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Am J Physiol Heart Circ Physiol 294: H668-H678, 2008. First published November 16, 2007; doi:10.1152/ajpheart.00869.2007
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Clinical correlates of frequency analyses of cardiovascular control after spinal cord injury

Victoria E. Claydon1 and Andrei V. Krassioukov1,2,3

1International Collaboration on Repair Discoveries, 2Division of Physical Medicine and Rehabilitation, Department of Medicine, University of British Columbia; and 3GF Strong Rehabilitation Centre, Vancouver Coastal Health Authority, Vancouver, British Columbia, Canada

Submitted 24 July 2007 ; accepted in final form 13 November 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Spinal cord injury (SCI) has profound effects on cardiovascular autonomic function due to injury to descending autonomic pathways, and cardiovascular diseases are the leading causes of morbidity and mortality after SCI. Evaluation of cardiovascular autonomic dysfunction after SCI and appraisal of simple noninvasive autonomic assessments that are clinically meaningful would be useful to SCI clinicians and researchers. We aimed to assess supine and upright cardiovascular autonomic function from frequency analyses of heart rate and blood pressure variability (HRV and BPV) after SCI. We studied 26 subjects with chronic cervical or thoracic SCI and 17 able-bodied controls. We continuously recorded R-R interval (RRI, by ECG) and beat-to-beat blood pressure (by Finometer) in supine and seated positions. Cardiovascular control was assessed from spectral analysis of RRI and blood pressure time series. Cardiac baroreflex control was assessed from cross-spectral analyses of low-frequency spectra. Supine and upright low-frequency HRV and BPV were reduced in cervical SCI subjects, as were total BPV and HRV. Supine high-frequency HRV was reduced in thoracic SCI subjects. Cardiac baroreflex delay was increased in cervical SCI subjects. Supine frequency domain indexes were correlated with sympathetic skin responses, orthostatic cardiovascular responses, and plasma catecholamine levels. SCI results in reduced sympathetic drive to the heart and vasculature and increased baroreflex delay in cervical SCI subjects and reduced cardiac vagal tone in thoracic SCI subjects. Frequency analyses of autonomic function are related to clinical measures of autonomic control after SCI and provide useful noninvasive clinical tools with which to assess autonomic completeness of injury following SCI.

baroreceptor reflex; autonomic nervous system; spectral analysis

SPINAL CORD INJURY (SCI) is associated with abnormal cardiovascular control that is related to the level and severity of injury to descending autonomic (sympathetic) pathways (10, 15, 35). The leading cause of morbidity and mortality in SCI individuals is cardiovascular disease (16, 45). This most commonly manifests as neurogenic shock (in acute SCI) (35); supine hypotension (35); orthostatic hypotension (marked decreases in blood pressure in the upright position) (10, 11); autonomic dysreflexia (profound and life-threatening blood pressure increases following afferent stimulation below the lesion) (35); ECG abnormalities and arrhythmia (38), particularly during autonomic dysreflexia (9, 14); and abnormal cardiovascular responses to exercise (8).

The severe impact of cardiovascular dysfunction on quality of life after SCI has prompted the search for simple physiological bedside assessments of autonomic function that can easily be performed in the clinic. These assessments should document the level/severity of damage to autonomic pathways, provide meaningful information concerning the severity of autonomic dysfunction an individual is likely to experience, and be able to track changes in function over time. The reasons for this search for simple measures of autonomic dysfunction following SCI are essentially threefold. 1) The current standard of assessment of SCI [American Spinal Injury Association (ASIA) examination (39)] evaluates motor and sensory pathways, but not severity of injury to autonomic pathways, and, thus, does not correlate well with tests of autonomic function (10). 2) Most autonomic function assessments were developed in able-bodied individuals and are not necessarily applicable to SCI individuals. 3) Autonomic function assessments often require specialized equipment, may be invasive, and, thus, can be difficult to perform routinely in the clinic.

One assessment that is noninvasive and simple to perform in SCI individuals is spectral analysis of cardiovascular parameters to evaluate autonomic tone from heart rate and blood pressure variability (HRV and BPV). These analyses are of particular interest, because they have been extensively applied to rodent models (6) and, thus, potentially provide a useful means with which to apply results from the bench to the bedside, and vice versa, promoting translational discovery science.

