| | Rapid Vascular Adaptations to Training and Detraining in Persons With Spinal Cord InjuryAbstract Thijssen DH, Ellenkamp R, Smits P, Hopman MT. Rapid vascular adaptations to training and detraining in persons with spinal cord injury. ObjectiveTo assess the time course of arterial adaptations during 6 weeks of functional electric stimulation (FES) training and 6 weeks of detraining in subjects with spinal cord injury (SCI). DesignIntervention study (before-after trial). SettingUniversity medical center. ParticipantsVolunteer sample of 9 subjects with SCI. InterventionsSix weeks of twice weekly FES cycling and 6 weeks of detraining. Main Outcome MeasuresVascular characteristics were measured by plethysmography (baseline and peak blood flow of the thigh) and echo Doppler (diameter of the femoral artery and flow-mediated dilation [FMD]). ResultsAfter 2 weeks of FES training, arterial characteristics changed significantly; there was an increase in baseline and peak blood flow, an increase in femoral artery diameter, and a decrease in FMD of the femoral artery. Detraining reversed baseline and peak thigh blood flow, vascular resistance, and femoral diameter toward pretraining values within 1 week. However, detraining did not restore the FMD of the femoral artery, even after 6 weeks. ConclusionsTwo weeks of hybrid FES training (4 exercise bouts) is sufficient to improve peak leg blood flow and arterial diameter, and to normalize FMD. In addition, detraining results in rapidly reversed vascular characteristics within 1 week.
EXERCISE TRAINING RESULTS in various physiologic adaptations that enhance athletic performance, but the cessation of training leads to a partial or complete reversal of these adaptations.1, 2 Accordingly, enforced inactivity or paralysis leading to extreme inactivity, as with people with spinal cord injury (SCI), results in marked adaptations of the vascular tissue such as decreased baseline and peak blood flow, decreased diameter, and diminished capillarization.3, 4, 5, 6, 7 The only method to effectively exercise the paralyzed legs of people with SCI is functional electric stimulation (FES) training. Although this method has frequently been evaluated for muscular8, 9, 10 and vascular characteristics,3, 4, 11, 12, 13 it is not clear whether the benefits are proportional to the time and effort the patients must invest in FES training.
Previous studies found that at least 4 weeks of dynamic,14 or 4 weeks of daily static15 FES exercise, resulted in arterial adaptations in subjects with SCI. The magnitude of these changes is comparable to that found in studies that used 6 or 8 weeks of stimulation.4, 6, 2, 13Although this suggests rapid vascular adaptation, little is known about the time course of these adaptations during FES training. In addition, the effects of detraining on vascular parameters in people with SCI are unknown. Recently, vascular adaptations were studied after onset of SCI. Adaptations were largely completed within 3 to 6 weeks postinjury.16 Whether detraining leads to a similar time course is debatable. Moreover, knowledge about detraining provides insight into the preservation of the benefits of FES training.
Our purpose in this study was to assess the time course of arterial vascular adaptations to training and detraining in subjects with SCI. The paralyzed legs of such subjects provide a unique human model with which to examine the time course of training and, especially, detraining. A period of FES training, which improves vascular and muscular characteristics, is followed by the cessation of the stimulus for the exercise-induced adaptations. Consequently, this abruptly restores the situation of extreme inactivity. To assess the time course, vascular adaptations in subjects with SCI were measured before and after 2 and 6 weeks of hybrid FES cycling exercise, and at 1 week and 6 weeks posttraining.
