INDIVIDUALS WITH MENTAL retardation have low levels. Chronotropic Incompetence in Persons With Down Syndrome

Transcription

1 1604 Chronotropic Incompetence in Persons With Down Syndrome Myriam Guerra, MD, PhD, Natalia Llorens, MD, Bo Fernhall, PhD ABSTRACT. Guerra M, Llorens N, Fernhall B. Chronotropic incompetence in persons with Down syndrome. Arch Phys Med Rehabil 2003;84: Objective: To investigate the chronotropic response to exercise through peak heart rate and the Chronotropic Response Index (CRI) in participants with Down syndrome (DS) and in nondisabled control participants. Design: Comparative study describing the acute exercise heart rate response. Setting: University sports medicine facility. Participants: Twenty participants with DS (mean age standard deviation, y) and 20 control participants without disabilities (age, y). Interventions: Not applicable. Main Outcome Measures: Maximal treadmill exercise tests with metabolic and heart rate measurements. Maximal heart rate and the CRI were considered main outcomes. Results: The peak oxygen consumption (41.7 vs 31.8mL kg 1 min 1 ) and peak heart rate ( vs beats/ min) were significantly lower in participants with DS than in controls (P.05). The CRI was below normal (.84.25) in participants with DS and was normal (.97.07) in controls. Conclusion: Both the CRI and the peak heart rates were indicative of chronotropic incompetence in participants with DS, but not in controls. The CRI of the participants with DS was similar to that reported for nondisabled populations who have a true chronotropic response to exercise. The CRI indicated that the low peak heart rate in our participants with DS was a true chronotropic response. Key Words: Down syndrome; Exercise; Heart rate; Rehabilitation by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation INDIVIDUALS WITH MENTAL retardation have low levels of work capacity and peak oxygen consumption (VO 2 peak). 1-6 These low levels are further exacerbated in individuals with Down syndrome (DS). 3,7-10 VO 2 peak for individuals with DS who are 16 to 30 years of age is typically between 22 and 27mL kg 1 min 1. 3,7,9,10 Furthermore, the VO 2 peak of persons with DS is significantly lower than it is in people with mental retardation who do not have DS. 3 Some 3,5,11,12 have suggested that the low VO 2 peak of persons with mental retardation is primarily a consequence of sedentary From the Physical Activity and Sports Sciences Department, Fundació Blanquerna, University Ramon Llull, Barcelona, Spain (Guerra); Sports Medicine Department, University of Barcelona, Barcelona, Spain (Llorens); and Exercise Science Department, Syracuse University, Syracuse, NY (Fernhall). Supported by the American Heart Association (grant no N). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Correspondence to Bo Fernhall, PhD, Exercise Science Dept, Syracuse University, 820 Comstock Ave, Rm 201, Syracuse, NY , bfernhal@syr.edu. Reprints are not available /03/ $30.00/0 doi: /s (03) lifestyles. Others 13,14 have suggested that lack of motivation and task understanding prevents these individuals from reaching appropriate levels of exertion during maximal exercise testing, thus contributing to their low VO 2 peak levels. Several investigators 1,3,5,15 have also suggested that low maximal heart rates, or chronotropic incompetence, contributes to low VO 2 peak levels in this population. Chronotropic incompetence may be of particular concern in persons with DS because they have much lower peak heart rates than do their peers without DS. A recent investigation 16 showed that maximal heart rates in persons with DS were approximately 30 beats/min lower than those predicted by the formula 220 minus age, whereas in individuals with mental retardation without DS, peak heart rates were approximately 15 beats/min lower than predicted rates. It is likely that chronotropic incompetence contributes to the VO 2 peak values in persons with DS as a result of limitations in cardiac output. This concept was supported by Fernhall et al, 3 who showed that VO 2 peak did not differ between individuals with and without DS when differences in peak heart rate were statistically controlled. 3 It is often difficult to distinguish poor motivation and effort during an exercise test from a true chronotropic response because poor effort will result in early test termination and a low peak heart rate. Recently, however, the Chronotropic Response Index (CRI) has been shown to be a better variable than peak heart rate for evaluating chronotropic incompetence. 