INTRODUCTION
Exercise capacity (peak oxygen consumption,
;)
O2peak) rapidly declines in the acute stage of stroke recovery and has been shown to be approximately 60% lower than that of age- and sex-matched peers.1 Several studies also corroborate these findings with low
O2peak levels in survivors of chronic stroke.2–8 The decline in exercise capacity is multifactorial, with stroke-related impairments found in the neuromotor, respiratory, and cardiovascular systems.1,2,9,10 However, aerobic exercise interventions have consistently shown improvements in
O2peak, the 6-minute walk test (6MWT),7,11–13 and gait13 in survivors chronic stroke. A limited number of studies have demonstrated improvements in cognition in response to an aerobic exercise intervention in chronic stroke.11,14 There have been only a few studies that have focused on exercise in subacute stroke, but the evidence supports improved
O2peak and walking endurance.10,15,16
While overall exercise capacity is reduced after stroke, there are reports that survivors of stroke demonstrate unique unilateral adaptations in the stroke-affected limb17–20 that may further contribute to fatigue with activity and to metabolic dysfunction.19 These unilateral changes have been observed in the stroke-affected limb for femoral artery diameter,17,18 vasomotor reactivity,19,20 blood flow,17,19–21 and tissue composition.21–24 Our previous work suggests that unilateral exercise improves femoral artery diameter and blood flow to the hemiparetic limb17 but does not improve cardiorespiratory fitness.21 Ivey and colleagues20 randomized survivors of chronic stroke to either a 6-month task-oriented treadmill intervention or a control group, which consisted of stretching exercises. When compared to the control group, individuals participating in the treadmill intervention showed significant improvements in
O2peak, leg blood flow and vasomotor reactivity.
Vasomotor reactivity via flow-mediated dilation (FMD) is calculated as the peak arterial diameter from the baseline value (% FMD) in response to an “acute increase in blood flow,”25 such as exercise or walking. Flow-mediated dilation in the brachial artery is impaired in acute26 and chronic27 stroke when compared to persons without stroke. Stroke-related changes in the brain, specifically in areas that regulate autonomic function, may have significant implications for blood pressure (BP) regulation (vasodilation/constriction of the vessel) and cardiac function during the early phase of stroke recovery.28,29 Gaining insight into vascular changes that occur poststroke may guide rehabilitation professionals to consider exercise interventions aimed at minimizing vascular decline. However, whether an aerobic exercise intervention in the subacute stage of stroke recovery facilitates improvements in vasomotor reactivity is yet to be explored.
Using a task-oriented treadmill exercise model has significant advantages related to physical performance outcomes, such as walking in addition to cardiovascular health and prescribing exercise.19,22 However, we concur with Tang and colleagues15 that performing aerobic exercise in persons with subacute stroke presents unique challenges related to excluding participants who have limited-to-no ambulatory function. In the study by Tang and colleagues,15 individuals were randomly assigned to either the exercise group, which participated in aerobic exercise using a recumbent cycle ergometer in addition to their inpatient rehabilitation, or the control group, which performed usual inpatient rehabilitation. Although both groups improved from baseline, the exercise intervention group demonstrated greater improvements in
O2peak and the 6MWT during inpatient rehabilitation.15 It is important to note that the participants assigned to the exercise group engaged in aerobic exercise for an average of only 9 days. Therefore, when compared with the control group, there was not a significant group-by-time interaction. Their study, however, laid the groundwork for clinicians and researchers to consider initiating exercise early in stroke recovery.
The purpose of this study was to determine whether an 8-week moderate- to high-intensity aerobic exercise intervention using a seated exercise modality (total body recumbent stepper [TBRS]) would improve cardiovascular health and physical performance in participants with subacute stroke (<6 months). We hypothesized that the aerobic exercise intervention would improve our primary outcome measure, brachial artery FMD bilaterally. For our secondary outcome measures, we also hypothesized that there would be a decrease in resting heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). From the exercise test, we hypothesized that there would be an increase in peak HR,
O2peak, exercise test time, and workload (W), and the distance covered during the 6MWT would increase following the exercise intervention. In addition, we wanted to explore whether any improvements would still be observed at 1 month postintervention. We hypothesized that at the 1-month follow-up, our outcomes measures would be significantly higher than baseline.
