It is estimated that more than 2 million people worldwide currently live with spinal cord injury (SCI). The age of major trauma leading to SCI shifted from a mean age of 36 yr in 1990 to 53.8 yr in 2013.1,2 SCI causes partial or total block of neural signal transmission across and below the level of the injury as a result of damage to the spinal cord or the spinal nerve roots within the spinal canal. SCI affects patient quality of life and psychological functioning, and also causes functional and economic hardship for the family.3
Cardiovascular disease (CVD) is the leading cause of death in patients with SCI,4 occurring more often and at an earlier age than in individuals without SCI.5 Patients with SCI are generally forced to lead a sedentary lifestyle and occupy the lower end of the physical activity spectrum. This population has limited ability to perform physical activities and their systemic response becomes blunted as a result of loss of somatic and autonomic control. The pathology of SCI and the reduced level of physical activity lead to deteriorations in patient body composition and metabolic profile.6 SCI also results in a sympathetic-parasympathetic imbalance in cardiovascular (CV) autonomic pathways.7,8 This deterioration in body composition and profile, paired with physical inactivity, increase the risk of CVD.
Rehabilitation is a lifelong process in patients with SCI, and there is currently a lack of effective clinical treatment for the recovery of spinal nerve function. The importance of physical exercise for improving CV function has been clearly demonstrated in able-bodied individuals.9 In patients without SCI, exercise exerts preventive effects by promoting antiatherogenic effects including improving whole-body composition and metabolism as well as other CVD risk factors.10 Many exercise programs involving active upper body exercise and passive cycling are commonly employed in patients with SCI.11 Here, we review recent research on the effects of exercise on autonomic and CV function, arterial stiffness, venous thromboembolism, metabolism, inflammation, and gene expression (see the Table). An understanding of the impacts of exercise may provide a tool to help to improve health in individuals with an SCI.
Effects of Exercise in Patients With SCI
||Level of Injury (n, Time Since Injury)
||Type of Exercise
||Change in Variable of Interest
|Abreu et al (2016)15
||C6-C7 (7, 65.1 ± 64.3 mo)
||One-hand cycle training
||Sympathetic activity: LF↓ SD2↓
Parasympathetic activity: rMSSD↓ HF↓ SD1↓
|Kyriakides et al (2019)14
||TSCI: C5-C8 (10, 7.9 ± 5.5 yr)
PSCI: T6-T10 (14, 12.9 ± 5.5 yr)
|Weekly 4-hr physical activity
TSCI: upper extremity exercises
PSCI: upper extremity exercises and regular use of standing frame
|Hubli et al (2014)34
||C2-T5 (20, 18 ± 8 yr)
Athletes (17 ± 4 hr/wk)
|Horiuchi and Okita (2017)51
||T8-L1 (17, 16 ± 7 yr)
||10-wk arm-cranking exercise training
PAI-1↓ BM↓ WC↓ SBP↓ TG↓
|Kim et al (2015)56
||T5-T11 (8, >6 mo)
||6-wk indoor hand-bike exercise program
BMI↓ body fat↓ WC↓ insulin↓ HOMA-IR↓
|Schneider et al (1999)57
Complete or incomplete (n = 6)
|Arm exercise in physically active paraplegic subjects (5, recreational basketball and 1, swimming)
||Rate of lipid utilization↑
|Nooijen et al (2012)58
72% motor complete (n = 30)
|Wheelchair, 5-12 mo
TC↓ TC/HDL ratio↓
|Nooijen et al (2017)59
62% motor complete (39, 150 ± 74 d).