Methods  Nine subjects with SCI (8 men, 1 woman; table 1) volunteered to participate in this study after receiving verbal and written information about its content and intent. Eight subjects had a traumatic complete motor and sensory spinal cord lesion (American Spinal Injury Association [ASIA] grade A), while 1 participant had a motor and sensory incomplete lesion (ASIA grade C). The level of injury varied from C5 to T12. No abnormalities were reported from physical examinations, which included medical history, a 12-lead resting electrocardiogram (ECG), and cardiac and pulmonary auscultation. Analysis of concentrations of blood cholesterol (5.7±0.7mmol/L), triglycerides (1.68±0.96mmol/L), low-density lipoprotein (3.82±0.79mmol/L), and high-density lipoprotein (1.18±0.25mmol/L) showed no abnormalities (compared with the normative range). None of the subjects had any cardiovascular diseases or used medication known to interfere with the cardiovascular system. Two subjects stopped smoking at least 2 weeks before the first measurement. Prior to testing, all subjects gave their written informed consent. The research was completed in accordance with the Declaration of Helsinki, and the ethics committee of the Radboud University Nijmegen Medical Centre approved the study. | | |  | Subject | Age (y) | Height (m) | Weight (kg) | Lesion Level | ASIA Grade⁎ | Time Since Lesion (y) | Medication | |
|---|
| 1 | 52 | 1.87 | 80 | T7 | A | 20 | Metanamine, furadantine | |
| 2 | 45 | 1.96 | 109 | T5 | A | 25 | | |
| 3 | 36 | 1.67 | 48 | T12 | C | 3 | Cibutine, antibiotics, sodium lauryl sulfoacetate with sodium citrate and sorbitol (Microlax) | |
| 4 | 38 | 1.82 | 84 | C7 | A | 13 | Dantrium, baclofen, oxybutinine | |
| 5 | 46 | 1.78 | 78 | T8 | A | 10 | | |
| 6 | 25 | 1.75 | 62 | T4 | A | 2 | Methylphenadate (Ritalin), imipramine | |
| 7 | 43 | 1.70 | 65 | C5 | A | 24 | Bisacodyl, baclofen | |
| 8 | 43 | 1.84 | 88 | T11 | A | 1 | | |
| 9 | 24 | 1.80 | 71 | T6 | A | 4 | | |
| Mean | 39±3 | 1.80±0.03 | 76±6 | | | 11±3 | | | | | |
|
⁎
ASIA grade is used to classify the completeness of the lesion: A, sensory and motor complete; B, sensory incomplete but motor complete; C, sensory and motor incomplete but no functional motor activity. |
Protocol Subjects were tested before and after 2 and 6 weeks of training to assess the time course of arterial adaptations to FES exercise. Subjects trained twice a week for 6 weeks under supervision of a researcher, with at least 1 day between training sessions. In addition, arterial characteristics were measured 1 week and 6 weeks after the training to assess the time course of detraining. Hybrid Training A stationary computer-controlled FES ergometera was used for hybrid FES cycling exercise that included stimulated asynchronous leg cycling and voluntary synchronous arm cranking. The FES ergometer provides stimulation via surface electrodesb (5×8cm) placed bilaterally over the hamstring, gluteal, and quadriceps muscles. Each training session started with a warm-up of 5 minutes with arm activity only. Thereafter, stimulation of the thigh and gluteal muscles started with 50mA. Intensity of stimulation was manually increased in steps of 10mA to a maximum of 150mA. Stimulation was increased based on a decrease in power output, which indicates fatigue of the stimulated muscle groups. Subjects with SCI trained for approximately 25 minutes with stimulation.14 Testing Procedure After a 12-hour overnight fast, evaluation measurements were started between 8:30 and 9:30 am. Subjects refrained from drinking caffeine, chocolate, kiwi, vitamin C supplements, and alcohol for at least 18 hours before the test. Room temperature was controlled at 23°±1°C. Subjects emptied their bladder 1.5 hours before the test to minimize the possibility of any sympathetic activity from bladder filling on the peripheral vascular tone. Subjects were positioned comfortably on a bed in the supine position with a slight elevation of the head. During an acclimatization period of 30 minutes, strain gauges and venous occlusion cuffs were positioned. The right arm was positioned about 5cm above heart level. A cuff (10cm) was placed proximally around the right upper arm and was connected to a rapid cuff inflator.c A mercury-in-silastic strain gaugec was placed at the widest girth of the forearm. To minimize the contribution of hand skin blood flow, 1 minute