METHODS
Study Design
A prospective study with a sample of convenience was used for a pre- and posttest design and a follow-up testing 1 month after completion of the exercise intervention. Adverse events related to the exercise testing and the intervention were monitored throughout the study. The study was approved by the Human Subjects Committee at the University of Kansas Medical Center. Institutionally approved written consent was obtained before enrollment.
Participants
Between December 2010 and January 2012, 40 individuals with a diagnosis of stroke were screened for inclusion into the Cardiovascular Regulation and Early Exercise Stroke Study. Inclusion criteria were as follows: (1) between 50 and 70 years of age, (2) diagnosis of a first-time, unilateral stroke that occurred less than 6 months before enrollment, (3) ability to walk with or without an assistive device and need only stand-by assist, and (4) ability to travel for all testing and exercise sessions. Individuals were not enrolled if the following exclusion criteria were present: (1) acute renal failure, (2) ischemic cardiovascular event or coronary artery bypass surgery less than 3 months ago, (3) severe peripheral artery disease (ankle-brachial index <0.40), (4) diagnosis of congestive heart failure, (5) current smoker, and (6) unable to position the upper extremity in 90° of shoulder abduction and elbow extension for optimal access of the brachial artery during ultrasound scanning.
Outcome Measures
Flow-Mediated Dilation
Participants were asked to refrain from food or caffeine for 12 hours and from vigorous activity for 24 hours before the FMD procedure. The participants were resting in a supine position for 20 minutes before the FMD procedure in a temperature controlled (22°C-24°C) and quiet, dimly lit room.1 Heart rate was monitored continuously, using a 3-lead electrocardiography, while resting BP was measured in a supine position after the 20-minute rest period. An automated cuff with rapid inflation system (D.E. Hokanson, Bellevue, WA) was placed just distal to the olecranon process.30,31 The arm to be scanned was placed on a stabilizing device to allow for optimal scanning of the brachial artery and avoid arm movements during the ultrasound imaging. The brachial artery was identified longitudinally always at the same reference point, 2 to 3 cm proximal to the antecubital fossa, using an ultrasound system and a 7.5-MHz linear-array transducer (Siemens Medical Solutions, Malvern, Pennsylvania). Once a satisfactory image of the brachial artery was obtained, the transducer was stabilized using a custom-designed holder. If needed, minor adjustments were made to the transducer placement for optimal imaging. We also captured Doppler velocity measurements at an insonation angle of 60°, using the ultrasound system. Baseline diameter and blood flow velocity were recorded continuously for 10 seconds. The pneumatic cuff was then inflated to suprasystolic pressure (220 mm Hg) and maintained for 5 minutes. Twenty seconds before cuff deflation, recording of diameter and blood flow velocity was resumed. At 5 minutes, the cuff was deflated while ultrasound images continued to be recorded for another 3 minutes. All images were stored on a computer and analyzed off-line using specialized software (Brachial Analyzer, Medical Imaging Applications, Coralville, Iowa). This edge detection software allows the operator to identify a region of interest at a specific, designated area of the vessel. The automated software identified the near and far wall properties of the vessel and tracked the diameter changes. Using an automated software system minimized investigator bias and more accurately detected changes in the FMD.32 In addition, using computerized edge detection and wall-tracking systems to detect changes in the FMD improve the validity and intra-rater reliability variation for the automated systems than for the manual technique.33–35
6-Minute Walk Test
The 6MWT is a valid and reliable test for assessing physical performance of people with stroke.5 The 6MWT was performed on the same day but after the FMD procedure. The 6MWT was performed in a 100-foot corridor with minimal distractions and was marked every 3 m to measure distance.36 A stopwatch was used to record time, and standardized verbal cues were given.36 Participants were allowed to use their assistive devices if needed during the test but were required to use the same assistive device for all testing sessions.
