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Invited Review

Cardiac, Autonomic, and Cardiometabolic Impact of Exercise Training in Spinal Cord Injury

A QUALITATIVE REVIEW

Vivodtzev, Isabelle PhD; Taylor, J. Andrew PhD

Author Information
Journal of Cardiopulmonary Rehabilitation and Prevention: January 2021 - Volume 41 - Issue 1 - p 6-12
doi: 10.1097/HCR.0000000000000564

The cardioprotective effect of regular aerobic exercise in the general population is broadly accepted, but its importance for those with spinal cord injury (SCI) may be even greater. Indeed, SCI is associated with greater risk for cardiovascular disease (CVD) compared with the general population.1 Both symptomatic and asymptomatic CVD prevalence is alarming in these patients2 who have almost three times the OR of developing heart disease and up to six times the risk for stroke compared with the general population.3 Furthermore, early death occurs because of higher rates of obesity,3 type 2 diabetes,4 and CVD.5

AUTONOMIC DYSFUNCTION

Alterations in autonomic function are a direct consequence of SCI that may explain higher susceptibility to CVD6 (Table 1). Indeed, damage to the spinal and/or central components of the autonomic nervous system leads to impaired neural control of the heart and blood vessels.7 Cardiac sympathetic nerve fibers that innervate the heart arise from the thoracic cord between T1 and T5.8 As a result, cardiovascular (CV) sympathetic control is impaired or absent in individuals with SCI above the T6 spinal segment. Therefore, most individuals with SCI above T6 experience persistent hypotension and bradycardia on a daily basis, with episodic falls in blood pressure with the upright posture. Furthermore, transient episodes of aberrantly low and high blood pressure can be life-threatening, presenting as clinical complications known as orthostatic hypotension and autonomic dysreflexia.9 In addition, heart rate variability (HRV), a noninvasive tool for assessing cardiac autonomic control, is markedly impacted with implications for the development of CVD after SCI.10 For example, lesser HRV is associated with cardiac diseases11 and is prognostic for those with known CVD.12 Moreover, HRV decreases with age, is lower in those with a sedentary life style, and is inversely related to inflammatory markers in both healthy individuals and those with CVD.13 On the other hand, there is a greater blood pressure variability in SCI, and greater variability has been associated with cardiac, vascular, and renal damage and with increased risk of CV events and mortality.14 We recently reported that the HRV decrease is seen within the first 24 mo after SCI, suggesting that this decline is due, in part, to a direct impact of SCI itself rather than long-term effect of living with SCI.15

Table 1 - Baseline Autonomic, Cardiac, and Metabolic Deficiencies in Spinal Cord Injury
Autonomic control
Sympathetic activity ↓ vasoconstriction in the periphery
↓ cardiovascular sympathetic control above T6 (complete loss above T1)
Resting vagal tone =but possible orthostatic hypotension and autonomic dysreflexia above T6
HR variability
BP variability
Autonomic reflexes
Baroreflex gain ↓ across almost all levels relies solely on cardiac vagal modulation above T1
Resting hemodynamic
Resting HR =
Resting BP ↓ across almost all levels of injury
Stroke volume =
Resting CO = or slightly lower
Diastolic function
Vascular structure and function
Endothelial function ↓ (impaired)
Arterial stiffness
Intima media thickness
Cardiac function
Left ventricular mass
Exercise responses
Maximal HR = up to T3
↓ above T3
Maximal stroke volume ↓ across all levels
Peak V˙o 2 Decreased across all levels
↓ with ↑ level of injury
Peak CO ↓ mostly above T6
Metabolism
Fat-free mass
Fat mass ↑ higher obesity rate
Type 2 diabetes
Abbreviations: BP, blood pressure; CO, cardiac output; HR, heart rate variability; V˙o2, oxygen uptake.

