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Exercise Induces Peripheral Muscle But Not Cardiac Adaptations After Stroke: A Randomized Controlled Pilot Trial

Open AccessPublished:January 04, 2016DOI:https://doi.org/10.1016/j.apmr.2015.12.018

      Abstract

      Objective

      To explore the physiological factors affecting exercise-induced changes in peak oxygen consumption and function poststroke.

      Design

      Single-center, single-blind, randomized controlled pilot trial.

      Setting

      Community stroke services.

      Participants

      Adults (N=40; age>50y; independent with/without stick) with stroke (diagnosed >6mo previously) were recruited from 117 eligible participants. Twenty participants were randomized to the intervention group and 20 to the control group. No dropouts or adverse events were reported.

      Interventions

      Intervention group: 19-week (3times/wk) progressive mixed (aerobic/strength/balance/flexibility) community group exercise program. Control group: Matched duration home stretching program.

      Main Outcome Measures

      (1) Pre- and postintervention: maximal cardiopulmonary exercise testing with noninvasive (bioreactance) cardiac output measurements; and (2) functional outcome measures: 6-minute walk test; timed Up and Go test, and Berg Balance Scale.

      Results

      Exercise improved peak oxygen consumption (18±5 to 21±5mL/(kg⋅min); P<.01) and peak arterial-venous oxygen difference (9.2±2.7 to 11.4±2.9mL of O2/100mL of blood; P<.01), but did not alter cardiac output (17.2±4 to 17.7±4.2L/min; P=.44) or cardiac power output (4.8±1.3 to 5.0±1.35W; P=.45). A significant relation existed between change in peak oxygen consumption and change in peak arterial-venous oxygen difference (r=.507; P<.05), but not with cardiac output. Change in peak oxygen consumption did not strongly correlate with change in function.

      Conclusions

      Exercise induced peripheral muscle, but not cardiac output, adaptations after stroke. Implications for stroke clinical care should be explored further in a broader cohort.

      Keywords

      List of abbreviations:

      6MWT (6-minute walk test), 10MWT (10-meter walk test), BBS (Berg Balance Scale), CRF (cardiorespiratory fitness), SLE (single limb exercise), TUG (timed Up and Go)
      An audio podcast accompanies this article.
      Cardiorespiratory fitness (CRF) levels are decreased after stroke,
      • Smith A.C.
      • Saunders D.H.
      • Mead G.
      Cardiorespiratory fitness after stroke: a systematic review.
      potentially leading to an increased risk of further cardiovascular disease.
      • Hackam D.G.
      • Spence D.
      Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study.
      The criterion standard measure of CRF is peak oxygen consumption, which is the product of the capacity of the cardiovascular system to supply oxygen (ie, cardiac output) and the capacity of skeletal muscles to use oxygen (ie, arterial-venous oxygen difference). In healthy individuals, peak oxygen consumption appears to be limited by the cardiovascular system.
      • Bassett D.R.
      • Howley E.T.
      Limiting factors for maximum oxygen uptake and determinants of endurance performance.
      The relation between peak oxygen consumption and oxygen supply and oxygen utilization has yet to be established poststroke. Two small cross-sectional studies have presented opposing views on the physiological basis of peak oxygen consumption poststroke. The first study
      • Tomczak C.R.
      • Jelani A.
      • Haennel R.G.
      • Haykowsky M.J.
      • Welsh R.
      • Manns P.J.
      Cardiac reserve and pulmonary gas exchange kinetics in patients with stroke.
      indicated that reduced peak oxygen consumption is secondary to a decline in peak and reserve cardiac output. The second, more recent study,
      • Jakovljevic D.G.
      • Moore S.A.
      • Tan L.-B.
      • Rochester L.
      • Ford G.A.
      • Trenell M.I.
      Discrepancy between cardiac and physical functional reserves in stroke.
      demonstrated that peak oxygen consumption and the ability of skeletal muscles to extract oxygen is reduced poststroke, but cardiac function and pumping capability are maintained.
      Investigating how exercise mediates central oxygen supply and peripheral oxygen utilization may lead to a greater understanding of peak oxygen consumption poststroke and how it can be improved. Stroke can lead to a number of negative peripheral skeletal muscle adaptations (eg, change in muscle fiber type and vasculature).
      • Billinger S.A.
      • Coughenour E.
      • Mackay-Lyons M.J.
      • Ivey F.M.
      Reduced cardiorespiratory fitness after stroke: biological consequences and exercise-induced adaptations.
      Central comorbidities such as heart disease and hypertension are also highly prevalent in this population.
      • Roth E.
      Heart disease in patients with stroke: incidence, impact, and implications for rehabilitation. Part I: Classification and prevalence.
      Exercise is a potential intervention capable of promoting both central and peripheral adaptations, and these changes may affect both function and CRF poststroke.
      This study aims to explore central and peripheral adaptations to exercise poststroke and the physiological mechanisms that are related to exercise-induced changes in peak oxygen consumption and function. Our hypotheses are that after stroke, (1) structured exercise will improve central oxygen supply and peripheral oxygen utilization; (2) exercise-induced change in peak oxygen consumption will be strongly associated with adaptations in both central oxygen supply and peripheral oxygen utilization; and (3) exercise-induced change in peak oxygen consumption and peripheral muscle oxygen utilization will be strongly associated with improvements in function.