High-frequency (HF, ~0.25 Hz) HRV represents cardiac vagal control (2, 4, 46). HF BPV results from mechanical changes in intrathoracic pressure associated with respiration (2, 4, 46). Low-frequency (LF, ~0.1 Hz) BPV represents sympathetic drive to the resistance vessels (4). LF HRV is more controversial but is generally accepted to be due to oscillations in vagal outflow generated through the baroreflex and driven by sympathetically induced LF BPV (1, 2, 7, 17). Additional cross-spectral analyses of heart rate and blood pressure time series can demonstrate their interactions and assess baroreflex function (4, 7, 22, 24) from the phase (baroreflex delay) and transfer function gain (baroreflex sensitivity) (7).

Although preliminary studies have shown that this technique is reproducible and reliable in SCI individuals (13), no study has correlated frequency domain indexes of autonomic tone with clinical measures of autonomic dysfunction after SCI. Furthermore, the evaluation of reflex delay using this technique has yet to be performed following SCI, despite the known link between increased baroreflex delay and other disorders of cardiac autonomic function (21, 23). We aimed, therefore, to perform spectral analyses of HRV and BPV and cross-spectral analyses of baroreflex sensitivity and delay in subjects with cervical and thoracic SCI and in healthy controls in the supine position and during orthostatic stress. We hypothesized that frequency domain indexes of cardiovascular autonomic function would be correlated with other clinical measures of autonomic control and may provide SCI clinicians and researchers with simple noninvasive tools with which to evaluate autonomic function following SCI.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Ethical approval. Ethical approval was obtained from the University of British Columbia and Vancouver Coastal Health Authority ethics committees. The investigation conforms to the Declaration of Helsinki. All subjects gave written informed consent. We studied 14 subjects with chronic (>1 yr) cervical SCI, 12 subjects with chronic thoracic SCI, and 17 able-bodied controls. All were apparently healthy, and none was taking cardiovascular medication or had known cardiovascular disease.

Assessment of SCI. SCI volunteers underwent the ASIA assessment of neurological level and severity of injury to motor and sensory pathways (39). Injury to descending (sympathetic) autonomic pathways was assessed from sympathetic skin responses (SSR), as described previously (8, 10). ASIA examinations and SSR were obtained on the same morning as data for the present study.

Procedure. On arrival at the laboratory, subjects were asked to empty their bladder to minimize the effects of bladder distension on sympathetic nervous activity. Women were studied in midcycle to avoid the possibility of triggering autonomic dysreflexia from menstrual cramps in female SCI subjects. Experiments were performed in the mornings following only a light breakfast. Subjects abstained from caffeine, alcohol, and smoking for ≥12 h before testing. Subjects rested supine on a standard procedure bed; assistance was given with transfers when necessary. The subjects were fitted with an electrocardiogram (lead II; Powerlab Model ML132, ADInstruments, Colorado Springs, CO) and beat-to-beat finger blood pressure monitor (Finometer, Finapres Medical Systems BV, Arnhem, The Netherlands). Throughout 15 min of supine rest and for 15 min in the upright seated position, recordings were made (sampling rate 1,000 Hz) using an analog-to-digital converter (Powerlab/16SP model ML795, ADInstruments) and stored for subsequent offline analyses (Powerlab version 5.0.2., ADInstruments). The "sit-up maneuver" was obtained passively by raising the head of the bed by 90° and lowering the legs from the knee by 90°, with the resultant position being as seated in a wheelchair, with the legs unsupported below the knee.

Spectral analyses. Offline beat-to-beat analyses of the digitized electrocardiogram and Finometer signals were performed at a temporal resolution of 1 ms. Time series of successive beats were extracted for R-R interval (RRI) and systolic (SAP), diastolic (DAP), and mean arterial pressures. Occasional ectopic beats were "corrected" by linear interpolation of adjacent normal beats. Any significant trends were removed by subtraction of the best polynomial function fitted to the data using low-pass filtering. An autoregressive monovariate model was fitted to each time series (3, 7, 22). LF (0.05–0.15 Hz), HF (0.15–0.3 Hz), and very LF (VLF, <0.03 Hz) peaks were identified for each spectrum, and the power and central frequency at each peak were calculated by computation of the residuals (31). When appropriate, powers were normalized by dividing the power by total variance minus VLF and multiplied by 100 (51).

Cross-spectral analysis. A bivariate autoregressive model (4) was fitted to the time series to quantify the frequency-related squared coherence, phase shift, and transfer function gain between SAP and RRI. Discrete values of these variables and of the central frequency of each peak were taken at the frequency corresponding to the maximal coherence value, where the estimate error is minimal (7, 32). Coherence represents the proportion of blood pressure to RRI covariance and ranges from 0 (no relationship) to 1 (perfect interdependence). Recordings were accepted only when the squared coherence was >0.5, indicating a statistically significant correlation between the two signals (52).

