Journal of Applied Physiology Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 94: 2158-2165, 2003. First published February 7, 2003; doi:10.1152/japplphysiol.00959.2002
8750-7587/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
94/6/2158    most recent
00959.2002v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (16)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fernhall, B.
Right arrow Articles by Otterstetter, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fernhall, B.
Right arrow Articles by Otterstetter, M.
Vol. 94, Issue 6, 2158-2165, June 2003

Attenuated responses to sympathoexcitation in individuals with Down syndrome

Bo Fernhall and Mari Otterstetter

Exercise Science Department, Syracuse University, Syracuse, New York 13244; and Exercise Science Department, George Washington University Medical Center, Washington, DC 20037


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

This study evaluated blood pressure and heart rate responses to exercise and nonexercise tasks as indexes of autonomic function in subjects with and without Down syndrome (DS). Twenty-four subjects (12 with and 12 without DS) completed maximal treadmill exercise, isometric handgrip (30% of maximum), and cold pressor tests, with heart rate and blood pressure measurements. Maximal heart rate and heart rate and blood pressure responses to the isometric handgrip and cold pressor tests were reduced in subjects with DS (P < 0.05). Both early (first 30 s) and late (last 30 s) responses were reduced. Obesity did not appear to influence the results, as both obese and normal-weight subjects with DS exhibited similar responses, and controlling for body mass index did not alter the results between controls and subjects with DS. Individuals with DS, without congenital heart disease, exhibit reduced heart rate and blood pressure responses to isometric handgrip exercise and cold pressor testing, consistent with autonomic dysfunction. Autonomic dysfunction may partially explain chronotropic incompetence observed during maximal treadmill exercise in individuals with DS.

exercise; hemodynamic responses; chronotropic incompetence


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

DOWN SYNDROME (DS), OR TRISOMY 21, is associated with physical and physiological perturbations, which may contribute to the low physical work capacity observed in this population (6, 11). Many individuals with DS have congenital heart disease (30-40%) (6), but physical work capacity is still low in individuals with DS without congenital heart disease (11, 35). Motivation, task understanding, and sedentary lifestyles have been suggested as contributors to low physical work capacity in individuals with DS (5, 42). Recent data suggest that these factors do not explain most of the deficit (10, 11, 34), but reduced heart rate (HR) response to exercise, or chronotropic incompetence, has been identified as a major contributor to reduced physical work capacity in populations with DS (8, 10, 11, 17, 18).

Although chronotropic incompetence has been demonstrated in a variety of other populations, the mechanism of blunted HR response to exercise is still uncertain but may be related to autonomic regulatory dysfunction (17, 25). In most populations with chronotropic incompetence, depressed sympathetic tone or response seems to contribute to a blunted HR response during exercise (25, 29, 32, 41), but incomplete vagal withdrawal has also been implicated (41).

Isometric handgrip exercise and cold pressor testing are two simple, noninvasive, and validated tests of sympathetic activation (21, 23, 40, 46). The HR and blood pressure (BP) responses are used as indicators of global sympathetic activation (cold pressor test) or sympathetic activation during exercise (isometric handgrip test). Preliminary data show that individuals with DS have significantly reduced HR and BP responses to isometric exercise compared with nondisabled control subjects (13), suggesting reduced sympathetic activation in this population during exercise. However, the subjects with DS had much higher body mass index (BMI) than controls; thus it is possible that obesity could explain these findings, because obesity has been related to altered autonomic function (28).

Considering the potential impact of chronotropic incompetence on exercise tolerance, exercise prescription, and cardiovascular risk, investigating the autonomic response to exercise and other sympathoexcitatory tasks will substantially enhance our understanding of possible factors related to chronotropic incompetence in individuals with DS. This study provides more definite insight regarding autonomic control of HR and BP in individuals with DS, by evaluating the autonomic response during both exercise and a nonexercise task and carefully evaluating the impact of obesity on these responses. Thus the purpose of this investigation was to 1) compare the HR and BP responses during isometric handgrip exercise and cold pressor testing between individuals with DS (without congenital heart disease) and a control group of age- and gender-matched healthy controls. We hypothesized that both HR and BP responses would be lower in individuals with DS, indicative of reduced sympathoexcitation. 2) The second purpose was to evaluate if the HR and BP changes during isometric handgrip and cold pressor testing were influenced by obesity in the subjects with DS, because obesity is very prevalent in this population. Because we have found that obesity does not influence the peak HR response in subjects with DS, we hypothesized that obesity would not alter the autonomic response in individuals with DS.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects

Twenty-four healthy subjects, 12 with DS and 12 without disabilities, between 17 and 39 yr of age, volunteered for the study. There were six men and six women in each group. All subjects were sedentary or moderately active, but none was participating in any extensive exercise training. Subjects were recruited from the local community and from local support groups for individuals with DS. All subjects were free of any overt disease based on medical history. Subjects were excluded from the study if they exhibited any of the following: 1) history of cardiovascular disease or a history of diabetes or any other metabolic disease that may affect the resting and exercise measurements; 2) any HR-altering medications or any other medication that may alter metabolic responses; 3) smoking; 4) any contraindications to exercise; 5) severe or profound mental retardation; 6) asthma or other significant respiratory disorders; 7) congenital heart disease; or 8) atlanto-axial instability. The nature of study participation was explained, and, after initial screening, all subjects signed informed consent. For subjects with DS, their parents also signed informed consent. The study protocol was approved by the University Medical Center Institutional Review Board at the George Washington University Medical Center.