|A behavioral intervention promoting physical activity
|Totosy de Zepetnek et al (2015)60
||C3-T11 (n = 12)
||PAG training involved ≥20 min of moderate-vigorous aerobic exercise and 3 × 10 repetitions of upper-body strengthening exercises 2 times/wk
||No changes in blood glucose insulin, lipid profiles, adipokines, PAI-1, IL-6, TNF-α
|Liusuwan et al (2017)61
||n = 20
||16-wk intervention. Perform aerobic and resistance programs 3 d/wk
||No changes in weight, BMI, BMI z-scores HDL, LDL, TC, TG
|Bakkum et al (2015)65
||Hybrid cycle group (9, ≥10 yr)
Hand cycle group (10, ≥10 yr)
|Twice/wk for 16 wk
||Insulin resistance↓ CRP↓ IL-6↓ IL-6/IL-10 ratio↓ fat percentage↓
No changes in TG, HDL-C, IL-10
|Sadowska-Krepa et al (2016)68
||C4-C8 (32, >3 yr)
||Wheelchair rugby (once/wk for 3 hr)
|Ordonez et al (2013)69
At or below T5 (n = 9)
|A 12-wk arm-cranking exercise program
TAS↑ GPX↑ MDA↓
Abbreviations: BDNF, brain-derived neurotrophic factor; BM, body mass; BMI, body mass index; CRP, C-reactive protein; EAP, enzymatic antioxidant potential index; GPX, glutathione peroxidase; HDL-C, high-density lipoprotein cholesterol; HF, high frequency power; HOMA-IR, homeostasis model of assessment-insulin resistance; IL-6, interleukin-6; IL-10, interleukin-10; LDL-C, low-density lipoprotein cholesterol; LF, low frequency power; MDA, malondialdehyde; PAG, physical activity guideline; PAI-1, plasminogen activator inhibitor 1; PSCI, pediatric spinal cord injury; PWV, pulse wave velocity; rMSSD, root of the mean squares differences of successive NN intervals; SBP, systolic blood pressure; SCI, spinal cord injury; SD1, standard deviation of short-term HRV; SD2, standard deviation of long-term HRV; TAS, total antioxidant status; TC, total cholesterol; TG triglyceride; TNF-α, tumor necrosis factor-α; TSCI, traumatic spinal cord injury; V˙o2peak, peak oxygen uptake; WC, waist circumference.
EFFECTS OF EXERCISE ON AUTONOMIC FUNCTION OF THE CARDIOVASCULAR SYSTEM FOLLOWING SCI
EXERCISE IMPROVES HEART RATE VARIABILITY
The heart accepts sympathetic innervation from the upper thoracic segments of the spinal cord (T1-T5) and parasympathetic innervations from the vagal nerve. Blood vessels in the upper body receive sympathetic innervations from T1 to T5 and the spinal sympathetic pre-ganglionic neuron, while the blood vessels of the lower body are controlled by the more caudal T5 to L2 spinal sympathetic neurons. SCI can thus affect cardiac autonomic function. Heart rate variability (HRV) measured by the variation in the beat-to-beat interval represents the ability of the heart to respond to a variety of internal and external stimuli and may reflect the residual CV sympathovagal regulation after SCI.12 Specifically, the high frequency (HF-HRV; 0.15-0.4 Hz) component reflects cardiac parasympathetic modulation, while the low frequency (LF-HRV; 0.04-0.15 Hz) component includes both parasympathetic and sympathetic modulations. The low frequency/high frequency (LF/HF) ratio has been described as a measure of the sympathovagal balance of the cardiac autonomic nervous system. Patients with SCI show significantly lower acceleration of heart rate during exercise and slower deceleration after exercise, and a lower HRV compared with sex- and age-matched controls.13,14
In general, exercise is beneficial in patients with CVD, and among others induces recovery of HRV. Quadriplegics with SCI, however, exhibited reduced sympathetic and parasympathetic activities during the recovery period after hand-cycle training, reflecting impaired CV autonomic response after acute exercise.15 Parasympathetic activity remained reduced in patients with SCI, even at 3 min after the end of training, suggesting a deficiency in parasympathetic reactivation in these patients. It has previously been suggested that exercise may improve HRV in myocardial vagal tone and decrease sympathetic activity.16 Investigations have also shown that paraplegic individuals who underwent regular physical exercise had more complex R-R interval series, lower sympathetic modulation, and higher parasympathetic modulation than sedentary paraplegic patients.17
Patients with different levels of SCI also present with different degrees of autonomic impairment of CV function. Previous studies showed that patients with SCI above T6 showed lower LF power (ms2), which reflects lower sympathetic activity, greater LF power (n.u.), lower HF power (ms2 and n.u.), and greater LF/HF ratio. Therefore, patients with SCI above T6 had greater CV autonomic dysfunction than patients with SCI below T6.18 Exercise had less effect on recovery after SCI in subjects with tetraplegia as compared with subjects with paraplegia. Subjects with paraplegia showed greater change in HF, LF, and LF/HF following sitting maneuver. Spectral parameters of HRV were associated with the level of the injury.14 Different types of damage may also show different responses to exercise in patients with SCIs at the same level. West et al19 reported that athletes with cervical autonomic incomplete SCI exhibited a faster time-trial time and a higher average speed, maximum heart rate, and average heart rate compared with patients with cervical autonomic complete SCI. However, there were no differences in heart rate or in time-trial time and speed between patients with thoracic autonomic complete versus incomplete SCI.19