      Methods

      Study design

      The study design was a single-center, single-blind, randomized controlled pilot trial. The trial was approved by the County Durham and Tees Valley Research and Ethics Committee. All participants gave informed written consent for the study. The study was performed in accordance with the ethical standards laid down in the 1975 Declaration of Helsinki and as revised in 2013. Primary outcomes for this study have been reported previously.
      • Moore S.A.
      • Hallsworth K.
      • Jakovljevic D.G.
      • et al.
      Effects of community exercise therapy on metabolic, brain, physical and cognitive function following stroke: a randomised controlled pilot trial.
      This article presents a subanalysis of the primary findings.

      Participants

      Eligibility criteria

      The inclusion criteria for the study were as follows: (1) age >50 years; (2) stroke diagnosed (>6mo previously) by a stroke specialist; (3) able to complete a 6-minute walk test (6MWT) with or without a stick; (4) living at home; (5) discharged from all conventional physiotherapy interventions; and (6) not already performing regular exercise (≥3times/wk, moderate intensity). The exclusion criteria were as follows: (1) the absolute and relative contraindications to exercise testing as stated by the American Heart Association
      • Fletcher G.
      • Balady G.
      • Amsterdam E.
      • et al.
      Exercise standards for testing and training: a statement for the healthcare professionals from the American Heart Association.
      ; (2) diabetes; (3) neurological disorders other than stroke; (4) pain on walking (visual analog scale score, >5); (5) inability to follow 2 stage commands; (6) cognitive impairment (Mini-Mental Scale Examination score, <24); and (7) untreated major depression.

      Setting

      Participants were recruited from community stroke services by National Institute for Health North East Stroke Local Research Network clinical trial officers, stroke health professionals, or advert.

      Exercise intervention

      The intervention was adapted from the Fitness and Mobility Exercise Program designed by Eng in 2006.
      • Eng J.
      • Dawson A.
      • Marigold D.
      • Pang M.
      Fitness and mobility exercise program: a community-based group exercise program for people living with stroke. Guidelines and manual.
      The intervention was a “mixed” exercise program consisting of functional exercises designed to improve flexibility, strength, aerobic capacity, and balance. The intervention was delivered using a previously described protocol.
      • Moore S.A.
      • Hallsworth K.
      • Jakovljevic D.G.
      • et al.
      Effects of community exercise therapy on metabolic, brain, physical and cognitive function following stroke: a randomised controlled pilot trial.
      In brief, classes were delivered in the community for 19 weeks by a fitness instructor and a physiotherapist (3times/wk, 45–60min). Participants wore a heart rate monitor,a and the intensity of the exercise was gradually increased, working within a heart rate zone determined using the Karvonen formula
      • Goldberg L.
      • Elliot D.L.
      • Kuehl K.S.
      Asessment of exercise intensity formulas by use of ventilatory threshold.
      (40%–50% of participant's maximum heart rate, with increasing increments of 10% every 4wk up to 70%–80%). Repetition and resistance were used to progress strength and balance exercises.

