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Despite exercise intolerance being predictive of outcomes in pulmonary arterial hypertension (PAH), its underlying cardiac mechanisms are not well described. The aim of the study was to explore the biventricular response to exercise and its associations with cardiorespiratory fitness in children with PAH. Participants underwent incremental cardiopulmonary exercise testing and simultaneous exercise echocardiography on a recumbent cycle ergometer. Linear mixed models were used to assess cardiac function variance and associations between cardiac and metabolic parameters during exercise. Eleven participants were included with a mean age of 13.4 ± 2.9 yr old. Right ventricle (RV) systolic pressure (RVsp) increased from a mean of 59 ± 25 mmHg at rest to 130 ± 40 mmHg at peak exercise ( P < 0.001), whereas RV fractional area change (RV-FAC) and RV-free wall longitudinal strain (RVFW-S l ) worsened (35.2 vs. 27%, P = 0.09 and -16.6 vs. -14.6%, P = 0.1, respectively). At low- and moderate-intensity exercise, RVsp was positively associated with stroke volume and O 2 pulse ( P < 0.1). At high-intensity exercise, RV-FAC, RVFW-S l , and left ventricular longitudinal strain were positively associated with oxygen uptake and O 2 pulse ( P < 0.1), whereas stroke volume decreased toward peak ( P = 0.04). In children with PAH, the increase of pulmonary pressure alone does not limit peak exercise, but rather the concomitant reduced RV functional reserve, resulting in RV to pulmonary artery (RV-PA) uncoupling, worsening of interventricular interaction and LV dysfunction. A better mechanistic understanding of PAH exercise physiopathology can inform stress testing and cardiac rehabilitation in this population. NEW & NOTEWORTHY In children with pulmonary arterial hypertension, there is a marked increase in pulmonary artery pressure during physical activity, but this is not the underlying mechanism that limits exercise. Instead, right ventricle-to-pulmonary artery uncoupling occurs at the transition from moderate to high-intensity exercise and correlates with lower peak oxygen uptake. This highlights the more complex underlying pathological responses and the need for multiparametric assessment of cardiac function reserve in these patients when feasible.

Children who experience early life stress demonstrate changes to their stress responses, which may modulate long-term health. Childhood cancer presents significant stress during diagnosis, treatment, and survivorship. We hypothesized that children who have completed chemotherapy treatment for ALL will demonstrate altered hormone patterns in response to a stressor compared with healthy controls. Twelve pediatric ALL survivors and 12 healthy controls completed the Trier Social Stress Test. Salivary samples, heart rate, and self-report ratings of stress were collected at baseline, pretest, and posttest. Between group comparison showed baseline (interleukin [IL]-8) was significantly higher in the survivor group versus controls (survivors: 89.9, 40.1-544.9 pg ml -1 ; controls: 30.7, 5.6-241.9 pg ml -1 , p = .001) as was peak (IL-8) (survivors: 147.1, 71.6-1177.6 pg ml -1 ; controls: 75.5, 28.6-698.6 pg ml -1 ). Peak salivary alpha-amylase (sAA) concentration was significantly lower in the survivor group (survivors: 69.3, 19.4-195.5 U ml -1 ; controls: 91.2, 27.7-213.7 U ml -1 ; p = .04). Repeated measures ANOVA revealed significant main effects for time on cortisol (F (2.35, 50.81)  = 5.9, p < .01), sAA (F (1.56, 33.17)  = 6.6, p < .01), stress ratings (F (3.42, 88.14)  = 53.4, p < .001), and heart rate (F (8, 83)  = 16.8, p < .05). Significant main effects for group were observed for IL-8 (F (1, 23)  = 8.2, p < .01) and tumor necrosis factor-α (F (1, 23)  = 6.8, p < .05). Significant interaction effects for group × time were found for sAA (F (5, 106)  = 2.8, p < .05). Our results indicate that childhood ALL survivors have similar responses to stress as healthy controls, but lower sympatho-adrenal-medullary reactivity. Therefore, altered stress regulation may present a pathway modulating long-term health in this population., (© 2022 Wiley Periodicals LLC.)