Study Design

All familiarizations and testing sessions were conducted between June 1999 and August 2000. Subjects were tested in a postprandial state (~3 h) on 2 separate days and refrained from exercise 24 h before each test day. Subjects were also asked to refrain from caffeine ingestion on testing days. Both testing sessions were completed within a 3-wk period for each subject. The maximal treadmill test was conducted on a separate day from the handgrip and cold pressor tests. The order of testing was randomized, and subjects rested in a supine position for 15-30 min between tests (handgrip and cold pressor) to ensure that HR and BP had returned to resting levels before commencing the second test.

Familiarization

Subjects with DS were familiarized with all testing protocols before data collection. The number and length of familiarization sessions depended on the response of the individual subject. Data collection started when a subject could satisfactorily conduct each test, including comfortably walking on a motorized treadmill. We have previously shown that, through this familiarization procedure, valid and reliable exercise data can be collected on this population (6, 9, 11, 14). Subjects without DS were familiarized with test procedures on the day of testing before each procedure and demonstrated that they could satisfactorily complete the test tasks before data collection.

Protocol

Treadmill exercise test. Cardiorespiratory fitness and maximal HR were evaluated by using a treadmill protocol individualized to the capabilities of each individual. Subjects started by walking at a comfortable speed for 3 min, followed by a fast walk for 2 min. Thereafter, the grade was increased 2.5% every 2 min until a grade of 12.5% was reached. From this point, treadmill speed was increased 1 mph every minute until exhaustion. Oxygen uptake (VO2) was measured with a computerized on-line breath-by-breath system (SensorMedics V-max), and the VO2 was averaged over 20 s. HR was measured by using a Polar HR monitor and was continuously monitored throughout the test. The test was terminated when the subject could no longer keep up with the treadmill speed or showed signs of volitional fatigue. The test was considered a valid peak effort if VO2 plateaued (less than a 150 ml/min increase) with an increase in work rate, or if there was a plateau in HR (less than a 2 beat/min increase) with an increase in work rate concomitant with a respiratory exchange ratio of >1.0. This protocol has been shown to yield valid and reliable data in subjects with and without DS (6, 9, 14).

Handgrip testing. Maximal grip strength was determined with the subject in a supine position by using the dominant hand. Grip strength was measured with an electronic handgrip dynamometer (TSD121C, Biopac Systems) interfaced with a computer with visual feedback on the computer monitor. Subjects were given standardized encouragement to produce maximal effort. Maximal voluntary contraction was determined by using the highest of three maximal contractions. This method has yielded valid and reliable strength measures in subjects with DS in our laboratory, with intraclass reliability coefficients >0.93. After several minutes of rest to allow hemodynamic variables to return to rest, the test was started with a 2-min rest period, followed by a 2-min isometric handgrip contraction at 30% of maximal voluntary contraction. We chose a 2-min contraction period to standardize length of contraction, and pilot testing revealed that 2 min was the longest contraction period possible to ensure inclusion of all subjects with DS. During the contraction phase of the test, subjects received visual feedback on the computer monitor to help them produce the correct force required. BP and HR were collected on-line, in real-time mode. Beat-to-beat BP was measured noninvasively by using arterial tonometry (CMD 7000, Colins Medical Instruments) in the nondominant arm, with the arm extended at heart level. The BP monitor was interfaced with a computer (Biopac systems). HR was collected by using a one-lead ECG (CM5), interfaced with a computer (Biopac systems). All HR and BP data were collected at 1,000 Hz and stored on the computer and analyzed off-line after completion of testing.

Cold pressor testing. The cold pressor test was performed in the supine position, and the subject's hand was immersed in cold water up to the wrist for 2 min, followed by a 2-min recovery period. Care was taken to ensure that the subject avoided any isometric contractions, breath holding, or performance of the Valsalva maneuver. HR and BP were continuously collected on-line, at rest and during immersion, in exactly the same manner as described for the handgrip test. Data were stored on the computer and analyzed off-line after completion of testing.