      Control group intervention

      The control group completed a matched duration home stretching program. Ten seated stretches were repeated 3 times for the upper and lower body. Participants were given an instruction booklet and diary to record activity and changes in medication/diet/physical activity and telephoned fortnightly for progress.

      Outcomes

      Primary outcomes have been published previously.
      • Moore S.A.
      • Hallsworth K.
      • Jakovljevic D.G.
      • et al.
      Effects of community exercise therapy on metabolic, brain, physical and cognitive function following stroke: a randomised controlled pilot trial.
      Outcomes listed below represent only the variables explored in this secondary analysis: cardiorespiratory and functional performance measures. Outcome assessment was conducted within 2 weeks preintervention and 1 week postintervention by trained assessors blinded to the study hypotheses and group assignment.

      Exercise testing

      Expired gases (METALYZER 3Bb) were collected at rest for 5 minutes and continuously during a maximal progressive exercise test conducted with an electromagnetically controlled recumbent bicycle ergometer (Corivalc). A warm-up was done at 20W for 3 minutes followed by 10-W increments every minute until volitional exhaustion. The 12-lead electrocardiogram (Custod) was continuously monitored, and blood pressure was recorded twice at rest, during exercise, and at peak exercise and recovery. Peak exercise was defined as a respiratory exchange ratio of >1.05; the absence of an increase in oxygen consumption despite a further increase in exercise intensity; a rating of perceived exertion of >18 on the category Borg scale or voluntary termination of the test.
      • Kaminsky L.
      • Bonzheim K.
      • Garber C.
      • et al.
      ACSM’s resource manual for guidelines for exercise testing and prescription.

      Cardiorespiratory fitness

      Peak oxygen consumption was calculated as the average oxygen uptake during the last minute of exercise (expressed in milliliters per kilogram per minute). Peak work rate was defined as the peak wattage on test termination.

      Cardiovascular system

      Cardiac hemodynamics were measured using a bioreactance system (NICOMe) following a previously described protocol.
      • Jakovljevic D.G.
      • Moore S.
      • Hallsworth K.
      • Fattakhova G.
      • Thoma C.
      • Trenell M.I.
      Comparison of cardiac output determined by bioimpedance and bioreactance methods at rest and during exercise.
      Bioreactance has been demonstrated to be a valid and reliable method for estimating cardiac output at rest and during the different stages of graded exercise testing, including maximal exertion.
      • Jakovljevic D.G.
      • Moore S.
      • Hallsworth K.
      • Fattakhova G.
      • Thoma C.
      • Trenell M.I.
      Comparison of cardiac output determined by bioimpedance and bioreactance methods at rest and during exercise.
      • Jones T.W.
      • Houghton D.
      • Cassidy S.
      • MacGowan G.A.
      • Trenell M.I.
      • Jakovljevic D.G.
      Bioreactance is a reliable method for estimating cardiac output at rest and during exercise.
      Cardiac output was calculated as stroke volume × heart rate. Mean arterial blood pressure was calculated as diastolic blood pressure + (1/3) (systolic blood pressure – diastolic blood pressure) (expressed in millimeter of mercury), and cardiac power output was calculated as (cardiac output × mean arterial blood pressure) × (2.22×10−3).
      • Jakovljevic D.G.
      • Moore S.A.
      • Tan L.-B.
      • Rochester L.
      • Ford G.A.
      • Trenell M.I.
      Discrepancy between cardiac and physical functional reserves in stroke.

      Peripheral muscle oxygen extraction

      Peak arterial-venous oxygen difference (expressed in milliliters of oxygen per 100 milliliters of blood) was calculated as the ratio between peak oxygen consumption and peak cardiac output.