Statistics. Statistical analyses were performed using GraphPad Instat version 3.00 for Windows 95 (GraphPad Software, San Diego, CA). Data were tested for normality using Kolmogorov and Smirnov distributions. Comparisons between groups were performed using ANOVA with Dunnett's, Tukey's, or Bonferroni's post hoc tests as appropriate. Statistical significance was assumed at P < 0.05. Sex differences were assessed using the {chi}2 test. Values are means ± SE. Correlations between variables were performed with previously published data (10) (collected in the same subjects, on the same day, and under the same conditions) using Pearson's or Spearman's correlation coefficients. Receiver operating characteristic (ROC) curves were generated for the spectral analysis parameters and clinical measures of cardiovascular dysfunction. The areas under the ROC curves were calculated for each parameter and compared.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Subject characteristics. There were no age or sex differences between groups: 33 ± 2 yr of age and 9 men in the cervical SCI group (n = 14), 36 ± 3 yr of age and 8 men in the thoracic SCI group (n = 12), and 33 ± 3 yr of age and 9 men in the control group (n = 17). Cervical SCI ranged from C4 to C7 with ASIA impairment scale (AIS) grade as follows: n = 7 grade A, n = 4 grade B, n = 2 grade C, and n = 1 grade D. Thoracic SCI ranged from T2 to T11 with AIS grade as follows: n = 9 grade A, n = 1 grade B, n = 1 grade C, and n = 1 grade D.

Spectral analysis of RRI. Supine RRI was longer in the cervical SCI group than the thoracic SCI and control groups (Table 1). RRI decreased in the upright position in all groups. Supine and upright HRV parameters are shown in Table 1. A representative power spectrum from a subject with cervical SCI and a control volunteer in supine and upright conditions can be seen in Fig. 1A.


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  		Table 1. Spectral analyses of time series created from consecutive RRI

 

Figure 1
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  		Fig. 1. Spectra of R-R interval (RRI) time series (A) and mean low-frequency (LF) and high-frequency (HF) power of RRI (B) in supine and upright positions. Power spectra are representative examples from a control subject and a subject with cervical spinal cord injury [SCI; C4, American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade B with severe injury to autonomic pathways]. *P < 0.05. **P < 0.01. ***P < 0.001.

 
VLF power was markedly reduced in the cervical SCI group compared with the control and thoracic SCI groups, contributing to reduced total variance in the cervical SCI group, particularly in the upright position (Table 1).

Normalized LF power was less in the cervical SCI group than in the thoracic SCI and control groups in supine and upright positions (Fig. 1B). Normalized LF power increased in the control group in the upright position; there was no significant change in the thoracic SCI or cervical SCI group. Normalized HF power was significantly less in the thoracic SCI group than the cervical SCI group in the supine position and tended to be greater in the cervical SCI group than in the thoracic SCI and control groups in the upright position. Normalized HF power decreased in the upright position in the control group but was not significantly affected in the thoracic SCI or cervical SCI group.

The LF-to-HF ratio was lower in the cervical SCI group than in the thoracic SCI and control groups in supine and upright positions (Table 1). In the upright position, LF-to-HF ratio increased in the control group but did not increase significantly in the cervical SCI or thoracic SCI group.

Spectral analysis of blood pressure. SAP was lower in the cervical SCI group than in the thoracic SCI and control groups in supine and upright positions (Table 2). SAP increased in the thoracic SCI and control groups in the upright position, but not in the cervical SCI group. Supine DAP was similar in all groups (Table 3). DAP increased in the control and thoracic SCI groups, but not in the cervical SCI group, so upright DAP was lower in the cervical SCI group than in the other two groups. A representative power spectrum of SAP BPV from a subject with cervical SCI and a control volunteer in supine and upright positions is shown in Fig. 2A. Supine and upright SAP and DAP spectral analysis results are shown in Tables 2 and Table 3.


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  		Table 2. Spectral analyses of time series created from consecutive SAP

 

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  		Table 3. Spectral analyses of time series created from consecutive DAP

 

Figure 2
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  		Fig. 2. Power spectra from systolic arterial pressure (SAP) time series (A) and mean low-frequency (LF) power of SAP (B) and diastolic arterial pressure (DAP, C) in supine and upright positions. Power spectra are representative examples from a control subject and a subject with cervical SCI (C4, AIS grade B with severe injury to autonomic pathways). *P < 0.05. **P < 0.01. ***P < 0.001.

