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Cardiovascular and Endocrine Systems

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Similar to the general population, cardiovascular disease has become one of the leading causes of death in the SCI population (DeVivo et al. 1989; DeVivo et al. 1993; Frankel et al. 1998).  There are multiple risk factors for its premature development due to physiological and functional changes following SCI (Bauman et al. 1994; Bauman & Spungen 2001a; Bauman & Spungen, 2001b).  For instance, many age-associated disorders such as carbohydrate intolerance, insulin resistance (Duckworth et al. 1980; Duckworth et al. 1983; Bauman et al. 1992a; Karlsson 1999) and lipid abnormalities (LaPorte et al. 1983; Brenes et al. 1986; Bauman et al. 1992b; Bauman & Spungen 2001a) are known to occur prematurely in persons with SCI.  Some have hypothesized that a marked decrease in physical activity (Myers et al. 2007), along with injury-related changes in metabolic function lead to an increased risk and premature development of cardiovascular disease (Bravo et al. 2004) and diabetes mellitus (Bauman et al.1992a).

Related to the metabolic changes noted above, there is a high prevalence of muscle weakness in persons with SCI attributed to a loss of lean body mass (Thompson & Yakura 2001) that is possibly linked to reduced activity, and abnormally low levels of endogenous anabolic hormones (i.e., human growth hormone and testosterone; Bauman et al. 1994).  In the general population, age-related declines in the endocrine systems also lead to decreases in lean muscle mass and an increase in fat (Tenover 1999).  However, these declines have been shown to be greater in persons with SCI (Bauman & Spungen 2001b).  Similarly, noted changes in insulin resistance are thought to account for the high rates of diabetes mellitus in persons with SCI (Yekutiel et al. 1989).  This in turn leads to an increased risk for cardiovascular disease since the development of diabetes impairs the circulatory system (Halter 1999).  As such, it may be that alterations in body composition, which occur early following SCI, contribute to premature development of these disorders as compared to the AB population (Bauman et al. 1994).  With some of the literature below, young adults with SCI are compared to young adults without SCI. Thus, aging effects due to SCI may be a factor when changes in the cardiovascular and endocrine systems occur in these young adults with SCI that would be typically expected to occur in older adults (e.g. characteristics associated heart disease such as poor lipid profiles, elevated glucose, high BMI).  However, it is not always possible to disentangle mechanisms involving premature aging versus direct effects on the organs from the SCI itself.

In this section, 3 longitudinal studies and 26 cross-sectional studies (see Table 3) on cardiovascular and endocrine systems after SCI are reviewed.

Table 3: Cardiovascular and Endocrine Systems

Discussion

Cardiovascular System

In this section, the evidence reviewed appears to support the notion that the cardiovascular system is prematurely aging.  With regard to risk factors for cardiovascular disease, Bauman and colleagues (2001a) found that regardless of age or sex, persons with SCI had significantly higher levels of plasma homocysteine than able bodied (AB) controls, and that older persons with SCI (>50 years) had higher levels than younger persons with SCI.  Plasma homocysteine is thought to promote coagulation and to decrease the resistance of the endothelium to thrombosis (Malinow 1994), and is a clear independent marker for the prediction of vascular disease (Clarke et al. 1991; Stampfer et al. 1992).  The findings regarding lipid profiles also support an increased risk for the development of cardiovascular disease.  Several studies (Demirel et al. 2001; Zlotolow et al. 1992; Bauman & Spungen 1994; Bauman et al. 1995; Bauman et al. 1999; Liang et al. 2007; Wang et al. 2007) found that serum high-density lipoprotein cholesterol (HDL-c) are depressed in persons with SCI compared to AB controls, which is associated with an increased risk for developing coronary heart disease (Goldbour & Medalie 1979; Castelli 1984).

An important factor influencing these variables might be lifestyle.  For instance, one longitudinal study (Shiba et al. 2010) on athletes with SCI (N = 7) found that physical capacity was maintained over a span of two decades.  The results of this study, however, are limited to individuals participating in strenuous sport activities, a sample that is not representative of the general SCI population (Maki et al. 1995). Although no blood pressure changes were noted, the sample did have a significantly higher BMI from baseline to 20-year follow-up.  Unfortunately, data on lipid profiles were not collected in this study.  Further work on the role of diet and physical activity is needed to help clarify their impact on aging with SCI.