      Functional outcome measures

      The functional outcome measures were as follows: 6MWT,
      • American Thoracic Society
      ATS statement: guidelines for the six-minute walk test.
      10-meter walk test (10MWT),
      • Lord S.E.
      • Rochester L.
      Measurement of community ambulation after stroke: Current status and future developments.
      timed Up and Go (TUG) test,
      • Podsialo D.
      • Richardson S.
      The timed “Up and Go”: a test of basic functional mobility for frail elderly persons.
      and Berg Balance Scale (BBS).
      • Blum L.
      • Korner-Bitensky N.
      Usefulness of the Berg Balance Scale in stroke rehabilitation: a systematic review.

      Randomization

      An allocation sequence to randomize to either the exercise or the control group was created using a computer “true” random number generator (www.random.org) and delivered after screening by an administrator not associated with the trial.

      Statistical methods

      There were no missing values in the data set; therefore, all participants were included in the analysis. Data were inspected for outliers using standard Z-distribution cutoffs and Mahalanobis distance tests. Normality of distribution was tested using a Kolmogorov-Smirnov test. Pre- and postintervention within-group analyses were performed using a paired t test if data conformed to the assumptions of normality; if not, then the Wilcoxon signed rank test was used. Between-group differences were assessed using change scores that were compared using independent sample t tests.
      Pearson (or Spearman rank) correlation coefficient was used to explore associations between change scores in different variables. Cutoff scores to interpret effect size were .10 for small, .30 for moderate, and .50 for large.
      • Cohen J.D.
      Statistical power analysis for the behavioural sciences.
      Statistical significance was indicated if P<.05. All data are presented as means ± SD or as otherwise indicated. The sample size calculation for the main trial was presented in our previous publication of the main trial findings.
      • Moore S.A.
      • Hallsworth K.
      • Jakovljevic D.G.
      • et al.
      Effects of community exercise therapy on metabolic, brain, physical and cognitive function following stroke: a randomised controlled pilot trial.

      Results

      Participant characteristics

      A review of baseline characteristics and trial feasibility has been described previously.
      • Moore S.A.
      • Hallsworth K.
      • Jakovljevic D.G.
      • et al.
      Effects of community exercise therapy on metabolic, brain, physical and cognitive function following stroke: a randomised controlled pilot trial.
      In brief, 400 patients were assessed to determine eligibility for the trial. Forty participants, with matching baseline characteristics, were randomized and completed the trial (see the CONsolidated Standards Of Reporting Trials diagram in fig 1). The trial sample size provided sufficient power to explore our primary outcome.
      • Moore S.A.
      • Hallsworth K.
      • Jakovljevic D.G.
      • et al.
      Effects of community exercise therapy on metabolic, brain, physical and cognitive function following stroke: a randomised controlled pilot trial.
      The cohort included 34 men (85%) and 6 women (15%) (mean age, 69±9 years). Time since stroke was on average 19±26 months (range, 6–144mo). Impairment levels of participants were mild to moderate (National Institute for Health Stroke Scale score range, 0–8). All participants achieved the prespecified criteria for peak exercise. Normality testing was performed for all variables as described in the Methods section, and all but 3 data sets conformed to the assumptions of normality.
      Figure thumbnail gr1
      Fig 1Flow diagram of study participants (CONsolidated Standards Of Reporting Trials diagram). Abbreviations: MMSE, Mini-Mental Scale Examination; MRI, magnetic resonance imaging.