before and during baseline blood flow measurement, the hand circulation was excluded by inflating a pediatric cuff around the wrist to 220mmHg.17 To measure thigh characteristics, a cuff (12cm) was placed proximally around the upper leg. Both legs were elevated and the lower legs rested on a platform 14cm high. The strain gauges were placed at mid-thigh, at least 10cm above the patella and at least 4cm below the cuff.18 Resistance vessels Baseline blood flow and vascular resistance of the forearm and thigh were measured unilaterally (at the right side) for 5 minutes using venous occlusion plethysmography. A cuff was inflated and ECG triggered, within 1 heart beat, to a cuff pressure of 50mmHg.19 This pressure was sustained for 9 heart beats, after which the cuff was instantaneously deflated (for 10 heart beats). Before each blood flow measurement, blood pressure was measured auscultatory at the left brachial artery using a sphygmomanometer, and mean arterial pressure (MAP) was calculated. Conduit arteries Systolic and diastolic vessel diameters of each artery were measured with an echo Doppler deviced with a 5- to 7.5-MHz broadband linear array transducer. For the femoral artery, images were made 2cm proximal of its bifurcation into the deep and superficial femoral artery. Carotid artery resting diameter and resting flow were measured 3cm proximal of the bifurcation of the left carotid artery into the external and internal carotid artery. Brachial artery images were obtained 3cm proximal of the olecranon process. The flow-mediated dilation (FMD) of the brachial and femoral arteries, representing endothelial function,20, 21 were assessed after 5 and 10 minutes of ischemia, respectively. After cuff deflation, hyperemic flow was recorded during the first 25 seconds. Diameter images were videotaped for 4 minutes to assess the maximal endothelium-dependent dilation of the artery offline. Training effects Leg cycling performance was assessed before and after the training using a computer–controlled leg cycling ergometer.e Stimulation was increased to achieve a pedaling rate of 50rpm. The test was terminated when maximal stimulation (140mA) was achieved and pedaling rate dropped below 35rpm.13 Data Analysis Resistance vessels Plethysmographic data were digitalized at a sample frequency of 100Hzf and analyzed with a customized computer program.g Blood flow (in mL·min−1·dL−1) was calculated as the slope of the volume change over a 4-second interval, starting directly after the inflation-induced cuff artifact (calf and forearm, 1s; thigh, 2s). Vascular resistance was calculated as blood flow divided by auscultatory MAP in mmHg per mL·min−1·dL−1.18 Conduit arteries To measure resting diameter, 3 consecutive images in the longitudinal view were frozen at the peak systolic and end-diastolic phase. Offline, 3 measurements were performed per diameter image, and the mean diameter (D) was calculated by using the formula:  by systolic diameter +  by diastolic diameter. Vessel diameters of the brachial and femoral artery during the FMD were measured offline from videotape at 50, 60, 70, 90, 120, 180, and 240 seconds after cuff release. FMD was expressed as the maximal absolute (in millimeters) and relative (in percentage) diameter change in end-diastolic baseline diameter. The ratio between the relative FMD response (%FMD) and the primary stimulus for vessel dilation (mean wall shear rate [MWSR]) was calculated. Regional MWSR was calculated as (4·Vmean/D) (s−1). Delta MWSR (ΔMWSR) was defined as the difference between rest and peak response and was used to calculate the amount of vasodilation per stimulus during the FMD.22 The hyperemic flow was measured during the initial 25 seconds after cuff release. The 2 highest flow profiles were accepted as the peak flow, peak MWSR, and peak wall shear rate (PWSR). Statistical Analysis Statistical analyses were performed using the SPSSh statistical software package. We used a paired t test to assess differences between pre- (0wk) and posttraining (6wk) in body mass, blood pressure, and leg volume. Leg cycling performance data of 3 subjects were missing, therefore, we used the nonparametric Wilcoxon signed-rank test. A repeated-measures analysis of variance (ANOVA) (dependent variable, time) was used to assess vascular changes during training and detraining at 5 time points; 0, 2, 6, 7 (6+1: 1wk detraining), and 