REDUCED CARDIORESPIRATORY FITNESS

The loss of metabolically active tissue and reduced capacity to routinely engage in aerobic exercise is another major effect of SCI.16 Cardiorespiratory fitness (CRF) is related to the level and extent of SCI and decreases by ∼5% with each level of injury from T11 to C4 such that those with high-level injuries have CRF <40% of their able-bodied peers.17 The demands of producing aerobic work require integrated responses across a number of systems.18 The functional limit of aerobic work, maximal oxygen uptake, is by definition the product of maximal systemic flow (ie, cardiac output [CO]) and active muscle oxygen use (ie, arteriovenous oxygen difference). On both fronts, individuals with SCI have much greater obstacles to overcome in achieving and maintaining high levels of CRF. For example, impaired sympathetic outflow precludes the normal vasoconstriction in nonexercising tissue to redistribute blood flow to active muscle. Indeed, to achieve high-intensity exercise levels, it is critical that blood flow is diverted from inactive tissues, including nonactive skeletal muscle. In those with low maximal CO, maximal CRF can be reduced as much as 40% without regional vasoconstriction.18 This is of particular relevance to those with injuries at T6 and above who have lessened sympathetically mediated tachycardia and contractility, with subsequent reduced stroke volume and CO.19 Moreover, the loss of muscle function and trunk control in those with tetraplegia impacts stability and hence the ability to engage in strenuous exercise. As a result, individuals with the highest level of SCI may not achieve exercise intensities required to reduce cardiometabolic risk.20

METABOLIC DYSFUNCTION

Because of a forced sedentary lifestyle, CV and metabolic diseases develop (such as hyperlipidemia, glucose intolerance, and systemic inflammation) that are superimposed upon the direct impact of SCI. Years of cumulative stresses due to nervous system dysfunction, limited mobility, and increased inflammation lead to a process of accelerated aging.21 For example, chronic hyperglycemia promotes arterial wall hypertrophy and fibrosis and impairs endothelial function.22 Moreover, systemic inflammation (interleukin-6, tumor necrosis factor α, and C-reactive protein) alters nitric oxide production, further contributing to endothelial dysfunction23 and increasing expression of adhesion molecules on activated endothelium, facilitating the formation of atheromatous plaque. Hence, although increased arterial stiffness is part of the normal aging process, systemic complications of SCI may contribute to a premature vascular aging effect. This is particularly true in older individuals with SCI and those with longer time of injury who have the greatest clustering of cardiometabolic risk factors.24

One main goal of rehabilitation is therefore to increase CRF and reduce the CV impact of SCI. For example, greater CRF decreases the risk for CVD mortality independent of age, ethnicity, and health conditions in able-bodied adults.25 A 3.5 mL/kg/min (1 metabolic equivalent [MET]) improvement in CRF relates to a 19% decrease in CVD mortality.26 Furthermore, the risk for all-cause mortality decreases in direct relation to exercise training intensity.27 However, the impact of exercise rehabilitation may differ in SCI depending on the nature of the injury. Although exercise is necessary in the acute/subacute phase of SCI, it may be even more important for older individuals with longer time since injury (TSI) who could benefit from its cardioprotective effect.

In this review, we searched for published studies investigating the CV impact of exercise training in SCI. PubMed and Web of Science databases were screened using the following key words and MeSH terms: [spinal cord injury] AND [training or exercise or rehabilitation] AND [cardiac or autonomic or CV or cardiometabolic]. Original studies that met the following criteria were included: (i) study design: within-group studies, nonrandomized between-groups studies, randomized controlled studies, cross-sectional studies, and cohort studies; (ii) participants: individuals with SCI, and (iii) outcomes: effect of an exercise-based intervention on peak oxygen uptake (V˙o2peak), cardiac structure or function, autonomic function, CV function, and/or cardiometabolic blood markers. Non–English language articles, case studies, review articles, and congress abstracts were excluded. Only original studies with a minimum number of subjects of n = 5 and training duration of 7 d were included. Furthermore, we dichotomized the effect of exercise training into two categories of patients: younger individuals (<40-45 yr) with shorter TSI (<10 yr), considered as those with low CV risk (low CVD risk factors [CVRF]) versus older individuals (∼≥40-45 yr) with longer TSI (≥10 yr) and higher CV risk (high CVRF).

