Approximately 1% of the global population has an intellectual disability (ID) (1). These individuals are characterized by a low IQ (<70–75) combined with limitations in adaptive behaviors that affect their daily living (2). In addition, a majority of this population has low fitness levels (3), poor nutrition (4), a high prevalence of obesity (5), and a more sedentary lifestyle than the general population (6). With the increased life expectancy of this population, this currently results in higher risk of unhealthy aging and unnecessary decline in daily functioning (7). Despite the health benefits of regular exercise for both health and activities of daily living (8), it remains difficult to motivate sedentary individuals with ID to become or remain physically active (8). Next to organizational, motivational, social, and psychological barriers to become or remain physically active, low physical fitness may pose an additional barrier for an active lifestyle, as shown in individuals with Down syndrome (DS) (9).
Compared with the general population, individuals with ID either with or without DS have demonstrated lower peak oxygen uptake (V˙O2peak, the gold standard measure of cardiopulmonary fitness) (3,10). In individuals with DS, one contributor to low V˙O2peak is chronotropic incompetence, or the inability to increase heart rate (HR) (11). This has been attributed to dysfunction of the autonomic nervous system (11,12), which regulates involuntary processes such as HR (13). Individuals with ID without DS have also shown lower HRpeak during maximal exercise, although to a lesser extent than individuals with DS (11,14).
Combined with few previous studies (15,16), this might suggest autonomic dysfunction in individuals with ID as well. However, according to the Fick equation, V˙O2peak is determined by HR, stroke volume, and the ability of the muscles to use oxygen (V˙O2peak = HRpeak × stroke volume × a-V˙O2 difference). Given lower HRpeak would only influence one aspect of V˙O2peak, it is important to acknowledge the dynamic and complex interaction between the cardiovascular, pulmonary, and skeletal muscle systems. In individuals with ID, we therefore need to improve our understanding of their response to exercise in a more comprehensive way (17).
Cardiopulmonary exercise tests (CPET) provide a broad array of physiological parameters indicative of cardiopulmonary function, including information on peak values of V˙O2, minute ventilation (V˙E), RER, and other physiologically relevant variables (17–19). Although a CPET is reliable in individuals with ID (3,20,21), current studies rarely include this population or have only reported peak values of V˙O2 and HR measured at the end of the test (11,22,23). A combination of these and other parameters can help elucidate the underlying physiologic limitations contributing to exercise intolerance (17,18,24). This in-depth evaluation creates the possibility to improve exercise guidelines to meet the needs of this target group. It will provide valuable information for structured exercise interventions to support a healthy and independent life in individuals with ID throughout their increasing life span. However, this in-depth evaluation has not been conducted to date. Therefore, the aim of this study was to evaluate and compare cardiopulmonary profiles during a CPET between individuals with ID and a control group without ID. We hypothesize that primarily the HR-related outcomes in the cardiopulmonary profile will be lower in individuals with ID.
This cross-sectional investigation of cardiopulmonary profiles was part of two larger studies in individuals with ID and performed at two different sites (Integrative Physiology Laboratory, University of Illinois at Chicago, Chicago, IL; the Erasmus MC University Medical Center in Rotterdam, The Netherlands) between October 2015 and October 2017. Ethical approval was provided by both the Institutional Review Board at the University of Illinois at Chicago, IL, and the Medical Ethics Committee of the Erasmus Medical Center in Rotterdam, The Netherlands.
Healthy individuals with mild to moderate ID (IQ 55–70) between 18 and 45 yr of age and age- and sex-matched healthy individuals without ID were included in the study. The participants were recruited from the Chicago area through flyers, a web recruitment ad for electronic communication, social media, and word of mouth. The participants from The Netherlands were recruited through organizations that provide support for individuals with ID or that organize activities in the Rotterdam area.