      Main results

      Hypothesis 1: Exercise will improve central oxygen supply and peripheral oxygen utilization

      Exercise significantly improved peripheral oxygen utilization as measured by peak arterial-venous oxygen difference. Exercise did not alter central oxygen supply as measured by baseline and peak cardiac output and cardiac power output (table 1).
      Table 1CRF and functional outcome measures at baseline and 19wk for exercise and control groups
      VariableExercise Group (n=20)Control Group (n=20)Group × Time (95% Confidence Interval)
      Baseline19wkΔPBaseline19wkΔP
      Cardiorespiratory measures
       Peak oxygen consumption (mL/(kg⋅min))18±521±53<.01
      P<.01.
      18±518±50.62<.01
      P<.01.
      (1.3 to 5.2)
       Peak work rate (W)112±36121±379<.01
      P<.01.
      105±34101±35−4.13<.01
      P<.01.
      (0.1 to 0.3)
       Peak arterial-venous oxygen difference (mL of O2/100mL of blood)9.2±2.711.4±2.92.2<.01
      P<.01.
      9.1±2.410.1±3.01<.05
      P<.05.
      0.09 (−0.2 to 2.5)
       Peak cardiac output (L/min)17.2±417.7±4.20.5.4416.2±2.915.8± 2.6−0.4.260.23 (−0.5 to 2.1)
       Peak cardiac power output (W)4.8±1.35.0±1.350.2.454.6±0.934.2±1.4−0.5.10.145 (−0.1 to 0.9)
       Baseline cardiac output (L/min)5.6±1.25.54±1.4−0.1.935.8±0.85.42±0.8−0.4.03
      P<.05.
      0.12 (−0.1 to 0.9)
       Baseline cardiac power output (W)1.26±0.41.26±0.40.911.29±0.21.25±0.2−0.0.360.6 (−0.1 to 0.18)
      Physical performance
       6MWT distance (m)428±131513±13185<.01
      P<.01.
      419±127441±12622<.05
      P<.05.
      <.01
      P<.01.
      (42 to 86)
       10MWT speed (m/s)1.2±0.41.5±0.30.3<.01
      P<.01.
      1.2±0.31.3±0.30.1.01
      P<.05.
      <.01
      P<.01.
      (0.1 to 0.3)
       TUG test score (s)11±98.4±6−2.6<.01
      P<.01.
      9.8±59±5−0.8.06<.05
      P<.05.
      (−3.5 to −2.4)
       BBS score50±455±25<.01
      P<.01.
      50±5.652±52<.05
      P<.05.
      <.01
      P<.01.
      (0.9 to 5)
      NOTE. Values are mean ± SD or as otherwise indicated. Group x time indicates between group differences using change scores (significance and confidence intervals).
      Abbreviation: Δ, change score.
      P<.01.
      P<.05.

      Hypothesis 2: Exercise-induced change in peak oxygen consumption will be strongly associated with adaptations in both central oxygen supply and peripheral oxygen utilization

      Peak arterial-venous oxygen difference increased by 24% with exercise (see table 1). Change in peak oxygen consumption was significantly correlated with change in arterial-venous oxygen difference (r=.51; P<.05), but not significantly correlated with either peak cardiac output (r=.06; P=.82) (fig 2) or peak cardiac power output (r=.01; P=.98).
      Figure thumbnail gr2
      Fig 2Relation (A) between peak oxygen consumption and cardiac output and (B) between peak oxygen consumption and arterial-venous oxygen difference.

      Hypothesis 3: Exercise-induced change in peak oxygen consumption and peripheral muscle oxygen utilization will be strongly associated with improvements in function

      Significant between-group differences were demonstrated in favor of the exercise intervention in all functional outcome measures including 6MWT, 10MWT, TUG test, and BBS (see table 1). Exercise-induced changes in peak oxygen consumption and peripheral muscle oxygen utilization were not strongly associated with improvements in function (table 2). A moderate significant correlation was observed between exercise-induced change in peak oxygen consumption and change in 10MWT and TUG test scores (see table 2). No other significant correlations were demonstrated between changes in peak oxygen consumption and peripheral muscle oxygen utilization and changes in function.
      Table 2Correlations between change in peak oxygen consumption and arterial-venous oxygen difference and change in functional outcome measures
      Functional Outcome Measure

      (Change Scores)
      Peak Oxygen Consumption

      Change Score

      (mL/(kg⋅min))
      Arterial-Venous Oxygen Difference Change Score

      (mL of O2/100mL of blood)
      6MWT
      r−.04−.02
      P.88.92
      10MWT
      r.48.15
      P<.05
      2-tailed significance level.
      .53
      TUG test
      r.47.04
      P<.05
      2-tailed significance level.
      .86
      BBS
      r−.25−.4
      P.28.12
      Abbreviations: P, 2-tailed significance level; r, Pearson correlation.
      2-tailed significance level.