17,18 The CRI is independent of effort and motivation because it is a submaximal exercise variable derived from the relative relation between heart rate and metabolic reserve. 17,18 Furthermore, Lauer et al 17 found that the CRI is independent of age, physical activity, physical fitness, and resting heart rate, whereas peak heart rate alone is dependent on these factors. Consequently, the CRI makes it possible to evaluate the chronotropic response to exercise without the influence of several major confounding factors. Chronotropic incompetence can also have major health consequences in that it is related to overt coronary heart disease 17,19,20 (CAD) and heart failure 21 in otherwise nondisabled populations. However, Lauer 17 and Sandvik et al 22 showed that chronotropic incompetence was present many years before heart disease developed. Furthermore, chronotropic incompetence is predictive of all-cause death in nondisabled populations, even after accounting for thallium perfusion defects, echocardiographic ischemia, and angiographic evidence of CAD Although it is unknown whether chronotropic incompetence is related to health outcomes in people with DS, it is possible that chronotropic incompetence is related to poor health outcomes in this population as well. Because persons with DS have very low peak heart rates, as well as low physical fitness and activity levels, the CRI could be useful in evaluating the chronotropic response to exercise in this population. Furthermore, because it is still unclear whether motivation to perform and task understanding limit peak effort in persons with DS, the CRI allows for an evaluation of the chronotropic response to exercise without the influence of these factors. Furthermore, if individuals with DS show true chronotropic incompetence, it may be related to poor health outcomes. Therefore, our purpose was to evaluate, through both maximal heart rate and the CRI, the chronotropic response to

2 CHRONOTROPIC INCOMPETENCE IN DOWN SYNDROME, Guerra 1605 exercise in a group of young people with DS and in a similarly aged, nondisabled comparison group. METHODS Participants Participants with DS were recruited from various local workshops, schools, and Special Olympics groups. They all lived at home or in group settings, and none was institutionalized. Individual intelligence quotient scores were not released, but all participants with DS were classified as having mild mental retardation. Twenty people (14 men, 6 women) between the ages of 17 and 29 years (mean age standard deviation [SD], y) volunteered to participate. Written, informed consent was obtained from all participants and from their parents or legal guardians (if indicated), and the study was approved by the university institutional review boards of the University of Barcelona and Syracuse University. A comparison group was recruited from among university students who participated in sport activity. We selected active sports participants because they had all previously visited our Sports Medicine Center and were familiar with laboratory testing. Furthermore, it is well established that exercise-trained individuals have decreased submaximal heart rates at a given exercise work rate and also have slightly reduced maximal heart rates. 18,26 Consequently, if DS per se is associated with chronotropic incompetence, comparing individuals with DS with exercise-trained, nondisabled participants would provide a more complete answer to whether individuals with DS show chronotropic incompetence, because it would be more difficult to observe potentially significant differences if participants with DS were compared with an exercise-trained comparison group. Twenty students (15 men, 5 women) between the ages of 16 and 25 years (mean age, y) volunteered to be in the comparison group and gave their informed consent to participate. All participants underwent a medical examination before enrollment in the study to screen for medical or physical disability problems that could interfere with their ability to perform exercise testing safely. Medical histories were also obtained through interviews with the comparison group participants and with the parents and legal guardians of participants with DS. Resting electrocardiograms (ECGs) were obtained for all participants, and standard echocardiograms (ECHOs) were also obtained for participants