Multiple sclerosis (MS), a disease affecting primarily young adults, is characterized by scatered demyelination of neurons in the central nervous system (16). Demyelination results in varying degrees of interruption of normal nerve transmission. In some cases, conduction may be blocked continuously. In others, conduction may be normal at times, but attenuated or blocked during certain conditions such as thermal or psychological stress (19). The variability of lesion location among patients, combined with the unpredictable effects of a given lesion, result in the heterogeneity of symptoms for which MS is noted.
There is probable evidence of neuro-cardiovascular involvement in MS. On autopsy, cardiovascular autonomic nuclei in paraventricular locations of the brain are frequently found to contain plaques in individuals with MS(17). Similar lesions are found in areas of the spinal cord containing B fibers of sympathetic nerves.
A number of investigations have focused on tests of autonomic cardiovascular reflexes performed at rest in patients with MS(1,2,10,15,17). As many as 50% of patients with MS tested have shown abnormal responses to at least one of the tests administered.
In normal individuals, regulation of circulation during physical and thermal stress is mediated by the autonomic nervous system(7,12). It can be hypothesized that individuals with MS lesions on or near neurons involved in these responses will show an abnormal heart rate and/or pressor response to exercise. Isometric handgrip exercise can be used to test this hypothesis. The attendant cardiovascular adjustments are almost entirely autonomic-mediated (8), and normal pressor responses to a variety of specific protocols have been well established (7,14,18).
The present study was designed to test the hypothesis that patients with MS would demonstrate attenuated heart rate and/or pressor responses to isometric exercise. Heart rate and arterial pressure responses to sustained submaximal isometric handgrip exercise were compared in patients with MS and control subjects. In addition, a regression equation predicting the pressor response of patients with MS to this protocol was calculated.
Study participants consisted of 104 patients with MS, aged 23-61 yr (mean± SD, 41.6 ± 8.4) and 25 healthy, normal controls aged 25-47 yr(mean 34.3 ± 5.5). All patients with MS were evaluated by a neurologist prior to testing to confirm MS diagnosis. Subjects were given a full explanation of the experiment and gave written consent in conformance with University of Northern Colorado and Jimmie Heuga Center guidelines. Patients with MS underwent diagnostic graded exercise tests prior to involvement in the study to screen for cardiovascular disease.
Handgrip exercise was performed on a Stoelting dynamometer (Stoelting, Chicago, IL), which was modified by connecting the Stoelting base to a load cell (Interface, Scottsdale, AZ). The load cell was powered by a 12 V source and interfaced with a physiograph recorder (Fisher Scientific, Denver, CO). A force calibration curve was generated by hanging known weight from the dynamometer and measuring the resultant deflections of the recorder tracing.
While lying in a supine position, subjects performed isometric handgrip exercise with their dominant arm. Maximal voluntary contraction (MVC) was established first by taking the average of the best two of three maximal contractions performed 1 min apart. Following a 5-min recovery period, subjects performed a handgrip contraction at a force output equal to 30% of their MVC. This force output was sustained until the point of fatigue, defined as a reduction in force of greater than 10% of the target for longer than 3 s. The physiograph was positioned so that subjects could monitor their force output and make corrections when necessary.
Surface electromyograph (EMG) electrodes were placed on the nonworking forearm of each subject. EMG activity was audible throughout the test. Subjects and investigators used increases in the level of EMG noise as evidence that the subject was contracting muscles not involved in the isometric handgrip. One investigator was responsible for reminding subjects to keep the noise at a low level by relaxing nonworking muscles. This was to help ensure that changes in heart rate and blood pressure were due solely to effort from the arm performing handgrip dynamometry.
During exercise, heart rate was determined from a computer-averaged pulse signal from a Finapres (see Arterial Pressure Measurement below). Blood pressure was recorded beat-by-beat with the Finapres. RPE was obtained every 30 s from rest until the point of exhaustion. Heart rate, systolic pressure, diastolic pressure, and MAP were calculated and reported at rest and at 20%, 40%, 60%, 80%, and 100% of time to fatigue. Each value except rest represented the average of 6 heartbeats prior to that specific percent of time to fatigue. Resting values represented data averaged over 30 s prior to initiation of exercise. The entire test was recorded by a video camera, which was positioned to record all data shown on the Finapres monitor.