REVIEW OF RELEVANT LITERATURE

EXERCISE TRAINING AND AEROBIC CAPACITY

Training Modalities

Our search identified 46 unique studies that fulfilled eligibility criteria. Thirty-one were in individuals with low CVRF and 15 in those with high CVRF. A substantial number of training modalities have been investigated, from wheelchair training to exoskeleton adapted walking (see Supplemental Digital Content 1, available at: http://links.lww.com/JCRP/A225, and Supplemental Digital Content 2, available at: http://links.lww.com/JCRP/A226). Most exercise training programs require only arms or only leg engagement (either voluntarily or using electrical stimulation devices), such as arm crank, hand cycling, functional electrical stimulation (FES) cycling, or body weight support treadmill training.28–56 These are the most commonly used in SCI rehabilitation due to accessibility and low cost. Less frequently, exercise training programs have employed FES of the lower extremities in combination with voluntary contraction of the arms, such as FES cycling + arm or FES rowing.15,57–62 These forms of exercise are considered as hybrid training since they allow simultaneous contractions of the upper and lower limb muscle groups. Nevertheless, hybrid forms of exercise require more assistance and learning (at least initially) but allow for greater exercise intensities for longer periods.63

Cardiorespiratory Fitness

On the whole, exercise training positively affects V˙o2peak in those with SCI. Indeed, we found 13 out of 16 studies reporting increase in V˙o2peak after training in low CVRF15,28–32,43–46,57,58,64,65 and 9 of 12 in high CVRF48,49,51,53,54,59,61,62,66 (ie, >75% of all studies; see Table 2 for summary; Supplemental Digital Content 1, available at: http://links.lww.com/JCRP/A225; and Supplemental Digital Content 2, available at: http://links.lww.com/JCRP/A226, for details). However, the range of increases in V˙o2peak was highly variable from 10-70% in both low- and high-CVRF individuals. For example, some studies showed >50% increase after only 8 wk of training30 while others showed only 12% improvement after >16 wk of training.54,60 This disparity may be due to the extreme variability in subject characteristics and training protocols. Adaptations to training can be impacted by level and completeness of injury. For example, patients with cervical injuries and/or complete injury have lower baseline V˙o2peak and potentially lower ability to sustain high-intensity exercise. Indeed, two studies reported improvement in V˙o2peak in subjects with thoracic but not cervical injuries, despite similar training program.30,32 As a result, a smaller improvement may be found in studies with a higher proportion of subjects with high-level SCI. Another factor that can account for different adaptation to training is the level of physical activity before or during the training program. Indeed, in most studies, patients are new to training but not always.31 This can explain lower response to training in studies with patients already engaged in rehabilitation. In addition, level of activity outside the study is almost never described, and it is important to note that cohort studies show that individuals engaged in regular physical activity have considerably higher V˙o2peak than those who are sedentary (∼+60%).64,66

IMPACT OF EXERCISE TRAINING ON THE CV SYSTEM

Cardiac Function

An important question is whether exercise training improves cardiac and CV health in SCI. As V˙o2peak is the product of CO and arteriovenous O2 difference, increases in V˙o2peak reflect changes at the cardiac and/or at the peripheral level. A first interesting finding is that 4 wk of quadriceps muscle training using electrical stimulation, followed by 6 mo of FES cycling increased left ventricular (LV) mass in young individuals within ∼6 yr after complete injury35 (Table 2, see Supplemental Digital Content 1, available at: http://links.lww.com/JCRP/A225, and Supplemental Digital Content 2, available at: http://links.lww.com/JCRP/A226). This may relate to increased leg muscle mass (+70%) and thigh blood flow (+115%) as reported in Taylor et al.36 In addition, FES-cycle training has been shown to increase peak CO.34 This 12- to 16-wk program of FES cycling led to a 24% improvement in V˙o2peak associated with a 13% increase in peak CO.34 These results suggest that the leg muscle pump may be important to gains in CO after training in SCI. In fact, CO may be enhanced via increased venous return to the heart leading to increased LV mass and stroke volume. Greater LV mass and/or diameter is, indeed, the most commonly reported finding in cross-sectional studies.64,66–68 Furthermore, only 8 wk of hybrid exercise can result in significant improvement in cardiac structure and function both in low- and high-CVRF individuals with SCI.58,61 This was obtained with concomitant improvement in V˙o2peak. Hence, changes in V˙o2peak seem to be mainly due to improvements at the cardiac level (peak CO, stroke volume, LV mass) in both subcategories. However, there is one report of increases in hemoglobin mass and concentration that could also be a factor in improved V˙o2peak, even without cardiac changes in individuals with SCI and high CVRF.66