AUTONOMIC DYSREFLEXIA IN SCI
Autonomic dysreflexia (AD) is characterized by life-threatening hypertension and orthostatic hypotension and is known to prevent or delay rehabilitation, and is the CV condition to directly cause death or irrevocable damage to individuals with SCI.20 AD occurs not only in patients with acute SCI, and is more frequent with time post-injury during the chronic phase of injury. AD had a reported incidence of 17.6% at 20 yr post-injury, compared with only 10.9% at 1 yr, 10.4% at 5 yr, and 10.6% at 10 yr.21 In addition to its increasing incidence, AD is exacerbated with time after injury.22 Liu et al23 reported that during urodynamics the systolic blood pressure (BP) increase in patients >2 yr after injury was significantly higher than in patients <2 yr after injury. Systolic BP change showed significantly positive correlations with years after injury.23 Although there is no clear evidence that AD is more common in patients with cervical compared with upper thoracic injury, among patients with complete lesions, AD was significantly more common in tetraplegics.24
Effects of exercise on AD have been investigated in animal models of SCI. In SCI Wistar rats, passive hind-limb cycling improved hemodynamic responses as well as the severity of AD.25 This study showed that even delayed exercise promoted similar improvements to early-initiated exercise in terms of cardiac and hemodynamic functions to those following early initiation. There was a rapid and sustained reduction in systolic BP and mean arterial pressure compared with pre-SCI after passive hind-limb cycling in experimental SCI.26 Passive hind-limb cycling reduced the severity of AD in SCI rats, accompanied by prevention of the SCI-induced increase in density of calcitonin gene-related peptide-positive afferents in the dorsal horn. This reduction in AD was correlated with changes in primary afferent morphology but had limited effects on the peripheral vasculature.11 However, so far only a few translational studies have been conducted in humans.
Patients with SCI sometimes exhibit abnormal responses to training, and Claydon et al27 observed that abnormal CV responses to exercise and transient post-exercise hypotension were common in patients with cervical injury. Lower-limb passive cycling caused only moderate increases in BP that was different from AD.28 Patients with incomplete tetraplegia had positive changes in CV autonomic regulation with body weight-supported treadmill training without worsening orthostatic intolerance.29
Increasing vascular stiffness is known to be associated with an increased risk of CVD in the able-bodied population. Chronic cervical SCI leads to a progressively accelerated increase in vascular stiffness.30 This increase in arterial stiffness subsequently affects HRV and is associated with increased systemic vascular resistance.31 An elevation in aortic pulse wave velocity (PWV) may lead to serious adverse CV events in people with SCI, and patients with paraplegia have been shown to have a higher PWV and more frequent abnormal aortic PWV than tetraplegic patients.32
Physical exercise clearly improves arterial stiffness in able-bodied individuals. Adults undergoing regular aerobic exercise demonstrated smaller or no age-associated increases in large elastic artery stiffness compared with their sedentary peers.33 Many investigations have also reported that exercise improves arterial stiffness after SCI,34,35 and chronic exercise training may benefit arterial health and potentially lower the risk of CVD in the SCI population. Furthermore, athletes with SCI had significantly lower aortic PWV than nonathletes with SCI (6.9 ± 1.0 vs 8.7 ± 2.5 m/sec).34 Exercise-induced improvement of arterial stiffness in patients with SCI may be related to reduced BP, lipid profiles, insulin resistance, inflammation, and improved autonomic CV function,36 factors known to affect artery thickness and stiffness.37,38 Structural changes occur in the blood vessels as a result of long-term sympathectomy. Indeed, collagen content in the vascular wall increases and local blood flow decreases in patients with SCI, thus changing the functioning of the endothelium and potentially acting as mechanisms to affecting arterial structural changes.39 Regular exercise significantly increased plasma apelin and nitric oxidex levels in able-bodied people undergoing training,9,40 thereby lowering CV risk. Apelin regulates endothelial nitric oxide synthase in endothelial cells,41 promoting nitric oxide production, which in turn contributes to the mechanisms underlying the effect of exercise. Nitric oxide causes vasodilation and inhibits the development of arteriosclerosis and atherosclerosis.42 Aerobic exercise training also increased plasma klotho concentrations and carotid artery compliance and decreased the β-stiffness index, suggesting a possible role for secreted klotho in the exercise-induced modulation of arterial stiffness. Studies showed that klotho, an enzyme that can be either membrane-bound or soluble, is involved in nitric oxide production in the endothelium43 and suppression of oxidative stress.44 However, further studies are needed to determine whether regular exercise can change plasma apelin, klotho, and nitric oxidex levels in patients with SCI.
