Comprehensive Analysis of Cardiopulmonary Exercise Testing Characterizes Age-Related Exercise Performance in Growing Children and Adolescents

doi:10.21203/rs.3.rs-3911874/v1

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Comprehensive Analysis of Cardiopulmonary Exercise Testing Characterizes Age-Related Exercise Performance in Growing Children and Adolescents

https://doi.org/10.21203/rs.3.rs-3911874/v1

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Background Cardiopulmonary exercise testing (CPET) estimates physical fitness level and cardiovascular reserve. How age-related growth and maturation affect exercise performance is complex, especially due to changes in body habitus during puberty.

Methods Peak and submaximal CPET parameters by cycle ergometer were retrospectively analyzed to characterize how age and sex affect exercise performance during adolescence.

Results One hundred sixty five young subjects were divided into six groups based upon their ages: ≤ 11 years old (yo) (24 males, 20 females), 12 to 15 yo (34 males, 41 females), and ≥ 16 yo (27 males, 19 females). Peak heart rate (HR) was comparable among all groups. Peak systolic blood pressure, peak oxygen consumption (VO2), peak work rate (WR), peak oxygen pulse (OP), and peak minute ventilation (VE) showed age-dependent increase in both sexes with more progressive increase in males than in females. Weight-indexed stroke volume estimate (D[VO2/kg]/DHR and peak OP/kg) was comparable in all male groups but was lower in female ³ 12 yo groups than in ≤ 11 yo group, whereas heart rate-dependency (DHR/D[WR/kg]) revealed continuous decrease with ages in males with no change in females. Regression lines between weight and peak VO2 demonstrated significant age-related increase of slope in males but not in females, suggesting age-related skeletal muscle enhancement only in males. Gradual increase in work efficiency (lower ΔVO2/ΔWR), ventilatory efficiency (lower ΔVE/ΔVCO2), and peak respiratory exchange ratio were noted with increase in ages independent of sex, indicating common functional maturation with age.

Conclusion Age-related increase in exercise performance during adolescence is complex, characterized by the increased body size due to linear growth (males more than females), sex-dependent pubertal changes (more muscle mass and strength in males and more fat mass in females), and sex-independent enhanced functional maturation. This unique and simple CPET analysis can provide us with a wealth of data representing underlying exercise physiology of ordinary adolescents. These noninvasive biomarkers would help us better understand the cardiopulmonary reserve in those with borderline physical conditioning and those with subclinical cardiovascular abnormalities.

Exercise performance

Body composition

Sex differences

Functional maturation

Submaximal exercise

Puberty

Cardiopulmonary exercise testing (CPET) is performed to assess overall functional reserve of the cardiovascular system as well as the pulmonary, musculoskeletal, and autonomic nervous systems that participate in oxygen delivery to working muscles [1]. Peak CPET values, especially peak oxygen consumption (pVO2), are highly predictive of daily functionality, quality of life, and prognosis of certain heart diseases [2]. Through CPET, functional cardiac reserve will be quantitatively measured, providing more advanced information regarding cardiovascular wellness, especially in patients with heart disease [3]. However, peak CPET values are not always consistently achieved in children, frequently due to lack of motivation, noncompliance, and physical deconditioning [4]. Submaximal CPET parameters represent a dynamic response to early and intermediate phases of exercise that can predict peak exercise status [5]. Submaximal CPET parameters are independent of reaching a peak exercise level or peak exercise effort but are often used to predict peak exercise level [6, 7].

Age-related growth and maturation bring various changes in body habitus and functional capacities, which collectively affect overall exercise performance in adolescents and young adults. These changes are expressed differently in males and females [8, 9]. Males tend to demonstrate increased muscle mass and strength, increased stroke volume (heart size), increased lung volume, and increased hemoglobin levels [8, 10]. Females tend to present with increased body fat during the course of puberty in addition to their physical growth [11]. Furthermore, age-related growth and functional maturation occur in multiple organ systems independent of sex-related maturation [12, 13]. Although the effects of pubertal changes on exercise performance in growing adolescents have been extensively studied [8, 9, 14], the plethora of scientific data have not been fully incorporated into daily clinical practice.

The aim of this study is to characterize how age-related growth and maturation affect overall exercise performance in growing adolescents by a conventional CPET method that can be used in routine clinical practice.