Exercise intolerance is a common adverse effect of childhood cancer, contributing to impaired health and well-being. While reduced aerobic fitness has been attributed to central cardiovascular deficiencies, the involvement of peripheral musculature has not been investigated. We studied peripheral muscle function in children following cancer treatment using noninvasive phosphorus-31 magnetic resonance spectroscopy. Ten acute lymphoblastic leukemia (ALL) and 1 lymphoma patient 8 to 18 years of age who completed treatment 6 to 36 months prior and 11 healthy controls participated in the study. Phosphorus-31 magnetic resonance spectroscopy was used to characterize muscle bioenergetics at rest and following an in-magnet knee-extension exercise. Exercise capacity was evaluated using a submaximal graded treadmill test. Both analysis of variance and Cohen d were used as statistical methods to determine the statistical significance and magnitude of differences, respectively, on these parameters between the patient and control groups. The patients treated for ALL and lymphoma exhibited lower anaerobic function ( P =0.14, d =0.72), slower metabolic recovery ( P =0.08, d =0.93), and lower mechanical muscle power ( d =1.09) during exercise compared with healthy controls. Patients demonstrated lower estimated VO 2peak (41.61±5.97 vs. 47.71±9.99 mL/min/kg, P =0.11, d =0.76), lower minutes of physical activity (58.3±35.3 vs. 114.8±79.3 min, P =0.12, d =0.99) and higher minutes of inactivity (107.3±74.0 vs. 43.5±48.3 min, d =1.04, P <0.05). Children treated for ALL and lymphoma exhibit altered peripheral skeletal muscle metabolism during exercise. Both deconditioning and direct effects of chemotherapy likely contribute to exercise intolerance in this population., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Magnetic Resonance Imaging (MRI) is well-suited for imaging peripheral blood flow due to its non-invasive nature and excellent spatial resolution. Although MRI is routinely used in adults to assess physiological changes in chronic diseases, there are currently no MRI-based data quantifying arterial flow in pediatric or adolescent populations during exercise. Therefore the current research sought to document femoral arterial blood flow at rest and following exercise in a pediatric-adolescent population using phase contrast MRI, and to present test-retest reliability data for this method. Ten healthy children and adolescents (4 male; mean age 14.8 ± 2.4 years) completed bloodwork and resting and exercise MRI. Baseline images consisted of PC-MRI of the femoral artery at rest and following a 5 × 30 s of in-magnet exercise. To evaluate test-retest reliability, five participants returned for repeat testing. All participants successfully completed exercise testing in the MRI. Baseline flow demonstrated excellent reliability (ICC = 0.93, p = 0.006), and peak exercise and delta rest-peak flow demonstrated good reliability (peak exercise ICC = 0.89, p = 0.002, delta rest-peak ICC = 0.87, p = 0.003) between-visits. All three flow measurements demonstrated excellent reliability when assessed with coefficients of variance (CV's) (rest: CV = 6.2%; peak exercise: CV = 7.3%; delta rest-peak: CV = 7.1%). The mean bias was small for femoral arterial flow. There was no significant mean bias between femoral artery flow visits 1 and 2 at peak exercise. There were no correlations between age or height and any of the flow measurements. There were no significant differences between male and female participants for any of the flow measurements. The current study determined that peripheral arterial blood flow in children and adolescents can be evaluated using non-invasive phase contrast MRI. The MRI-based techniques that were used in the current study for measuring arterial flow in pediatric and adolescent patients demonstrated acceptable test-retest reliability both at rest and immediately post-exercise., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Exercise intolerance is common in people with CF (pwCF), but not universal among all individuals. While associated with disease prognosis, exercise intolerance is not simply a reflection of the degree of lung disease. In people with severe CF, respiratory limitations may contribute more significantly to impaired exercise capacity than in those with mild-moderate CF. At all levels of disease severity, there are peripheral factors e.g., abnormal macro- and micro-vascular function that impair blood flow and reduce oxygen extraction, and mitochondrial defects that diminish metabolic efficiency. We discuss advances in understanding the central and peripheral mechanisms underlying exercise intolerance in pwCF. Exploring both the central and peripheral factors that contribute to exercise intolerance in CF can help inform the development of new therapeutic targets, as well as help define prognostic criteria., (Copyright © 2021. Published by Elsevier B.V.)

