Physiological Benefits of Exercise Programs for Youths with Down Syndrome. A Systematic Review

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Introduction
Down Syndrome (DS) is a chromosomal irregularity assignable to total or partial trisomy of Chromosome 21 (C21) which carries enormous medical and social costs [1] (Kamezie al., 2016). It is classified as the most prevalent genetic abnormality in the world [2,3]. The severity and range of the syndrome vary significantly as result of an adaptative cellular response to stress [4]. Physical exercise affects people with DS just as it does the general population; it has a direct effect on the great number of physiological problems that influence their health [5]. This study focuses on physiology, given that physiological parameters indicate functional modifications caused by exercise or physical training, and because exercise constitutes an excellent model to exhibit different homeostatic mechanisms. Exercise also helps people maintain a healthy weight [6]. This area of study is important because functional capacity and exercise are inversely correlated with cardiovascular failure [7] as well as with long-term mortality caused by cardiovascular and neoplastic disease [8].
People with DS often have a very sedentary lifestyle which can affect their health [9]. This behavior has been linked to heart impairments, overweight, hypotonicity, gross motor impairments and lack of transportation [10]. Furthermore, Banky and Shields 2) Characteristics commonly associated with DS 3) A lack of accessible programs and Some of these features can affect the practice of physical exercise, since they cause reduced exercise capacity in this population; for instance, deficient cardiorespiratory condition compared to persons of the same age and sex without DS [23,24], hypertension, hypercholesterolemia, obesity, etc. [25]. The evaluation of these physiological parameters is an objective way of discovering the body response to different exercise programs. They are also health markers associated with daily physical activity and physical exercise [26]. The cardiorespiratory system is responsible for capturing, transporting and using oxygen during physical activity.
Maximum oxygen consumption (VO2max) is described as the maximum combined capability of the cardiovascular, pulmonary, and muscular systems to intake, carriage and use oxygen, respectively [27]. In aerobic exercise (treadmill, elliptical training, walking, cycling, rowing, swimming, stair climbing), the mode, intensity, duration and frequency of the activity must all be taken into account. Studies have shown that in the prevention of mortality and cardiovascular disease, intensity is more effective than duration [28,29]. In 2015, Wee et al. studied the effect of DS and obesity on aerobic capacity and peak heart in adults and youths. Their results suggested that DS decreases equally heart rate peak (HRpeak) and VO 2 peak, in spite of age group and obesity severity. Nevertheless, obesity was related to minor VO 2  Since HDL is that fraction of cholesterol which is transported to the liver for metabolization and excretion by the biliary system, it is not associated with risk of disease [30]. People with DS have a higher risk of dyslipidemia, with a consequently greater risk of cardiopathy. While some authors have stated a low prevalence of atherosclerotic abnormalities in adults with DS, which could decrease the risk of coronary events [31], other researches reveal that these adult patients have a four times greater risk of mortality by ischemia, cardiac disease and cerebrovascular events than the people without DS [32]. In addition, [33] assessed the frequency of dyslipidemia in adolescents and children with DS and found a high incidence of this pathology, nearly 60%. Therefore, lipid profiles must be performed in patients with DS from a young age, regardless of the risk factors for dyslipidemia. In order to control and reduce cholesterol levels, the custom of physical exercise could be a favorable strategy [34].
The formation of free radicals is a normal and irrevocable process in the body due to chemical reactions in the cell. These radicals introduce oxygen into the cells, producing oxidation of their components and alterations in DNA [35]. It is commonly believed that the Superoxide Dismutase (SOD) (an antioxidant enzyme) catalyzes the dismutation of superoxide anion (O2-) in hydrogen peroxide (H 2 O 2 ), which is subsequently transformed into water through enzymatic mechanism of enzymes like Glutathione Peroxidase (GPX) and catalase. Oxidative stress in people with DS has been linked to trisomy of the 21 st chromosome, occasioning the DS phenotype in addition to immune disorders, intellectual disability, biochemical abnormalities, various morphological abnormalities and premature aging [36].
The cause of the upsurge in Reactive Oxygen Species (ROS) may be due to over-expression of the SOD gene, as well as an imbalance between SOD activity and GPX and CAT activity [37]. This lack of balance between the antioxidant and pro-oxidant states would produce an increase in stress in DS; this may affect the mitochondria which are the main origin and target of ROS [38,39]. Moreover, mitochondria are the organelles in which Adenosine Triphosphate (ATP) is generated, and the chronic and continued production of ROS causes a decrease in the synthesis of ATP, which occurs during cellular aging. This review adds a combination of 'physiological parameters' such as some blood analyses assessing objectively and quantitatively the consequences of the training program on participants. The study of these physiological systems simplifies the evaluation of health markers associated with daily physical activity and physical exercise (Ortega et al., 2019). Consequently, the purpose of the current review is to verify if different exercise programs improve cardio-respiratory, lipid and antioxidant responses in young individuals with DS using health markers associated with daily physical activity and physical exercise Boolean operators were used: ("Down syndrome" OR "trisomy 21" OR "chromosome 21" OR "intellectual disability") AND ("sport" "OR "physical fitness" OR "training program") AND ("physiological parameters" OR "peroxidation" OR "oxygen consumption" OR "antioxidant capacity") AND ("intervention").