12 (6+6: 6wk detraining) weeks. Post hoc analysis assessed significant changes between the different time points. Power analysis for the study’s 3 main parameters to detect a moderate effect (baseline blood flow, 0.5mL·min−1·dL−1; baseline diameter, 0.7mm; FMD, 3.0%), resulted in a group size of 9 subjects. Data are presented as means ± standard deviation. The level of statistical significance was set at 5%. Results One subject did not finish the training period and was excluded from the analysis. Data from 2-week training and 1-week detraining were missing for 1 subject. These data were intrapolated in order to maintain the power of the statistical analysis. FES training did not result in changes in body mass (pre, 74±18kg; post, 75±18kg; t test, P=.52) or MAP (pre, 92±7mmHg; post, 92±12mmHg; t test, P=.86). Leg volume was increased after the training period (pre, 7.48±0.48L; post, 7.86±0.50L; t test, P=.02). The workload during the Ergys leg cycling performance test increased after training (pre, 1.5±1.9kJ; post, 4.2±4.1kJ; Wilcoxon, P=.03). Resistance Vessels Thigh baseline blood flow and vascular resistance tended to change (ANOVA, P=.078 and P=.057) during the period of training and detraining (figs 1A, C). Post hoc analysis revealed that vascular resistance decreased significantly after 2 (0 vs 2, P=.01) and 6 weeks (0 vs 6, P=.04) of training. During detraining, thigh vascular resistance returned to pretraining values within 1 week of detraining (post hoc 0 vs 6+1, P=.51). Thigh baseline blood flow significantly increased within 2 weeks (post hoc 0 vs 2, P=.03) and tended to increase after 6 weeks of FES cycling (post hoc 0 vs 6, P=.08). Forearm baseline blood flow and vascular resistance did not change during the study (figs 1B, D). The postocclusive peak blood flow of the femoral artery was significantly altered during training and detraining (ANOVA, P=.04) (fig 2A). Peak femoral blood flow tended to increase after 2 and 6 weeks of training (post hoc 0 vs 2 and 0 vs 6, P=.059). In addition, the peak blood flow returned to pretraining values within 1 week of detraining (post hoc 0 vs 6+1, P=.76; 6 vs 6+1, P=.04). Brachial artery reactive hyperemia did not change (fig 2B). Conduit Arteries The diameter of the femoral artery changed during the training. Post hoc analysis revealed that the diameter increased within 2 weeks by 6% (0 vs 2, P=.02), with no additional increase after 6 weeks (2 vs 6, P=.28) (fig 3). After the training, diameter of the femoral artery reversed toward pretraining values within 1 week (post hoc 0 vs 6+1, P=.053; post hoc 6 vs 6+1, P=.069). Carotid and brachial resting diameter did not change during training (2 and 6wk) and detraining (6+1wk and 6+6wk) (table 2). Carotid, brachial, and femoral artery baseline flow and MWSR and PWSR did not change during the study. The FMD of the femoral artery showed a significant decrease (ANOVA, P=.002) within 2 weeks of training (post hoc 0 vs 2, P=.01) with no further decrease thereafter (2 vs 6, P=.15) (fig 4A). During detraining, post hoc analysis showed an increase in FMD within 1 week (6 vs 6+1, P=.046). However, FMD of the femoral artery was still significantly lower compared with pretraining values after 1 week (0 vs 6+1, P=.04) and 6 weeks (0 vs 6+6, P=.049) of detraining. FMD was corrected for the eliciting stimulus,21, 22 and results show a similar pattern to the uncorrected FMD (ANOVA, P=.026); (fig 4C). Brachial FMD (figs 4B, D) did not change during the study. Discussion The main finding of this study was that FES training in subjects with SCI provides a strong exercise stimulus leading to rapid vascular adaptations in the exercised area within 2 weeks after exercise training begins. After FES training, the state of extreme inactivity in the paralyzed legs of subjects with SCI is restored. The paralyzed legs of these subjects, therefore, offer a unique model with which to examine the effects of detraining in human vascular tissue. Interestingly, cessation of FES cycling rapidly reversed vascular characteristics toward pretraining values within only 1 week. Therefore, another principle finding of this study was that the vascular adaptations to training or detraining have a different time course, which suggests that detraining is not simply the reverse process of training. Time Course During Training Two weeks of FES cycling (including 4 exercise