Data Analyses

Descriptive characteristics between groups were compared by using independent t-tests. The HR and BP response to handgrip and cold pressor testing were evaluated by using 30-s averages of beat-to-beat data. The change from resting values was compared with the first 30 s and the last 30 s of handgrip exercise or cold pressor responses, as indicators of early vs. late responses (40, 46), by using a 2 × 2 ANOVA with repeated measures [group (DS vs. non-DS) by time (change from rest to 30 s; change from rest to 120 s)]. Because BMI differed between groups, and obesity can influence HR and BP responses to handgrip and cold pressor testing, we repeated the ANOVA analyses using BMI as a covariate to help control for the influence of obesity. To further evaluate the potential impact of obesity, we also divided the group with DS into two subgroups: obese and nonobese subjects, using a BMI of >30 to classify subjects as obese and a BMI of <30 as nonobese. Seven of the 12 subjects with DS were classified as obese and five as nonobese. We used a 2 × 3 ANOVA [group by time (rest, 30 s, 120 s)] with repeated measures to evaluate the HR and BP responses to isometric handgrip and cold pressor testing in these two groups of subjects. Statistical significance was set at P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subject characteristics and treadmill exercise data are shown in Table 1. Both groups were of similar age, but all other variables were significantly different between groups. During the maximal treadmill testing, seven of the controls and nine of the subjects with DS achieved a plateau in VO2. Both maximal HR achieved on the maximal treadmill test and the change in HR from rest to maximal exercise were significantly higher in the control group. The change in HR during the cold pressor test (A) and handgrip test (B) are shown in Fig. 1. There was a significant group-by-time interaction for both tests, showing that the overall change in HR differed between groups during both tests, caused by a lower increase in HR in subjects with DS. Controlling for BMI did not alter these results.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Descriptive characteristics and maximal treadmill performance of individuals with and without Down syndrome



View larger version (15K):
[in this window]
[in a new window]
  		Fig. 1.   Mean heart rate changes (Delta ) during cold pressor testing (A) and isometric handgrip exercise (B) at 30% of maximal voluntary contraction in subjects with Down syndrome (DS) and controls. bpm, Beats/min. Values are means ± SE. * Both early and late responses were significantly reduced (P < 0.05) in subjects with DS.

Changes in mean arterial BP (MAP) during the cold pressor (A) and handgrip tests (B) are shown in Fig. 2. There was a significant group-by-time interaction effect for both tests, showing that the comparison group increased MAP significantly more than the group with DS for both time points. Controlling for BMI did not alter these results.


View larger version (14K):
[in this window]
[in a new window]
  		Fig. 2.   Delta Mean arterial blood pressure (MAP) during cold pressor testing (A) and isometric handgrip exercise (B) at 30% of maximal voluntary contraction in subjects with DS and controls. Values are means ± SE. * Both early and late responses were significantly reduced (P < 0.05) in subjects with DS.

The comparison of the obese and nonobese subjects with DS is shown in Table 2. None of the responses was significantly different between groups. A careful examination of Table 2 reveals that both the HR and BP responses were very similar between groups, with the nonobese subjects exhibiting slightly smaller changes, but this was not significant.

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Absolute heart rate, systolic and diastolic blood pressure responses of nonobese (BMI < 30) and obese (BMI > 30) subjects with Down syndrome to 2-minute cold pressor and isometric handgrip (30% MVC) testing


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The main finding of this study was that both HR and BP responses to cold pressor testing and isometric handgrip exercise were reduced in subjects with DS without congenital heart disease. It appears that this was not a function of the higher BMI observed in the group with DS. Statistically, controlling for BMI did not alter our results. Furthermore, there was no difference in the HR or BP responses to handgrip and cold pressor testing between obese and nonobese subjects with DS. All subjects with DS exhibited markedly reduced hemodynamic responses to all tests, regardless of obesity status, suggesting that obesity status did not influence the responses of subjects with DS. Our data are consistent with the notion that HR responses to sympathetic tasks are reduced in individuals with DS, and this reduced HR response to sympathetic tasks may partially explain chronotropic incompetence during maximal treadmill exercise in individuals with DS.

Impact of Obesity

Obesity impairs autonomic control of HR and BP (28, 36, 49). However, responses to isometric handgrip exercise have been varied. Obese individuals have been shown to exhibit both higher (49) and lower (45) BP responses during isometric handgrip exercise. Obese patients have also been shown to exhibit lower sympathetic response to cold exposure (28). In our study, because the group with DS had significantly higher BMI compared with controls, it is possible that our observed differences could be attributed to obesity and not to DS per se. However, when we compared obese and nonobese subjects with DS, there was no difference between the groups, and the response trends were nearly identical. We also statistically controlled for BMI when comparing subjects with DS and controls, and this did not alter our findings. Thus it is unlikely that obesity can account for the reduced HR and BP responses in subjects with DS.

Significance of the Cold Pressor Test

Cold pressor testing is often used to evaluate the sympathetic influence on circulation in humans (31, 46). HR and BP responses in normal subjects are well characterized (16, 43, 46), and differential responses have been observed in a variety of clinical populations (31, 37, 48). In normal subjects, HR is expected to increase 7-12 beats/min during the first 1-2 min of immersion and may stabilize or decrease with more prolonged immersion (43, 46). Our control group showed the expected change in HR, but the response was greatly diminished in our subjects with DS (Fig. 1). Victor et al. (46) showed that the cold-induced increase in HR was entirely a function of sympathetic activation, because HR changes were completely abolished by beta -adrenergic blockade (propranolol). This suggests that our subjects with DS exhibited reduced HR responses as a result of reduced sympathetic activation in response to cold.