A retrospective, a single-centered, cross-sectional chart review of healthy children who underwent CPET was conducted. All procedures were performed in accordance with the Hospital guidelines and regulations.

2.1 Patients

Normal healthy patients without heart disease were recruited from the Exercise Laboratory of the Nemours Cardiac Center, Nemours Children’s Health Delaware database from 2005 to 2019. These patients underwent CPET for evaluation of exercise-related symptoms or ECG abnormalities and were cleared from further cardiology follow up with no evidence of underlying cardiac issues. Anthropometric measurements included height (cm), weight (kg), and body mass index (BMI: kg/m²) at the time of CPET. Patients with a BMI greater than 30 kg/m² were excluded from the study. The enrolled patients were divided into three groups by age in both males and females: ≤ 11 years old (yo), 12 yo to 15 yo, and ≥ 16 yo.

2.2 Cardiopulmonary Exercise Testing

The CPET was performed via an electronically braked bicycle ergometer following the RAMP (Raise, Activate, Mobilize, Potentiate/Performance) protocol with continuous incremental work rate (WR) increase (15–25 watts/min, usually set at approximately 0.3 watts/kg). Heart rate (HR) was continuously monitored by a 12 lead-electrocardiogram throughout the study. Blood pressure (BP) and oxygen saturation were recorded regularly. Peak exercise effort was determined by achievement of peak respiratory exchange ratio (pRER) ≥ 1.1 or peak HR ≥ 90% of estimated peak HR for age (= 220 – age). During CPET, patients breathed through a mouthpiece connected to a calibrated respiratory gas analysis system (Vmax Sensor Medics, Palm Springs, CA) for measuring minute ventilation (VE), VO2, carbon dioxide (CO2) production (VCO2), and RER (= VCO2/VO2). Oxygen pulse (OP) was calculated by VO2/HR. These parameters were presented as absolute values and/or weight-indexed values.

Ventilatory anaerobic threshold (VAT) was determined by the V-slope method. Submaximal slope parameters were obtained from plotting two values simultaneously to assess slope values: WR and VO2, WR and HR, WR/kg and HR, HR and VO2, HR and VO2/kg, and VCO2 and VE. These submaximal parameters represent:

DVO2/DWR Oxygen consumption per work (oxygen cost)

DHR/DWR or DHR/D[WR/kg] HR increase in response to work rate (HR-dependency)

DVO2/DHR or D[VO2/kg]/DHR A surrogate of stroke volume

DVE/DVCO2 Inverse of ventilatory efficiency or ventilatory equivalent of CO2

2.3 Two-Dimensional Analysis

Two CPET parameters (including weight) were simultaneously plotted in x and y axis to characterize how age-related growth and functional maturation influenced the exercise performance. Correlations between weight (kg) and pVO2 (L/min), DHR/DWR and DVO2/DHR, VAT (L/min) and pVO2 (L/min), and pVE (L/min) and pVO2 (L/min) indicate group trends of skeletal muscle effects, stroke volume reserve, exercise endurance beyond AT, and ventilatory efficiency of oxygen uptake, respectively [15–17].

2.4 Statistics

Distribution of patients’ demographics and CPET parameters were compared between the three subgroups in each sex and between age-matched males and females. Continuous variables were presented as mean ± standard deviation. Two-sample t-test was used to compare the means of continuous variables. One-way analysis of variance (ANOVA) was used to compare the variables between the three groups. Analysis of covariance (ANCOVA) was used to compare the regression lines between the two groups. Statistical analysis was performed by GraphPad Prizm 6 (GraphPad, San Diego, CA). A p value less than 0.05 was determined as statistically significant.

3.1 Demographic Profile

The CPET of 165 healthy subjects ranging in age from 7 to 18 years (85 males and 80 females) was reviewed. Enrolled subjects were divided into six subgroups upon their age: male ≤ 11 yo (n = 23), female ≤ 11 yo (n = 19), male 12 to 15 yo (n = 34), female 12 to 15 yo (n = 41), male ≥ 16 yo (n = 27), and female ≥ 16 yo (n = 19). Weight and height showed progressive increase with age in both sexes except that no significant difference was noted in females between 12 to 15 yo and ≥ 16 yo groups. Males exhibited comparable BMI in all age groups whereas females showed higher BMI in ≥ 12 yo groups, although normal, than in ≤ 11 yo group (Table 1).

