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.

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.

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.

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.

Resistive Training and Molecular Regulators of Vascular-Metabolic Risk in Chronic Stroke.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC-1α) gene and Sirtuin-1 (SIRT-1) respond to physiological stimuli and regulate insulin resistance. Inflammatory markers tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and the soluble forms of intracellular adhesion molecule (sICAM-1) and vascular CAM-1 (sVCAM-1) are associated with increased risk of diabetes and coronary heart disease. Resistive training (RT) reduces hyperinsulinemia and improves insulin action in chronic stroke. Yet, the molecular mechanisms for this are unknown. This study will determine the effects of RT on skeletal muscle PGC-1α and SIRT-1 mRNA expression and inflammatory and vascular markers. METHODS: Stroke survivors (50-76 years) underwent a fasting blood draw for measurement of TNF-α, IL-6, CRP, serum amyloid A, sICAM-1, sVCAM-1, and bilateral vastus lateralis biopsies before and after RT. Participants were also assessed using bilateral multislice thigh computed tomography scans from the knee to the hip, a total body scan by dual-energy X-ray absorptiometry, and 1-repetition maximum strength testing. Subjects performed 2 sets of 3 lower extremity RT exercises 3 times per week for 12 weeks. RESULTS: Bilateral leg press and leg extension strength increased ~30-50% with RT (P < .001). Body weight, total body fat mass, and fat-free mass did not change. Thigh muscle area and volume increased in both legs (P < .05). Nonparetic muscle PGC-1α mRNA expression increased 14% (P < .05) after RT and SIRT-1 mRNA decreased 24% (P < .05) and 31% (P < .01) in paretic and nonparetic muscles. There were no significant changes in plasma inflammation with training. DISCUSSION: RT in chronic stroke induces changes in key skeletal muscle regulators of metabolism, without effecting circulating inflammation.

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.

Dynamic Balanced Reach: A Temporal and Spectral Analysis Across Increasing Performance Demands.

Standing balanced reach is a fundamental task involved in many activities of daily living that has not been well analyzed quantitatively to assess and characterize the multisegmental nature of the body's movements. We developed a dynamic balanced reach test (BRT) to analyze performance in this activity; in which a standing subject is required to maintain balance while reaching and pointing to a target disk moving across a large projection screen according to a sum-of-sines function. This tracking and balance task is made progressively more difficult by increasing the disk's overall excursion amplitude. Using kinematic and ground reaction force data from 32 young healthy subjects, we investigated how the motions of the tracking finger and whole-body center of mass (CoM) varied in response to the motion of the disk across five overall disk excursion amplitudes. Group representative performance statistics for the cohort revealed a monotonically increasing root mean squared (RMS) tracking error (RMSE) and RMS deviation (RMSD) between whole-body CoM (projected onto the ground plane) and the center of the base of support (BoS) with increasing amplitude (p < 0.03). Tracking and CoM response delays remained constant, however, at 0.5 s and 1.0 s, respectively. We also performed detailed spectral analyses of group-representative response data for each of the five overall excursion amplitudes. We derived empirical and analytical transfer functions between the motion of the disk and that of the tracking finger and CoM, computed tracking and CoM responses to a step input, and RMSE and RMSD as functions of disk frequency. We found that for frequencies less than 1.0 Hz, RMSE generally decreased, while RMSE normalized to disk motion amplitude generally increased. RMSD, on the other hand, decreased monotonically. These findings quantitatively characterize the amplitude- and frequency-dependent nature of young healthy tracking and balance in this task. The BRT is not subject to floor or ceiling effects, overcoming an important deficiency associated with most research and clinical instruments used to assess balance. This makes a comprehensive quantification of young healthy balance performance possible. The results of such analyses could be used in work space design and in fall-prevention instructional materials, for both the home and work place. Young healthy performance represents "exemplar" performance and can also be used as a reference against which to compare the performance of aging and other clinical populations at risk for falling.

Task-specific ankle robotics gait training after stroke: a randomized pilot study.