 
Total variance and VLF BPV were less in the cervical SCI group than in the thoracic SCI and control groups in supine and upright positions (Tables 2 and 3).

Normalized LF SAP was less in the cervical SCI group than in the thoracic SCI and control groups in supine and upright positions (Fig. 2B). LF SAP was intermediate in the thoracic SCI group. There was no significant change in LF SAP in any group in the upright position. Normalized LF DAP was less in the cervical SCI group than in the thoracic SCI and control groups in supine and upright positions (Fig. 2C). LF DAP was intermediate in the thoracic SCI group and significantly less in the thoracic SCI group than in the control group, particularly in the supine position. LF DAP increased in all groups in the upright position; this was statistically significant only in the cervical SCI group.

Normalized HF power of SAP and DAP tended to be greater in the cervical SCI group in supine and upright positions, but this was not significant (data not shown). Normalized HF power was not significantly affected by the upright posture in any group.

Cross-spectral analysis of baroreflex control. The LF central frequency of oscillations was not significantly different between groups in supine or upright positions and was not affected by orthostatic stress (Table 4). Coherence was >0.5, and values used in our analyses in the supine position in 10 of 14 cervical SCI subjects, 15 of 17 controls, and 10 of 12 thoracic SCI subjects and in the upright position in 7 of 14 cervical SCI subjects, 16 of 17 controls, and 8 of 12 thoracic SCI subjects. Supine coherence was similar in all groups. Coherence increased in the upright position in the control and thoracic SCI groups, but not in the cervical SCI group. Thus upright coherence was lower in the cervical SCI group than in the other groups. Supine and upright transfer function gain was similar in all groups. Reflex gain decreased in the upright position in the cervical SCI group. Phase was greater in the cervical SCI group than in the control group in supine and upright positions. Phase decreased in controls in the upright position. Reflex delay (seconds) was greater in the cervical SCI group than in controls in supine and upright positions. A representative example from a subject with cervical SCI and a control volunteer and the time series from which they were derived can be seen in Fig. 3.


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  		Table 4. Cross-spectral analyses of cardiovascular parameters in supine and upright positions

 

Figure 3
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  		Fig. 3. Cross-spectral analysis of RRI and SAP in a representative control subject and a subject with cervical SCI (C4, AIS grade B with severe injury to autonomic pathways) in supine position. A: RRI and SAP time series from which spectral components are derived. B: cross-spectral parameters. Note increased LF phase shift (delay) in SCI subject (arrow).

 
Relationship between frequency domain characteristics and other indexes of cardiovascular autonomic control. To determine whether there were correlations between frequency domain characteristics of cardiovascular parameters and other indexes of autonomic control, we further analyzed data collected in the present study with data collected previously (10) from the same subjects on the same day (Table 5). We found significant correlations between many supine parameters of spectral and cross-spectral analysis and the level of injury; integrity of descending sympathetic pathways, assessed by palmar SSR to median nerve stimulation; plasma catecholamine levels; supine cardiovascular control; and cardiovascular responses to orthostatic stress. Multiple regression analyses revealed that several frequency domain parameters were independently correlated with clinical indexes of cardiovascular autonomic function (P < 0.05; Table 5). Sample correlations showing the relationship between supine LF-to-HF ratio of RRI and supine heart rates and heart rate responses to orthostatic stress and between supine LF SAP and the severity of supine hypotension and supine norepinephrine levels can be seen in Fig. 4.


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  		Table 5. Correlations between frequency domain parameters and level of SCI, severity of injury to autonomic pathways, supine cardiovascular control, and cardiovascular responses to orthostatic stress

 

Figure 4
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  		Fig. 4. Correlations between LF-to-HF ratio of RRI (top) and LF oscillations in SAP (bottom) and relevant clinical data. Note significant correlations between supine heart rate and heart rate responses to orthostatic stress and LF-to-HF ratio of RRI and between severity of supine hypotension and supine norepinephrine (NE) levels and LF SAP. bpm, Beats/min.