      Discussion

      This is the first study to explore the effect of exercise on cardiac and peripheral muscle adaptations poststroke. It is also the first study to explore physiological mechanisms associated with exercise-induced changes in peak oxygen consumption and function poststroke. Community-based exercise led to marked improvements in peak oxygen consumption and peripheral muscle oxygen utilization. Exercise did not alter central hemodynamics. Exercise-induced change in peak oxygen consumption was related to the ability of the skeletal muscles to extract oxygen, rather than cardiac function. Although exercise-induced improvements were demonstrated in both peak oxygen consumption and functional outcome measures, these improvements were not strongly related.
      We have previously reported that the ability of skeletal muscles to extract oxygen is reduced poststroke, but cardiac function and pumping capability are not altered.
      • Jakovljevic D.G.
      • Moore S.A.
      • Tan L.-B.
      • Rochester L.
      • Ford G.A.
      • Trenell M.I.
      Discrepancy between cardiac and physical functional reserves in stroke.
      Present findings extend this knowledge, demonstrating that structured exercise led to an improvement in peripheral muscle oxygen utilization, but did not alter cardiac function. These findings may reflect that the individuals studied had adequate cardiac output and cardiac power output at study baseline; therefore, there was no potential for improvement in contrast to the improvements observed in peripheral muscle oxygen utilization.
      To our knowledge, only 1 other study
      • Tang A.
      • Eng J.J.
      • Krassioukov A.V.
      • et al.
      Exercise-induced changes in cardiovascular function after stroke: a randomized controlled trial.
      has investigated the effect of exercise on cardiac function poststroke. Although cardiac hemodynamics were assessed using echocardiography in this study, not bioreactance as in our trial, the study used an exercise intervention of a similar frequency, duration, and intensity. To our own meaning, findings may be comparable. In line with our findings, most cardiac measures did not alter with exercise, with right atrial emptying fraction percentage being the only measure to alter.
      • Tang A.
      • Eng J.J.
      • Krassioukov A.V.
      • et al.
      Exercise-induced changes in cardiovascular function after stroke: a randomized controlled trial.
      The study assessed cardiac function only at rest, whereas our study also analyzed cardiac function at peak exercise. Assessing cardiac function at peak exercise may be a more accurate representation of cardiac function as it takes into account cardiac adaptability to functional demand. In line with measures taken at rest, cardiac measures taken at peak exercise also did not alter with exercise, providing further novel evidence that cardiac hemodynamics may not be altered by exercise poststroke. However, in both studies participants were recruited at least 6 months poststroke. The participants may have initially presented with reduced cardiac function in the early stages of stroke, which may have been resolved by early physiotherapy and exercise interventions. To our knowledge, little research has been conducted on cardiac function and how it is affected by exercise in the early stages of poststroke and this area warrants further investigation.
      Although no change was noted in cardiac hemodynamics in our study, exercise-induced change was observed in peripheral muscle oxygen utilization. Stroke can lead to peripheral impairments including severe unilateral muscle atrophy,
      • Ryan A.S.
      • Dobrovolny C.L.
      • Smith G.V.
      • Silver K.H.
      • Macko R.F.
      Hemiparetic muscle atrophy and increased intramuscular fat in stroke patients.
      an increase in intramuscular fat,
      • Ryan A.S.
      • Buscemi A.
      • Forrester L.
      • Hafer-Macko C.E.
      • Ivey F.M.
      Atrophy and intramuscular fat in specific muscles of the thigh.
      a shift toward fast twitch, fatigue prone muscle fibers,
      • De Deyne P.G.
      • Hafer-Macko C.E.
      • Ivey F.M.
      • Ryan A.S.
      • Macko R.F.
      Muscle molecular phenotype after stroke is associated with gait speed.
      and a marked increase in the expression of tumor necrosis factor α.
      • Hafer-Macko C.E.
      • Yu S.
      • Ryan A.S.
      • Ivey F.M.
      • Macko R.F.
      Elevated tumor necrosis factor-alpha in skeletal muscle after stroke.
      Peripheral changes including vascular remodeling
      • Billinger S.A.
      • Kluding P.M.
      Use of Doppler ultrasound to assess femoral artery adaptations in the hemiparetic limb in people with stroke.
      and a reduction in blood flow
      • Landin S.
      • Hagenfeldt L.
      • Saltin B.
      • Wahren J.
      Muscle metabolism during exercise in hemiparetic patients.
      have also been observed poststroke in the femoral artery of the affected lower limb.
      The exercise-induced improvements in peripheral muscle observed during this study indicate that it may be possible to use exercise to mediate peripheral complications resulting from stroke. The most effective form of exercise to promote these peripheral changes, however, has yet to be discovered. Our intervention combined functional strengthening, balance work, flexibility, and aerobic exercise. A more specific peripheral training regime, however, may have increased peripheral adaptation.