with DS. Subjects were included in the study if they had no history of any cardiac problems, metabolic disease, or orthopedic problems that interfered with walking; were not taking any heart rate altering medications; had normal ECGs and ECHOs; and had no cardiac or metabolic problems. Familiarization Familiarity with laboratory testing procedures is essential for persons with DS; consequently, we followed procedures suggested by Fernhall et al 1 and Pitetti et al. 5 Briefly, the participants with DS visited the laboratory 2 or 3 times before testing. The first visit was devoted to getting acquainted with the setting and with the laboratory staff and to practicing with the mouthpiece and nose clip. Subjects were also taught how to walk on the treadmill. Subsequent visits were devoted to practicing treadmill walking until the participants could comfortably walk on the treadmill. The number of familiarization sessions depended on how fast participants with DS became accustomed to treadmill walking and the mouthpiece. Subjects in the comparison group were already accustomed to treadmill walking and running, so there were no familiarization sessions for this group. Protocol Exercise responses were evaluated by using a graded exercise treadmill test to exhaustion. The protocol was specially designed for the individuals with DS and was based on pilot testing and information gathered during the familiarization process. These participants initially walked at 4km/h at a 5% grade for 8 minutes. After 8 minutes, the speed was increased by 0.5km/h every 2 minutes until the subject reached exhaustion, which was defined as an inability to keep up with the treadmill speed. Participants were verbally encouraged to push themselves. Participants in the comparison group initially walked at a speed of either 4km/h (women) or 6km/h (men) and at a 5% grade for 2 minutes. Thereafter, speed was increased by 2km/h every 2 minutes until subjects reached exhaustion, as defined above. We specifically adopted a protocol with slow increases in work rate because it is more appropriate for measuring chronotropic responses. 27 It should be noted that the CRI is independent of the protocol we used. 18 Expired air was analyzed breath by breath for oxygen, carbon dioxide, and ventilation with an on-line metabolic system. a The gas analyzers were calibrated with a known gas and the pneumotach was calibrated with a known volume before each test. The metabolic data were displayed in 30-second averages, with the highest 30-second average used as the VO 2 peak. Heart rate was collected from a 1-lead ECG and recorded every 30 seconds. Calculation of the CRI The CRI is derived by calculating the ratio of heart rate to metabolic reserve. 17 This calculation can be done at any stage during the exercise and is a reflection of the association between the heart rate response and metabolic work. 17 We chose to evaluate the CRI at 80% of VO 2 peak for each individual. The following formulas were used: %metabolic reserve 80% (METS 80% METS rest )/ (METS peak METS rest ) 100 %HR reserve 80% (HR 80% HR rest )/ (age predicted HR peak HR rest ) 100 CRI %HR reserve 80% /%metabolic reserve 80%, where METS indicates metabolic equivalents and HR is the heart rate. A normal ratio is approximately 1, whereas a low ratio denotes chronotropic incompetence. We chose a CRI breakpoint of 0.9 to denote chronotropic incompetence, which we based on previous research showing that normal populations (those without chronotropic incompetence) always show a mean CRI above 0.9 and that disease and mortality risks are higher and predictable in persons with a CRI between 0.8 and ,23,27 Statistical Analyses Statistical procedures were performed with SPSS version 10.0, b for Windows. Descriptive statistics were calculated for all variables. Group data were compared using a multivariate analysis of variance, and statistical significance was set at P less than.05. Data are displayed as mean SD. RESULTS Descriptive and exercise data are shown in table 1. The participants with DS were significantly older and shorter and