Background: The roles of physical activity (PA) and exercise within the management of cystic fibrosis (CF) are recognised by their inclusion in numerous standards of care and treatment guidelines. However, information is brief, and both PA and exercise as multi-faceted behaviours require extensive stakeholder input when developing and promoting such guidelines., Method: On 30 th June and 1 st July 2021, 39 stakeholders from 11 countries, including researchers, healthcare professionals and patients participated in a virtual conference to agree an evidence-based and informed expert consensus about PA and exercise for people with CF. This consensus presents the agreement across six themes: (i) patient and system centred outcomes, (ii) health benefits, iii) measurement, (iv) prescription, (v) clinical considerations, and (vi) future directions. The consensus was achieved by a stepwise process, involving: (i) written evidence-based synopses; (ii) peer critique of synopses; (iii) oral presentation to consensus group and peer challenge of revised synopses; and (iv) anonymous voting on final proposed synopses for adoption to the consensus statement., Results: The final consensus document includes 24 statements which surpassed the consensus threshold (>80% agreement) out of 30 proposed statements., Conclusion: This consensus can be used to support health promotion by relevant stakeholders for people with CF.

Background: Data are limited regarding the use of implantable cardioverter-defibrillators (ICDs) in diverse populations. This study explores cardiovascular (CV) outcomes and mortality from ICD randomized controlled trials (RCTs), by sex, race, and age., Methods: Five electronic databases (PubMed, Emcare, Embase, MEDLINE, and Cumulative Index to Nursing & Allied Health Literature CINAHL) were searched for dates from their inception to July 12, 2021, for RCTs of ICD therapy in adult patients. Data were analyzed for clinical outcomes, including all-cause or CV death, and heart failure hospitalization (HFH)., Results: Among 5 RCTs (mean age: 63 years; 78% male; 76% White) with moderate overall risk of bias, clinical outcomes in patients with an ICD (n = 3260) vs a control group (n = 3685) were compared. No between-group sex differences were observed for all-cause death (odds ratio [OR] 0.86, P  = 0.51), CV death (OR 0.98, P  = 0.96), HFH (OR 0.95, P  = 0.87), or HFH and all-cause death (OR 0.83, P  = 0.51) in the ICD group, in a comparison of male vs female sex. All-cause death (OR 1.20, P  = 0.67) did not differ for White vs Black patients receiving ICD therapy. Outcomes data for other non-White, non-Black race groups were often unreported. Most RCTs originated in North America, had male leadership, and were evenly sponsored by industry vs peer-reviewed funding., Conclusions: Outcomes data are sparse, by sex, race, and age, in current RCTs evaluating ICD therapy. Although ICD patient outcomes did not significantly differ by sex or race, improved data analyses and reporting are needed to determine the relationship between these sociocultural factors and clinical outcomes among distinct ICD patient cohorts., (© 2021 The Authors.)

Stress is a ubiquitous experience that can be adaptive or maladaptive. Physiological stress regulation, or allostasis, can be disrupted at any point along the regulatory pathway resulting in adverse effects for the individual. Children with cancer exhibit significant changes to these pathways in line with stress dysregulation and long-term effects similar to those observed in other early-life stress populations, which are thought to be, in part, a result of cytotoxic cancer treatments. Children with cancer may have disruption to several steps in the stress-regulatory pathway including cognitive-affective function, neurological disruption to stress regulatory brain regions, altered adrenal and endocrine function, and disrupted tissue integrity, as well as lower engagement in positive coping behaviours such as physical activity and pro-social habits. To date, there has been minimal study of stress reactivity patterns in childhood illness populations. Nor has the role of stress regulation in long-term health and function been elucidated. We conclude that consideration of stress regulation in childhood cancer may be crucial in understanding and treating the disease.