Eligibility was checked by e-mail or telephone by asking the participant or caregiver for presence of any of the following exclusion criteria: 1) history of cardiovascular disease, diabetes, or any other metabolic disease that may affect the resting and exercise measures; 2) inflammatory disease; 3) asthma or other significant respiratory disorders; 4) cancer in the last 6 months; 5) any medication that may alter HR or metabolic responses; 6) smoking or smoking cessation within 6 months before screening; 7) any contraindications to exercise, assessed with the revised Physical Activity Readiness Questionnaire; 8) motor impairments that would limit treadmill exercise; 9) pregnancy; or 10) any other contraindications to perform a CPET. Individuals with ID were further screened for exclusion for 1) presence of DS, Prader–Willi syndrome, or Rett syndrome or 2) severe or profound ID.
All participants and/or their legal representatives provided written informed consent before participating in the study; the informed consent for the individuals with ID who were not capable of providing consent themselves was provided by their parents or legal guardians, coupled with assent by the participants.
Participants were asked to refrain from the consumption of coffee, alcohol, or recreational drugs and from any intense physical activities for 24 h before their visits. All participants fasted for 3 h before the start of a visit. The CPET was performed on the second visit for all participants, except for the control group at UIC who performed the CPET on the first visit. The second visit for all other groups was at least 48 h but no more than 2 wk apart from the first visit. The first visit consisted of basic anthropometric measurements; resting HR, systolic blood pressure, and diastolic blood pressure; and assessment of activity levels with the International Physical Activity Questionnaire (IPAQ). The IPAQ was scored using the official calculation sheets to calculate MET-minutes and to determine whether participants met the physical activity guidelines (25). For individuals with ID, this was followed by a familiarization session, in which the CPET was explained (both verbally and visually demonstrated by the investigators), and treadmill walking was practiced with the participants. These familiarization sessions were necessary to ensure the participants understood and could perform the study procedures as required. Familiarization sessions continued until the participant could comfortably walk on the treadmill with the headgear and breathing mask.
The CPET was conducted on a motorized treadmill. Expiratory gases were analyzed using two valid and reliable open-circuit spirometry systems (26,27) (Chicago: True One, Parvo Medics, Sandy, UT; Rotterdam: Jaeger Vmax Vyntus CPX, Mettawa, IL), which were calibrated before each test according to the manufacturers’ standards, with known volumes and gas concentrations. Before the start of the test, all participants were instrumented with a breathing mask (Hans Rudolph) and an HR monitor (Polar Electro Oy, Kempele, Finland). A manual sphygmomanometer was used to measure blood pressure every 4 min during the CPET.
Each test was performed using a validated and reliable incremental test protocol for individuals with and without ID (11,23). The protocol started with a 2-min warm-up at a comfortable walking speed. After the warm-up, the speed was adjusted to a brisk walking speed. After 2 min of walking at a brisk speed and 0% grade, grade was increased every 2 min by 2.5% until a 12.5% grade was reached. From that point on, grade was held constant, whereas speed increased by 1.6 or 0.8 km·h−1 every minute until exhaustion. The exercise test was terminated when the participant could no longer keep up with the treadmill speed or had reached volitional fatigue. Only the data of participants who satisfied two or more of the following four criteria of peak effort were included in the final sample and data analyses: 1) test ended because of volitional exhaustion, 2) V˙O2 or HR plateau with an increase in work rate (V˙O2 plateau defined as an increase less than 150 mL·min−1; HR plateau defined as an increase less than a 2 bpm), 3) HRpeak within 5 beats of predicted HRpeak according to the formulas of Fernhall et al. (11), and 4) an RER >1.10. Plateauing of V˙O2 or HR is considered a valid means to assess effort (18), although the American College of Sports Medicine (28) and Wasserman et al. (17) both report that individuals with disabilities or those who are sedentary may not achieve a plateau during maximal exercise testing. Thus, by combining volitional exhaustion with of any of the three strict objective criteria, a peak effort was ensured.