MAP is also expected to increase 15-30 mmHg during the first 2 min of cold immersion (16, 43, 46), consistent with our observations in the comparison group. However, our subjects with DS showed virtually no change in MAP (Fig. 2) during the cold pressor test. Studies of muscle sympathetic nerve activity have shown that the increase in MAP is caused by increased sympathetic activation (31, 46), as changes in MAP are closely mirrored by changes in muscle sympathetic nerve activity. Thus the reduced BP responses during cold pressor testing in our subjects with DS are also consistent with reduced sympathetic activation in these subjects.

It is possible that the reduced hemodynamic responses during the cold pressor test in subjects with DS were influenced by impaired peripheral somatosensory function in this population. Recent data showed that both sensory nerve conduction velocity and action potential amplitudes were significantly reduced in individuals with DS compared with controls (1). Furthermore, Hennequin et al. (19) showed that individuals with DS experienced increased pain latency in response to ice placed on the hand and forehead. Thus both sensory nerve and nociceptor function may be altered in persons with DS, which could at least partially explain the reduced hemodynamic response to cold that we observed in this population.

Significance of the Handgrip Test

Two minutes of isometric handgrip exercise at 30-35% of maximal voluntary contraction are expected to induce HR increases in the magnitude of 15-20 beats/min (22, 40, 43). Our comparison group exhibited the expected increase in HR, but our subjects with DS showed only 50% of the expected increase (Fig. 1). The increase in HR during the first minute of isometric handgrip exercise at this intensity is mediated primarily by vagal withdrawal, as it is not affected by beta -blockade but is either mostly, or completely, abolished by atropine (15, 22, 26). A gradual increase in sympathetic activation, together with vagal withdrawal, accounts for HR changes after the first minute (20, 22, 40, 43). Our data, showing that the subjects with DS exhibited reduced increases in HR at both the 30- and 120-s time periods, suggest that subjects with DS exhibit both increased parasympathetic and decreased sympathetic modulation of HR during isometric handgrip exercise.

MAP increases 25-40 mmHg with 2 min of isometric handgrip exercise at contraction intensities between 30 and 35% of maximal voluntary contraction (21, 22, 40, 43). The BP changes observed in our comparison group are within these expected increases (Fig. 2). Conversely, the BP changes in our group with DS were approximately one-half of the expected response after the 2-min contraction. Furthermore, the initial response (first 30 s) was a slight decrease in both systolic and diastolic pressure in our subjects with DS, which is in the opposite direction of the expected response. Seals et al. (40) showed that the initial increase in arterial BP during isometric contractions >25% of maximum was a function of tachycardia, and the increase after the initial 1-1.5 min was due to increased sympathetic stimulation, as they showed by increases in muscle sympathetic nervous activity. Because the initial increase in HR is due to vagal withdrawal (22), it is likely that the initial increase in arterial BP is a function of increased cardiac output as a function of increased HR, caused by vagal withdrawal. Actual measurements of cardiac output during isometric handgrip support this notion, as stroke volume does not change (43). Consequently, the reduced BP response during isometric handgrip exercise in the subjects with DS was probably a function of reduced vagal withdrawal and reduced sympathetic stimulation.

Evidence in Support of Blunted Vagal Withdrawal

The main evidence in support of blunted vagal withdrawal in subjects with DS from our study is the reduced HR response during the first 30 s of the handgrip test. The cold pressor test is primarily a test of global sympathetic activation, as shown by Victor et al. (46); thus the reduced HR response during this test is not an indication of blunted vagal withdrawal. Because Maciel et al. (26, 27) and Flessas and Ryan (15) have shown that beta -blockade slightly diminishes, but does not eliminate, the early HR response to isometric handgrip exercise, the contribution of sympathetic stimulation to the early HR increase is minimal. However, atropine almost completely eliminates the early HR response (15, 26, 27); thus this increase appears to be caused by parasympathetic withdrawal. The blunted HR response at 30 s in our subjects with DS is consistent with blunted vagal withdrawal. In support of this notion, we have observed blunted vagal withdrawal, measured by HR variability analysis, during handgrip exercise in a small number of subjects with DS (unpublished observations). We have also observed greater vagal influence at rest, through HR variability analyses (47), in subjects with DS, suggesting that parasympathetic influence is greater in this population. However, Sacks and Smith (39) showed greater pupil dilation in response to an anticholinergic agent in individuals with DS, consistent with enhanced cholinergic sensitivity. Because enhanced receptor sensitivity can be a function of receptor upregulation in response to reduced cholinergic function, they interpreted their findings as reduced cholinergic drive in subjects with DS. This is in contrast to our findings, but studies that simultaneously investigate cholinergic drive and receptor sensitivity in subjects with DS are lacking.