Autonomic Function

Few studies have investigated the effect of training on autonomic function in SCI and most of them enrolled subjects with low CVRF. These studies are uniform in finding no effect of endurance training on autonomic function in SCI (Table 2, Supplemental Digital Content 1, available at: http://links.lww.com/JCRP/A225, and Supplemental Digital Content 2, available at: http://links.lww.com/JCRP/A226). This was found despite improved V˙o2peak15 and despite training modalities that engaged the whole body.15,37,54,69 This lack of change may indicate that damaged autonomic pathways after SCI cannot adapt to exercise training as in uninjured individuals. There could be an effect of endurance training on peak heart rate during training sessions55 but this does not seem to impact HRV. Nevertheless, we recently reported that high-intensity exercise training (FES rowing) improved baroreflex gain by 30% after 6 mo of training, compared with a decrease in a matched control group (Solinsky et al).70 Here, again, only individuals in the subacute period after injury (<2 yr) were investigated. In addition, the effects of exercise training on orthostatic hypotension have not been systematically studied in SCI. Further studies will be needed to confirm this result and to understand the mechanisms. Importantly, studies should investigate whether exercise training could have an impact on baroreflex sensitivity in those with high CVRF. Furthermore, more studies should provide quantitative assessment of change in orthostatic tolerance with exercise training in SCI.

Table 2 - Training Effects on Fitness, Cardiac, Autonomic, and Cardiometabolic Functions in Spinal Cord Injurya
Low CVRF High CVRF
Exercise testing
Peak V˙o 2 ↑↑↑ ↑↑↑
Peak PO ↑↑↑ ↑↑
Peak HR = or ↓ ↑↑
Peak VE = or ↑ =
Peak lactate = NS
Peak CO
Cardiac structure and function
Left ventricular mass ↑↑
Stroke volume = or ↑
Resting CO = NS
Diastolic function ↑↑
Autonomic function
Resting HR = or ↓ NS
Maximal HR during training NS
HR variability = NS
BP variability = NS
Resting BP = NS
Baroreflex gain NS
Cardiovascular function
Endothelial function ↑↑ NS
Femoral compliance ↑↑ NS
Thigh blood flow NS
Arterial stiffness
Intima media thickness ↓↓ NS
Blood markers of cardiovascular risk
Fat-free mass NS
Fat mass
Insulin sensitivity = or ↑ =
HDL cholesterol ↑↑
Triglycerides ↓↓ =
IL-6
TNF-α
CRP NS
PTAS NS
Abbreviations: BP, blood pressure; CO, cardiac output; CRP, C-reactive protein; CVRF, cardiovascular risk factors; Hb, hemoglobin; HDL, high-density lipoprotein; HR, heart rate; IL-6, interleukin 6; NS, no study; PO, power output; PTAS, plasmatic total antioxidant status; TNF-α, tumor necrosis factor α; VE, ventilation; V˙o2, O2 uptake.
aOne arrow: only one study reporting the effect of training. Two arrows: two or more and less than five studies agreeing on the same effect of training. Three arrows: Five or more studies agreeing on the same effect of training.

Metabolic Markers and CV Function

A substantial number of studies have investigated the CV and metabolic impact of exercise training in SCI. Studies agree on an overall positive effect of exercise on cardiometabolic parameters in SCI (Table 2, see Supplemental Digital Content 1, available at: http://links.lww.com/JCRP/A225, and Supplemental Digital Content 2, available at: http://links.lww.com/JCRP/A226).

Indeed, at least four studies in individuals with low CVRF and two in those with high CVRF report an increase in lean body mass30,45,62 and/or a reduction in plasma lipids with training.43–45,47 In addition, training can decrease plasma leptin,47 a well-known hormone associated with obesity-linked metabolic and vascular diseases in SCI. All but one study also reported concomitant improvement in V˙o2peak with training, suggesting that metabolic improvements occur when intensity is sufficient to increase CRF. Furthermore, both resistance training45 and high-intensity aerobic exercise (75% heart rate reserve)43 can improve insulin sensitivity, suggesting that muscular anabolism is involved in this adaptation. For example, lower-limb FES training increases both muscle mass and insulin sensitivity after only 10 sessions in mice.71 Finally, exercise training can reduce systemic inflammation and oxidative stress in SCI. The inflammatory cytokines interleukin-6, tumor necrosis factor α, and C-reactive protein, as well as lipid and protein peroxidation were decreased by exercise training,46,47,56 while anti-oxidant capacity was increased.46 Interestingly, femoral and aortic compliances were also improved after training38,42,72 while carotid intima-media thickness was decreased.41 This could be the result of a concomitant reduction in hyperglycemia and systemic inflammation, two main factors of CV function alteration in SCI. These observations are confirmed by cross-sectional comparisons of athletes versus sedentary or nonelite individuals with SCI,73,74 suggesting once again that a high volume and/or intensity of exercise are key components for CV protection in SCI. However, most studies have been in individuals with low CVFR and more studies are needed to confirm a positive impact in those with high CVRF.

