.55 ng/mL, P < .05). Adiponectin levels were 62% higher in patients with stroke than control subjects (9.29 +/- 0.62 v 5.80 +/- 0.40 ng/mL, P < .001) despite greater fasting insulin levels (81%) and 120-minute insulin (70%) in stroke survivors than control subjects (P < .05). HOMA-IR was 78% higher and ISI(M) was 81% lower in stroke survivors than control subjects (P < .05). CONCLUSIONS: Plasma adiponectin levels are associated with age and insulin sensitivity but not adiposity in stroke survivors. The paradoxical finding that the more IR stroke survivors had higher adiponectin levels than more insulin-sensitive control subjects suggests that perhaps anti-inflammatory cytokines increase to counter an inflamed and IR state in stroke survivors.

A proteomics analysis of the effects of chronic hemiparetic stroke on troponin T expression in human vastus lateralis.

Stroke disability is attributed to upper motor neuron deficits resulting from ischemic brain injury. We have developed proteome maps of the Vastus lateralis to examine the effects of ischemic brain injury on paretic skeletal muscle myofilament proteins. Proteomics analyses from seven hemiparetic stroke patients have detected a decrease of three troponin T isoforms in the paretic muscle suggesting that myosin-actin interactions may be attenuated. We propose that ischemic brain injury may prevent troponin T participation in complex formation thereby affecting the protein interactions associated with excitation-contraction coupling. We have also detected a novel skeletal troponin T isoform that has a C-terminal variation. Our data suggest that the decreased slow troponin T isoform pools in the paretic limb may contribute to the gait deficit after stroke. The complexity of the neurological deficit on Vastus lateralis is suggested by the multiple changes in proteins detected by our proteomics mapping.

Hemiparetic stroke alters vastus lateralis myosin heavy chain profiles between the paretic and nonparetic muscles.

Skeletal muscle phenotype alterations following hemiparetic stroke contribute to disabilities associated with stroke. The phenotypic response following stroke is undefined. This investigation examined the myosin heavy chain (MHC) composition of the vastus lateralis (VL) of stroke survivors in paretic (P) and nonparetic (NP) muscle. Protein obtained from VL of 10 stroke survivors was isolated and purified, and MHC gel electrophoresis was performed. The MHC bands were quantified, and a paired sample two-tailed T test with significance set at p < or = 0.05 was performed. MHC I expression was significantly less in P versus NP VL (.93 vs. 1.00 arbitrary units [AU]). Significantly more IIx MHC was found in the P versus NP VL (1.33 vs. 1.0). No significant differences in type IIa MHC (1.07 P vs. 1.00 NP) were found. These changes in MHC composition suggest an alteration in muscle function due to stroke or the altered activity patterns of muscle following stroke.

Reduced skeletal muscle capillarization and glucose intolerance.

OBJECTIVE: Reduced capillarization in hemiparetic skeletal muscle of chronic stroke patients can limit insulin, glucose, and oxygen supply to muscle, thereby contributing to impaired glucose metabolism and cardiovascular deconditioning. We hypothesized that compared to sedentary controls, stroke subjects have reduced skeletal muscle capillarization that is associated with glucose intolerance and reduced peak oxygen consumption (Vo(2peak)). METHODS: Twelve chronic stroke subjects (ages, 62.1+/-2.8 years), and matched sedentary controls with impaired (n=12) or normal (n=12) glucose tolerance underwent oral glucose tolerance tests, exercise tests, and vastus lateralis biopsies. RESULTS: Stroke subjects had lower capillarization in hemiparetic muscle than in nonparetic muscle and normal glucose tolerant controls ( approximately 22 and approximately 28%, respectively; P<0.05) and had similar bilateral capillarization, compared to controls with impaired glucose tolerance. Capillary density in hemiparetic muscle inversely correlated with 120-minute glucose (r=-0.70, P<0.01) and glucose area under the curve (r=-0.78, P<0.01). Vo(2peak) was approximately 40% lower in stroke subjects, compared to controls (P<0.001), but did not correlate with capillarization (P=n.s.). CONCLUSIONS: Hemiparetic muscle capillarization is reduced after stroke, and reduced capillarization is associated with glucose intolerance in stroke and control subjects. Interventions to increase skeletal muscle capillarization may prove beneficial for improving glucose metabolism in chronic stroke patients.