bouts only) resulted in a significant increase in peak leg blood flow and diameter of the femoral artery, and a decrease in leg vascular resistance and FMD. After these initial adaptations, no significant additional changes were seen, which may indicate that the largest part of the potential vascular adaptations to FES exercise is reached after a few exercise bouts. Moreover, the exercise-induced changes in baseline blood flow, resting diameter, and FMD within 2 weeks of training are comparable to adaptations reported after longer and more intensive periods of FES training.3, 4, 13, 14, 15 For example, our study results indicated a 6% increase in femoral diameter after 2 weeks, while previous studies reported a 5% to 8% enhancement after 4 to 6 weeks of training.3, 4, 13, 14, 15 Also, the 30% increase in leg baseline blood flow after 2 weeks of FES cycling is in range with the 30% to 50% increase in resting blood flow after 6 weeks to 7 years of training, using plethysmography4 or echo Doppler.6, 13 Finally, the 48% decrease of the corrected FMD is comparable to the 40% decrease after 4 weeks of daily electric stimulation.15 These findings indicate a rapid onset of FES exercise-induced vascular changes within 2 weeks, followed by minimal adaptations thereafter. The possibility exists that the initial exercise bouts provide a significant stimulus to the onset of gene expression,23 which could have led to the observed vascular adaptations. Further, because angiogenesis-related gene expression rapidly attenuates during training,24 this could have accounted for the failure to observe continued adaptations in vascular changes with continued training (ie, 2–6wk). To achieve additional vascular adaptations, training intensity must be increased dramatically. Interestingly, the 25% increase in peak femoral blood flow, which represents structural peripheral adaptations,22 found after 2 and 6 weeks of FES cycling, was lower than in previous studies that used a longer or more frequent training design. For example, 6 weeks of FES training 3 times a week showed an increase of 44%13 and 8 weeks of training 4 times a week increased peak blood flow by 80%.3 Because exercise-induced structural vascular adaptations occur more gradually, it appears that adaptations in peak blood flow are dependent on the duration of the exercise period. Time course of vascular adaptations may differ between different vascular beds (ie, conduit vs resistance vessels), as has been indicated in exercise training studies in animals25 and humans.26 Olive et al5 reported a close relation between the peak hyperemic flow and muscle volume with no differences in a cross-sectional study of long-term SCI subjects and healthy subjects, after correcting hyperemic flow for units of muscle mass. Based on this, one may question whether peak blood flow and muscle mass are also linked during training. Interestingly, in line with vascular adaptations, adaptations in muscle mass to FES training seem to depend on the duration of the exercise period. The 9% increase in thigh volume found in this study is lower than the 21% and 22% to 39% increases found after 8 weeks of daily FES cycling9 or 98 bouts of FES cycling in about 38 weeks.27 It is well known that aerobic exercise training in healthy subjects or in patients with a disease28, 29 leads to an enhanced FMD of the brachial artery. Adaptations in the FMD response have even been reported to occur after 4 days of aerobic training.30 In contrast, extreme inactivity (such as with the paralyzed legs of subjects with SCI) seems to have strikingly different effects. A relatively high FMD of the superficial femoral artery in long-term SCI has been reported.31 In addition, this high FMD was reported to decrease toward normative values after 4 weeks of daily FES training in SCI.15 Our findings are in agreement with these previous SCI studies.15, 31 In addition, 732 or 5233 days of bedrest, another model of inactivity, in healthy subjects resulted in an increase of the FMD. Clearly, our results indicate that inactivity is not just the opposite of exercise training. It is hypothesized that the bioavailability of nitric oxide (NO) or the sensitivity of the smooth muscles to NO, an important endothelium-derived relaxing factor, plays a role in the inactivity-related elevation of FMD. More research is necessary to unravel the mechanism behind the