Background: Cardiac resynchronization therapy (CRT) is beneficial in patients who have heart failure with reduced ejection fraction or arrhythmic events. However, most randomized controlled trials (RCTs) showing survival benefits primarily enrolled older white men. This study aims to evaluate CRT efficacy by sex, race, and age in RCTs., Methods: Five electronic databases (CINAHL, Embase, Emcare, Medline, and PubMed) were searched from inception to July 12, 2021 for RCTs with CRT in adult patients. Data were analyzed for clinical outcomes including all-cause or cardiovascular (CV) death, worsening heart failure (HF), and HF hospitalization (HFH) according to sex, race, and age., Results: Among six RCTs with up to moderate risk of bias, 54% (n = 3,630 of 6,682; mean age 64 years, 22% female, 8% black patients) had CRT device implantation. All-cause death (odds ratio [OR], 0.51; P  = 0.053) was reduced in female versus male CRT patients, whereas CV death, HFH, or all-cause death with worsening HF or HFH did not differ significantly. No difference was seen in CRT patients for all-cause death and worsening HF (OR, 1.32; P  = 0.46) among white vs black patients or for all-cause death and HFH (OR, 1.19; P  = 0.55) among ≥ 65 versus < 65 years., Conclusions: Whereas all-cause death was lower in female CRT patients, other reported outcomes did not significantly differ by sex, race, or age. Only 6 studies partially reported outcomes. Thus, enhanced reporting and analyses are required to overcome such paucity of data to evaluate the impact of these factors on clinical outcomes in distinct patient cohorts with CRT indication., (© 2021 The Authors.)

Low levels of habitual physical activity in children and adolescents with congenital heart disease (CHD) leads to various negative health outcomes, yet review of the literature indicates that many physicians, caregivers, and patients restrict physical activity owing to safety concerns. There is no evidence supporting absolute restriction of physical activity in pediatric patients with CHD; in fact, physically active lifestyles are as important for pediatric patients living with CHD as for the general population. To encourage long-term maintenance of physically active lifestyles, physical activity counselling and exercise prescription should be started early in childhood and be a core component of every patient encounter. Physical activity counselling should include clear messaging from physicians about recommended physical activities-not just restrictions-and a personalised written exercise prescription for the patient and family. Regular follow-up is essential to ensure adherence to recommendations, monitor patient responses to the increased physical activity level, and long-term surveillance. This review discusses the importance of a physically active lifestyle in children and adolescents with and without surgically repaired CHD and hypertrophic cardiomyopathy, excluding those with electrical abnormalities and channelopathies. It outlines gaps in knowledge regarding best practices for physical activity promotion in these patient populations, and provides recommendations on how to include physical activity promotion and exercise prescription in clinical practice based on existing literature. An important role for clinicians is identified, because the type of messaging they provide regarding physical activity will have a major impact on patients' and families' decisions to adopt an active lifestyle., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Massage therapy is a common postexercise muscle recovery modality; however, its mechanisms of efficacy are uncertain. We evaluated the effects of massage on systemic inflammatory responses to exercise and postexercise muscle performance and soreness. In this crossover study, nine healthy male athletes completed a high-intensity intermittent sprint protocol, followed by massage therapy or control condition. Inflammatory markers were assessed pre-exercise; postexercise; and at 1, 2, and 24 h postexercise. Muscle performance was measured by squat and drop jump, and muscle soreness on a Likert scale. Significant time effects were observed for monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor alpha (TNFα), drop jump performance, squat jump performance, and soreness. No significant effects for condition were observed. However, compared with control, inflammatory marker concentrations (IL-8, TNFα, and MCP-1) returned to baseline levels earlier following the massage therapy condition ( p < 0.05 for all). IL-6 returned to baseline levels earlier following the control versus massage therapy condition ( p < 0.05). No differences were observed for performance or soreness variables. MCP-1 area under the curve (AUC) was negatively associated with squat and drop jump performance, while IL-10 AUC was positively associated with drop jump performance ( p < 0.05 for all). In conclusion, massage therapy promotes resolution of systemic inflammatory signaling following exercise but does not appear to improve performance or soreness measurements.