DISCUSSION

The current body of literature suggests that the cardioprotective goal of exercise training is partially reached in SCI. Indeed, CRF is increased by training in ∼75% of the studies analyzed. Furthermore, improvement in V˙o2peak is almost always associated with improvements in CV health. Indeed, although it fails to alter autonomic function, exercise training can increase peripheral blood flow and reverse the deleterious effects of deconditioning. Improvements in cardiac structure and function (mainly increased LV mass and CO), body composition (increased lean body mass), lipid status, systemic inflammation (reduced circulatory cytokines and increased anti-oxidant capacity), and CV function (reduced arterial stiffness and improved endothelial function) have been consistently reported across studies. Given the increased risk of CV mortality in SCI, such adaptations are of primary importance. Moreover, these adaptations occur not only in those in the acute phase of recovery post-injury but also in those with longer TSI and considered at high CV risk. Hence, adaptations to training are not dependent on baseline CVRF but rather on the ability to engage in high-intensity level of exercise. Indeed, CV stress during exercise needs to be sufficient to obtain a CV effect of training. One main outcome seems to be the magnitude of V˙o2 that can be achieved during exercise training. The lack of CV adaptations with training approaches using low intensity of exercise52,60 strongly supports this observation. Furthermore, cross-sectional studies between athletes and sedentary subjects show the greatest differences between trained and untrained individuals. On the contrary, functional improvement after training (increase in power output) does not necessarily relate to increases in V˙o2peak. Indeed, increase in power output often occurs before changes at the metabolic level due to a learning effect and a better coordination at the muscular level during exercise. Hence, a training program may improve the ability to perform a task but not result in CV adaptations.

THE BENEFIT OF HYBRID FORMS OF TRAINING

Studies of whole-body hybrid approaches (FES cycling + arms or FES rowing) have led to more consistent (∼12%, range: 8-24%) improvements in V˙o2peak than arms or legs-only training, in those with both low and high CVRF.15,57,58,60–62 This level of improvement may reflect a certain specific physiological adaptation. Hybrid forms of exercise create a leg muscle pump in synchrony with the upper body exercise. Moreover, hybrid exercise can require a high cardiopulmonary demand compared with arms/legs-only exercise in SCI due to the greater muscle mass engaged.63 Hence, higher gains in V˙o2peak from hybrid FES row training should be expected compared with FES cycling alone.63 Furthermore, these forms of exercise may lead to greater cardioprotection. Given that risk for mortality decreases in association with higher exercise intensities27 and that there is a 6 MET exercise intensity threshold below which the reduction in risk may be minimal,75 there is need for training approaches that generate the greatest V˙o2 demand. Hence, combined forms of exercise might be most appropriate for those with SCI, given the more consistent improvements in V˙o2peak with training.

INNOVATIVE APPROACHES

Ventilatory Capacity and V˙o2peak in High-Level SCI

Although active muscle oxygen use is a key determinant of V˙o2peak, aerobic exercise also requires sufficient ventilation to provide oxygen to working muscles.76 In most able-bodied individuals, ventilatory capacity is more than adequate to meet metabolic demands for all exercise intensities.77 However, SCI is characterized by profound respiratory compromise usually proportional to the level of injury, with those with injuries above T3 having the most profound loss.6 There is little impact during arms-only exercise, due to the proportional denervation of both skeletal and pulmonary muscles such that the respiratory system is still able to cope with the demands of arms-only exercise, even after training.78 However, as mentioned previously, hybrid FES exercise can overcome the limited muscle mass and result in higher peak CRF than arms-only or FES legs-only exercise. As a result, aerobic adaptations to exercise in those with high-level injuries can be constrained by reduced ventilatory capacity.57 If this ventilatory limitation could be overcome, greater improvements in CRF could be expected with hybrid FES exercise training.