Evidence in Support of Decreased Sympathetic Modulation

The data from both the cold pressor and the handgrip test show that sympathetic modulation is reduced in individuals with DS. Both the HR and BP response to the cold pressor test are primarily caused by sympathetic stimulation (46), and these responses were greatly diminished in our subjects with DS. Furthermore, both the late HR and BP responses during handgrip testing are caused primarily by sympathetic stimulation (40), and these responses were also reduced in our subjects with DS. The notion that individuals with DS have reduced sympathetic responses to stress is supported by Eberhard et al. (4), who showed that circulating catecholamines in response to incremental cycle ergometer exercise were reduced in individuals with DS. Udeschini et al. (44) showed no increase in catecholamines after 1 min of cold pressor testing in individuals with DS, whereas controls showed an increase, but there was no difference between controls and subjects with DS. This study also showed reduced HR and BP responses to cold pressor testing in subjects with DS, but these were also not different from controls. It is likely that these nonsignificant findings were due to the low number of subjects in the study (n = 5), and power analyses on their data show that, with 18-20 subjects per group, the responses of the individuals with DS would be significantly different from those of controls.

It is possible that reduced levels of circulating catecholamines contribute to the lower maximal HRs in individuals with DS, as reduced sympathetic drive or response has been postulated to be the cause of chronotropic incompetence in other populations (25, 29, 32, 41). Consistent with this notion, human skin fibroblasts from individuals with DS were hyperresponsive to beta -adrenergic stimulation, suggesting receptor upregulation (30). This would also be consistent with lower levels of plasma dopamine beta -hydroxylase activity in individuals with DS, because this enzyme converts dopamine to norepinephrine (24). However, despite the lower levels of beta -hydroxylase, resting and standing levels of plasma norepinephrine were higher in subjects with DS compared with controls (24). These conflicting findings suggest that more research is needed on the mechanism of the reduced sympathetic response to exercise and cold stress in individuals with DS.

Possible Impact of Impaired Baroreceptor Function

It is possible that abnormal baroreceptor function, manifested through an impaired baroreflex, could alter the HR and BP responses to both static and dynamic exercise. In normal healthy controls, the arterial baroreflex gain is reset during both static and dynamic exercise (20, 38), allowing HR to increase in the presence of increased BP. It is possible that an impaired baroreflex could affect the HR increase during exercise in subjects with DS; however, little evidence exists to support this concept. Anecdotal observations of excessive drops in BP with standing (orthostatic hypotension) have been reported (2), but no systematic studies reporting orthostatic hypotension in subjects with DS exist. The orthostatic index has been shown to be lower in subjects with DS than controls (3), indicating a lesser increase in HR in response to standing. We recently showed lower HR increases in response to a 10-min upright tilt in subjects with DS compared with healthy controls (7), but neither of these studies (3, 7) measured BP. Others have shown no differences in orthostatic responses between individuals with DS and healthy controls. Both HR and BP changes during a sit-to-stand task were slightly lower in subjects with DS (24), but these differences were not significant. Udeschini et al. (44) supported these findings, showing no difference in the HR and BP responses from sitting to standing between subjects with DS and controls. Thus there are conflicting reports regarding the HR response to an orthostatic challenge in individuals with DS, but little evidence for an abnormal baroreflex in this population.

Chronotropic Incompetence

Chronotropic incompetence in response to maximal exercise is well documented in persons with DS (8, 10-12). The low maximal HR in this population is not caused by lack of effort or poor motivation (10-12), but has been speculated to be a physiological consequence of DS (6, 10). The physiological mechanism for the chronotropic incompetence is unknown, but it has been speculated that altered autonomic function plays an important role in populations without DS (25, 32). Our data support the notion that autonomic dysfunction may explain the chrontropic response to exercise in individuals with DS, showing both reduced vagal withdrawal and blunted sympathetic response to isometric exercise and cold stress. Both reduced vagal withdrawal and reduced sympathetic drive have been implicated as possible mechanisms for chronotropic incompetence in populations without DS (25, 41).

Limitations

There are several limitations to this study. First, we did not directly measure sympathetic and parasympathetic modulation of the HR and BP responses but made inferences based on information from prior studies regarding control of these responses during handgrip and cold pressor testing. Thus we can only speculate on possible mechanisms for observed responses. However, the control mechanisms for HR and blood changes during these tasks are well established. Although HR variability analyses may provide additional insight, such analyses require 5-min steady-state data. This was not possible in our study, because both HR and BP changed throughout the 2-min measurement periods. Thus steady state was not achieved, and our measurement periods were too short to yield reliable HR variability results. Second, DS is a genetic disorder with diverse physiological consequences. It is not known if our results are generalizable to other populations of subjects with DS. However, physical work capacity and HR responses to maximal exercise are remarkably consistent in the literature, and our present data are similar to previously reported data. Third, maximal treadmill exercise and handgrip exercise are effort dependent; thus it is possible that our subjects with DS may have produced lower effort than our control subjects. We used validated protocols and accepted criteria for peak effort during the maximal treadmill testing, which were achieved by all of our subjects. During handgrip exercise, several peak efforts were produced, and we used the best response, which is an accepted method for determining peak handgrip strength and is a reliable measure of handgrip strength in subjects with (intraclass reliability >0.93 in our laboratory) and without DS (33). During the submaximal 2-min handgrip task, computer feedback was used to aid subjects to maintain the correct effort. The investigators also provided feedback to ensure that the appropriate level of contraction was maintained. The response during cold pressor testing is not effort dependent and yielded similar results. Thus we do not believe that our data were substantially influenced by lack of effort in our subjects with DS.