Table 1

Cardiopulmonary exercise testing (CPET) in normal males and females.
	Male			Female
	≤ 11 yo	12 to 15 yo	≥ 16 yo	≤ 11 yo	12 to 15 yo	≥ 16 yo
Age (years)	10.2 ± 1.0	13.6 ± 1.1	16.5 ± 0.6	9.6 ± 1.2	14.3 ± 0.8	16.6 ± 0.6
Number	24	34	27	20	41	19
Weight (kg)	42.2 ± 12.1	55.6 ± 14.1 †	69.1 ± 12.5 †§	37.5 ± 7.8	56.1 ± 9.2 †	60.5 ± 7.8 †
Height (cm)	145 ± 10	164 ± 11 †	175 ± 8 †§	144 ± 11	161 ± 6 †	165 ± 6 †
BMI (kg/m²)	19.9 ± 4.5	20.3 ± 3.7	22.5 ± 3.2	17.8 ± 1.8	21.5 ± 2.9 †	22.2 ± 2.8 †
Rest HR (bpm)	75 ± 13	74 ± 12	69 ± 16	82 ± 12	83 ± 16	76 ± 11
Peak HR (bpm)	182 ± 12	187 ± 14	186 ± 10	187 ± 12	187 ± 10	181 ± 9
Rest SBP (mmHg)	101 ± 9	111 ± 13	117 ± 31	99 ± 9	104 ± 10	109 ± 15
Peak SBP (mmHg)	140 ± 17	161 ± 24 †	180 ± 23 †§	136 ± 13	148 ± 16 †	156 ± 15 †
Peak VO2 (L/min)	1.67 ± 0.33	2.42 ± 0.56 †	3.11 ± 0.82 †§	1.46 ± 0.20	1.89 ± 0.39 †	1.90 ± 0.35 †
Peak VO2/kg (ml/kg/min)	40.8 ± 7.6	44.8 ± 7.6	44.5 ± 6.8	39.8 ± 6.3	34.1 ± 5.9 †	31.5 ± 5.5 †
Peak WR (watts)	109 ± 22	170 ± 43 †	225 ± 48 †§	87.9 ± 16.8	137 ± 27 †	138 ± 25 †
Peak WR/kg (watts/kg)	2.69 ± 0.68	3.11 ± 0.58 †	3.26 ± 0.45 †	2.40 ± 0.46	2.46 ± 0.1	2.51 ± 0.41
peak OP (ml)	9.2 ± 1.6	13.2 ± 3.0 †	17.0 ± 3.2 †	7.9 ± 1.1	10.2 ± 2.0 †	10.6 ± 1.8 †
Peak OP/kg (ml/kg)	0.23 ± 0.04	0.24 ± 0.04	0.25 ± 0.03	0.21 ± 0.03	0.18 ± 0.03†	0.18 ± 0.03†
Peak VE (L/min)	62 ± 13	89 ± 22 †	117 ± 3.1 †§	54.5 ± 11.3	70.2 ± 16.9 †	70.0 ± 14.5 †
Peak RER	1.13 ± 0.07	1.18 ± 0.08	1.20 ± 0.09 †	1.13 ± 0.06	1.18 ± 0.06 †	1.21 ± 0.09 †
VAT (L/min)	1.67 ± 0.33	1.58 ± 0.43 †	1.86 ± 0.46 †§	1.08 ± 0.16	1.31 ± 0.29 †	1.22 ± 0.36
VAT/kg (ml/kg/min)	30.0 ± 6.6	29.7 ± 7.7	26.8 ± 4.8	29.5 ± 4.6	23.7 ± 5.5 †	20.2 ± 5.8 †
DVO2/DHR (ml)	15.6 ± 2.6	19.7 ± 4.8 †	23.8 ± 4.8 †§	12.8 ± 0.6	15.1 ± 4.1 †	15.6 ± 3.8
D[VO2/kg]/DHR (ml/kg)	0.36 ± 0.09	0.36 ± 0.07	0.35 ± 0.07	0.35 ± 0.06	0.29 ± 0.07 †	0.26 ± 0.06 †
DHR/DWR (60J^− 1)	0.87 ± 0.17	0.56 ± 0.17 †	0.45 ± 0.09 †§	1.02 ± 0.24	0.67 ± 0.17 †	0.62 ± 0.10 †
DHR/D[WR/kg] (kg/60J)	34.9 ± 8.9	29.2 ± 5.1 †	30.7 ± 5.9	37.2 ± 6.3	36.5 ± 8.1	37.6 ± 7.3
DVO2/DWR (ml/60J)	12.7 ± 1.8	10.9 ± 1.5 †	10.7 ± 1.2 †	12.7 ± 1.3	10.5 ± 1.7 †	9.8 ± 2.0 †
DVCO2/DVE	27.4 ± 3.5	24.9 ± 2.9 †	23.5 ± 2.4 †	27.3 ± 1.8	25.5 ± 2.8 †	24.0 ± 3.2 †
BMI: body mass index, HR: heart rate, SBP: systolic blood pressure, VO2: oxygen consumption, WR: work rate, OP: oxygen pulse, VE: minute ventilation, RER: respiratory exchange ratio, VAT: ventilatory anaerobic threshold, VCO2: carbon dioxide production. Watt = J/sec. †: p < 0.05 compared with ≤ 11 yo group, §: p < 0.05 compared with 12 to 15 yo group.