Primary prevention of CV disorders during the early years following SCI warrants greater attention.30 However, Phillips et al45 found no association between CV and PWV even though moderate to vigorous CV was significantly correlated with both large and small artery compliance in patients with SCI, similar to that in able-bodied individuals.
Deep vein thrombosis (DVT) is more common in patients with SCI compared with the able-bodied population.41 One study showed that, among 151 patients with acute SCI, 17 (11%) had symptomatic venous thromboembolism (9 pulmonary embolisms, 6 lower-extremity DVT, 1 upper-extremity DVT, and 1 with DVT and pulmonary embolisms).46 DVT occurs not only during acute but also during chronic SCI as a result of immobilization of the paralyzed lower limbs.47 DVT is associated with endogenous risk factors like homocysteine, inhibitor of plasminogen activator inhibitor 1 (PAI-1).48 On a molecular level, PAI-1, an inhibitor of tissue-type urokinase-type plasminogen activator, which regulates the fibrinolytic system, coincides with DVT. Reducing PAI-1 is considered as a target biomarker in the prevention of DVT.49 Also, sedentary subjects have higher PAI-1 and lipoproteins levels than highly trained athletes.50 One study showed that arm-cranking exercise training reduced PAI-1 in patients with SCI. Changes in abdominal fat may be related to changes in PAI-1 in the SCI population.51 Exercise also can affect body metabolism to reduce the risk of venous thromboembolism.
Hyper- and dyslipidemia, glucose intolerance, and insulin resistance occur after SCI and are more frequent compared with the able-bodied population. These metabolic disorders, paired with reduced CV, represent risk factors for CVD.52 In SCI, total cholesterol (TC) was increased in 21.2%,49 low-density lipoprotein cholesterol (LDL-C) in 24.4%, triglycerides in 31%, and the TC/high-density lipoprotein cholesterol (HDL-C) ratio in 65.7% of patients, while HDL-C was <40 mg/dL in 79.5% of patients.
Lipid optimization comprises a therapeutic cornerstone of primary and secondary CVD prevention. However, nutritional education programs alone do not have adequate beneficial effects on weight and lipid profiles.52 Exercise has been shown to improve complications secondary to obesity in populations with SCI,53 and Myers et al54 reported significant improvements in weight, plasma insulin, homeostatic model assessment insulin resistance, and TC/HDL ratio. An experimental cross-sectional study also found that 30 min of exercise (15% above ventilatory threshold 1) increased glucose and LDL in wheelchair basketball players with SCI compared with able-bodied controls.55
Indoor hand-bike significantly decreased body mass index (22.0 ± 3.7 vs 21.7 ± 3.5 kg/m2), fasting insulin (5.4 ± 2.9 vs 3.4 ± 1.5 μU/mL), and homeostatic model assessment insulin resistance (1.0 ± 0.6 vs 0.6 ± 0.3, P = .03) compared with those in the control group.56 Meanwhile, patient exercise tolerance increased in terms of both exercise duration and exercise intensity, and measurements of CV health before and after training revealed substantial increases (20%) in peak oxygen uptake (V˙o2peak) and orthostatic tolerance over the course of the program.
Another study found a significantly higher percentage of V˙o2peak in paraplegic patients (58.9 ± 1.7%) compared with able-bodied individuals (50.0 ± 2.8%).57 These results indicate that chronic daily wheelchair activity results in local adaptations in the functional upper-body musculature, leading to reduced glycogenolysis and an increased rate of lipid utilization (lower respiratory exchange ratio) during arm exercise. Other investigation found that HDL and the LDL/HDL and TC/HDL ratios showed significant and favorable relationships with V˙o2peak, peak power output, and muscle strength. Triglycerides were positively related to peak power output and muscle strength, and an increase in CV level was significantly related to increases in V˙o2peak and peak power output, and favorable effects on the lipid profile.58 Results suggested that behavioral intervention promoting CV after discharge, which decreased diastolic BP, TC, and LDL-C, may further improve the lipid profile and reduce risk factors for CVD in patients with SCI.59 Together, these studies demonstrate that exercise training is associated with potential CV and functional improvements also in SCI.