 
To better evaluate the predictive power of spectral analyses to identify cardiovascular dysfunction and completeness of injury to autonomic pathways, we performed ROC analyses and assessed sensitivity and specificity for the various spectral parameters (Fig. 5). Using only the LF-to-HF ratio of power of RRI and LF and total power of SAP (absolute units) from the supine data, we were able to predict, with a high degree of confidence, the extent of cardiovascular dysfunction and severity of injury to sympathetic pathways. The best predictor of orthostatic hypotension and, hence, potentially, one of the more clinically useful variables was the total power of SAP. A scattergram showing the degree of separation of total power of SAP between groups and the relationship with complete destruction of descending autonomic pathways, as assessed by SSR (10), can be seen in Fig. 6.


Figure 5
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  		Fig. 5. Receiver operating characteristic (ROC) curves showing diagnostic power of spectral analyses to predict clinical cardiovascular dysfunction. Data were compared for the ability to predict low plasma norepinephrine levels (<0.5 nmol/l), supine hypotension (SAP <100 mmHg), supine bradycardia [heart rate (HR) <60 beats/min], absent palmar sympathetic skin response (SSR) in response to median nerve stimulation, orthostatic hypotension (OH, decrease in SAP >20 mmHg or DAP >10 mmHg), and abnormal heart rate responses to orthostatic stress (maximum heart rate <75 beats/min). Area under the curve (AUC) >0.75 indicates assessments with good prognostic value. Using these parameters, we were able to predict, with a high degree of sensitivity (SN) and specificity (SP), low plasma norepinephrine (SN = 100%, SP = 88%), supine hypotension (SN = 77%, SP = 80%), supine bradycardia (SN = 100%, SP = 60%), absence of palmar SSR (SN = 91%, SP = 72%), orthostatic hypotension (SN = 90%, SP = 70%), and abnormal heart rate responses to orthostatic stress (SN = 56%, SP = 100%).

 

Figure 6
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  		Fig. 6. Scattergram showing total power of oscillations in SAP for each individual. bullet, Individuals with complete destruction of descending autonomic pathways, as determined from complete absence of palmar SSR after 10 attempts to elicit responses from median nerve stimulation (10). *P < 0.05; ***P < 0.001 vs. cervical SCI. Solid horizontal bars denote group mean value.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We have described cardiovascular control in the frequency domain in subjects with SCI compared with able-bodied controls at rest and during orthostasis. Frequency analyses revealed abnormal cardiovascular regulation after SCI that is correlated with the level of SCI and the severity of injury to autonomic pathways. We also showed that frequency analyses of cardiovascular control are correlated with clinical measures of autonomic function with a high degree of sensitivity and specificity. This suggests that spectral analyses may provide a simple noninvasive tool with which to evaluate cardiovascular autonomic control after SCI. We have also highlighted increased delay of the cardiac baroreflex response after SCI that is correlated with the extent of injury to autonomic pathways and cardiovascular responses to orthostatic stress. This may contribute to the orthostatic intolerance that is commonly seen in SCI individuals.

VLF variability. Total HRV and BPV were reduced after cervical SCI, largely due to marked reductions in VLF variabilities. This finding is compatible with reduced diurnal cardiovascular oscillations in cervical SCI (43). VLF HRV represents numerous influences on the heart, including thermoregulation, the renin-angiotensin system, and endothelial factors (12, 46). Reduced HRV is associated with increased cardiovascular morbidity and mortality (33), with reduced VLF HRV being a particularly strong independent predictor of all-cause cardiovascular mortality (33). VLF BPV is modulated by catecholamines, angiotensin, heat stress, and hypovolemia (12, 46) and has recently been suggested to be largely due to L-type calcium channel-dependent mechanisms generated by myogenic vascular responses to spontaneously occurring perturbations in blood pressure (36). Abnormal BPV is also an indicator of cardiovascular disease risk (47). Given that cardiovascular disease is the leading cause of cardiovascular morbidity and mortality after SCI (16, 45), these data have important implications for the identification of cardiovascular disease risk after SCI (16, 45) and stress the importance of myogenic vascular responses for cardiovascular health (36).