Arterial pressure was recorded continuously and non-invasively with a fully automated system, the Finapres 2300 (Ohmeda Monitoring Systems, Englewood, CO). A number of validation studies have determined that Finapres measurements provide an accurate estimate of direct intra-arterial blood pressure measurement under a variety of conditions (5,11).
As part of the neurological examination, each patient with MS received scores on the Kurtske Expanded Disability Status Scale (EDSS) and the Incapacity Status Scale (ISS). These are clinical tools commonly used to evaluate the scope and severity of MS-related disability. The EDSS runs from 0(absence of symptoms) to 10 (death due to MS symptoms) and the ISS ranges from 0 to 60, also reflective of increasing severity of symptoms.
A factorial analysis of variance was used to compare between group differences at each designated percentage of exercise duration with alpha level set at 0.05. A stepwise regression analysis employed six predictor variables: age, gender, years with MS, EDSS score, ISS score, and the sum of the bowel and bladder dysfunction scores from the ISS (range from 0 to 8). The dependent variable in this analysis was change in MAP from rest to fatigue.
Table 1 shows age, gender, resting heart rate and arterial pressure in control subjects and patients with MS. There were no pre-test differences between groups for heart rate or blood pressure. There was a significant difference in age between MS and controls (P < 0.05). Table 2 shows force production and time to fatigue during isometric handgrip testing for MS and control subjects. MVC was greater for controls; therefore, the 30% MVC work rate had a higher absolute value(P < 0.05). Time to fatigue was almost 50 s longer in the control group (P < 0.05).
Comparison of RPE (Fig. 1) shows that perceived effort increased linearly to 10 (maximal) at fatigue for both groups. RPE at each percentage of exercise duration was nearly identical.
Table 3 shows group changes in systolic pressure during isometric handgrip exercise. Both groups showed a linear increase from rest to the point of fatigue. The MS response was significantly attenuated at each percentage of exercise duration (P < 0.05).
Table 3 demonstrates that changes in diastolic and mean arterial pressure were similar to systolic pressure. Again, both groups increased linearly to the point of fatigue. The increases were significantly attenuated in patients with MS at each percentage of exercise duration for both variables (P < 0.05).
Figure 2 is a frequency distribution that shows the fraction of each group (percent of subjects) against the dependent variable,ΔMAP, at 100% exercise duration. This shows a fairly tight distribution around the mean of +47.9 mm Hg for control subjects. The range of values was 47 mm Hg (30-77 mm Hg). The group with MS, by contrast, showed a much wider distribution around its mean of 28.2 mm Hg. The MS range was larger than control by a factor of 1.5 (72 mm Hg) with a minimum of -6 mm Hg and a maximum of 66 mm Hg (Table 3). Fifty-eight percent of the patients with MS were distributed below the lowest value recorded by a control subject(+30 mm Hg). Eighteen patients with MS achieved increases in MAP at the point of fatigue ranging from -6 mm Hg to 15 mm Hg.
Changes in heart rate are shown in Table 3. The control group was significantly higher than the MS group (P < 0.05) at 20% of exercise duration. The increase in heart rate at the point of fatigue was normal in both groups. Table 4 summarizes changes in arterial pressure at the point of fatigue for MS patients and controls.
Prediction of Pressor Response
Table 5 shows means and standard errors for 5 of the 6 independent variables (gender is omitted) in the stepwise regression analysis. ISS score was the first variable entered, with an R2 of 0.13. The second variable entered was age, bringing R2 to 0.26. Thus, ISS score and age combine to account for 26% of the variability in change in MAP at the point of fatigue in patients with MS. No other variables added significantly to the predictability of the MAP response.
This protocol provides a method of accurately measuring beat-by-beat changes in arterial pressure that occur during isometric exercise. The normative response to isometric handgrip exercise at 30% MVC has been well established through several investigations over the last three decades(3,4,9,18). This allowed assessment of the validity of control group data and of methodology in this study. Controls in this study showed pressor responses similar to normal individuals evaluated in previous studies, thus justifying use of our control group as a normative standard against which the MS responses could be evaluated. Although the question of whether gender influences the pressor response to handgrip dynamometry has not been thoroughly addressed in the literature, data from this study do not support a gender effect. In the control group, the mean increase in MAP (±SEM) at the point of fatigue for females was 47.4± 3.2 mm Hg. Male controls increased 47.9 ± 2.4 mm Hg. In the MS group, the increases for females and males were, respectively, 28.1 ± 1.7 and 28.5 ± 2.5 mm Hg. The failure of arterial pressure to increase to expected levels in MS patients may be interpreted as resulting from autonomic dysfunction.