Cardiovascular Health and Peak Exercise Test
Exercise testing was conducted on a separate day from that of the FMD procedures and the 6MWT. Participants were asked not to consume food or drink (except water) within 2 and 3 hours of the exercise tests and to avoid caffeinated products for 6 hours before the exercise test. Participants were asked to avoid vigorous physical activity for 24 hours before testing. All participants had an opportunity to use the exercise device TBRS (NuStep, T5XR; NuStep, Inc, Ann Arbor, Michigan) to practice the alternating, reciprocal movement pattern, step rate (80 steps per minute) and were familiarized with the Borg Rating of Perceived Exertion (RPE) scale. This was performed before the maximal exercise-testing day.
Before each exercise test and after 15 minutes of sitting quietly, resting HR, SBP, and DBP measures were obtained and recorded. Oxygen uptake was measured and analyzed through the collection of expired gases using the ParvoMedics metabolic measurement system (ParvoMedics Inc, Sandy, Utah). Gas and flow meter calibrations were performed on the metabolic cart according to the specifications of the manufacturer. To reduce the likelihood of an operator error, the calibration of the metabolic cart was performed by the same individual. We used identical exercise testing methodology and the mTBRS-XT protocol.6 Briefly, the mTBRS-XT is a 2-minute incremental exercise test to assess
O2peak and other metabolic parameters. The mTBRS-XT has been shown to be a valid exercise test for people poststroke6 and has been sensitive enough to detect changes in
O2peak.11 A physician was present for all the exercise tests.
Intervention
Aerobic Exercise Training
The exercise sessions were held at the University of Kansas Medical Center Research in Exercise and Cardiovascular Health laboratory. Since few studies have performed moderate- to high-intensity aerobic exercise37 in subacute stroke, we used the following exercise prescription guidelines: (1) SBP less than 220 mm Hg and DBP less than 100 mm Hg, (2) RPE between 12 and 16/20, and (3) exercise intensity was prescribed at 50% to 59% of HR reserve (derived from the exercise test) for 4 weeks and then increased to 60% to 69% of HR reserve for the remaining 4 weeks. Individuals wore Polar HR monitors (Polar Electro Oy, Oulu, Finland) and were given cueing if needed and encouragement to maintain exercise intensity to stay in the prescribed target HR range for the duration of the session. Exercise sessions were 3 times per week for 8 weeks. Exercise compliance for attendance was recorded in the exercise log.
Each exercise session began with preexercise vital signs; for those with diabetes, blood glucose was recorded, and we inquired whether there were any changes in medication(s). If a medication was added or removed or if the dosage was changed, we documented this in the exercise log. Ten stretching exercises for the upper and lower body were performed before commencement of the exercise session. After stretching, each session began with a 5-minute warm-up at 15 to 25 W at a comfortable, self-selected pace. After 5 minutes, the exercise intensity was increased to the prescribed workload. Exercise intensity for each session began at the low end of the targeted HR range (THRR) and increased in intensity so that the remaining 10 minutes were spent at the upper portion of the THRR (ie, ∼59% of HR reserve). Once 20 minutes of exercise was performed with an RPE less than 13, the duration was increased to 30 minutes. No aerobic exercise session exceeded 40 minutes in duration. Intensity was adjusted according to physiologic response but did not exceed the THRR. We documented in the exercise log, the amount of time spent in the prescribed heart rate range. Heart rate, BP, and RPE were assessed within 1 minute before the end of the exercise training to capture exercise response. A 5-minute cool-down was then employed.
Follow-up
No specific information related to exercise or physical activity was provided for the 4-week period. Once the time period had elapsed, individuals returned for final testing.
Sample Size Justification
The primary outcome of interest for the proposed work was the percentage change in the vasomotor reactivity after the exercise program. No data exist regarding brachial artery vasomotor reactivity response to an exercise intervention in people poststroke. The sample size for this study was based on our previous work using a within-group treatment design, and the outcome measure was a change in blood flow after unilateral exercise training.17 On the basis of the power analysis with an effect size, d = 4.37, power of 0.95, we needed 5 people to determine significant changes. However, since we are examining a different outcome (vasomotor reactivity) and expected a smaller effect size, we chose a conservative approach and overenrolled to include 10 participants.