BACKGROUND: An unsettled question in the use of robotics for post-stroke gait rehabilitation is whether task-specific locomotor training is more effective than targeting individual joint impairments to improve walking function. The paretic ankle is implicated in gait instability and fall risk, but is difficult to therapeutically isolate and refractory to recovery. We hypothesize that in chronic stroke, treadmill-integrated ankle robotics training is more effective to improve gait function than robotics focused on paretic ankle impairments. FINDINGS: Participants with chronic hemiparetic gait were randomized to either six weeks of treadmill-integrated ankle robotics (n = 14) or dose-matched seated ankle robotics (n = 12) videogame training. Selected gait measures were collected at baseline, post-training, and six-week retention. Friedman, and Wilcoxon Sign Rank and Fisher's exact tests evaluated within and between group differences across time, respectively. Six weeks post-training, treadmill robotics proved more effective than seated robotics to increase walking velocity, paretic single support, paretic push-off impulse, and active dorsiflexion range of motion. Treadmill robotics durably improved gait dorsiflexion swing angle leading 6/7 initially requiring ankle braces to self-discarded them, while their unassisted paretic heel-first contacts increased from 44 % to 99.6 %, versus no change in assistive device usage (0/9) following seated robotics. CONCLUSIONS: Treadmill-integrated, but not seated ankle robotics training, durably improves gait biomechanics, reversing foot drop, restoring walking propulsion, and establishing safer foot landing in chronic stroke that may reduce reliance on assistive devices. These findings support a task-specific approach integrating adaptive ankle robotics with locomotor training to optimize mobility recovery. CLINICAL TRIAL IDENTIFIER: NCT01337960. https://clinicaltrials.gov/ct2/show/NCT01337960?term=NCT01337960&rank=1.

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.

Dorsiflexion Specific Ankle Robotics to Enhance Motor Learning After Stroke: A Preliminary Report.

Background: Robotics has emerged as a promising avenue for gait retraining of persons with chronic hemiparetic gait and footdrop, yet there is a gap regarding the biomechanical adaptations that occur with locomotor learning. We developed an ankle exoskeleton (AMBLE) enabling dorsiflexion assist-as-needed across gait cycle sub-events to train and study the biomechanics of motor learning stroke. This single-armed, non-controlled study investigates effects of nine hours (9 weeks × 2 sessions/week) locomotor task-specific ankle robotics training on gait biomechanics and functional mobility in persons with chronic hemiparetic gait and foot drop. Subjects include N = 16 participants (8 male, 8 female) age 53 ± 12 years with mean 11 ± 8 years since stroke. All baseline and post-training outcomes including optical motion capture for 3-D gait biomechanics are conducted during unassisted (no robot) over-ground walking conditions. Findings: Robotics training with AMBLE produced significant kinematic improvements in ankle peak dorsiflexion angular velocity (°/s, + 44 [49%], p < 0.05), heel-first foot strikes (%steps, + 14 [15%], p < 0.01) toe-off angle (°, + 83[162%], p < 0.05), and paretic knee flexion (°, + 20 [30%], p < 0.05). Improvements in gait temporal-spatial parameters include increased paretic step length (cm, + 12 [20%], p< 0.05), reduced paretic swing duration (%GC, -3[6%], p < 0.05), and trend toward improved step length symmetry (-16 [11%], p = 0.08). Functional improvements include 10-meter comfortable (m/s, + 13 [16%], p < 0.01) and fastest (m/s, + 13 [15%], p<0.01) walking velocities, 6-minute timed walk distance (m, + 16 [19%], p < 0.01) and Dynamic Gait Index scores (+15 [15%], p < 0.01). Subjects' perceived improvements surpassed the minimal clinically important difference on the Stroke Impact Scale (SIS) mobility subscale (+11 [19%], p < 0.05). Conclusions: AMBLE training improves paretic ankle neuromotor control, paretic knee flexion, and gait temporal-distance parameters during unassisted over-ground walking in persons with chronic stroke and foot drop. This locomotor learning indexed by an increase in volitional autonomous (non-robotic) control of paretic ankle across training translated to improvements in functional mobility outcomes. Larger randomized clinical trials are needed to investigate the effectiveness of task-specific ankle robotics, and precise training characteristics to durably improve gait, balance, and home and community-based functional mobility for persons with hemiparetic gait and foot drop. Clinical trial identifier: NCT04594837.

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.

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.

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.

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.