Table 1 provides a description of all main outcome measures of the cardiopulmonary profile. The following variables were directly measured during the test: volume of oxygen uptake (V˙O2, L·min−1) and volume of carbon dioxide production (V˙CO2, L·min−1), ventilation (V˙E, L·min−1), and HR (bpm). Data were averaged using 15-s epochs. Calculated outcome measures of the cardiopulmonary profile were RER, predicted HRpeak, difference between predicted and measured HRpeak (difference from predicted HRpeak), oxygen uptake efficiency slope (OUES), O2 pulse, HR reserve, and V˙E/V˙CO2 slope. Ventilatory threshold (VT) was determined with the V-slope method by two independent, blinded observers.
Predicted HRpeak was calculated according to the formulas of Fernhall et al. (11):
The OUES was determined by the method of Baba et al. (19), by the following equation:
The steeper the slope or the higher the OUES, the more efficient the oxygen uptake of the participant. The O2 pulse represents the relationship between V˙O2 (y axis) and HR (x axis). It is calculated as the linear slope over the duration of the exercise and reflects the volume of O2 ejected from the ventricles with each cardiac contraction (17). HR reserve was calculated by subtracting the measured HR at baseline from the measured HRpeak (17). Resting HR was derived through an automated arm cuff, with the participant in supine position before the autonomic protocol that was not further included in this study. By subtracting measured HRpeak with predicted HRpeak, the difference between HRpeak predicted and HRpeak measured was calculated. According to the equation proposed by Wasserman et al., V˙E/V˙CO2 slope is derived from plotting V˙E (L·min−1) as a function of V˙CO2 (L·min−1). This slope represents the matching of ventilation and perfusion within the pulmonary system, also known as ventilatory efficiency (17).
All data are presented as means with SD, unless otherwise specified. Normality was assessed with visual inspections of the frequency distribution and analyzed with the Kolmogorov–Smirnov test. Descriptive characteristics of the two groups were tested for differences using chi-square tests for nominal variables, t-tests for continuous variables, or Mann–Whitney U tests when the data were not normally distributed. The differences in CPET data between both groups were also examined using independent t-tests and Mann–Whitney U tests. Variables not normally distributed were body mass index (BMI), hip circumference, physical activity in MET-minutes, V˙O2peak (L·min−1), peak CO2 expenditure (L·min−1), O2 pulse, RER, and V˙O2 at VT. To control for the potential effect of confounding factors, multiple linear regression analyses were performed for each of the cardiopulmonary outcome variables as a dependent variable, with sex (male = 0, female = 1), age, BMI, group (control = 0, ID = 1), and complying with physical activity guidelines (0 = no, 1 = yes) all entered simultaneously as independent variables. Collinearity between variables was assessed by examining the variance inflation factor; a value >10 was considered unacceptable (31). All analyses were performed using SPSS version 22 (IBM Corporation, Armonk, NY). An a priori alpha level of P < 0.05 was deemed to be statistically.
Of the 73 participants from both study sites, 62 participants with and without ID had a valid CPET (n = 27 for ID, n = 35 for controls). Descriptive characteristics of the study population are presented in Table 2. Waist circumference, level of physical activity, resting HR, and resting diastolic blood pressure were different (P < 0.05) between groups.
Differences in cardiopulmonary outcome variables
Main CPET outcomes are presented in Table 3. Individual data on V˙O2peak, V˙E/V˙CO2 slope and OUES are presented in Figure 1. Individuals with ID had significantly lower results for all CPET outcomes except V˙E/V˙CO2 slope, which was significantly higher than controls. VT expressed as a percentage of V˙O2peak did not differ between groups (P = 0.98). Explained variances and coefficients for all the regression models are presented in Table 4. Taking the potential confounders sex, age, BMI, and physical activity levels into account, the linear regression analysis showed that having ID remained a significant and independent predictor of reduced physiologic function for all of the cardiopulmonary outcomes, except for VT expressed as a percentage of V˙O2peak (Table 4).