One study provides evidence that C-reactive protein levels were higher in men with SCI (N = 62) compared to AB controls (N = 29), which could also account for the decreases in total cholesterol, low-density lipoprotein and high-density lipoprotein.  At the same time, increases in C-reactive protein levels may also partly explain why persons with SCI are nonetheless at increased risk for accelerated atherogenesis (Wang et al. 2007).  A risk factor for vascular disease in both symptomatic (Budoff et al. 2005) and asymptomatic (Raggi 2000) populations is coronary artery calcification (CAC), which is a component of atherosclerotic plaque.  Orakzai and colleagues (2007) found significantly higher levels of CAC in persons with SCI (N = 82) compared to AB controls (N = 273), and that the risk was higher for males and for persons with tetraplegia.

Sustaining a SCI also affects blood pressure by altering the sympathetic activity to blood vessels.  There is evidence that men with tetraplegia (Yamamoto et al. 1999) and paraplegia (Petrofsky & Laymon 2002) have increased blood pressure responses during exercise compared to AB controls.  As well, Petrofsky and Laymon (2002) found that their group with paraplegia had a larger change in blood pressure both at rest and during exercise and was more associated with aging than for the controls.  Disturbingly, static exercise has been found to cause tachycardia in AB controls, but not in persons with SCI (Petrofsky & Laymon 2002; Orakzai et al. 2007) when paralyzed muscles were engaged.  Several studies highlight that irregular blood pressure responses post-SCI have significant implications for cardiovascular health (Bluvshtein et al. 2011; Groothuis et al. 2010a; Groothuis et al. 2010b; La Fountaine et al. 2010; Yasar et al. 2010). Overall, these findings are indicative of altered autonomic control, but not necessarily of aging.  Further work is needed to determine the long-term implications for cardiovascular health.

Decreases in physical activity may contribute to the development of cardiovascular disease, which may be reflected in body composition changes following SCI.  Two longitudinal studies from the same author (de Groot et al. 2010; 2013) found that body mass index (BMI) increases over time in individuals with SCI. In the de Groot et al. (2010) study of 184 individuals, BMI was observed to significantly increase the year after discharge from in-patient rehabilitation.  In the de Groot et al. (2013) study of 130 individuals, BMI was observed to increase from discharge to a 5-year follow up. Individuals in this study, however, showed no change in their lipid profie over the 5 years of observation.  Similar BMI findings have been reported by Crane and colleagues (Crane et al. 2011). However, studies comparing BMI between individuals with SCI and AB individuals have demonstrated mixed results.  One study (Spungen et al. 2000) found greater BMI levels in persons with SCI compared to AB controls, whereas other studies found the opposite (Bauman et al. 1999; Bauman et al. 2004; Wang et al. 2007), or no differences at all (Zlotolow et al. 1992; Jones et al. 2003; Bauman et al. 1996).

Given these contradictory findings, BMI may not be an appropriate measure for SCI since studies that also examined lean and fat mass tissue (Bauman et al. 1996; Bauman et al. 1999; Spungen et al. 2000; Bauman et al. 2004; Jones et al. 2004) found that persons with SCI had significantly higher levels of fat mass tissue and lower levels of lean tissue than AB controls.  These differences in lean and fat mass tissue appear to be attributable to YPI, and not age.  For instance, Spungen et al. (2000) found lower lean mass and higher fat mass in persons with SCI who were matched with their AB monozygotic twin, which was directly related to YPI.  As well, Bauman and colleagues (2004) concluded from their monozygotic SCI twin study that reductions in lean muscle tissue lead to reduced energy expenditure, which appeared to be related – albeit not significantly – to YPI.  These findings are congruent with SCI-only cross-sectional studies examining body composition (Cardus & McTaggart 1985; Shizgal et al. 1986; Rossier et al. 1991).