Data Analysis
Data analysis was performed with SPSS Version 18.0 (SPSS Inc, Chicago, IL) for Windows. For each of the outcome measures, descriptive statistics were performed. For our primary outcome, we tested the FMD in bilateral brachial arteries. For our secondary outcomes, we assessed resting HR, SBP, and DBP. From the exercise test, we assessed peak HR,
O2peak, exercise test time, workload (W), and the distance covered during the 6MWT. Baseline and (1) postintervention data and (2) 1-month follow-up comparisons were made using a 1-tailed paired t test. Because of multiple comparisons and the risk of inflating our type I error, we adjusted our P value to be significant when P was 0.02 or less.
RESULTS
Ten people completed the initial screening and consented to participate. One individual had an echocardiogram before her discharge from inpatient hospitalization, and a blood clot was found in the aorta. The individual was no longer eligible for participation in the study. Therefore, an additional person was screened and enrolled. Ten people completed the initial testing and began the training intervention. One person discontinued the training after completion of week 4 due to schedule conflicts and could not commit to attending the training session 3 times per week. For the remaining 9 participants, exercise adherence was 85% (range: 75%-100%). The primary reason for missing a session for those less than 80% adherence was transportation. Average time in the prescribed HR zone was 66% for the 8-week intervention. In the first 4 weeks, approximately 70% of the exercise session was spent in the THRR (50%-59% of peak HR) while the last 4 weeks were 63% of THRR (60%-69% of peak HR). No serious cardiac or other adverse events related to exercise testing or the intervention were reported. There were no additions of medications for BP, cardiac arrhythmias, or cholesterol. In addition, for those taking cardiovascular medications, no changes in medication dosage were reported. One individual began taking pregabalin (Lyrica) after week 3 of the exercise intervention. Since a known side effect of this medication is weight gain, this may have contributed to the 20-pound increase in weight that was observed at the postintervention testing. This likely affected the group mean value for body weight (in kilograms). Participant demographics are presented in Table 1.
Table 1: Baseline Participant Demographics
Brachial Artery Diameter and FMD
Baseline brachial artery diameter was significantly smaller in the stroke-affected arm than in the other side. Furthermore, the stroke-affected side demonstrated a significantly reduced FMD response than the other limb (P < 0.02). After the 8-week exercise intervention, significant improvements were reported bilaterally for both artery diameter (P < 0.01) and FMD (P < 0.01). At the 1-month follow-up, no significant differences were found for artery diameter when compared to baseline values (P > 0.05). However, the FMD remained higher than baseline bilaterally, but this was not statistically significant (P > 0.02). One person experienced significant bouts of coughing during the scan, which increased his tone in the stroke-affected arm. We tried several rest breaks, but ultimately, he was unable to maintain a quiet, resting position for the duration of the scans. Therefore, because of excessive movement, we were unable to capture a continuous, clear image of the brachial artery for the duration of the ultrasound scan. Therefore, this individual's ultrasound data were not included in the follow-up (Table 2).
Table 2: Brachial Artery Measuresa
6-Minute Walk Test
From baseline to postintervention, we observed a 38.7-m increase (12.7%) in the distance walked (304.1 ± 167.5 to 342.8 ± 185.6 m, P < 0.002). For the 8 individuals who returned for the follow-up visit, there was an additional gain of 9.8 m between the mean distance walked at postintervention compared to the 1-month follow-up. However, when the 1-month follow-up was compared with baseline, participants significantly increased (P < 0.005) the distance walked by 44.9 m.
Cardiovascular Health and Peak Exercise Testing
Baseline values for resting HR, SBP, DBP, and exercise testing outcomes are listed in Table 3. This group of survivors of stroke could tolerate higher workloads during the exercise test than those in our previous work.6 Therefore, we added additional 2 stages (stage 9 = 145 W, stage 10 = 160 W) to the mTBRS-XT protocol.