To our knowledge, this is the first study examining the full cardiopulmonary profile during CPET in individuals with ID. The overall results of this study indicate that individuals with ID have significantly lower cardiopulmonary outcomes during CPET compared with matched controls, and these differences still occur after correcting for sex, age, BMI, and physical activity level.
As hypothesized, individuals with ID achieved a lower HRpeak compared with individuals without ID (172 ± 15 vs 191 ± 8 bpm), consistent with previous research (14). Both absolute V˙O2peak (L·min−1) and V˙O2peak relative to body weight (mL·kg−1·min−1) were significantly lower in the group of individuals with ID. These lower V˙O2peak values are comparable with other findings in non-DS ID (23). Using the reference formula for absolute V˙O2peak in the general population, our ID group performed below the predicted value (2.1 vs 2.4 L·min−1), whereas the control group performed better than expected (2.8 vs 2.6 L·min−1) (24). In comparison with relative V˙O2max normative values, the individuals with ID would be classified in the bottom 10th percentile, indicative of very poor fitness, whereas our controls would fall within the “good” category (28). Together, the data support that individuals with ID have lower V˙O2peak than a healthy, control population.
An often-mentioned explanation for the differences in V˙O2peak between individuals with and without ID is their baseline physical activity level, BMI, and lack of motivation. However, when ensuring maximal effort and after controlling for physical activity and BMI in the regression analyses, having ID still significantly predicted lower cardiopulmonary profile outcomes. Instead, explanations for the low V˙O2peak might be found in the specific characteristics from the cardiopulmonary profile.
OUES is a marker of deconditioning and is not influenced by exercise intensity or effort (24). In combination with other outcomes, the OUES can also provide insight into ventilatory limitations and perfusion mismatch (32,33). Compared with the OUES reference values reported by Buys et al. (34) in healthy individuals (n = 1411, OUES = 3070), both our control group (OUES = 2721) and the group with ID (OUES = 1967) had a lower OUES. Our findings were even lower than the results of Mendonca et al. (32) who compared the OUES in sedentary or lightly active controls and individuals with DS (controls, 3111; DS, 2113). These lower values imply deconditioning in individuals with ID, which is also supported by a lower O2 pulse. In addition to deconditioning, low OUES is associated with increased pulmonary dead space and a perfusion mismatch (32,33). In our findings, the mean V˙E/V˙CO2 slopes for the group with ID versus the control group were significantly higher (mean difference = 2.31, P = 0.047). In combination with a low OUES, this could suggest skeletal muscle hypoperfusion in the individuals with ID. This area requires further exploration but could be related to an impairment in blood flow regulation to the working and the non-working muscles.
The OUES has also been shown to be highly correlated with forced expiratory volume (35). The low OUES in the individuals with ID in this study suggests that a ventilatory limitation may be present (36). This is in agreement with the finding of a significantly lower peak minute ventilation (V˙Epeak) in our group with ID. Low V˙Epeak is indicative of exercise intolerance or dyspnea related to a pulmonary limitation, such as chest wall disorders, restrictive lung disorders, or obstructive lung disorders (17,18). In line with exercise intolerance, individuals with ID had a lower VT in comparison with healthy controls. However, individuals with ID present a similar relative VT (VT expressed as a percentage of V˙O2peak) as controls. This finding is in line with previous research on the VT in individuals with DS (37). Currently, it is unknown if low V˙Epeak could be explained by ID-specific characteristics, as they do not have common features such as small nasal passages and reduced airway size as present in individuals with DS.
Combining the CPET outcomes allows for an integrated view of the exercise intolerance in the individuals with ID (17,18,24). If the differences in V˙O2peak were mostly due to deconditioning, we would expect that individuals with ID would exhibit a low O2 pulse and low OUES, coupled with normal to high V˙E/V˙CO2 slope, normal or high V˙Epeak, and a normal HRpeak (18,24,30). However, all of these variables were significantly lower in persons with ID (except for V˙E/V˙CO2, which was significantly higher), suggesting that the lower V˙O2peak cannot be entirely explained by low physical activity and physical deconditioning. Instead, the low maximal HR and O2 pulse, coupled with low OUES and high V˙E/V˙CO2, suggest that the low V˙O2peak in individuals with ID is likely due a to a combination of reduced cardiac output, skeletal muscle hypoperfusion, and ventilatory limitations associated with perfusion mismatch in the lungs, in addition to deconditioning.