3.2 Cardiopulmonary Exercise Testing Parameters

The CPET parameters were presented in the latter part of Table 1. Peak HR was comparable among all groups. Peak systolic BP progressively increased with age in male groups, whereas the age-related increase was less robust in females with no significant difference between 12 to 15 yo and ≥ 16 yo groups.

All absolute CPET parameters, including pVO2, pWR, pOP, pVE, VAT, and DVO2/DHR, were incrementally higher in older groups than younger groups in both sexes, consistent with the increase in body size (height and weight). When indexed by body weight, however, pVO2/kg and pOP/kg in 12 to 15 yo and ≥ 16 yo female groups were significantly lower than those in < 12 yo females whereas no difference was seen in these parameters within male groups. Peak WR/kg was significantly higher in 12 to 15 yo and ≥ 16 yo than in ≤ 11 yo group in males, but there was no age-related increase of peak WR/kg in females.

Weight-indexed submaximal parameters, VAT/kg and D[VO2/kg]/DHR, exhibited the same trend as pVO2/kg and pOP/kg in both sexes; there was no age-related changes in males whereas 12 to 15 yo and ≥ 16 yo female groups showed significantly lower levels than ≤ 11 yo group. DHR/DWR decreased progressively with age in both sexes except no difference between 12 to 15 yo and ≥ 16 yo groups in female. DHR/D[WR/kg] was significantly lower in 12 to 15 yo than in ≤ 11 yo group in males but was comparable in all female groups.

Peak RER was significant higher in ≥ 16 yo group than ≤ 11 yo and 12 to 15 yo groups in males and higher in 12 to 15 yo and ≥ 16 yo groups than ≤ 11 yo group in females. DVO2/DWR was significantly lower in ≥ 12 yo groups than ≤ 11 yo group in both sexes, suggesting better work efficiency in older groups. DVE/DVCO2, an inverse of ventilatory efficiency, was significantly lower in 12 to 15 yo and ≥ 16 yo groups than ≤ 11 yo group in both sexes, indicating better ventilatory efficiency in older groups independent of sex.

3.3 Two-Dimensional CPET Analysis

(i) Weight and pVO2

Figure 1 shows a very good positive correlation between weight (kg) and absolute pVO2 (L/min) in all six groups. Males showed progressive increase in slope with increase in age, whereas there was no notable difference in slope in female groups. This male pattern of age-related increasing slope values indicates not only increased skeletal muscle mass but also enhanced efficiency of muscle metabolism due to physical growth in males. This phenomenon is concordant with the significantly higher WR/kg in ≥ 12 yo male groups than in ≤ 11 yo group; female groups showed nearly overlapping regression lines with comparable WR/kg in all age groups. By ANCOVA, there is a significant difference between ≥ 16 yo and ≤ 11 yo groups in males (p = 0.0012) whereas no significant difference was noted between the same age groups in females.