Haematopoietic stem cell transplant (HSCT) is an intensive therapy for some pediatric hematological illnesses. Survivors are at risk for adverse effects including exercise intolerance. Peripheral tissue dysfunction may contribute to exercise intolerance; therefore, we examined the feasibility of a magnetic resonance spectroscopy (MRS) protocol to evaluate skeletal muscle metabolism in children post-HSCT. We measured demographic characteristics, aerobic exercise capacity (YMCA protocol), and skeletal muscle function in response to exercise (MRS; Siemens 3T MRI) in five children post-allogeneic HSCT and five age/body mass index-matched healthy controls (HCs). The mean age (± standard deviation) of the HSCT group and HC group were 11 ± 1.2 and 12.8 ± 2.4 years, respectively. Children post-HSCT had a lower peak aerobic exercise capacity compared to HCs (27.8 ± 3.4 vs. 40.3 ± 8.1 mL kg -1 min -1 , respectively; p = 0.015). Exercise MRS testing protocols were successfully completed by all HSCT and HC participants; however, MRS-derived skeletal muscle metabolism variables were not different between the two groups. In conclusion, the use of exercise protocols in conjunction with MRS to assess peripheral skeletal muscle metabolism was achievable in children post-HSCT. In the future, larger studies should determine if skeletal muscle function is associated with exercise capacity in children post-HSCT.

Background: Physical activity (PA) is associated with a diverse range of health benefits. International guidelines suggest that children should be participating in a minimum of 60 min of moderate to vigorous intensity PA per day to achieve these benefits. However, current guidelines are intended for healthy children, and thus may not be applicable to children with a chronic disease. Specifically, the dose of PA and disease specific exercise considerations are not included in these guidelines, leaving such children with few, if any, evidence-based informed suggestions pertaining to PA. Thus, the purpose of this narrative review was to consider current literature in the area of exercise as medicine and provide practical applications for exercise in five prevalent pediatric chronic diseases: respiratory, congenital heart, metabolic, systemic inflammatory/autoimmune, and cancer., Methods: For each disease, we present the pathophysiology of exercise intolerance, summarize the pediatric exercise intervention research, and provide PA suggestions., Results: Overall, exercise intolerance is prevalent in pediatric chronic disease. PA is important and safe for most children with a chronic disease, however exercise prescription should involve the entire health care team to create an individualized program., Conclusions: Future research, including a systematic review to create evidence-based guidelines, is needed to better understand the safety and efficacy of exercise among children with chronic disease.

The aortic pulse wave velocity (PWV) measured via cardiac magnetic resonance (CMR) can be used to non-invasively assess changes in arterial stiffness and potential underlying vascular dysfunction. This technique could unmask early arterial dysfunction in overweight and obese youth at risk for cardiovascular disease. We sought to determine the association between vascular stiffness, percentage body fat, body mass index (BMI), and cardiac function in adolescents across the weight spectrum through both CMR and standard applanation tonometry (AT)-based PWV measurements. PWV and left-ventricular cardiac function were assessed using 3.0 T CMR in obese and overweight (OB/OW) participants (n = 12) and controls (n = 7). PWV was also estimated via carotid-femoral AT. OB/OW participants did not differ from healthy-weight controls regarding cardiometabolic risk factors or physical activity levels, but there was a trend towards higher levels of triglycerides in obese/overweight participants (P = 0.07). Mean PWV was higher in obese participants when corrected for age and sex (P = 0.01), and was positively associated with BMI (β = 0.51, P = 0.02). PWV estimated through AT was not significantly different between groups. Cardiac function measured by left-ventricular ejection fraction z-score was inversely associated with mean PWV (β = -0.57, P = 0.026). Increasing arterial stiffness and decreasing cardiac function were evident among our overweight and obese cohort. PWV estimated by CMR could detect early increases in arterial stiffness vs. traditional AT measurements of PWV., (© 2017 World Obesity Federation.)