HRV. Decreased LF HRV in cervical SCI subjects at rest probably predominantly reflects reduced cardiac sympathetic control in cervical SCI. The fact that LF oscillations were not abolished after cervical SCI suggests that 1) some of the LF HRV after cervical SCI is mediated by parasympathetic mechanisms (2, 17, 34), 2) sympathetic oscillations may occur in the absence of descending sympathetic control, e.g., due to rhythmic firing patterns of spinal sympathetic neurons (25, 34), and 3) the destruction of descending sympathetic pathways was incomplete in some subjects with cervical SCI (10). There is probably some contribution from all these potential mechanisms in the generation of LF HRV after cervical SCI. However, it is particularly likely that incomplete injury to autonomic pathways is a contributing factor, because some of these cervical SCI subjects were shown previously to have at least partial preservation of palmar SSR (10), which requires integrity of descending sympathetic pathways to the upper thoracic cord. The fact that LF RRI oscillations were strongly correlated with norepinephrine levels also attests to the likely role of incomplete injury to sympathetic pathways. Previous studies examining HRV in cervical SCI have not evaluated autonomic completeness of injury, but LF RRI oscillations were reported, although with reduced power, in tetraplegics, and those with incomplete motor and sensory SCI were seen to have greater LF RRI oscillations (5, 19, 20, 29, 34), suggesting that they also had less severe injury to descending sympathetic pathways. This has been proposed previously, whereby LF RRI oscillations were directly proportional to DAP (an indirect measure of sympathetic vasoconstrictor activity) (34). Thus it seems that individuals with cervical SCI and significant LF oscillations in RRI may have autonomically incomplete SCI. The similar LF HRV in thoracic SCI subjects and controls suggests preservation of sympathetically mediated oscillations in heart rate in most thoracic SCI subjects. Sympathetic innervation of the heart arises from T1–T5 spinal segments (11), and because SCI at or above this level was associated with injury to autonomic pathways (as assessed by SSR) in only two thoracic SCI subjects (10), it is not surprising that, as a group, subjects with thoracic SCI had normal HRV. Interestingly, HRV was abnormal in the two subjects with high thoracic SCI and absent palmar SSR.

At rest, HF HRV was increased in the cervical SCI group compared with the thoracic SCI and control groups. The increased HF power and, thus, presumed increased vagal tone after cervical SCI are compatible with the slower heart rates (8, 10). Combined with the reduced LF-to-HF ratio, this suggests parasympathetic predominance after cervical SCI, indicating that reduced sympathetic outflow was not balanced by reduced vagal outflow. This is contrary to the findings of some groups (19, 29) but has been reported previously (5, 20, 27, 28). The reduced HF power in thoracic SCI subjects suggests reduced vagal tone (33, 46, 51), which is supported by their higher heart rates. The mechanisms underlying higher heart rates and reduced vagal tone in thoracic SCI subjects are uncertain, but these phenomena have been documented previously (10, 26, 29) and have also been reported in rodent models of SCI (37). They may reflect compensation for decreased stroke volume after thoracic SCI (30) and/or compensatory reductions in vagal tone in individuals with high, autonomically complete, thoracic SCI to maintain autonomic balance (29).

In the upright position, a decrease of LF power in the cervical SCI group was associated with increased heart rate and decreased HF power. Decreased HF power and increased heart rate probably reflect baroreflex-mediated vagal withdrawal. This also explains the reduced LF power, which is mediated by parasympathetic and sympathetic control (2, 17), and suggests that there is little increase in sympathetic drive to the heart in the upright position in these individuals. In thoracic SCI, the upright posture elicited modest tachycardia associated with a trend for increased LF power (53), again suggesting baroreflex-mediated tachycardia (due to vagal withdrawal and increased cardiac sympathetic drive) during orthostasis. That the increase in LF power was not significant may be due to the heterogeneous nature of this group, which included two subjects with presumed loss of descending cardiac sympathetic control as indicated by SSR, and/or the reduced vagal component of HRV in the thoracic SCI group. There was little change in HF power in the upright position in the thoracic SCI group, presumably because vagal tone was already low in these subjects, and there was, therefore, little reserve remaining for further reductions in vagal tone in the upright position.

The control group showed the expected increase in LF power and decrease in HF power in the upright position, reflecting increased sympathetic and decreased parasympathetic control of the heart due to baroreflex stimulation (42).

Although we have shown abnormalities in autonomic control of heart rate after SCI, using the techniques employed in the present study, we cannot determine with certainty whether this is an indirect effect related to the impaired sympathetic vascular control or a direct effect of loss of sympathetic control of the heart.

BPV. LF BPV in supine and upright positions was reduced in the cervical SCI group, as reported previously (26, 27, 44). This probably reflects reduced sympathetic outflow to resistance vessels (2, 12, 46) due to interruption of descending sympathetic pathways (27), which is supported by the lower blood pressures in the cervical SCI group. LF BPV in the thoracic SCI group tended to be reduced compared with controls, although to a lesser extent than in the cervical SCI group. These results are similar to those of others (25, 27, 44). This probably reflects reduced sympathetic drive to the lower body in individuals with autonomically complete thoracic SCI.