(ii) DHR/DWR and DVO2/DHR

Figure 2 demonstrates the relation between ΔHR/ΔWR (HR-dependency) and DVO2/DHR (surrogate of stroke volume) in 3 different age groups in both males and females. As DHR/DWR decreases, DVO2/DHR increases exponentially, indicating lower HR dependency tends to be associated with higher stroke volume and vice versa. The trends almost overlap between 3 different groups in both males and females, suggesting the relationship between HR and stroke volume is very similar independent of ages. The difference is the distribution pattern where age < 11 yo group tends reveal higher DHR/DWR and lower DVO2/DHR than age 12 to 15 yo and ≥ 16 yo groups in both males and females. These findings are concordant with significantly higher pVO2, pWR, and pOP in older groups than in younger groups in both sexes (Table 1).

(iii) VAT and pVO2

The relationship between VAT and pVO2 was studied (Fig. 3). There is a very good to excellent positive correlation between VAT and pVO2 in all six groups. The slope of the regression line indicates the endurance beyond AT or tolerance to anaerobic metabolism around the peak exercise. In males, there was a progressive augmentation of this capacity with increasing ages whereas this age-related difference was relatively modest in females. When comparing regression lines representing ≥ 16 yo group and ≤ 11 yo group by ANCOVA, there is a statistically significant difference in both male and female groups (both p < 0.0001). The more marked age-dependent enhancement of endurance capacity beyond AT in males may indicate characteristic male dominant advantage related to puberty.

(iv) pVE and pVO2

Figure 4 demonstrates very good positive linear correlations between pVE and pVO2 in both males and females in all age groups. Just like VAT-pVO2 relationship, males demonstrated age-dependent progressive enhancement of pVE-pVO2 relationship indicating better oxygen uptake efficiency per ventilation with increase in age whereas the age-related changes in female groups are less obvious. When comparing ≥ 16 yo group with ≤ 11 yo by ANCOVA, the two groups showed statistically significant difference in both males (p = 0.00014) and females (p = 0.0006).

(v) Sex Differences in Age-Related Changes

Age-dependent sex differences were presented at ≤ 11 yo and ≥ 16 yo (Fig. 5). Although there was no sex difference in relationships between WR and pVO2, VAT and pVO2, or VE and pVO2 in ≤ 11 yo groups, significant differences were recognized in ages ≥ 16 yo, suggesting different physical conditions most likely due to pubertal changes. Skeletal muscle effects, endurance after AT, and breathing efficiency for oxygen uptake were significantly augmented in males compared with females.

In 165 healthy children and adolescents ranging from 7 to 18 years of age, we examined how age and sex affect exercise performance with peak and submaximal CPET parameters and two-dimensional analysis. With this combined approach, the age-related exercise performance may mainly be characterized by a) age-related increase of body size (height and weight), b) sex-dependent changes due to differences in body composition, and c) sex-independent functional maturation.

4.1 Enhanced Exercise Performance with Increased Physical Growth

Rapid growth of body size or growth spurt commonly occurs during adolescence consisting of increase in bone length and mass, skeletal muscle mass, heart size, intravascular volume, and lung volume, all of which are known to contribute to increased pVO2 and exercise performance [8, 18]. Strong positive linear relationships between weight and pVO2 in both males and females support this phenomenon (Fig. 1) [19]. In our cohort, males showed progressive physical growth even after age 15, whereas females did not, as shown in Table 1, indicating a growth spurt in females may complete earlier than that in males. This is in parallel with peak CPET parameters which still increase beyond age 16 in males whereas there is no significant difference between 12 to 15 yo and ≥ 16 yo groups in females. DVO2/DHR and pOP, both surrogate parameters of stroke volume during submaximal and at peak exercise, respectively, increased in proportion to the body growth (Table 1), suggesting corresponding heart size increase with physical growth [20, 21]. Peak VE also increased with physical growth, suggesting growth of lung volume and augmentation of respiratory muscle with growth spurt in both sexes. Increase of peak SBP, pVO2 (L/min), and pWR also occurred in concordance with the physical growth. These findings regarding age-related changes in exercise performance are agreeable with the previously published studies [8, 22].