Table 3: Cardiovascular Health and Exercise Testing Outcomesa
Resting HR, SBP, and DBP all decreased after the exercise intervention, but SBP was significantly lower. Neither
O2peak (P = 0.04) nor peak HR (P = 0.25) was significantly improved after the intervention, and respiratory exchange ratio was essentially unchanged (1.1 ± 0.1, P = 0.44). The perception of their exertion level following the intervention was lower with RPE at 17.7 ± 2.8 but nonsignificant (P = 0.08). Mean exercise test time increased from the initial assessment at baseline, while peak workload was significantly higher. At the 1-month follow-up, only RPE and peak watts remained significantly different from baseline (Table 3).
DISCUSSION
This study examined whether an 8-week aerobic exercise intervention using a recumbent exercise device could improve cardiovascular health and physical performance during the subacute stage of stroke recovery. This is the first investigation to demonstrate that the brachial artery vasomotor reactivity was improved after exercise in both the stroke-affected and nonaffected sides. As hypothesized, we found that the intervention improved cardiovascular health and physical performance (6MWT). Furthermore, we chose a 1-month follow-up to assess whether any improvements gained from the exercise intervention would be maintained, and found this to be the case for some of the outcome measures.
Vasomotor Reactivity
Even in the early stages poststroke, we report between-limb differences in vasomotor reactivity. Since blood flow regulation and vessel wall diameter are controlled by both metabolic demand and autonomic control,38 these unilateral changes may be, in part, a result of the stroke rather than only due to decreased physical inactivity or muscle loss. Since this study did not examine the influence of any mechanistic factors (ie, inflammation or lesion location such as the insula), it may be premature to suggest that these unilateral changes are an absolute, direct result of the stroke. Further study is warranted to identify the underlying mechanisms contributing to unilateral vascular differences or whether beginning exercise within days poststroke would mitigate these differences.
Exercise has been shown to be beneficial in improving brachial artery vasomotor reactivity in those with acute myocardial infarction,37 recipients of heart transplant,39 and those with hypothyroidism40 but has not been assessed in subacute stroke. We chose to use a recumbent stepper for the exercise intervention versus a treadmill because of the potential challenges in balance and walking in people poststroke. After the intervention, our findings demonstrate improvements in the FMD in the stroke-affected and nonaffected (18.5% and 19.4%) limbs. These results are similar to those reported in chronic stroke.19 It is important to note that the greater changes in brachial artery FMD have been observed in other clinical populations, using a higher intensity of prescribed exercise.39,41,42 Taking into account that survivors of stroke have existing cardiovascular disease and the exercise intervention was well-tolerated by our small group of participants, future work should expand upon this study and consider a randomized controlled trial further examining exercise dose and intensity to improve vasomotor reactivity.39
Walking Endurance
Aerobic exercise training has been effective at improving endurance and distance walked during the 6MWT in subacute and chronic stroke. After the exercise intervention, participants increased their 6-minute walking distance by 38.7 m. These results fall between a small and moderate meaningful change for survivors of stroke.43 We found these results to be noteworthy since the exercise intervention was not walking but rather a recumbent stepper. Since the TBRS has been a preferred exercise modality for older adults44 and can accommodate various people with neurologic impairments,6,45,46 we believe that this information will be useful to clinicians in stroke rehabilitation settings.
Cardiovascular Health and Exercise Testing
As indicated by our laboratory results2 and others,1,47,48 survivors of stroke have very poor levels of exercise capacity.
O2peak values for our group of survivors of stroke were in the very poor fitness category.37 Although improvements for mean
O2peak were observed, only 2 participants increased their fitness level sufficient enough to move upward into another category. However, these values were considered “poor” when compared to age- and sex-matched counterparts.37 This study further highlights the need for continued, aggressive exercise programming during stroke rehabilitation and continuing into community programming.