The findings from a cross sectional study (Hosier et al. 2012) comparing cardiometabolic risk profiles in pre and post-menopausal women reported that post-menopausal women with SCI have higher triglycerides, total cholesterol, and low density lipoprotein than pre-menopausal women. No differences were observed in BMI or glycemic indices. The authors suggest that post-menopaual women with SCI have risk profiles that are similar to those observed in women without SCI, characterized by increases in triglycerides, total cholesterol, and low density lipoprotein, despite favorable BMIs and glycemic indices.

Endocrine System

Metabolic changes after SCI may also be associated with changes in body composition, and may increase the risk of developing diabetes mellitus.  Tsitouras and colleagues (1995) posited that impaired hGH secretion may be partially responsible for SCI- and aging-associated lean body and muscle mass depletion.  Several identified studies (Shetty et al. 1993; Bauman et al. 1994; Tsitouras et al. 1995) provide evidence that serum IGF-I levels are lower in persons with SCI compared to age-matched controls, and that this depletion is associated with impaired hGH.  Bauman et al. (1994) found that the average IGF-I was significantly lower in younger individuals with SCI than that in younger AB controls, but not in those greater than 45 years of age.  As such, this pattern of IGF-I levels in younger males with SCI appears to be similar to those of elderly AB individuals (Bauman et al. 1994).

Related to this, Bauman and Spungen (1994) found that persons with SCI had a higher mean glucose and insulin levels, and lower mean fasting plasma glucose levels than the AB control group.  This intolerance was found to be present in two-thirds of their group with tetraplegia, and in half their group with paraplegia.  Further, 22% of the persons with SCI met the diagnostic criteria for having diabetes mellitus, whereas only 6% of the AB controls were found to be diabtetic.  Since these adverse clinical features occurred at younger ages in their SCI sample, Bauman and Spungen (1994) interpreted their findings as being a model of premature aging.  The findings of Jones and colleagues (2004), and LaVela and colleagues (2006) appear to support this hypothesis as they both found higher rates of metabolic syndrome and diabetes in their SCI samples compared to the AB population. Conversely, Liang et al. (2007) found that males with SCI (N = 185) were not at higher risk for metabolic syndrome compared to AB controls (N = 185).  This discrepancy may be due to some of the study’s limitations (i.e. reliance on self-report height and weight to calculate BMI) and because they used a standard, rather than a modified, criteria for the syndrome which is not appropriate for persons with SCI.

The predisposition to diabetes and lipid abnormalities is thought to be largely a consequence of extreme inactivity, and the constellation of metabolic changes (i.e. human growth hormone deficiency, testosterone deficiency) appears to be occurring prematurely in persons with SCI (Bauman & Spungen 1994). As well, several studies have shown evidence of thyroid impairment after SCI compared to the AB population (Wang et al. 1992; Huang et al. 1993; Cheville & Kirshblum 1995).All of these findings suggest that persons with SCI may be frequently physiologically comprised, and more susceptible to minor pathologic insults.  Along with associated changes in body composition, an increased risk for the development of cardiovascular disease, diabetes mellitus, and infection is higher following SCI (Bauman & Spungen 2001b).

Conclusion

There is Level 5 evidence from one cross-sectional study (Bauman & Spungen 2001a) that plasma homocysteine levels are higher in persons with SCI compared to the AB population, with the greatest discrepancy in older adults with SCI (> 50 years).

There is Level 5 evidence from nine cross-sectional studies (Zlotolow et al. 1992; Huang et al. 1993; Bauman & Spungen 1994; Bauman et al. 1996; Huang et al. 1998; Bauman et al. 1999; Demirel et al. 2001; Liang et al. 2007; Wang et al. 2007) that lipid profiles are altered after SCI which may contribute to the development of cardiovascular disease. 

There is Level 4 evidence (Shiba et al. 2010) that physical capacity can be maintained long-term in male athletes with SCI.

There is Level 4 evidence from one longitudinal study (de Groot et al. 2013) that lipid profiles in adults with SCI remain stable during the 5 years after inpatient rehabilitation.

There is Level 4 evidence (Apstein & George 1998) that total cholesterol (TC), total glycerides (TG), and low-density lipoproteins (LDL) increased while LDL/high-density lipoproteins (HDL) ratios decreased for males with tetraplegia and paraplegia from the acute phase until 1 YPI.  All lipid profiles were significantly depressed compared to controls.

