Exercise training and NR supplementation to improve muscle mass and fitness in adolescent and young adult hematopoietic cell transplant survivors: a randomized controlled trial {1}.

2022

795

07/2022

1471-2407

BACKGROUND: Advances in hematopoietic cell transplantation (HCT) have led to marked improvements in survival. However, adolescents and young adults (AYAs) who undergo HCT are at high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the developing musculoskeletal system. HCT survivors who have sarcopenia also have excess lifetime risk of non-relapse mortality. Therefore, interventions that increase skeletal muscle mass, metabolism, strength, and function are needed to improve health in AYA HCT survivors. Skeletal muscle is highly reliant on mitochondrial energy production, as reflected by oxidative phosphorylation (OXPHOS) capacity. Exercise is one approach to target skeletal muscle mitochondrial OXPHOS, and in turn improve muscle function and strength. Another approach is to use "exercise enhancers", such as nicotinamide riboside (NR), a safe and well-tolerated precursor of nicotinamide adenine dinucleotide (NAD), a cofactor that in turn impacts muscle energy production. Interventions combining exercise with exercise enhancers like NR hold promise, but have not yet been rigorously tested in AYA HCT survivors.

METHODS/DESIGN: We will perform a randomized controlled trial testing 16 weeks of in-home aerobic and resistance exercise and NR in AYA HCT survivors, with a primary outcome of muscle strength via dynamometry and a key secondary outcome of cardiovascular fitness via cardiopulmonary exercise testing. We will also test the effects of these interventions on i) muscle mass via dual energy x-ray absorptiometry; ii) muscle mitochondrial OXPHOS via an innovative non-invasive MRI-based technique, and iii) circulating correlates of NAD metabolism via metabolomics. Eighty AYAs (ages 15-30y) will be recruited 6-24 months post-HCT and randomized to 1 of 4 arms: exercise + NR, exercise alone, NR alone, or control. Outcomes will be collected at baseline and after the 16-week intervention.

DISCUSSION: We expect that exercise with NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. We will apply the insights gained from this trial to develop individualized, evidence-supported precision initiatives that will reduce chronic disease burden in high-risk cancer survivors.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT05194397. Registered January 18, 2022, https://clinicaltrials.gov/ct2/show/NCT05194397 {2a}.

10.1186/s12885-022-09845-1

BMC Cancer

35854224

Impact of Maternal-Fetal Environment on Mortality in Children With Single Ventricle Heart Disease.

2022

e020299

2022 Jan 18

2047-9980

<p>BACKGROUND Children with single ventricle heart disease have significant morbidity and mortality. The maternal-fetal environment (MFE) may adversely impact outcomes after neonatal cardiac surgery. We hypothesized that impaired MFE would be associated with an increased risk of death after stage 1 Norwood reconstruction. METHODS AND RESULTS We performed a retrospective cohort study of children with hypoplastic left heart syndrome (and anatomic variants) who underwent stage 1 Norwood reconstruction between 2008 and 2018. Impaired MFE was defined as maternal gestational hypertension, preeclampsia, gestational diabetes, and/or smoking during pregnancy. Cox proportional hazards regression models were used to investigate the association between impaired MFE and death while adjusting for confounders. Hospital length of stay was assessed with the competing risk of in-hospital death. In 273 children, the median age at stage 1 Norwood reconstruction was 4&nbsp;days (interquartile range [IQR], 3-6 days). A total of 72 children (26%) were exposed to an impaired MFE; they had more preterm births (18% versus 7%) and a greater percentage with low birth weights &lt;2.5&nbsp;kg (18% versus 4%) than those without impaired MFE. Impaired MFE was associated with a higher risk of death (hazard ratio [HR], 6.05; 95% CI, 3.59-10.21; &lt;0.001) after adjusting for age at surgery, Hispanic ethnicity, genetic syndrome, cardiac diagnosis, surgeon, and birth era. Children with impaired MFE had almost double the risk of prolonged hospital stay (HR, 1.95; 95% CI, 1.41-2.70; &lt;0.001). CONCLUSIONS Children exposed to an impaired MFE had a higher risk of death following stage 1 Norwood reconstruction. Prenatal exposures are potentially modifiable factors that can be targeted to improve outcomes after pediatric cardiac surgery.</p>

10.1161/JAHA.120.020299

J Am Heart Assoc

35014861