We used a 1-month follow-up to examine whether improvements from the exercise intervention would be maintained above baseline measures. At the follow-up testing, we noticed improvements in some of our measures. When we inquired about what the participants did during this follow-up, many said that they continued to be physically active. Since, we were not expecting the participants to continue to be physically active, we did not collect information regarding their activity levels. Certainly, we were encouraged by their desire to continue to exercise, and in our future studies we plan to collect this information.
There are challenges associated with exercise testing in the stroke population, and
O2peak should not be the only outcome measure when examining exercise performance. After the exercise intervention,
O2peak values increased 9% while power output (W) increased 26.3% with a perception of reduced exertion using the RPE. The participants gave good effort with mean respiratory exchange ratio values of 1.1 at all time points.49 In addition, we report improvements in resting HR and BP after the exercise intervention. It has been suggested that as little as a 5-mm Hg decrease in SBP could reduce mortality associated with stroke by 14%.50 After the exercise intervention, our findings showed an 11-mm Hg decrease in resting SBP and a 1.4-mm Hg drop in DBP. Since survivors of stroke are considered at high cardiac risk,37 it is advantageous to consider interventions that modify these risk factors. While many issues may contribute to fluctuations in HR and BP, we monitored medications for dose and frequency changes. We recognize that this is a small sample size with a pre- and posttest design. Therefore, data need to be interpreted with caution. On the basis of the results of this study, individuals in the subacute phase of stroke recovery tolerated moderate- to high-intensity aerobic exercise. No serious or cardiac adverse events were reported as a result of this intervention. The findings of this study are encouraging and demonstrate the need to extend this work to a randomized controlled trial.
CONCLUSIONS
Aerobic exercise in subacute stroke was associated with favorable outcomes for cardiovascular health and physical performance. Individuals in the subacute stage of stroke participated in an 8-week moderate- to high-intensity exercise training intervention, using a recumbent stepper. After the exercise intervention, improvements were observed in brachial artery vasomotor reactivity as well as cardiovascular and physical performance. Future work should focus on examining the effects of an exercise intervention on cardiovascular health through a randomized controlled trial.
ACKNOWLEDGMENTS
The authors thank Eileen Coughenour, Melanie Simpson, and Stephanie Schifferdecker for their assistance with data collection and entry and Sara Karcher with the manuscript preparation. They also thank the participants for their time and efforts on the study.
REFERENCES
1. Mackay-Lyons MJ, Makrides L. Exercise capacity early after stroke. Arch Phys Med Rehabil. 2002;83(12):1697–1702.
2. Billinger SA, Taylor JM, Quaney BM. Cardiopulmonary response to exercise testing in people with chronic stroke: a retrospective study. Stroke Res Treat. 2012;2012:987637.
3. Macko RF, Smith GV, Dobrovolny CL, Sorkin JD, Goldberg AP, Silver KH. Treadmill training improves fitness reserve in chronic stroke patients. Arch Phys Med Rehabil. 2001;82(7):879–884.
4. Mackay-Lyons MJ, Makrides L. Longitudinal changes in exercise capacity after stroke. Arch Phys Med Rehabil. 2004;85(10):1608–1612.
5. Eng JJ, Dawson AS, Chu KS. Submaximal exercise in persons with stroke: test-retest reliability and concurrent validity with maximal oxygen consumption. Arch Phys Med Rehabil. 2004;85(1):113–118.
6. Billinger SA, Tseng BY, Kluding PM. Modified total-body recumbent stepper exercise test for assessing peak oxygen consumption in people with chronic stroke. Phys Ther. 2008;88(10):1188–1195.
7. Pang MY, Eng JJ, Dawson AS, Gylfadottir S. The use of aerobic exercise training in improving aerobic capacity in individuals with stroke: a meta-analysis. Clin Rehabil. 2006;20(2):97–111.
8. Ivey FM, Macko RF, Ryan AS, Hafer-Macko CE. Cardiovascular health and fitness after stroke. Top Stroke Rehabil. 2005;12(1):1–16.