4.2 Sex-Dependent Effects on Exercise Performance

In addition to physical growth-dependent increase in CPET parameters, there were certain sex differences in exercise performance more evident in older groups, especially in ≥ 16 yo groups, suggesting the effects of puberty on exercise performance (Fig. 5). A growth spurt is induced by a growth hormone surge, followed by a burst of sex hormones, androgen and estrogen for males and females, respectively. Androgen generates strong anabolic effects as well as virilization that further increases bone and muscle mass, whereas estrogen enhances deposition of body fat in a special manner [23]. Additionally, heart size and stroke volume were noted to be higher in adolescent males [24] as well as lung volume and minute ventilation [25], thus allowing males to exhibit better exercise performance.

In Fig. 1, males demonstrated progressive increase in weight-pVO2 slope with age whereas there were no such age-related slope changes in female groups. Peak WR increased in accordance with physical growth in both sexes, but only males showed significantly higher pWR/kg in ≥ 12 yo groups than in ≤ 11 yo group, suggesting not only increase in muscle mass but also augmented power production efficiency in older males. Enhanced skeletal muscle performance in older males is also supported by the age-related changes in regression lines between VAT and pVO2 (Fig. 3), indicating more sustainable muscle metabolism under an anaerobic condition beyond AT in older males [26]. This may be explained, in part, by higher glycogen utilization in skeletal muscles of males than females [27, 28]. This male puberty-induced enhanced skeletal muscle performance at peak exercise enables post-pubertal adolescent males to take on a greater pWR. Similar age-related enhanced ventilatory efficiency for oxygen uptake indicated by pVE-pVO2 relationship was more prominent in males than in females (Fig. 4) with significant sex difference in ≥ 16 yo (Fig. 5). A larger chest cavity, larger lung volume, and stronger respiratory muscle in male may explain this phenomenon.

Another pattern identified was female age-dependent disadvantages in exercise performance likely due to their body composition. Despite significant increase of pVO2 in 12 to 15 yo and ≥ 12 yo groups compared with that in ≤ 11 yo group, pVO2/kg was significantly lower in 12 to 15 yo and ≥ 16 yo than in ≤ 11 yo groups, suggesting the increased body fat mass in older adolescents most likely due to female puberty. Similar trend was also noted in pOP/kg, VAT/kg, and D[VO2/kg]/DHR (Table 1). During female puberty, estrogen and progesterone levels rise significantly resulting in a large increase in body fat by approximately 6–10% in female adolescents [8]. When pVO2 is calculated relative to lean body mass instead of total body mass, these sex differences are reduced by approximately one half [29]. The difference in peak VO2 between males and females disappears when pVO2 is indexed by estimated leg muscle mass [30]. Overall differences in exercise performance between male and female ≥ 16 yo are likely attributed to both male pubertal advantages with higher body stature and considerably increased muscle mass, strength, and endurance and female pubertal disadvantages with higher body fat mass.

4.3 Sex-Independent Functional Maturation

We also identified age-related enhanced functional maturation in exercise performance independent of sex. These include a significantly higher peak RER, lower ΔVO2/ΔWR, and lower ΔVE/ΔVCO2 in older groups than those in ≤ 11 yo groups (Table 1), suggesting age-related substrate utilization in favor of carbohydrate metabolism, better work efficiency (or lower oxygen cost per work rate), and higher ventilatory efficiency, respectively [22]. Lower ΔVO2/ΔWR in 12 to 15 yo and ≥ 16 yo than ≤ 11 yo in both sexes may indicate maturation of energy metabolism, suggesting more efficient kinetics of high-energy phosphate metabolism in muscle cells in older groups [31, 32]. Ventilatory response to exercise, represented by DVE/DCO2 slope, decreased with age because of changes in the control of ventilation that permits higher values of arterial CO2 partial pressure during exercise in adolescents [33]. Higher DVE/DCO2 implies either higher physiological dead space and/or increased ventilation-perfusion mismatch. One study indicates an element of advantageousness associated with motor learning rather than motor performance that is enhanced during adolescence [12]. This can be attributed to maturation of the central nervous system that is enhanced with age.