3 1606 CHRONOTROPIC INCOMPETENCE IN DOWN SYNDROME, Guerra weighed less, although their body mass index (BMI) was higher compared with subjects in the control group. Participants with DS also showed significantly lower peak exercise responses for VO 2, expired volume (VE), and heart rate. Resting heart rate was significantly higher in the group with DS, but the increase in heart rate with exercise was significantly lower, as was the CRI. Because BMI was significantly higher in the group with DS, we conducted an analysis of covariance on maximal heart rate and the increase in heart rate with exercise, controlling for BMI. This analysis did not alter our findings. Displayed in table 2 is a further breakdown of the heart rates and CRI of participants with CRIs above and below 0.9. Most participants with DS had a CRI of less than 0.9, and those participants had very low peak heart rates. Participants without DS who had a CRI below 0.9 still showed peak heart rates within normal limits, and only 4 participants without DS had a CRI below 0.9. Although 8 participants with DS had a normal CRI ( 0.9), their peak heart rates were still low. Only 1 subject had a peak heart rate of 190 beats/min, the others had values of 181 beats/min or less. Thus, the mean peak heart rate was significantly lower in participants with DS, although their CRIs were similar to those of controls. DISCUSSION Our main findings were that individuals with DS have low peak heart rates and low CRI scores compared with their nondisabled counterparts. There was a 27-beat/min mean difference in peak heart rate between groups, which is consistent with other studies. 3,10 The mean peak heart rate of the control group was within normal limits, whereas it was more than 2 SDs below the predicted maximal heart rate in the group with DS. 20 The CRI data also support the findings of chronotropic incompetence in individuals with DS. The CRI of this group was significantly lower than that of the control group. The mean CRI of the group with DS was also similar to that reported for nondisabled individuals in the Framingham Heart Study who showed chronotropic incompetence during exercise (.84 vs.86). 17 Thus, the average person with DS in our study clearly showed chronotropic incompetence during exercise, as shown by both peak heart rate and the CRI. According to both peak heart rate and CRI measures, not all individuals with DS would be classified as having chronotropic incompetence (table 2). Twelve of the 20 participants with DS had a CRI below 0.9 (in the lowest tertile, based on data from the Framingham Heart Study 17 ) and had peak heart rates that Table 1: Resting Characteristics and Exercise Responses of Individuals With DS and Control Subjects Variable Group With DS Control Group Age (y) * Height (cm) * Weight (kg) * BMI (kg/m 2 ) * VO 2 peak (ml kg 1 min 1 ) * VEpeak (L/min) * HRpeak (beats/min) * Resting HR (beats/min) * HR increase (beats/min) * CRI.84.24* NOTE. Values are mean SD. Abbreviations: BMI, body mass index; VEpeak, peak expired exercise volume; HR increase, increase in heart rate from rest to peak exercise. *Denotes significant differences between groups, P.05. Table 2: CRI and Maximal Heart Rate of Individuals With DS and Control Subjects Variable Group With DS Control Group CRI 0.9 Subjects (n) 12 4 HRmax (range) Mean HRmax SD * Mean CRI SD.68.16* CRI 0.9 Subjects (n) 8 16 HRmax (range) Mean HRmax SD * Mean CRI SD *DS significantly lower compared with controls, P.05. are consistent with a poor chronotropic response. However, although 4 control participants had a CRI of less than 0.9, only 1 had an attenuated heart rate response to peak exercise. Similarly, 8 participants with DS had a CRI above 0.9, but all except 1 showed an attenuated heart rate response to peak exercise. Control participants with a CRI above 0.9 all showed normal peak heart rate responses. These data show that a low peak heart rate is a more common finding than a low CRI in participants with DS and that, in general, low peak heart rate better differentiates participants with DS from their nondisabled peers. Ellestad and Wan 20 first described chronotropic incompetence and defined it as an inappropriate heart rate response to maximal exertion. They defined mild chronotropic incompetence as a peak heart rate more than 1 SD below age-predicted maximal heart rate and severe chronotropic incompetence as 2 SDs below age-predicted maximal heart rate. More recently, chronotropic incompetence has been defined as failure to reach 85% of age-predicted maximal heart rate. 17,23,24,28 With the criteria for chronotropic incompetence of failure to reach 85% of maximal heart rate, the mean cutoff heart rate for the group with DS would be 167 beats/min, which shows that the mean peak heart rate for that group would be classified as