In conclusion, we observed blunted HR and BP responses during cold pressor testing and isometric handgrip exercise in individuals with DS. The blunted HR response during these tasks may explain the chronotropic incompetence observed during maximal treadmill exercise in subjects with DS. Our results apply only to individuals with DS without congenital heart disease, because no subjects with congenital heart disease were included in this study.


    ACKNOWLEDGEMENTS

The authors gratefully acknowledge Dr. Viswanath Unnithan for helpful editorial comments during the preparation of this manuscript.

This study was supported by American Heart Association Grant-in-Aid 005028N.


    FOOTNOTES

Address for reprint requests and other correspondence: B. Fernhall, Rm. 201, Exercise Science Dept., Syracuse Univ., 820 Comstock Ave., Syracuse, NY 13244 (E-mail: bfernhal{at}syr.edu).

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.

First published February 7, 2003;10.1152/japplphysiol.00959.2002

Received 16 October 2002; accepted in final form 5 February 2003.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Brandt, B, and Rosen I. Impaired peripheral somatonsensory function in children with Down syndrome. Neuropediatrics 26: 310-312, 1995[Web of Science][Medline].

2.   Carpenter, P. Cardiovascular and autonomic function in Down syndrome-prescribing implications. Br J Psychiatry 167: 118-119, 1995[Web of Science][Medline].

3.   Eberhard, Y, Eterradossi J, and Rapacchi B. Physical aptitudes to exertion in children with Down's syndrome. J Ment Defic Res 33: 167-174, 1989.

4.   Eberhard, Y, Etarradossi J, and Therminarias A. Biochemical changes and catecholamine response in Down's syndrome adolescents in relation to incremental maximal exercise. J Ment Defic Res 35: 140-146, 1991.

5.   Fernhall, B. Physical fitness and exercise training of individuals with mental retardation. Med Sci Sports Exerc 25: 442-450, 1993[Web of Science][Medline].

6.   Fernhall, B. Mental retardation. In: ACSM's Exercise Management for Persons with Chronic Disease and Disability. Champaign, IL: Human Kinetics, 1997, p. 221-226.

7.   Fernhall, B, Figuerao A, Giannopoulou I, Collier S, Baynard T, and Otterstetter M. Chronotropic incompetence and autonomic dysfunction in individuals with Down syndrome (Abstract). Med Sci Sports Exerc 34: S47, 2002.

8.   Fernhall, B, McCubbin J, Pitetti K, Rintala P, Rimmer J, Millar AL, and de Silva A. Prediction of maximal heart rate in individuals with mental retardation. Med Sci Sports Exerc 33: 1655-1660, 2001[Web of Science][Medline].

9.   Fernhall, B, Millar AL, Tymeson G, and Burkett LN. Maximal exercise testing of mentally retarded adolescents and adults: reliability study. Arch Phys Med Rehabil 71: 1065-1068, 1990[Web of Science][Medline].

10.   Fernhall, B, and Pitetti K. Limitations to work capacity in individuals with intellectual disabilities. Clin Exerc Physiol 3: 176-185, 2001.

11.   Fernhall, B, Pitetti K, Rimmer JH, McCubbin JA, Rintala P, Millar AL, Kittredge J, and Burkett LN. Cardiorespiratory capacity of individuals with mental retardation including Down syndrome. Med Sci Sports Exerc 28: 366-371, 1996[Web of Science][Medline].

12.   Fernhall, B, Pitetti K, Stubbs N, and Stadler L. Validity and reliability of the 1/2 mile run-walk as an indicator of aerobic fitness in children with mental retardation. Pediatric Exercise Science 8: 130-142, 1996.

13.   Fernhall, B, Renaud M, Holden H, and Slotter C. Autonomic control during exercise is altered in Down syndrome (Abstract). Sci Sports 15: 288, 2000.

14.   Fernhall, B, and Tymeson G. Graded exercise testing of mentally retarded adults; a study of feasibility. Arch Phys Med Rehabil 63: 363-365, 1987.

15.   Flessas, A, and Ryan T. Atropine-induced cardioacceleration in patients on chronic propranolol therapy: comparison with the positive chronotropic effect of isometric exercise. Am Heart J 105: 230-234, 1983[Web of Science][Medline].