One of the main strengths of this study is the strict criteria to evaluate effort, as the exercise tests were valid based on achievement of established criteria for V˙O2peak assessment. The validity of a maximal effort on the CPET is critical to the interpretation of the measured peak values of the present study, and therefore we used more strict validation criteria than previously done in a population with ID. Our study has several limitations to address. First, our study population might be influenced by a selection bias. Individuals that did not want, or were not able, to perform a CPET test would be less likely to participate in our study, as all forms of communication provided information about this beforehand. It is likely that our study population with ID represents a relatively active group with better walking ability, compared with the total population with ID. Furthermore, there is some conflicting evidence about the validity of the IPAQ, with a potential underestimation of physical activity levels in individuals with ID (38). Other studies have also shown that individuals with ID have a higher energy expenditure compared with the general population for given tasks (39); therefore, differentiating between light- and moderate-intensity activities within the IPAQ might not be accurate within the population with ID. This would further support the assumption that the differences between our groups are not due to the lower physical activity. In this study, information on etiology was not collected. Although the most prevalent genetic syndromes with known autonomic dysfunction were excluded (DS, Prader–Willi syndrome, and Rett syndrome), other rare genetic syndromes may have been included in our sample and unknowingly influenced the results. Last, testing spirometry would provide more detailed information about the pulmonary function of the participants, which would help further discriminate the origin of exercise intolerance in our group with ID (17). However, in a population with ID, these tests are often not feasible and were therefore not measured in the current study (40).
The results in our study are highly clinically relevant and provide valuable information for structured exercise interventions to support a healthy and independent life in individuals with ID throughout their life span. Our results show that individuals with ID are likely being asked to exercise at a higher intensity than is suggested by different exercise prescription guidelines when training loads are prescribed based on estimated maximal HR (11,28). The overestimation of HRpeak and subsequent intensity prescription may lead to demotivation and physiological exhaustion, resulting in an even more impaired exercise performance instead of improving exercise tolerance and performance. Exercise, leisure time activities, and even daily chores might be more strenuous than previously assumed for individuals with ID, and therefore it is important to adjust activities to an appropriate intensity level, both in free-living or in structured exercise settings.
Future research should focus on the underlying causes of low HRpeak, ventilatory limitations and potential skeletal muscle hypoperfusion, and the potential effect of regular physical activity and exercise to improve the response to exercise in individuals with ID. In addition, it would be of great interest to include the rate of decline of oxygen uptake and HR in the early postexercise phase, as oxygen kinetics may further inform us about the ability of individuals with ID to meet metabolic requirements during and after exercise.
Individuals with ID exhibit exercise intolerance supported by physiological alterations related to HR and ventilatory function. The data also suggest the possibility of peripheral muscle hypoperfusion. The previously reported exercise intolerance and lower cardiorespiratory fitness in this population may therefore have a cardiac, pulmonary, and muscle etiology.
The authors thank all the participants of both of the studies for participating. They also thank Emma Huizinga (Erasmus MC), Marco van Maurik (Erasmus MC), and David Benschop (Radboudumc) for their assistance in data collection. Furthermore, they thank Dr. Baynard (UIC), Mr. Griffith (UIC), Mr. Sneekes (Erasmus MC), Dr. Rozenberg (Erasmus MC), Dr. Timmers (Radboudumc), Ms. Kersten (Radboudumc), and Mr. Massa (Radboudumc) for their guidance and feedback during this investigation.
The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement no. 625455.
The authors do not have any conflict of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
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