Search Strategy
The indicators of the PRISMA statement were followed.

Selection Criteria
The inclusion criteria for article selection were studies

Study Selection Process
Article screening was conducted independently by three reviewers (R.C., J.C., and F.R.

Data Extraction
The first (R.C), third (J.C) and fourth (F.R.) author extracted the following data from each article chosen for this review and reaching at an agreement on all items. The next data was obtained from the articles:  and a study with a score from 5 to 0 is considered as evidence level 2 (4-5: acceptable; < 4: poor) [41]. This process implicated a separate analysis by two evaluators (R.C. and F.R.). When there was no consensus, J.C. reviewed the study until the classification was confirmed. The final ranking of every study in each scale was reached by unanimity in a video conference discussion.

Two bibliometric indicators, Burton and Kebler's "half-life" and
Prince Index, was evaluated by the fist (R.C.) and fourth F.R.). Burton and Kebler's "half-life" (age or obsolescence) is the difference between the publication date of the article or publication analyzed; and the Price Index, that is, the percentage of references that are less than five years old (ratio between the number of references with less than 5 years and the total number of references for that year, multiplied by 100 (PI=(references-5 years)/total X100) [47].
The descriptive analysis was performed using an Excel spreadsheet.

Risk Bias
The scores of the Physiotherapy Evidence Database scale for each study incorporated in this review is shown in Table 1. Five of the studies [43][44][45][46]48] achieved a score of 6, therefore they were considered to have high methodological quality [41]. None of the studies made use of a system of concealment of group assignment. Due to 7 studies [24,[42][43][44][45][46]48] evaluated physical training programs in a control group and in an intervention group, the therapist and participants could not be blinded in any study.
The lowest score gotten was 5 [24,42]. One study was not evaluated [25]. With respect to possible bias in the articles included in this review, no study assigned blinded treatment. Of all types of bias detected, the greatest were performance bias and detection bias; none of the studies blinded participants. Attrition bias was detected in two articles [24,42]. As for the remaining criteria described on the PEDro scale, results were satisfactory (PEDro).