This study provides evidence that some patients with MS are unable to increase arterial pressure in response to a strong stimulus such as isometric handgrip exercise. Although 42% of the cohort tested were within normal limits as defined by the control group, the remaining 58% were below normal. Failure to increase MAP by more than 15 mm Hg (seen in 18 of 104 subjects) is evidence of a profoundly abnormal pressor response to exercise. This may result from MS lesions located in hypothalamic nuclei or areas of the spinal cord associated with autonomic control of cardiovascular reflexes.
While the difference in age between MS and control subjects (7.3 yr) was statistically significant, its influence as a confounding factor in this study is doubtful. A recent study (18) showed no difference in pressor response between young (mean age = 26 yr) and elderly (age = 66 yr) men using the same protocol as this study.
Of great interest is the difference in time to fatigue (TTF) between the two groups. Since the MS group averaged 48.8 s less to fatigue than controls, the failure of patients with MS to generate a normal increase in arterial pressure may be due to their shorter duration of exercise, and not to autonomic dysfunction. However, this possibility is unlikely for two reasons. First, the pressor response in patients with MS was attenuated at every reported percentage of exercise duration, not just at fatigue. Moreover, if TTF was a factor in determining the magnitude of the pressor response, then there should be a significant correlation between TTF and ΔMAP at fatigue. In fact, the correlation between these two variables in patients with MS was 0.07. For the controls this correlation was r = 0.17. For all subjects combined, r = 0.18. These data seem to eliminate TTF as a factor influencing the pressor response to isometric handgrip exercise at 30% MVC.
A between-groups difference in MVC was on the order of 12%. This meant that 30% MVC represented a higher absolute force output in the control subjects. Size of the active muscle mass can be an important factor in the sympathetic-mediated pressor response to protocols like the one used in this study. However, studies demonstrating this have compared different muscle groups with huge differences in size. When subjects are using the same muscle group, the critical factor influencing the pressor response is the attainment of a valid point of fatigue, not absolute force generated or (by inference) size of the muscle mass recruited.
A stepwise regression analysis was employed to determine whether the pressor response to handgrip exercise might be predicted from clinical data commonly available to health care professionals who work with patients with MS. Unfortunately, none of the variables we used (neither demographic data nor measures of disability) were found to predict the pressor response, either alone or in combination. ISS had the highest individual correlation with pressor response, with R2 = 0.13; when age was entered into the equation with ISS, R2 = 0.26. Future studies may identify variables that predict this response with greater accuracy.
The clinical implications of the abnormal pressor response demonstrated in this study are not clear. One concern is that patients with MS might be unable to maintain perfusion pressure to working muscles commensurate with their metabolic demand during sustained dynamic exercise. This hypothesis needs to be tested, since it is known that the mechanisms governing the pressor response to dynamic exercise are not identical to those operative during isometric exercise (13). If the above hypothesis is correct, it could mean that some patients with MS are unable to achieve an exercise training intensity or duration necessary to yield desired physiological adaptations.
Another potential consequence of inadequate pressor response to exercise is reduced brain blood flow, which could cause dizziness or syncope. Clearly the safety and efficacy of standard exercise prescription as applied to the MS population has not been thoroughly established. The work described in this paper should be expanded to elucidate pressor responses to varying intensities of dynamic exercise in a large cohort of patients with MS. Exercise prescriptions may have to be modified for certain patients based on their level of autonomic involvement in the disease process. A simple inexpensive test, such as the handgrip test described here, may prove useful in identifying such patients. At a time when it is becoming common to prescribe exercise training for patients with MS who desire it (6), these questions should be investigated to ensure that exercise is safe and effective for this population.
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Keywords:©1996The American College of Sports Medicine
AUTONOMIC NERVOUS SYSTEM; HANDGRIP EXERCISE; CARDIOVASCULAR REFLEXES; DYSAUTONOMIA