There is Level 4 evidence (Apstein & George 1998) that persons with tetraplegia had low HDL and elevated LDL/HDL ratios, which places them at an increased risk for coronary artery disease. 

There is Level 5 evidence (Wang et al. 2007) that C-reactive protein levels are higher in males with SCI, which could also account for the decreases in TC, LDL, and HDL.  Elevated C-reactive protein levels may also partly explain why persons with SCI are at increased risk for accelerated atherogenesis.  

There is Level 5 evidence (Orakzai et al. 2007) that persons with SCI have greater atherosclerotic burden compared to an AB reference population.

There is Level 5 evidence from two studies that men with complete paraplegia (Petrofsky & Laymon 2002) and with complete Tetraplgia (Yamamoto et al. 1999) have an abnormal (absent) heart rate response to isometric exercise.

There is Level 5 evidence that men with complete tetraplegia demonstrate increased blood pressure (Yamamoto et al. 1999) response to isometric contraction.

There is Level 5 evidence (Wang et al. 1992: 63 men; Tsitouras et al. 1995; Shetty et al. 1993) that there is lower secretion of testosterone and human growth hormone levels in men with SCI compared to AB controls.

There is Level 5 evidence from two studies (Tsitouras et al. 1995; Bauman et al. 1994) that serum IGF-I levels are impaired in persons with SCI compared to the AB population, which may be a sign of premature aging.

There is Level 5 evidence from three studies (Bauman & Spungen 1994; Jones et al. 2004; Liang et al. 2007) that glucose tolerance is impaired after SCI, which may lead to an increased risk for premature diabetes mellitus.

There is Level 5 evidence (LaVela et al. 2006) that diabetes mellitus occurs prematurely in male veterans with SCI compared to AB individuals in the general population, but not veteran controls.

There is Level 5 evidence (Lewis et al. 2010) that men with SCI have slower plasma-free cortisol responses than AB controls.

There is Level 4 evidence from three longitudinal studies (de Groot et al. 2010 & 2013; Crane et al. 2011) that BMI increases significantly over time in persons with SCI.

Seven studies (Nuhlicek et al. 1988; Bauman et al. 1996; Bauman et al. 1999; Spungen et al. 2000; Jones et al. 2003; Jones et al. 2004; Emmons et al. 2011) provide Level 5 evidence that persons with SCI are likely to have higher levels of fat mass, and that age-related declines of lean tissue in males with SCI may occur at a significantly faster rate than the AB population.

There is Level 5 evidence from one monozygotic twin study (Bauman et al. 2004) that basal and resting energy expenditures are lower in males with SCI compared to their AB twin.

There is Level 5 evidence from one cross-sectional study (Hosier et al. 2012) that post-menopaual women with SCI have cardiometabolic risk profiles that are similar to those observed in women without SCI.

  • Greater levels of arthersclerotic burden, higher levels of C-reactive protein levels and abnormal lipid profiles compared to the able-bodied population increases the risk for the development of cardiovascular disease in persons with SCI.

    Men with complete SCI have abnormal heart rate and blood pressure responses to isometric exercise compared to able-bodied controls, which are indicative of altered autonomic control, but this may not represent premature aging.

    Impaired secretion of both testosterone and human growth hormone in men with SCI may be due to SCI, and not from advancing age per se.

    Serum IGF-I levels may be impaired compared to the able-bodied population, which may be a sign of premature aging.

    Glucose tolerance and slower plasma-free cortisol responsesmay be impaired in persons with SCI, which may lead to an increased risk for premature diabetes mellitus.

    Persons with SCI are at higher risk for the development of cardiovascular disease and diabetes mellitus than the able-bodied population.

    Persons with SCI may have higher levels of fat mass than the able-bodied population. Although BMI increases over time in people with SCI, an active lifestyle may help to preserve physical capacity.

    Age-related declines of lean tissue in males with SCI may occur at a significantly faster rate than the able-bodied population.

    Age of onset may not influence hematologic abnormalities at the acute phase post-SCI (within first week post-injury).