16.   Green, MA, Boltax AJ, Lustig GA, and Rogow E. Circulatory dynamics during the cold pressor test. Am J Cardiol 16: 54-60, 1965[Web of Science][Medline].

17.  Guerra M, Cuadrado F, Llorens N, and Fernhall B. Chronotropic incompetence in individuals with Down Syndrome. Arch Phys Med Rehabil In Press.

18.   Guerra Balic, M, Mateos EC, Blasco CG, and Fernhall B. Physical fitness levels of physically active and sedentary adults with Down syndrome. Adapted Physical Activity Quarterly 17: 310-321, 2000.

19.   Hennequin, M, Morin C, and Feine J. Pain expression and stimulus localisation in individuals with Down's syndrome. Lancet 356: 1882-1868, 2000[Web of Science][Medline].

20.   Iellamo, F, Pizzinelli P, Massaro L, Raimondi G, Peruzzi G, and Legramante JM. Muscle metaboreflex contribution to sinus node regulation during static exercise. Insights from spectral analysis of heart rate variability. Circulation 100: 27-32, 1999[Abstract/Free Full Text].

21.   Khurana, RK, and Stetty A. The value of the isometric hand-grip test-studies in various autonomic disorders. Clin Auton Res 6: 211-218, 1996[Web of Science][Medline].

22.   Kjaer, M, and Secher NH. Neural influence on cardiovascular and endocrine responses to static exercise in humans. Sports Med 13: 303-319, 1992[Web of Science][Medline].

23.   Lafleche, AB, Pannier BM, Lalous B, and Safar ME. Arterial response during cold pressor test in border-line hypertension. Am J Physiol Heart Circ Physiol 275: H409-H415, 1998[Abstract/Free Full Text].

24.   Lake, C, Ziergler M, Coleman M, and Kopin J. Evaluation of the sympathetic nervous system in trisomy-21 (Down Syndrome). Psychiatry Res 15: 1-6, 1979.

25.   Lauer, MS, Okin PM, Larson MG, Evans JC, and Levy D. Impaired heart rate response to graded exercise. Prognostic implication of chronotropic incompetence in the Framingham Heart Study. Circulation 93: 1520-1526, 1996[Abstract/Free Full Text].

26.   Maciel, B, Gallo LJ, Marin Neto J, and Martins L. Autonomic nervous control of the heart rate during isometric exercise in normal man. Pflügers Arch 408: 173-177, 1987[Web of Science][Medline].

27.   Maciel, B, Gallo LJ, Marin-Neto J, Terra-Filho J, and Manco J. Efficacy of pharmacological blockade of the cardiac parasympathetic system with atropine in normal men. Braz J Med Biol Res 18: 303-308, 1985[Web of Science][Medline].

28.   Matsumoto, T, Miyawaki T, Ue H, Kanda T, Zenji C, and Moritani T. Autonomic responsiveness to acute cold exposure in obese and non-obese young women. Int J Obes Relat Metab Disord 23: 793-800, 1999[Web of Science][Medline].

29.   Matsuyama, T, Sato H, Kitabatake A, Ozaki H, Imai K, Ishida Y, Hori M, Inoue M, and Kamada T. Blunted cardiac responses to exercise induced sympathetic stimulation in non-failing aortic regurgitation: insight into role of cardiac dilation in hyporesponse of failing hearts. Jpn Circ J 56: 117-127, 1992[Medline].

30.   McSwigan, J, Hanson D, Lubiniecki A, Heston L, and Sheppard J. Down syndrome fibroblasts are hyperresponsive to beta -adrenergic stimulation. Proc Natl Acad Sci USA 78: 7670-7673, 1981[Abstract/Free Full Text].

31.   Mizushima, T, Tajima F, Nakamura T, Yamamoto M, Lee KH, and Ogata H. Muscle sympathetic nerve activity during cold pressor test in patients with cerebrovascular accidents. Stroke 29: 607-612, 1999.

32.   Nagaoka, H, Sachio S, Lizuka T, Imai S, and Nagai R. Relation between depressed cardiac response to exercise and autonomic nervous activity in mildly symptomatic patients with idiopathic dilated cardiomyopathy. Chest 109: 925-932, 1996[Abstract/Free Full Text].

33.   Peolsson, A, Hedlund R, and Oberg B. Intra- and inter-tester reliability and reference values for hand strength. J Rehabil Med 33: 36-41, 2001[Web of Science][Medline].

34.   Pitetti, KH, Millar AL, and Fernhall B. Reliability of peak performance treadmill test for children and adolescents with and without mental retardation. Adapted Physical Activity Quarterly 17: 322-332, 2000.

35.   Pitetti, KH, and Tan DM. Effects of a minimally supervised exercise program for mentally retarded adults. Med Sci Sports Exerc 23: 594-601, 1991[Web of Science][Medline].

