The current manuscript has been adapted from the official position statement of the UK Strength and Conditioning Association on youth resistance training. It has subsequently been reviewed and endorsed by leading professional organisations within the fields of sports medicine, exercise science and paediatrics. The authorship team for this article was selected from the fields of paediatric exercise science, paediatric medicine, physical education, strength and conditioning and sports medicine.
Children and young adults with single ventricle physiology have abnormal exercise capacity after Fontan operation. A medication capable of decreasing pulmonary vascular resistance should allow for improved cardiac filling and improved exercise capacity.
Methods and Results
This study was a double-blind, placebo-controlled, crossover trial conducted in children and young adults after Fontan. Subjects were randomized to receive placebo or sildenafil (20 mg tid) for 6 weeks. After a 6-week washout, subjects crossed over for an additional 6 weeks. Each subject underwent an exercise stress test at the start and finish of each phase. Following sildenafil subjects had a significantly decreased respiratory rate and decreased minute ventilation at peak exercise. At the anaerobic threshold subjects had significantly decreased ventilatory equivalents of carbon dioxide. There was no change in oxygen consumption during peak exercise although there was a suggestion of improved oxygen consumption at the anaerobic threshold. Improvement at the anaerobic threshold was limited to the subgroup with single left or mixed ventricular morphology and to the subgroup with baseline serum brain natriuretic peptide levels ≥ 100 pg/ml.
In this cohort, sildenafil significantly improved ventilatory efficiency during peak and sub-maximal exercise. There was also a suggestion of improved oxygen consumption at the anaerobic threshold in two subgroups. These findings suggest that sildenafil may be an important agent to improve exercise performance in children and young adults with single ventricle physiology following Fontan operation.
Subclinical changes suggestive of ischemia might occur despite patent neo-coronary ostia, notably after ARCA repair. The implication of these results on indication for surgery and subsequent sudden death risk is unknown. Serial EST, SE, and MPS are essential in evaluating ongoing ischemia risk after AAOCA repair.
ObjectivePrevious studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF‐kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose‐ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435).MethodsSixty‐nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5–300 mg/day.ResultsOmaveloxolone was well tolerated, and adverse events were generally mild. Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day. No significant changes were observed in the primary outcome, peak work load in maximal exercise testing (0.9 ± 2.9 W, placebo corrected). At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (P = 0.0001) and by 2.3 points versus placebo (P = 0.06). Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus). In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (P < 0.0001) and by 4.4 points versus placebo (P = 0.01) at the 160 mg/day.InterpretationTreatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.
The objective of this study was describe the impact of sildenafil on echocardiographic measures of myocardial performance in children and young adults with a functional single-ventricle physiology late after Fontan surgery. A double-blind, placebo-controlled, crossover trial was conducted in children and young adults after the Fontan operation at a single pediatric center. Subjects were randomized to receive placebo or sildenafil (20 mg tid) for 6 weeks. After a 6-week washout period, subjects were crossed for an additional 6 weeks. Each subject underwent an echocardiogram at the start and finish of each phase. A total of 27 subjects completed study testing at a mean age of 14.9 years and a mean time from Fontan surgery of 11.3 years. After sildenafil, subjects demonstrated improvement in their myocardial performance index (MPI; −0.051; 95% CI −0.095, −0.0077; p 0.02) and in the product of the velocity time integral (VTI) of the dominant outflow tract and the heart rate (HR; 110 cm × bpm; 95% CI 7.5, 220; p = 0.04). Measures of diastolic performance, including inflow velocities, myocardial velocities, and the ratio of blood pool velocity to myocardial velocity during passive inflow, did not change. In this cohort, there were significant improvements in both the MPI and the product of the VTI × HR after 6 weeks of treatment with sildenafil. These findings suggest that sildenafil may be a useful therapy to improve or maintain ventricular performance in select patients after the Fontan operation.
The Fontan operation can create a stable circulation from childhood through early adulthood. However, the absence of a sub-pulmonary pumping chamber leads to a physiology in which exercise capacity is limited and decreases with age starting in adolescence. The limitation in exercise capacity is more pronounced at peak levels of exercise, but is still present during more modest levels of activity. The underlying causes of exercise impairment relate to both central cardiovascular factors (oxygen delivery) and peripheral factors (oxygen extraction). Interventions to improve cardiac preload and to improve lean muscle mass may help to improve exercise capacity and, perhaps, will alter the "natural history" of the progressive decline.
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