9. Billinger SA, Coughenour E, Mackay-Lyons MJ, Ivey FM. Reduced cardiorespiratory fitness after stroke: biological consequences and exercise-induced adaptations. Stroke Res Treat. 2012;2012:959120.
10. Duncan P, Studenski S, Richards L, et al. Randomized clinical trial of therapeutic exercise in subacute stroke. Stroke. 2003;34(9):2173–2180.
11. Kluding PM, Tseng BY, Billinger SA. Exercise and executive function in individuals with chronic stroke: a pilot study. J Neurol Phys Ther. 2011;35(1):11–17.
12. Tang A, Marzolini S, Oh P, McIlroy WE, Brooks D. Feasibility and effects of adapted cardiac rehabilitation after stroke: a prospective trial. BMC Neurol. 2010;10:40.
13. Macko RF, Ivey FM, Forrester LW, et al. Treadmill exercise rehabilitation improves ambulatory function and cardiovascular fitness in patients with chronic stroke: a randomized, controlled trial. Stroke. 2005;36(10):2206–2211.
14. Quaney BM, Boyd LA, McDowd JM, et al. Aerobic exercise improves cognition and motor function poststroke. Neurorehabil Neural Repair. 2009;23(9):879–885.
15. Tang A, Sibley KM, Thomas SG, et al. Effects of an aerobic exercise program on aerobic capacity, spatiotemporal gait parameters, and functional capacity in subacute stroke. Neurorehabil Neural Repair. 2009;23(4):398–406.
16. Letombe A, Cornille C, Delahaye H, et al. Early post-stroke physical conditioning in hemiplegic patients: a preliminary study. Ann Phys Rehabil Med. 2010;53(10):632–642.
17. Billinger SA, Gajewski BJ, Guo LX, Kluding PM. Single limb exercise induces femoral artery remodeling and improves blood flow in the hemiparetic leg poststroke. Stroke. 2009;40(9):3086–3090.
18. Billinger SA, Kluding PM. Use of Doppler ultrasound to assess femoral artery adaptations in the hemiparetic limb in chronic stroke. Cerebrovasc Dis. 2009;27:552–558.
19. Ivey FM, Hafer-Macko CE, Ryan AS, Macko RF. Impaired leg vasodilatory function after stroke: adaptations with treadmill exercise training. Stroke. 2010;41(12):2913–2917.
20. Ivey FM, Gardner AW, Dobrovolny CL, Macko RF. Unilateral impairment of leg blood flow in chronic stroke patients. Cerebrovasc Dis. 2004;18(4):283–289.
21. Billinger SA, Guo LX, Pohl PS, Kluding PM. Single limb exercise: pilot study of physiological and functional responses to forced use of the hemiparetic lower extremity. Top Stroke Rehabil. 2010;17(2):128–139.
22. Ryan AS, Ivey FM, Prior S, Li G, Hafer-Macko C. Skeletal muscle hypertrophy and muscle myostatin reduction after resistive training in stroke survivors. Stroke. 2011;42(2):416–420.
23. Prior SJ, McKenzie MJ, Joseph LJ, et al. Reduced skeletal muscle capillarization and glucose intolerance. Microcirculation. 2009;16(3):203–212.
24. Hafer-Macko CE, Yu S, Ryan AS, Ivey FM, Macko RF. Elevated tumor necrosis factor-alpha in skeletal muscle after stroke. Stroke. 2005;36(9):2021–2023.
25. Padilla J, Johnson BD, Newcomer SC, et al. Adjusting flow-mediated dilation for shear stress stimulus allows demonstration of endothelial dysfunction in a population with moderate cardiovascular risk. J Vasc Res. 2009;46(6):592–600.
26. Chen PL, Wang PY, Sheu WH, et al. Changes of brachial flow-mediated vasodilation in different ischemic stroke subtypes. Neurology. 2006;67(6):1056–1058.
27. Stenborg A, Terent A, Lind L. Endothelium-dependent vasodilatation in forearm is impaired in stroke patients. J Intern Med. 2006;259(6):569–575.