In the upright position, LF BPV increased in all groups. This was sufficient to increase upright blood pressures in the control and thoracic SCI groups, but not in the cervical SCI group. The increased LF power probably reflects baroreflex-mediated increases in sympathetic tone in the thoracic SCI and control groups (2, 12, 46). Indeed, sympathetic control of the upper one-fourth or more of spinal sympathetic neurons is reported to be sufficient to preserve sympathetic blood pressure regulation (44). In the cervical SCI group, increased upright LF power could be due to 1) autonomically incomplete injury to descending sympathetic pathways, as discussed earlier (8, 10); 2) generation of LF BPV at a spinal level, without supraspinal control (26, 44); and 3) augmented sympathetic activity from excitation of the isolated spinal cord (autonomic dysreflexia) (29). It is not likely that the latter is the case. We were careful to avoid possible triggers of autonomic dysreflexia, and no subject had symptoms or signs of autonomic dysreflexia during the study. LF BPV could be generated at a spinal level in subjects with SCI (26, 44). Indeed, LF HRV and BPV are reported to increase over time following injury, presumably due to emerging spinal rhythmicity of oscillations in sympathetic outflow (25, 26) or recovery of descending sympathetic pathways. However, in some subjects, injury to descending autonomic pathways is not complete (8, 10), and in this study LF BPV was correlated with other indexes of preservation of sympathetic control after SCI, including SSR, plasma norepinephrine levels, and blood pressure control. Furthermore, LF BPV was shown previously to be reduced in subjects with high-level injury and low plasma norepinephrine levels in whom blood pressure dropped substantially with orthostatic stress (44). Thus LF BPV probably reflects completeness of injury to descending sympathetic pathways involved in vascular tone.

HF BPV tended to be greater in the cervical SCI group than the other two groups, as reported previously (25, 27). HF BPV is thought to represent the generation of oscillations in blood pressure by mechanical alterations in intrathoracic pressure due to breathing (12, 46). The mechanism for increased HF BPV in cervical SCI is uncertain but could represent a "feedforward" mechanism, whereby HF oscillations in heart rate generate HF oscillations in blood pressure (2). Since the HF oscillations in RRI were greater in the cervical SCI group, this may promote greater HF BPV.

Baroreflex function. Although cardiac baroreflex sensitivity was similar in all groups, phase delay and, thus, time delay of the baroreflex were increased in the cervical SCI group. There was also less coherence in the cervical SCI group in the upright position, which may be a consequence of increased reflex delay and subsequent failure to engage the baroreflex. Interestingly, increased cardiac (21, 22, 24) and vascular resistance (23) baroreflex delay have been implicated in other disorders of blood pressure control and are associated with reduced coherence (22). Increased baroreflex delay is proposed to lead to instability of blood pressure homeostasis and an increased risk of orthostatic intolerance (21), a common feature in subjects with cervical SCI (10). Although the increased cardiac baroreflex delay of ~1.3 s in cervical SCI subjects may seem small, it represents an increased latency of ~70%, which is not inconsiderable. Similar increases in latency have been seen in other pathological conditions of blood pressure regulation (21–24) and in the elderly (50), in whom baroreflex responses and blood pressure control are impaired (40, 41). However, the cross-spectral estimates of cardiac baroreflex function may or may not be reflected in baroreflex control of sympathetic vascular regulation.

Only two previous studies have examined baroreflex control from cross-spectral analyses in subjects with SCI (18, 44). However, both studies included HF respiratory components and may not accurately reflect baroreflex control. Indeed, phase in the HF range is close to zero, implying that the oscillations occur simultaneously, which is not compatible with a baroreflex mechanism. These groups reported conflicting results, with baroreflex sensitivity being reduced in paraplegics compared with controls (18) and, conversely, similar baroreflex sensitivity between subjects with cervical and thoracic SCI subjects and controls (44). The discrepancy between these studies and the present study is most likely explained by the inclusion of nonbaroreflex HF oscillations in the earlier analyses. Nevertheless, the finding of similar sensitivity between SCI subjects and controls by Munakata et al. (44) is compatible with our results, and they also noted reduced coherence after SCI.