Data Extraction
Eight studies with a total of 241 participants (intervention group (IG) n= 173; control group (CG) n=68) were included in this review. Respecting the number of participants, the smallest sample size was reached by [24] (n=14), in while the highest number of participants was observed by [46] (n=40). With respect to geographic region where the study was conducted, 6 out of 8 were carried out in Spain [24,25,[44][45][46]48] one in Portugal [42] and the other in Greece [43]. As regard gender, only two studies [24,25] included men and women in their intervention group. Regarding participant age, the highest mean values (24.6 years) were recorded in the study of [43], while the lowest (14) were found in the study carried out by [25]. Demographic characteristics are shown in Table 2. All studies [42][43][44][45][46]48,24,25] investigated the physiological response of exercise programs. Five out of eight studies described a 12-week interval treadmill training programmed [43-46, 48,25] one study increasing speed (1 km.hr-1) and time every minute until volitional exhaustion [43]; three studies increasing intensity and time every three weeks [44,48,45]. One study described 16-week rowing ergometry training regimen, increasing slope every two minutes and sped every 1 minute [42]. One study used a 30- week program based on sport-games (athletics, handball, football, basketball or volleyball) and swimming [25]. Two studies used circuit training, one including a 21-week plyometric jumps circuit increasing set of series and set of repetitions [24] and other including 12 week-six station lower and upper body activities circuit [46].
Concerning the expected physiological response, four studies [42,43,24,25] evaluated cardio-respiratory capacity. One study [42] reported that cardiovascular fitness (VO2peaks) did not improve, but the participants gained in work performance. However, three out of four studies reported a positive outcome for VO2max [24,25,43]. Three studies assessed the efficiency of training programs on catalase, malondialdehyde and allantoin in other ways in order to evaluate the improvement of antioxidant systems [44,45,48].
In contrast with the baseline, the values of the catalase activity after a 12-week training program did not increase significantly-1,607.0 (231) U/g Hb vs 1,663.2 (280) U/g Hb; (p = 0.151)-. No significant differences were found in controls.
Price´s index of fast-growing scientific specialties might be as high as 80% [49,50]. The studies included in this review reached a "half-life" of eight years and a Prince´s index of 25%, which indicates a low scientific growth in the evaluated area. It is very interesting and necessary that researchers continue to delve into the physiological benefits of exercise programs in people with DS. The quality score of five articles incorporated in this review according to PEDro scale was acceptable. With respect to possible bias in the articles included in this review, no study assigned blinded treatment. Of all types of bias detected, the greatest were performance bias and detection bias; none of the studies blinded participants. Attrition bias was detected in two articles [24, 42,].
Only one article [25] was not evaluated by The PEDro scale for not being consider Randomized Controlled Trial. As for the remaining criteria described on the PEDro scale, results were satisfactory (http://www.pedro.org.au).
All studies [24,25,[42][43][44][45][46]48] divided the intervention into phases: warm-up, exercise and cool down. We agree that it is essential to include a warm-up phase in this type of intervention, provides neurological, physiological and physiological improvements physiological, preparing the body for the exercise phase [51]. The cool-down phase aids the physiological and psychological normalization of the individual [52]. We suggest the training session should not be finished without a progressive cool-down phase in order to lower blood pressure, normalize body temperature, respiration, and heart rate and return to the body's normal metabolic level when not making an extra effort [52]. It is of interest to note that only one of the studies revised [46] reported using stretching exercises in the calm down phase. Other studies [24,25,[42][43][44][45]48] did not include this data.
Participants in the studies selected ranged in age from 14 to in intervention programs [54,55]. Besides, young people in this age range have less difficulty planning and organizing activities and understand the benefits of exercise better (improved health and physical condition, weight loss) [56].