4.5 Two-Dimensional CPET Analysis

In this study, we used “two-dimensional CPET analysis,” unique and simple CPET interpretation methods, to aid understanding of exercise physiology [15, 16, 34]. In addition to interpreting each isolated CPET value, we assessed one CPET value in context with other parameters to understand the difference of general trends of two groups. Figure 1 showed how body weight affects pVO2, demonstrating the degree of skeletal muscle effects, both quantitatively (muscle mass) and qualitatively (efficiency of muscle energy metabolism), at a given weight. There was an age-dependent increase in slope of the regression lines in males whereas there was no significant difference in females. Exercise endurance beyond AT was assessed by the relationship between VAT and pVO2 (Fig. 2), which presents upward shift of regression lines with age in males, suggesting male growth provides better endurance under anaerobic condition [27]; this upward shift was relatively modest in females. The slope of regression lines between pVE and pVO2 in males demonstrated progressive upward and rightward shift with increase in age whereas such age-related differences were not as prominent in females. Data from this new approach are closely aligned with existing data of both peak and submaximal parameters [1, 4, 35]..

Our study has several important limitations. First, body composition was analyzed only through BMI, not by a direct measurement of lean body mass and/or body fat mass. The estimation of body composition only by BMI has an intrinsic limitation. Second, sex maturation was not individually assessed in our study. Presence of puberty or sexual maturation was only estimated by the age. Onset, speed and duration of puberty may also be variable among individuals, which were not assessed in this study. Third, the degree of physical conditioning was not controlled in this study. Fourth, although we used pOP and DVO2/DHR as surrogates of stroke volume, these values are also affected by hemoglobin levels and peripheral oxygen extraction, neither of which was measured in this study. Last, a small cohort size limits the power of statistical analysis. Despite these limitations, our study clearly characterized the changes in exercise performance during age-related growth and functional maturation by relatively simple methods that can be easily introduced in routine clinical practice for better understanding of exercise physiology and cardiopulmonary reserve.

We identified three factors affecting age-related augmentation of exercise performance during growth acceleration in adolescence; (1) age-related body size increases, more prominent in males than in females, (2) sex-dependent changes in body composition representing enhanced muscle mass, strength, and endurance in older male adolescents (male-dominant pubertal advantage) and increased body fat mass in older female adolescents (female-dominant pubertal disadvantages), and (3) sex-independent age-related enhanced functional maturation that contributed to altered substrate utilization under anaerobic metabolism and breathing efficiency. A combined analysis of peak and submaximal CPET parameters utilized in this study enabled mechanistic interpretation of age-related exercise performance.

BMI

body mass index

blood pressure

CO2

carbon dioxide

CPET

cardiopulmonary exercise testing

heart rate

oxygen pulse

OUES

oxygen uptake efficiency slope

peak

RER

peak respiratory exchange ratio

RAMP

Raise, Activate, Mobilize, Potentiate/Performance

VAT

ventilatory anaerobic threshold

VCO2

carbon dioxide production

minute ventilation

VO2

oxygen consumption

work rate

Research Funding

No financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

No conflict of interest.

Contribution Summary

TT conceptualized the study design. KK mainly participated in data collection. Both authors analyzed the collected data and created the Tables and Figures. KK wrote an original draft, which was repeatedly edited by TT. Both authors reviewed and approved the final version of the manuscript.

Acknowledgments

Ms. Katerina Kourpas was supported by Nemours summer student research program 2021. The authors thank Ms. Gina D’Aloisio, MS for supporting data collection from the CPET database and Ms. Kimberly Eissmann for editing the manuscript text.

Ethics approval and consent to participate: The study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by Institutional Review Board of Nemours Children’s Health Delaware (IRBNet ID: 1378351-7). Informed consent was obtained by all participants or, if participants are under age 18, from a parent and/or legal guardian.

Consent for publications: N/A

Availability of data and materials: Available upon request.

Competing interests: N/A

Funding: N/A

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No competing interests reported.

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Comprehensive Analysis of Cardiopulmonary Exercise Testing Characterizes Age-Related Exercise Performance in Growing Children and Adolescents

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Abstract

Figures

1. Background

2. Patients and Methods

2.1 Patients

2.2 Cardiopulmonary Exercise Testing

2.3 Two-Dimensional Analysis

2.4 Statistics

3. Results

3.1 Demographic Profile

3.2 Cardiopulmonary Exercise Testing Parameters

3.3 Two-Dimensional CPET Analysis

4. Discussion

4.1 Enhanced Exercise Performance with Increased Physical Growth

4.2 Sex-Dependent Effects on Exercise Performance

4.3 Sex-Independent Functional Maturation

4.5 Two-Dimensional CPET Analysis

5. Limitations

6. Conclusion

Abbreviations

Declarations

References

Additional Declarations

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