Clinical correlates. The subjects in this study also participated in other studies in our laboratory examining orthostatic cardiovascular control (10); thus we were able to perform correlations between the indexes of autonomic control derived from our frequency domain evaluations and other clinical assessments of autonomic function. HRV and BPV measures were significantly correlated with numerous other indexes of autonomic function, including SSR, supine and upright blood pressures, supine and upright heart rates, and supine and upright catecholamine levels (Table 5). ROC curves identified the strongest predictors of autonomic function from the HRV and BPV data (LF-to-HF ratio of RRI and total power and LF power of SAP), all of which had high sensitivity, specificity, and strong prognostic potential. This suggests that frequency domain analyses may provide useful information concerning cardiovascular control after SCI. Further studies are required to determine whether these analyses are also correlated with autonomic dysreflexia and all-cause cardiovascular morbidity and mortality in SCI individuals. Since indexes of HRV and BPV are strong predictors of cardiovascular morbidity and mortality in able-bodied individuals (33, 47), it may be that this would also be the case in SCI individuals.

Clinical applicability of spectral analyses. The present study highlights the potential for spectral analyses to provide promising markers of cardiovascular autonomic function after SCI. This has been recognized in the able-bodied population, and the apparently easy derivation of this measure has popularized its use (51). Indeed, since many commercial devices provide an automated measurement of HRV, this technique has long been recommended in cardiological evaluations, for clinical and research applications, and clinical guidelines for its use have been published (51). BPV yields important information that is not provided by HRV and is equally simple to evaluate but requires beat-to-beat blood pressure data. The increasing availability of noninvasive finger plethysmography is likely to facilitate the use of BPV in clinical and research settings. Although the spectral analysis algorithms can be complex, they are becoming increasingly automated and, as such, are being incorporated more and more into routine clinical evaluations. However, in addition to its ease of use, this technique has some potential clinical advantages. 1) It requires relatively short (10–15 min) recording periods in a rested state. 2) No positional changes are required (all clinical correlations were identified with the supine analyses), in contrast to orthostatic stress testing, which is certainly beneficial when individuals with impaired mobility, such as after SCI, are evaluated. 3) It is noninvasive; therefore, it is preferable to measures of catecholamine function, particularly given that invasive techniques may themselves influence cardiovascular control (49). 4) It provides measures of sympathetic and parasympathetic control of the cardiovascular system and, in the case of BPV, also examines sympathetic control of the vasculature; cross-spectral analyses may be performed to evaluate cardiac baroreflex control. Other techniques are often unable to tease out the relative contributions of cardiovascular control mechanisms or provide only indirect assessments, e.g., by examining sympathetic cholinergic responses from SSR. Furthermore, many other autonomic function assessments, such as SSR, can be technically challenging. However, it is important to be aware of the potential to obtain misleading results if sections of data with numerous artifacts or ectopic beats are utilized; this assessment would not be suitable in individuals with pronounced cardiac arrhythmia. Also, although in chronic SCI (as in the present study) HRV and BPV are highly reproducible (13), this is not likely to be the case in acute SCI, when the cardiovascular consequences of the injury are not stable. It may be that HRV and BPV evaluations would be able to track the evolution of cardiovascular function with time after SCI, but this has yet to be examined.

Implications. Autonomic evaluation of individuals with SCI is not routinely performed, although there is growing belief that this deficit in the management of SCI individuals must be addressed (48). The present study indicates that cardiovascular variability analyses would aid classification of the level and physiological sequelae of SCI (5). Furthermore, spectral analyses may demonstrate completeness of injury to autonomic pathways after SCI. These analyses are particularly useful, because they can be relatively simply performed, require only standard hospital equipment (electrocardiogram and beat-to-beat blood pressure), are noninvasive, and provide largely objective measures of autonomic control. These analyses are correlated with meaningful clinical measures of autonomic function and have been extensively validated in able-bodied individuals (13, 46), with preliminary studies in SCI individuals confirming their use as reproducible indexes of autonomic cardiovascular regulation (13). Finally, the use of these measures may also be valuable in clinical trials evaluating changes in autonomic function over time or due to interventions aimed at improving autonomic function after SCI. The extensive application of spectral and cross-spectral analyses to rodent models (6) also potentially provides a useful means whereby results from the bench can be applied to the bedside, and vice versa.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by a grant from the Rick Hansen Man in Motion Research Foundation and start-up funds from the International Collaboration on Repair Discoveries/University of British Columbia awarded to A. V. Krassioukov.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. V. Krassioukov International Collaboration on Repair Discoveries (ICORD), 6270 Univ. Blvd., Univ. of British Columbia, Vancouver, BC, Canada V6T 1Z4 (e-mail: krassioukov{at}icord.org)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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