chronotropic incompetence. However, 7 individuals with DS achieved a peak rate greater than 85% of their age-predicted maximum, suggesting that they did not have chronotropic incompetence. Applying the more liberal criteria of Ellestad and Wan, 20 all participants with DS showed at least mild chronotropic incompetence. None of the control subjects failed to reach 85% of age-predicted maximum heart rate, and only 3 would be classified as having mild chronotropic incompetence, according to Ellestad and Wan. 20 Thus, the heart rate response to peak exercise is clearly attenuated in participants with DS, and their response can be classified as chronotropic incompetence. Evaluating the chronotropic response to exercise through the peak heart rate response can be confounded by a participant s effort and motivation. However, all of our participants met standardized criteria for peak efforts, such as a high respiratory exchange ratio, a plateau in heart rate or VO 2 with an increase in work rate, or an inability to keep up with the treadmill speed. We and others have previously shown that the exercise protocols used yield valid and reliable results in persons with DS. 1,2,6,29 Thus, it is unlikely that poor effort or motivation to perform explain the findings. Furthermore, the CRI can be distinguished from the effects that age, resting heart rate, and physical fitness can have on peak heart rate, 17,18 reflecting instead the submaximal relation between heart rate and meta-

4 CHRONOTROPIC INCOMPETENCE IN DOWN SYNDROME, Guerra 1607 bolic work during exercise. The CRI is not dependent on functional capacity, exercise protocol, or the stage of exercise that is used for measurement. 17,18 Thus, the CRI is a submaximal evaluation of chronotropic incompetence, and it was also low in the group with DS. Therefore, the attenuated peak heart rate response in participants with DS appears to depend on the symptom and not on task understanding, the effort produced, or the motivation to perform. Although the relation between chronotropic incompetence and ischemic heart disease and all-cause death is unknown in individuals with DS, it is unlikely that any of our participants had ischemic heart disease. There were all young and healthy and had undergone a full medical examination, including an ECHO, with normal findings. Furthermore, none showed any ischemic electrocardiographic changes during the exercise test. This is consistent with data from Ylä-Herttuala et al 30 and Murdock et al, 31 who, through autopsy studies, showed that the coronary arteries of persons with DS had a lower percentage of raised lesions or were lesion free in comparison with agematched peers without DS. Such findings suggest that coronary ischemia may not be an issue in this population, which is consistent with our findings. The findings might also suggest that chronotropic incompetence may not be related to mortality and morbidity in persons with DS. More research is needed, however, to clarify the relation between chronotropic incompetence and health outcomes in this population. In addition, more research is needed into the apparent lack of significant atherosclerosis in persons with DS, especially because their life expectancy has increased significantly in the past 20 years. 32 Thus, older individuals with DS may be more likely to have ischemic responses to exercise, but this is unproven at this time. Several investigators 17,23,33 have speculated that chronotropic incompetence is related to autonomic dysfunction. This may result from a decrease in sympathetic drive, as is seen in patients with heart failure, 34 or from a decrease in heart rate variability. 17,35 However, we have previously shown that individuals with DS have increased heart rate variability at rest compared with their nondisabled peers, 36,37 which suggests an increased vagal influence in this population. Because it has been shown that there is vagal modulation of heart rate during exercise, 38 it is possible that increased vagal tone may influence peak heart rate in persons with DS. Interestingly, previous data showing no difference in autonomic balance during exercise between participants with and without DS 36,37 suggest that there may not be any influence. Others have found that chronotropic incompetence during exercise was related to ventricular dilation, both in patients with heart failure 33 and in asymptomatic, otherwise healthy patients. 