      A 4-week (3times/wk) program of single limb exercise (SLE) has been shown to effectively modify peripheral hemodynamics.
      • Billinger S.
      • Gajewski B.
      • Guo L.
      • Kluding M.
      Single limb exercise induces femoral artery remodeling and improves blood flow in hemiparetic leg post stroke.
      The SLE program increased femoral artery blood flow and diameter, which may have enhanced oxygen uptake in the hemiparetic limb. Although the SLE program led to vascular changes, the overall peak oxygen consumption was not altered, limiting the application of this intervention.
      • Billinger S.A.
      • Guo L.X.
      • Pohl P.S.
      • Kluding P.M.
      Single limb exercise: pilot study of physiological and functional responses to forced use of the hemiparetic lower extremity.
      Reasons for the lack of change in peak oxygen consumption may have been due to the relatively short training period used in the study and methods used for measuring CRF (exercise testing was performed on a total body recumbent stepper). A longer SLE training regime may lead to peripheral adaptations and greater improvements in peak oxygen consumption. An SLE program focusing on the hemiparetic limb, however, may not lead to the global improvements in CRF and function observed in response to the functional training program delivered in our study.
      • Moore S.A.
      • Hallsworth K.
      • Jakovljevic D.G.
      • et al.
      Effects of community exercise therapy on metabolic, brain, physical and cognitive function following stroke: a randomised controlled pilot trial.
      Patient dissatisfaction after stroke is often related to functional outcome, rather than reduced CRF as measured by peak oxygen consumption.
      • Soloman N.A.
      • Glick H.A.
      • Russo C.J.
      • Lee J.
      • Schulman K.A.
      Patient preferences for stroke outcomes.
      The exercise intervention delivered in this trial led to significant improvements in all the functional measures undertaken. Although previous data have demonstrated that peak oxygen consumption levels are associated with functional outcome measures in various conditions,
      • Cahalin L.P.
      • Pappagianopoulos P.
      • Prevost S.
      The relationship of the 6-min walk test to maximal oxygen consumption in transplant candidates with end-stage lung disease.
      • Cahalin L.P.
      • Mathier M.A.
      • Semigran M.J.
      The six-minute walk test predicts oxygen uptake and survival in patients with advanced heart failure.
      our results demonstrated only a moderate significant correlation between exercise-induced change in peak oxygen consumption and 2 of the functional outcome measures: walking speed and TUG test. No significant relations were observed between peak oxygen consumption and the other functional outcome measures (10MWT and BBS) and between peripheral muscle oxygen utilization and all the 4 functional outcome measures.
      Previous cross-sectional studies
      • Pang M.Y.
      • Eng J.J.
      • Dawson A.S.
      Relationship between ambulatory capacity and cardiorespiratory fitness in chronic stroke: influence of stroke-specific impairments.
      • Tang A.
      • Sibley K.M.
      • Bayley M.T.
      • McIlroy W.E.
      • Brooks D.
      Do functional walk tests reflect cardiorespiratory fitness in sub-acute stroke?.
      have demonstrated that after stroke, measures of CRF do not correlate strongly with functional outcome measures such as 6MWT. Our study supports these findings, demonstrating that exercise-related improvements in peak oxygen consumption were not strongly related to functional improvements as first hypothesized. This lack of relation between function and physiology could be due to impairments associated with stroke, such as balance, fatigue, cognition, and mood, affecting performance on functional tests that may not have affected performance on the exercise test conducted while sitting on a recumbent bike. Indeed, balance appears to be one of the strongest predictors of 6MWT distance,
      • Pang M.Y.
      • Eng J.J.
      • Dawson A.S.
      Relationship between ambulatory capacity and cardiorespiratory fitness in chronic stroke: influence of stroke-specific impairments.
      and 6MWT distance has also been previously correlated to quality-of-life measures.
      • Muren M.A.
      • Hutler M.
      • Hooper J.
      Functional capacity and health-related quality of life in individuals post stroke.
      An interesting finding yet to be discussed was the improvement observed in the control group in peak arterial-venous oxygen difference and 3 of the functional outcome measures. There is some evidence to suggest that measures such as 6MWT may be subject to learning effects.
      • Jenkins S.
      • Cecins N.M.
      Six-minute walk test in pulmonary rehabilitation: do all patients need a practice test?.
      Learning effects may have accounted for the functional improvements observed; however, maximal cycle ergometer testing has not been linked to the same type of effect.
      • Dideriksen K.
      • Mikkelsen U.R.
      Reproducibility of incremental maximal cycle ergometer tests in healthy recreationally active subjects.
      The intervention delivered to the control group was a low-intensity stretching program that was not designed to improve function or fitness, but may have led to the physiological and functional changes observed in the control group. However, the between-group analysis demonstrated that any improvements in the control group were significantly lower than those in the exercise group.