Ventilatory Support During Exercise

Ventilatory support during exercise could be one approach to overcome this ventilatory limitation. Indeed, we previously found that one single session of noninvasive ventilation led to 12% improvement in CRF during hybrid FES rowing in an individual with an acute, high-level SCI whose CRF had been plateauing for 18 mo despite regular training.79 Moreover, we recently showed that changes in peak alveolar ventilation and V˙o2peak were strongly correlated such that improvement in peak ventilation with ventilatory support resulted in improvement in V˙o2peak during a single session of FES rowing.80 In fact, ventilatory support can improve respiratory pattern, resulting in slower and deeper breathing, a potentially more efficient pattern for the increasing oxygen demand of exercise.80 Not all patients would respond to ventilatory support, but those with higher level of injury, shorter TSI, and incomplete injury seem to be the best responders with a potential increased exercise capacity.80

Limitation of the Current Literature

One important limitation of the current literature, is the low quality of the studies. Studies have a relatively small sample size (sometimes n ≤ 5) and are underpowered. In addition, many studies are not controlled, making the contribution of natural recovery during the subacute period or spontaneous activity independent of the study difficult to ascertain. When studies are randomized as exercise versus control, significant changes with training are usually found compared with baseline only, not supporting the superiority of training. Furthermore, important selection or methodological bias makes any comparison difficult. For example, some studies include unmatched groups of subjects (up to >10-yr difference in age or >5-yr difference in TSI).33,53 In general, study discrepancies (level of injury, TSI, training procedures) do not allow for comparison among studies. In addition, some studies omitted to consider criteria of maximality for V˙o2peak testing. Indeed, some authors have termed their values V˙o2peak but did not use standardized protocol or follow the widely accepted criteria to ensure achievement of true V˙o2max. Other studies do not provide details on either protocol or criteria. Only a few studies reported objective V˙o2peak using at least three criteria of maximality.15,57,58,61,63 As a result, the magnitude of physiological adaptations could have been misestimated in some studies. Finally, whether training effects are maintained has never been investigated prospectively. Studying training effects in SCI is very difficult due to significant interindividual differences, a relatively small patient population, and complexity of care. Despite these constraints, prospective and randomized controlled studies, with larger samples of well-matched individuals, will be required to provide more robust evidence of cardiac and CV improvements after training in SCI.

Future Directions

Any forms of exercise allowing for high-intensity level of exercise training should be developed and further investigated. Among them, combinatorial therapies are promising approaches in SCI. For example, endurance training can be associated with muscle strengthening45 and/or with ventilatory support for high-level injury.80 Furthermore, new technologies will soon allow for greater intensity level of exercise with robotic-assisted training or underwater training approaches.55 Finally, motivation is a key determinant of long-term training compliance. New technologies with digitalized platform and social networking may offer longer adherence to training, which could be interesting to investigate in SCI.

SUMMARY

Cardiovascular complications are the result of the direct and indirect consequences of SCI. Years of accumulated relative inactivity lead to an accelerated aging and a high risk of CV death. Exercise training is a cornerstone of rehabilitation in SCI due to its potential cardioprotection. Although its effect on autonomic dysfunction seems to be lacking, exercise training does have an important role in counterbalancing the effect of deconditioning, preserving cardiac function, and improving cardiometabolic outcomes such as lean body mass, blood lipids, and systemic inflammation. However, a major facet of exercise as underscored from current studies is that adequate training intensity, volume, and frequency are essential for CV gains. More recently, forms of combined exercise training (whole-body hybrid leg FES + arms) have been shown to produce the highest V˙o2 during exercise. However, increasing peak ventilatory capacity may be necessary for those with high-level SCI to allow for increased CRF with this form of exercise. Nonetheless, there is a need for future studies with bigger sample sizes, well-matched subject groups, and randomized controlled designs to investigate whether high-intensity hybrid forms of training result in greater CV gains.

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Keywords:

autonomic; cardiac rehabilitation; cardiovascular; exercise training; spinal cord injury

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