The cardiorespiratory function of people with DS is insufficient;
it has been detected that they have a lower VO2max than people without DS [23]. This may be due to i. maximum HR decreasing cardiac output, and hence VO 2 max [57,58]; ii. Respiratory anomalies suffered by individuals with DS [58]; and iii. An excessive amount of body fat [59,60].
Four of the eight revised studies evaluated the aerobic capacity of the participants [24,25,42,43]. In the one hand, three of the studies [24,25,43] concluded that the training program chosen ameliorated the cardiorespiratory condition with increasing VO2max. On the other hand, one study [42] described improvements in performance measures without improvement in VO2max. In accordance with La Course (2009), the increase in performance should not be underestimated since it will influence an enhance in the capacity to do activities of daily living and therefore in the quality of life. This may be due to the fact that the intensity of the exercise used by [24,25,43] was greater than that used by [42]. Because aerobic training can be done at varying intensities and durations, [42] recognized that physical fitness can not only be enhance with training, but that there are also factors such as motivation for the type of exercise, decrease in anxiety] or acclimation with exercise tests [61]. Also, [24] established not only an improvement in cardio-respiratory endurance parameters in adolescents and children with DS, but also an augmentation in lean and bone mass, which benefits the health of these people. Therefore, we can state that cardiovascular resistance is closely related to an individual's cardiovascular health. The fact that it improves with aerobic training is very important this population has a serious risk of cardiovascular disease as well as diseases related to bone health [62]. [25,29] presenting that young people with DS optimized their VO2max by 30%, achieved healthier values resembling those of individuals without DS [63].
However, as they did not contrast their results with a control group, they could not demonstrate that the changes were the effect of training and not a consequence of physiological changes linked to growth. We believe that these results are not of quality because this study had risk of bias. In any case, it has been documented that the In exercise, lipids are an important source of energy; demand increases as the duration of the exercise is prolonged [66].
Insulin resistance and obesity, which are recurrent among people with DS, are linked to harmful (more atherogenic) lipid profiles, characterized by elevated triglycerides and low HDL cholesterol [67]. This alteration in the lipid profile contributes to a higher rate of myocardial infarction and cerebrovascular accidents than in a population without DS. Previous findings paralleling lipoprotein and lipid concentrations in people with and without DS resulted in conflicting outcomes [68,69]. Furthermore, it is uncertain whether people with DS have an especially atherogenic lipid profile before evolving diabetes and obesity [67]. On the other hand, changes in production of thyroid hormones (hypotiroidism) can influence the lipid profile of this population [70]. Thus, to ensure that triglyceride and cholesterol levels remain at the correct levels, monitoring thyroid hormone level is important.
In their research, [46] found that the percentage of fat mass and low-density cholesterol lipoprotein (LDL) levels decreased very significantly in DS youths subjected to a strength training circuit program. In turn, an increase in HDL cholesterol levels was observed in addition to a reduction in fat mass. The latter prevents obstruction of the arteries and transports excess cholesterol to the liver so that it can be excreted, preventing heart disease [71]. In people with DS, a diminution in HDL cholesterol and an increase in body mass is linked to the development of metabolic syndrome [72].
Therefore, we can state that lipoperoxidation could be predicted in other contexts, given that in this study the control group consisted of people with SD, adjusted for age and sex, thus avoiding the bias caused by using controls without Trisomy-21.
Although to prevent oxidative damage a balance is necessary between enzyme activity in the first and second steps (that is, the quotient of SOD/GPX + catalase), overexpression of the SOD gene located in chromosome 21 would lead to an excess in the production of H2O2, which could transform into hydroxyl radicals. This fact would explain, at least in part, the higher sensitivity of trisomic cells to oxidative injury [73]. However, instead of a rise in SOD activity being favorable, augmented lipid peroxidation is linked to increased expression; similarly, researches on transgenic animals and bacteria indicate that high levels of SOD produce an increase in lipid peroxidation and hypersensitivity to oxidative stress [73].
Erythrocytes, which contain a high content of antioxidant enzymes, provide a great deal of information about physiological processes occurring in other tissues; this information can be accessed using a minimally invasive technique [74]. Therefore, [44], studied the effect of regular exercise on erythrocyte catalase activity in the DS population with the purpose of increasing their redox metabolism.  [77,78].
Malondialdehyde is a final product of the oxidation of polyunsaturated fatty acids. It is used as an oxidative degradation marker in the cell membrane [48,79,80] observed that plasma levels of malondialdehyde decrease significantly in individuals with DS who exercise regularly. This decrease indicates that there is a decline in oxidative stress, improving the antioxidant system and protecting against the damage those free radicals can cause [81].
Allantoin is a water-soluble product that is easily eliminated by the kidneys. It is composed of two urea molecules that, together with ammonia and uric acid, contribute to the excretion of excess nitrogen. [45] used a 12-week aerobic training program for adolescents with DS; they observed a reduction in plasma levels of allantoin and the allantoin/uric acid ratio after exercise. This may be due to the fact that regular exercise was performed at a low to moderate intensity that improved the activity of antioxidant enzymes, which dampens the oxidation of uric acid.
It has been observed that in individuals with DS who exercise daily, elimination of uric acid in urine is reduced; this could be due in part to the increase in free radicals and reactive oxygen species generated with physical exercise. The quality of life of this population improves as results of a decrease in uric acid [82]. Three studies [44,45,48] only measure a single physiologic parameter related to oxidative stress. Thus, after assessing their results it could be said that physical activity has a useful effect on people with DS who participate in a 12-weeks exercise program [83][84][85][86][87][88]. However, we propose the effect of exercise on physiological parameters that indicate oxidative stress should be studied in greater depth [89-91].

Strengths
In terms of strengths, we may say this review offers a more complete view of different training programs than a single article can provide. This systematic review addresses an important topic and will help to inform the approach to beneficial physical activity programs for people with DS. This review also offers a major contribution to improving the wellbeing of people with DS through exercise [92].

Limitations
The particular limitations of the present review must be emphasized. On the one hand, we paid attention to articles published in databases, not including annual activities or reports, conference proceedings, newsletters, etc. On the other hand, we focused on aerobic workouts lasting between 12 and 30 weeks, considering that less time does not imply appreciable physiological change in the participants. The key words chosen may have limited our review.
In assessing the resulting data quality of this review, readers should take into account that we did not examine for articles previous to 2000. Nonetheless, we followed the bibliometric criteria suggested by Juan [49]. Though only six databases were used, they covered the subject matter very well. The search was carried out in duplicate to decrease the option of incorrectly eliminating important studies.
The response of lipid profiles to exercise was only evaluated in one article; data relating to individuals with DS was taken into account, and those referring to other intellectual disabilities were excluded.
Several studies were carried out by the same groups of researchers; therefore, there may be some overlap of participants in the various training programs. Our review includes a relatively small number of studies; therefore, caution must be employed in generalizing with regard to the results.

Funding
This research lacks external funding.

Disclosure Statement
No potential conflict of interest is reported.