      Study limitations

      The strength of this study lies in the novel exploration of exercise-induced peripheral and central adaptations poststroke. The study is, however, not without limitations. The trial did not allow for follow-up; therefore, we were not able to establish whether short-term changes were maintained. To be eligible to take part in the trial, participants had to be able to complete a 6MWT and they were from a single center, limiting the applicability of the study findings to a broader population with stroke. The cohort recruited was also predominantly male, with mild disability also reducing external validity. However, it is still important to explore responses in patients with nondisabling strokes as they are linked to further stroke, cardiovascular events, and death.
      • Kernan W.N.
      • Viscoli C.M.
      • Brass L.M.
      • et al.
      The Stroke Prognosis Instrument II (SPI-II): a clinical prediction instrument for patients with transient ischemia and nondisabling ischemic stroke.

      Conclusions

      This study is the first to explore the effect of exercise on cardiac and peripheral muscle adaptations and the relation between exercise-induced changes in physiology and function. The exercise program led to significant improvements in peak oxygen consumption and peripheral muscle oxygen utilization, with no improvement in cardiac output and cardiac power output. Exercise-induced change in peak oxygen consumption was related to peripheral adaptations, but not to central adaptations or function. Future research should establish the most effective interventions to promote change in peripheral muscle oxygen utilization, peak oxygen consumption, and function poststroke.

      Suppliers

      • a.
        Heart rate monitor RS400; Polar, Finland.
      • b.
        METALYZER 3B; Cortex, Leipzig, Germany.
      • c.
        Corival; Lode, Groningen, The Netherlands.
      • d.
        Custo; CustoMed GmbH, Ottobrunn, Germany.
      • e.
        CHEETAH NICOM; Cheetah Medical, Vancouver.

      Acknowledgments

      We thank the National Institute for Health North East Stroke Research Network for assistance with recruiting participants and undertaking blinded outcome assessments and Simon Clark for assistance with the exercise intervention.

      Supplementary data

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