Vitamin K Intake in Chronic Stroke: Implications for Dietary Recommendations.

Previous research has identified a possible association between vitamin K intake and cardiometabolic disease. This could mean that the assessment of vitamin K intake is a meaningful tool when monitoring individuals with preexisting cardiovascular disease. Sixty chronic stroke survivors (men and women, body mass index (BMI) 30.36 ± 6.61 kg/m2, age 61.7 ± 7.2 years) completed food records which were analyzed for energy, macronutrient, micronutrient, and food group servings. Participants were divided into two groups: below vitamin K recommendation (BEL, n = 49) and met vitamin K recommendation (MET, n = 11). Energy and macronutrient intake did not differ between groups (all p > 0.127). Vegetable intake was higher in the MET group (p = 0.0001). Vitamin K intake was higher in the MET group (p = 0.0001). Calcium (p = 0.003), vitamin A (p = 0.007), and vitamin E (p = 0.005) intakes were higher in the MET group. There were no differences in sodium, potassium, vitamin D, vitamin C, and iron intakes between groups (all p > 0.212). In this sample of chronic stroke survivors, 82% reported consuming below the Dietary Reference Intake (DRI) for vitamin K. Given that the majority of this study population did not reach the DRI for vitamin K, it is advisable to promote the adequate intake of food rich in vitamin K. Further work is needed to determine the significance of low vitamin K intake in this population.

Insulin Resistance in Skeletal Muscle of Chronic Stroke.

A stroke can lead to reduced mobility affecting skeletal muscle mass and fatty infiltration which could lead to systemic insulin resistance, but this has not been examined and the mechanisms are currently unknown. The objective was to compare the effects of in vivo insulin on skeletal muscle glycogen synthase (GS) activity in paretic (P) and nonparetic (NP) skeletal muscle in chronic stroke, and to compare to nonstroke controls. Participants were mild to moderately disabled adults with chronic stroke (n = 30, 60 ± 8 years) and sedentary controls (n = 35, 62 ± 8 years). Insulin sensitivity (M) and bilateral GS activity were determined after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Stroke subjects had lower aerobic capacity than controls, but M was not significantly different. Insulin-stimulated activities of GS (independent, total, fractional), as well as absolute differences (insulin minus basal) and the percent change (insulin minus basal, relative to basal) in GS activities, were all significantly lower in P versus NP muscle. Basal GS fractional activity was 3-fold higher, and the increase in GS fractional activity during the clamp was 2-fold higher in control versus P and NP muscle. Visceral fat and intermuscular fat were associated with lower M. The effect of in vivo insulin to increase GS fractional activity was associated with M in control and P muscle. A reduction in insulin action on GS in paretic muscle likely contributes to skeletal muscle-specific insulin resistance in chronic stroke.

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.

Aerobic Exercise Recommendations to Optimize Best Practices in Care After Stroke: AEROBICS 2019 Update.

Most stroke survivors have very low levels of cardiovascular fitness, which limits mobility and leads to further physical deconditioning, increased sedentary behavior, and heightened risk of recurrent stroke. Although clinical guidelines recommend that aerobic exercise be a part of routine stroke rehabilitation, clinical uptake has been suboptimal. In 2013, an international group of stroke rehabilitation experts developed a user-friendly set of recommendations to guide screening and prescription-the Aerobic Exercise Recommendations to Optimize Best Practices in Care after Stroke (AEROBICS 2013). The objective of this project was to update AEROBICS 2013 using the highest quality of evidence currently available. The first step was to conduct a comprehensive review of literature from 2012 to 2018 related to aerobic exercise poststroke. A working group of the original consensus panel members drafted revisions based on synthesis. An iterative process was used to achieve agreement among all panel members. Final revisions included: (1) addition of 115 new references to replace or augment those in the original AEROBICS document, (2) rewording of the original recommendations and supporting material, and (3) addition of 2 new recommendations regarding prescription. The quality of evidence from which these recommendations were derived ranged from low to high. The AEROBICS 2019 Update should make it easier for clinicians to screen for, and prescribe, aerobic exercise in stroke rehabilitation. Clinical implementation will not only help to narrow the gap between evidence and practice but also reduce current variability and uncertainty regarding the role of aerobic exercise in recovery after 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.

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.