However, studies questioning these effects do exist. Totosy de Zepetnek et al60 reported that 16 wk of adherence to CV guidelines in adults with SCI was insufficient to improve many markers of CVD risk, including blood glucose control, lipid profiles, fasting insulin, adipokines (leptin, adiponectin), pro-inflammatory markers interleukin-6, tumor necrosis factor-α, and prothrombotic markers (PAI-1). Another group reported that a 16-wk intervention consisting of a behavioral approach to lifestyle change, exercise, and nutrition education was insufficient to improve lipid profiles,61 which does not question the beneficial effects of exercise but rather sheds doubt on the design of such programs, which do not sufficiently emphasize and monitor exercise training.
OXIDATIVE STRESS AND INFLAMMATION
C-reactive protein (CRP) and interleukin-6 are known pro-inflammatory mediators. CRP levels were 74% higher in patients with tetraplegia than in those with paraplegia, consistent with an increased CVD risk. Participants with high CRP (3.1-9.9 mg/L) had greater waist circumference, body mass index, percent fat mass, and homeostasis model of assessment (HOMA) values than those with lower CRP.62 Inflammatory factors play an important role in the development of insulin resistance and atherosclerotic plaques.62,63 Mean CRP levels also increased in line with decreasing mobility (motorized wheelchair > hand-propelled wheelchair > walk with an assistive device > walk independently). Common clinical characteristics in patients with chronic SCI have been associated with plasma CRP.64 CV and exercise may reduce interleukin-6 and CRP and improve systemic markers of inflammatory status in patients with SCI.65 Notably, exercise-induced changes in interleukin-6 and CRP levels seem to be greater in patients with paraplegia compared with those with tetraplegia.66
Individuals with SCI have also been shown to have more extensive resting and exercise-enhanced oxidized LDL-potentiated platelet activation and higher levels of preformed lipid peroxides than those without SCI.67 Exercise has been shown to induce antioxidant effects. Among others, wheelchair rugby players had lower malondialdehyde and higher levels of overall enzymatic antioxidant potential index compared with sedentary manual wheelchair users, potentially reflecting an increase in the blood antioxidant capacity due to wheelchair rugby training. Wheelchair rugby training also induced activation of brain-derived neurotrophic factor signaling, which may also be associated with antioxidant defense capacity.68 Ordonez et al69 reported that a 12-wk arm-cranking exercise program improved the antioxidant defense system in adults with chronic SCI. At the end of the training program, total antioxidant status and erythrocyte glutathione peroxidase activity were significantly increased in the exercise group, while plasma levels of malondialdehyde and carbonyl groups were significantly reduced.69 The increases in plasma malondialdehyde and protein carbonyls immediately after exercise were significantly correlated with lactate levels. Lower levels of exercise-induced oxidative damage and higher antioxidant gene expression (catalase and glutathione peroxidase) have also been shown in less active paraplegics.
Changes in gene expression are also involved in the secondary pathophysiological processes in SCI. MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that can function as gene regulators by binding to the 3'-untranslated region of target mRNAs. Some studies have suggested that some miRNAs may be specific to certain cell types.70 miRNAs exhibited changes before and after SCI, indicating that the expression of some miRNAs may play important roles in the pathophysiology of SCI.71 These changes in miRNAs were associated with risk factors for CVD or CVD itself,72 while exercise also potentially regulated miRNA function in the heart.73 Adams et al74 indicated that exercise training exerted beneficial effects on the CV system via multiple factors, including molecular changes in Ca2+ handling, stem cell proliferation, catabolism, and anabolism capillaries. Some reports have suggested that cycling exercise may modulate the PTEN/mTOR and apoptosis-associated pathways after SCI in rats, and indicated that cycling exercise may also provide a noninvasive means of potentiating the regenerative efforts of neurons affected by SCI.75 These above investigations indicated that exercise may have beneficial CV effects in patients with SCI. Nonetheless, more studies are needed to confirm this hypothesis.
Exercise training helps prevent CVD and improves CV function also in SCI. Exercise regulates CV function by improving HRV, reducing the severity of AD and arterial stiffness, and reducing venous thromboembolism. Exercise may also regulate gene expression and have beneficial effects on the metabolic profile, oxidative stress, and inflammation. This review suggests that the decrease in CV function differs among patients with different-level injuries, such that the same exercise program may have different effects in different patient populations. Suitable exercise programs should thus be designed for SCIs at different levels. Development of cardiometabolic health indicators will improve the quality of SCI rehabilitation. Furthermore, exercise programs differ among research groups, making it difficult to compare the effects of exercise among studies. It is therefore necessary to develop standardized exercise training programs to allow their effects to be assessed accurately.
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