28 However, patients with heart failure show improvements in peak heart rate with exercise training, 21 whereas peak heart rate does not change with exercise training in individuals with DS. 9,39 This suggests that the mechanism of chronotropic incompetence differs between individuals with heart failure and people with DS. Furthermore, obesity can affect autonomic function and maximal heart rate, and the participants with DS had a higher BMI than did our control subjects. However, the mean BMI of our participants with DS was not in the obese category. We also compared maximal heart rates between groups, covarying for BMI, and this did not alter our findings. Finally, other studies have shown that BMI did not impact maximal heart rate in participants with DS. 3,16,36 This may not be entirely surprising, because persons with DS are typically short in stature; thus, BMI may not be a good measure of obesity in this population. It is possible that more specific indices of obesity, such as percentage of body fat, may be related to autonomic function in this group. Thus, the mechanism behind chronotropic incompetence in persons with DS is unclear and needs to be investigated. This study has several limitations. All participants were volunteers; thus, we cannot ascertain that those with DS were actually representative of the DS population, especially considering our limited subject numbers. However, our exercise data are consistent with other data about individuals with DS. 3,8,14,16 It was difficult to ensure that the participants with DS gave true maximal efforts, but, as discussed above, we used test methods that have been validated for this population, and all participants appeared to produce valid efforts, inasmuch as the tests were stopped only when participants could no longer keep up with the treadmill speed. Nevertheless, a small possibility exists that some participants were limited in their motivation and effort, which would influence the interpretation of peak heart rate. Also, we do not know whether chronotropic incompetence is related to poor outcomes such as increased mortality or morbidity in populations with DS; this has never been investigated. We also do not know the mechanism of the poor chronotropic response seen in individuals with DS. CONCLUSION We found that persons with DS have an attenuated heart rate response to exercise that can be classified as chronotropic incompetence, as determined by both the peak heat rate response and the CRI. The mechanism behind this reduced chronotropic response in persons with DS is unknown at this time, but it does not appear to be related to effort and motivation to perform. References 1. Fernhall B, Tymeson G. Graded exercise testing of mentally retarded adults: a study of feasibility. Arch Phys Med Rehabil 1987;63: Fernhall B, Millar AL, Tymeson G, Burkett LN. Maximal exercise testing of mentally retarded adolescents and adults: reliability study. Arch Phys Med Rehabil 1990;71: Fernhall B, Pitetti K, Rimmer JH, et al. Cardiorespiratory capacity of individuals with mental retardation including Down syndrome. Med Sci Sports Exerc 1996;28: Pitetti K, Tan DM. Cardiorespiratory responses of mentally retarded adults to air-brake ergometry and treadmill exercise. Arch Phys Med Rehabil 1990;71: Pitetti KH, Rimmer JH, Fernhall B. Physical fitness and adults with mental retardation: an overview of current research and future directions. Sports Med 1993;16: Pitetti KH, Millar AL, Fernhall B. Reliability of peak performance treadmill test for children and adolescents with and without mental retardation. Adapt Phys Act Q 2000;17: Fernhall B, Tymeson G, Millar AL, Burkett LN. Cardiovascular fitness testing and fitness levels of adolescents and adults with mental retardation including Down syndrome. Educ Train Ment Retard 1989;68: Guerra M, Roman B, Geronimo C, Violan MA, Cuadrado E, Fernhall B. Physical fitness levels of sedentary and active individuals with Down syndrome. Adapt Phys Act Q 2000;17: Millar AL, Fernhall B, Burkett LN, Tymeson G. Effect of aerobic training in adolescents with Down syndrome. Med Sci Sports Exerc 1993;25: Pitetti KH, Climstein M, Campbell KD, Barrett PJ, Jackson JA. The cardiovascular capacities of adults with Down syndrome: a comparative study. Med Sci Sports Exerc 1992;24: Fernhall B. Physical fitness and exercise training of individuals with mental retardation. Med Sci Sports Exerc 1993;25: Pitetti KH, Campbell KD. Mentally retarded individuals-a population at risk? Med Sci Sports Exerc 1991;23: Seidl L, Reid G, Montgomery DL. A critique of cardiovascular fitness testing with mentally retarded persons. Adapt Phys Act Q 1987;4:

5 1608 CHRONOTROPIC INCOMPETENCE IN DOWN SYNDROME, Guerra 14. Eberhard Y, Etarradossi J, Therminarias A. Biochemical changes and catecholamine response in Down s syndrome adolescents in relation to incremental maximal exercise. J Ment Deficiency Res 1991;35: Kittredge JM, Rimmer JH, Looney M. Validation of the Rockport fitness walking test for adults with mental retardation. Med Sci Sports Exerc 1994;26: Fernhall B, McCubbin J, Pitetti K, et al. Prediction of maximal heart rate in individuals with mental retardation. Med Sci Sports Exerc 2001;33: Lauer MS, Okin PM, Larson MG, Evans JC, Levy D. Impaired heart rate response to graded exercise. Prognostic implication of chronotropic incompetence in the Framingham Heart Study. Circulation 1996;93: Wilkoff BL, Miller RE. Exercise testing for chronotropic assessment. Cardiol Clin 1992;10: Hinkle LW, Carver ST, Plakun A. Slow heart rates and increased risk of cardiac death in middle-aged men. Arch Intern Med 1972; 129: Ellestad MH, Wan MK. Predictive implications of stress testing: follow-up of 2700 subjects after maximum treadmill stress testing. Circulation 1975;51: Keteyian SJ, Brawner CA, Schairer JR, et al. Effects of exercise training on chronotropic incompetence in patients with heart failure. Am Heart J 1999;138: Sandvik L, Erikssen J, Ellestad M, et al. Heart rate increase and maximal heart rate during exercise as predictors of cardiovascular mortality: a 16-year follow-up study of 1960 healthy men. Coron Artery Dis 1995;6: Dresing TJ, Blackstone EH, Pashkow FJ, Snader CE, Marwick TH, Lauer MS. Usefulness of impaired chronotropic response to exercise as a predictor of mortality, independent of the severity of coronary artery disease. Am J Cardiol 2000;86: Lauer MS, Francis GS, Okin PM, Pashkow FJ, Snader CE, Marwick TH. Impaired chronotropic response to exercise stress testing as predictor of mortality. JAMA 1999;281: Lauer MS, Mehta R, Pashkow FJ, Okin PM, Lee K, Marwich TH. Association of chronotropic incompetence with echocardiographic ischemia and prognosis. J Am Coll Cardiol 1998;32: Zavorsky GS. Evidence and possible mechanisms of altered maximum heart rate with endurance training and tapering. Sports Med 2000;29: Camm AJ, Fei L. Chronotropic incompetence part II: clinical implications. Clin Cardiol 1996;19: Lauer MS, Larson MG, Evans JC, Levy D. Association of left ventricular dilatation and hypertrophy with chronotropic incompetence in the Framingham Heart Study. Am Heart J 1999;137: Fernhall B, Pitetti KH, Vukovich MD, et al. Validation of cardiovascular fitness field tests in children with mental retardation. Am J Ment Retard 1998;102: Ylä-Herttuala S, Luoma J, Nikkari T, Kivimäki T. Down s syndrome and atherosclerosis. Atherosclerosis 1989;76: Murdoch J, Rodger J, Rao S, Fletcher C, Dunnigan M. Down s syndrome: an atheroma-free model? BMJ 1977;2: Hayden M. Mortality among people with mental retardation living in the United States: research review and policy application. Ment Retard 1998;36: Colucci WS, Ribeiro J, Rocco MG, et al. Impaired chronotropic response to exercise in patients with congestive heart failure: role of postsynaptic -adrenergic desensitization. Circulation 1989;2: Francis GS, Goldsmith SR, Ziesche S, Nakajima H, Cohn JN. Relative attenuation of sympathetic drive during exercise in patients with congestive heart failure. J Am Coll Cardiol 1985;5: Tsuji H, Venditti FJ, Manders ES, et al. Reduced heart rate variability and mortality risk in an elderly cohort: the Framingham Heart Study. Circulation 1994;90: Fernhall B, Pitetti K, Renaud M, Wondra V. Autonomic control of resting and exercise heart rate in adolescents with Down syndrome [abstract]. Pediatr Exerc Sci 1999;11: Waddell T, Renaud M, Pitetti K, Guerra M, Fernhall B. Heart rate variability and exercise in persons with Down syndrome [abstract]. Sci Sports 2000;15: Marraccini P, Orsini E, Nassi G, L Abbate A. Effects of parasympathetic blockade on ischemic threshold in patients with exerciseinduced myocardial ischemia. Am J Cardiol 1991;68: Varela AM, Sardinha LB, Piletti KH. Effects of an aerobic rowing training regimen in young adults with Down syndrome. Am J Ment Retard 2001;106: Suppliers a. Medical Graphics Corp, 350 Oak Grove Pkwy, St Paul, MN b. SPSS Inc, 233 S Wacker Dr, 11th Fl, Chicago, IL