36.   Quilliot, D, Fluckiger L, Zannad F, Drouin P, and Ziegler O. Impaired autonomic control of heart rate and blood pressure in obesity: role of age and of insulin-resistance. Clin Auton Res 11: 779-786, 2001.

37.   Raizner, AE, Chahine RA, Ishimori T, Verani MS, Zacca N, Jamal N, MIller RR, and Luchi RJ. Provocation of coronary spasm by the cold pressor test: hemodynamic arteriographic and quantitative angiographic observations. Circulation 62: 925-932, 1980[Free Full Text].

38.   Raven, P, Potts J, Xiangrong S, and Pawelczyk J. Baroreceptor-mediated reflex regulation of blood pressure during exercise. In: Exercise and Circulation in Health and Disease, edited by Saltin B, Boushel R, Secher NH, and Mitchell J.. Champaign, IL: Human Kinetics, 2000.

39.   Sacks, B, and Smith S. People with Down's syndrome can be distinguished on the basis of cholinergic dysfunction. J Neurol Neurosurg Psychiatry 52: 1294-1295, 1989[Abstract/Free Full Text].

40.   Seals, DR, Chase PB, and Taylor JA. Autonomic mediation of the pressor responses to isometric exercise in humans. J Appl Physiol 64: 2190-2196, 1988[Abstract/Free Full Text].

41.   Seals, DR, Taylor JA, Ng AV, and Esler MD. Exercise and aging: autonomic control of the circulation. Med Sci Sports Exerc 26: 568-576, 1994[Web of Science][Medline].

42.   Seidl, L, Reid G, and Montgomery DL. A critique of cardiovascular fitness testing with mentally retarded persons. Adapted Physical Activity Quarterly 4: 106-116, 1987.

43.   Stratton, JR, Halter JB, Hallstrom AP, Caldwell JH, and Ritchie JL. Comparative plasma catecholamine and hemodynamic responses to handgrip, cold pressor, and supine bicycle exercise testing in normal subjects. J Am Coll Cardiol 2: 93-104, 1983[Abstract].

44.   Udeschini, G, Casati G, Bassani G, Picotti G, and Culotta P. Plasma catecholamines in Down's syndrome, at rest and during sympathetic stimulation. J Neurol Neurosurg Psychiatry 48: 1060-1061, 1985[Abstract/Free Full Text].

45.   Valensi, P, Bich Ngoc P, Idriss S, Paries J, Cazes P, Lormeau B, and Attali J. Haemodynamic response to an isometric exercise test in obese patients: influence of autonomic dysfunction. Int J Obes Relat Metab Disord 23: 543-549, 1999[Web of Science][Medline].

46.   Victor, RG, Leimbach WN, Seals DR, Wallin BG, and Mark AL. Effects of the cold pressor test on muscle sympathetic nerve activity in humans. Hypertension 9: 429-436, 1987[Abstract/Free Full Text].

47.   Waddell, T, Renaud M, Pitetti K, Guerra M, and Fernhall B. Heart rate variability and exercise in persons with Down syndrome (Abstract). Sci Sports 15: 316, 2000.

48.   Wood, DL, Sheps SG, Evleback LR, and Schirger A. Cold pressor test as a predictor of hypertension. Hypertension 6: 301-306, 1984[Abstract/Free Full Text].

49.   Zahorska-Markiewicz, B, Kuagowsak E, Kucio C, and Klin M. Heart rate variability in obesity. Int J Obes Relat Metab Disord 17: 21-23, 1993[Web of Science][Medline].

J APPL PHYSIOL 94(6):2158-2165
8750-7587/03 $5.00 Copyright © 2003 the American Physiological Society


This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
K. S. Heffernan, J. J. Sosnoff, E. Ofori, S. Y. Jae, T. Baynard, S. R. Collier, S. Goulopoulou, A. Figueroa, J. A. Woods, K. H. Pitetti, et al.
Complexity of force output during static exercise in individuals with Down syndrome
J Appl Physiol, April 1, 2009; 106(4): 1227 - 1233.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
J. M. Lignon, Z. Bichler, B. Hivert, F. E. Gannier, P. Cosnay, J. A. del Rio, D. Migliore-Samour, and C. O. Malecot
Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21
Physiol Genomics, April 1, 2008; 33(2): 230 - 239.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
S. Y. Jae, B. Fernhall, K. S. Heffernan, M. Kang, M.-K. Lee, Y.-H. Choi, and W. H. Park
Chronotropic response to exercise testing is associated with carotid atherosclerosis in healthy middle-aged men
Eur. Heart J., April 2, 2006; 27(8): 954 - 959.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
F. Iellamo, A. Galante, J. M. Legramante, M. E. Lippi, C. Condoluci, G. Albertini, and M. Volterrani
Altered autonomic cardiac regulation in individuals with Down syndrome
Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2387 - H2391.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
94/6/2158    most recent
00959.2002v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (16)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fernhall, B.
Right arrow Articles by Otterstetter, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fernhall, B.
Right arrow Articles by Otterstetter, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.