28. Henderson LA, Richard CA, Macey PM, et al. Functional magnetic resonance signal changes in neural structures to baroreceptor reflex activation. J Appl Physiol. 2004;96(2):693–703.
29. Rincon F, Dhamoon M, Moon Y, et al. Stroke location and association with fatal cardiac outcomes: Northern Manhattan Study (NOMAS). Stroke. 2008;39(9):2425–2431.
30. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39(2):257–265.
31. Thijssen DH, Black MA, Pyke KE, et al. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011;300(1):H2–H12.
32. Williamson EB, Bronas UG, Dengel DR. Automated edge detection versus manual edge measurement in analysis of brachial artery reactivity: a comparison study. Ultrasound Med Biol. 2008;34(9):1499–1503.
33. Preik M, Lauer T, Heiss C, Tabery S, Strauer BE, Kelm M. Automated ultrasonic measurement of human arteries for the determination of endothelial function. Ultraschall Med. 2000;21(5):195–198.
34. Sonka M, Liang W, Lauer RM. Automated analysis of brachial ultrasound image sequences: early detection of cardiovascular disease via surrogates of endothelial function. IEEE Trans Med Imaging. 2002;21(10):1271–1279.
35. Woodman RJ, Playford DA, Watts GF, et al. Improved analysis of brachial artery ultrasound using a novel edge-detection software system. J Appl Physiol. 2001;91(2):929–937.
36. Crapo R, Casaburi R, Coates A, et al. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111–117.
37. American College of Sports Medicine. Guidelines for Exercise Testing and Prescription. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.
38. Segal SS. Regulation of blood flow in the microcirculation. Microcirculation. 2005;12(1):33–45.
39. Hermann TS, Dall CH, Christensen SB, Goetze JP, Prescott E, Gustafsson F. Effect of high intensity exercise on peak oxygen uptake and endothelial function in long-term heart transplant recipients. Am J Transplant. 2011;11(3):536–541.
40. Xiang GD, Pu J, Sun H, Zhao L, Yue L, Hou J. Regular aerobic exercise training improves endothelium-dependent arterial dilation in patients with subclinical hypothyroidism. Eur J Endocrinol. 2009;161(5):755–761.
41. Lavrencic A, Salobir BG, Keber I. Physical training improves flow-mediated dilation in patients with the polymetabolic syndrome. Arterioscler Thromb Vasc Biol. 2000;20(2):551–555.
42. Vona M, Rossi A, Capodaglio P, et al. Impact of physical training and detraining on endothelium-dependent vasodilation in patients with recent acute myocardial infarction. Am Heart J. 2004;147(6):1039–1046.
43. Perera S, Mody SH, Woodman RC, Studenski SA. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. 2006;54(5):743–749.
44. Looney MA, Rimmer JH. Aerobic exercise equipment preferences among older adults: a preliminary investigation. J Appl Meas. 2003;4(1):43–58.
45. Dalleck LC, Borresen EC, Parker AL, et al. Development of a metabolic equation for the NuStep recumbent stepper in older adults. Percept Mot Skills. 2011;112(1):183–192.
46. Mendelsohn ME, Connelly DM, Overend TJ, Petrella RJ. Validity of values for metabolic equivalents of task during submaximal all-extremity exercise and reliability of exercise responses in frail older adults. Phys Ther. 2008;88(6):747–756.
47. Ryan AS, Dobrovolny CL, Smith GV, Silver KH, Macko RF. Hemiparetic muscle atrophy and increased intramuscular fat in stroke patients. Arch Phys Med Rehabil. 2002;83(12):1703–1707.
48. Ivey FM, Hafer-Macko CE, Macko RF. Exercise rehabilitation after stroke. NeuroRx. 2006;3(4):439–450.
49. Balady GJ, Arena R, Sietsema K, et al. Clinician's Guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation. 2010;122(2):191–225.
50. Whelton PK, He J, Appel LJ, et al. Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. 2002;288(15):1882–1888.