adaptations during (de)training of the FMD. Time Course During Detraining Our results indicate that baseline and peak leg blood flow, femoral diameter, and femoral artery FMD reversed toward pretraining values within 1 week after the training ended (table 3). Previous studies did not examine the time course of vascular adaptations during the first weeks of detraining but only reported vascular characteristics after 6 or 8 weeks of detraining in healthy subjects,29, 34, 35, diabetes,36 and patients with chronic heart failure.37, 38, 39 In healthy subjects, the cross-sectional area of the femoral artery34 and forearm skin blood flow35 returned to pretraining values after 6 and 8 weeks detraining, respectively. Detraining in patients with chronic heart failure or diabetes showed FMD to decrease to pretraining values after 637 or 8 weeks.36, 38, 39 Collectively, the effects observed after 6 to 8 weeks of detraining in health and disease34, 35, 36, 37, 38, 39 are in line with our findings after only 1 week of detraining in SCI. This may suggest that the previous studies of detraining after 6 to 8 weeks may have underestimated the rapid time course of this process. However, because exercise training improves physical fitness in healthy subjects and patients, many of these subjects stay physically active after the training, inhibiting the process of detraining. In contrast, after subjects with SCI end the training, their paralyzed legs become inactive again. The paralyzed legs of people with SCI, therefore, provide a unique model with which to examine the effects of detraining in human vascular tissue. | | | | Parameter | Training | Detraining | |
|---|
| 2 Weeks | 6 Weeks | 6+1 Weeks | 6+6 Weeks | |
|---|
| Baseline BF | ↑ | ↑ (.08) | = | = | |
| Baseline VR | ↓ | ↓ | = | = | |
| Peak BF | ↑(.06) | ↑(.06) | = | = | |
| Diameter | ↑ | ↑ | = | = | |
| FMD (%) | ↓ | ↓ | ↓ | ↓ | |
| FMD (%)/MWSR | ↓ | ↓ | = | ↓ | | | | |
Remarkably, after 6 weeks detraining in SCI subjects, the normalized FMD after training was still not reversed to pretraining values. Previous studies of the FMD response in able-bodied subjects36, 37, 38, 39 found that the enhanced FMD after training was decreased to pretraining values after 6 to 8 weeks. This unexpected finding may be explained by the fact that the FMD response in the paralyzed legs of SCI subjects (decreases by training) represents a different physiologic mechanism than that in healthy subjects (improves by training). Clinical Relevance Previous longitudinal studies in subjects with SCI with FES cycling used intensive exercise training6, 11, 13 for extended periods of at least 6 weeks. Based on the findings of the present study, we suggest that only minimal training effort (4 training sessions of ≈25min of stimulation) is sufficient to initiate rapid vascular adaptations. Moreover, the present study advocates the increase in training duration or intensity after the initial period, since the adaptations after 2 weeks of FES cycling reported in our study are in line with adaptations found after longer and more intensive training periods. In addition, our study results indicate that detraining rapidly reverses the exercise-induced vascular adaptations and, therefore, an exercise program is necessary to maintain the vascular benefits of exercise in subjects with SCI. Conclusions Our findings demonstrated that just 2 weeks of hybrid FES training (4 exercise bouts) markedly improved baseline and peak leg blood flow, and arterial diameter, and normalized FMD. In addition, detraining resulted in a rapid reversal of the vascular characteristics, that is, within 1 week after cessation of training. Suppliers
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MEDLINE a Department of Physiology, Institute for Fundamental and Clinical Human Movement Sciences, the Netherlands b Department of Pharmacology, Radboud University Nijmegen Medical Centre, the Netherlands  Correspondence to Maria T. Hopman, MD, PhD, Dept of Physiology, RUNMC, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Reprints are not available from the author.
Supported by the Johan van Drongelen Foundation. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. PII: S0003-9993(05)01383-3 doi:10.1016/j.apmr.2005.11.005 © 2006 American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved. | |
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