Background: Obesity is associated with cardiometabolic disturbances, which may have significant implications for musculoskeletal health and exercise tolerance., Objective: We sought to determine the association between muscle structure, function, and metabolism in adolescents across the weight spectrum., Methods: This cross-sectional case-control study included overweight and obese participants (n = 24) 8-18 years of age with a body mass index (BMI) ≥ 85th percentile for age and gender, and non-obese participants (n = 24) with a BMI < 85 th percentile. Body composition, physical activity, peak aerobic capacity, cardiometabolic blood markers and insulin resistance (measured by the homeostatic model assessment of insulin resistance, HOMA-IR), skeletal muscle mitochondrial oxidative capacity (via 31 Phosphorous-Magnetic Resonance Spectroscopy, 31 P-MRS, to assess phosphocreatine (PCr) recovery after exercise), and extramyocellular and intramyocellular lipid (IMCL) levels (via 1 Hydrogen-MRS) were assessed. Stepwise regression was performed to examine the factors associated with oxidative capacity., Results: bese and overweight patients had similar age, height, and physical activity to non-obese controls, but obese and overweight participants exhibited higher insulin resistance. Obese and overweight participants had longer PCr recovery than non-obese controls following 5x30s of moderate-intensity exercise (51.2 ± 20.1 s vs. 23.9 ± 7.5 s, p = 0.004). In univariate correlation analysis, impaired PCr recovery was associated with a higher BMI z-score (r s  = 0.51, p < 0.001), circulating triglycerides (r s  = 0.41, p = 0.005), and HOMA-IR (r s  = 0.46, p = 0.001). In stepwise multivariate regression analysis, impaired PCr recovery was associated with a higher BMI z-score (β = 0.47, p = 0.002), but not insulin resistance (β = 0.07, p = 0.07) or circulating triglycerides (β = 0.16 p = 0.33)., Conclusion: A slower phosphocreatine recovery following aerobic exercise is strongly associated with increasing adiposity. A slower metabolic recovery following aerobic exercise stress suggests that endurance exercise training in obese adolescents may be an optimal strategy to target exercise intolerance in this cohort., (© 2016 World Obesity Federation.)

Human experimentation investigating the contribution of limb movement frequency in determining the fast exercise drive to breathe has produced controversial findings. To evaluate the role of limb movement frequency in determining the fast exercise drive to breathe, endurance runners and recreationally-active controls performed two sinusoidal exercise protocols on a cycle ergometer. One protocol was performed at constant workload with sinusoidal pedaling cadence, and a second with sinusoidal workload at constant cadence. Metabolic rate (VO2) increases and means were matched between these two experiments. The ventilatory response was significantly faster when limb movement speed was varied, compared to when pedal loading was varied (18.49 ± 15.6s vs. 50.5 ± 14.5s, p<0.05). Ventilation response amplitudes were significantly higher during pedal cadence variation versus pedal loading variation (3.99 ± 0.25 vs. 2.58 ± 0.17 L/min, p<0.05). Similar findings were obtained for endurance athletes, with significantly attenuated ventilation responses to exercise versus control subjects. We conclude that fast changes in limb movement frequency are a potent stimulus for ventilation at submaximal workloads, and that this response is susceptible to attenuation through training., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Object: There have been no studies to investigate the effects of cycling exercise protocols, as well as repeated bouts of exercise, on the blood oxygen level-dependent (BOLD) response in the quadriceps muscles. This study characterized BOLD signal recovery following non-ischemic bouts of exercise in the quadriceps muscles of healthy adults in order to provide a basis for application of a protocol for clinical populations., Materials and Methods: Healthy male subjects (23.7 ± 2.0 years of age, n = 10) completed three cycles of one-minute exercise (65 % of maximum workload), with two minutes of rest between each bout, on an MRI-compatible ergometer. The BOLD responses during recovery were fitted to a sigmoid model, and response kinetics (post-exercise intensity [S0]), response time (α), change in baseline BOLD signal (κ), and inflection point (β)] were measured., Results: The sigmoid function fit well to the post-exercise BOLD data (r (2) = 0.95 ± 0.04). The mean response time was 10.5 ± 3.8 seconds, change in baseline BOLD intensity was 0.15 ± 0.068, and time to half-peak was 20.2 ± 8.6 seconds., Conclusion: The proposed sigmoid model is a robust method for quantifying quadriceps BOLD response post-exercise without induced ischemia. Extension of this model to evaluate microvascular responses in patients with chronic disease could improve our understanding of exercise intolerance.