Muscle oxygen utilization and ventilatory parameters during exercise in people with cystic fibrosis: Role of HbA1c.

INTRODUCTION: Glycated hemoglobin can interfere with oxygen delivery and CO2 removal during exercise. Additionally, pancreatic insufficiency increases oxidative stress and exacerbates exercise intolerance in people with cystic fibrosis (PwCF). This investigation sought to test the hypotheses that elevated Hemoglobin A1c (HbA1c) can negatively affect exercise parameters in PwCF and that reductions in oxidative stress can improve tissue oxygenation in individuals with elevated HbA1c. METHODS: Twenty four PwCF were divided into two groups; normal HbA1c <5.7% (N-HbA1c) and elevated HbA1c >5.7% (E-HbA1c). A maximal exercise test was conducted to obtain peak oxygen uptake (VO2peak), VO2 at ventilatory threshold (VT), ventilatory parameters (VE/VCO2 slope and end-tidal CO2 (petCO2)). Near-Infrared Spectroscopy (NIRS) was used to assess muscle oxygenated/deoxygenated hemoglobin during exercise. A subset of individuals with E-HbA1cwere given an antioxidant cocktail (AOC) for 4 weeks to determine the effects on tissue oxygenation during exercise. RESULTS: A negative relationship between HbA1c and VO2peak at VT was observed (r = -0.511; p = 0.018). In addition, a positive relationship between HbA1c and VE/VCO2 slope (r = 0.587;p = 0.005) and a negative relationship between HbA1c and petCO2 at maximal exercise (r = -0.472;p = 0.031) was observed. N-HbA1c had greater VO2peak (p = 0.021), VO2 at VT (p = 0.004), petCO2 (p = 0.002), and lower VE/VCO2 slope (p = 0.004) compared with E-HbA1c. Muscle deoxygenated hemoglobin at VT was higher in N-HbA1c vs. E-HbA1c and 4 weeks of AOC improved skeletal muscle utilization of oxygen. CONCLUSION: Findings demonstrate that glycated hemoglobin may lead to tissue oxygenation impairment and ventilation inefficiency during exercise in PwCF. In addition, antioxidant supplementation may lead to improved tissue oxygenation during exercise.

The effects of whole-body vibration amplitude on glucose metabolism, inflammation, and skeletal muscle oxygenation.

Whole-body vibration (WBV) is an exercise mimetic that elicits beneficial metabolic effects. This study aims to investigate the effects of WBV amplitude on metabolic, inflammatory, and muscle oxygenation responses. Forty women and men were assigned to a high (HI; n = 20, Age: 31 ± 6 y) or a low-amplitude group (LO; n = 20, Age: 33 ± 6 y). Participants engaged in 10 cycles of WBV [1 cycle =1 min of vibration followed by 30 s of rest], while gastrocnemius muscle oxygen consumption (mVO2 ) was assessed using near-infrared spectroscopy (NIRS). Blood samples were collected PRE, POST, 1H, 3Hs, and 24H post-WBV and analyzed for insulin, glucose, and IL-6. In the LO group, Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) at 3 h (0.7 ± 0.2) was significantly lower compared to PRE (1.1 ± 0.2; p = 0.018), POST (1.3 ± 0.3; p = 0.045), 1H (1.3 ± 0.3; p = 0.010), and 24H (1.4 ± 0.2; p < 0.001). In addition, at 24H, HOMA-IR was significantly lower in the LO when compared to the HI group (LO: 1.4 ± 0.2 vs. HI: 2.2 ± 0.4; p = 0.030). mVO2 was higher (p = 0.003) in the LO (0.93 ± 0.29 ml/min/100 ml) when compared to the HI group (0.63 ± 0.28 ml/min/100 ml). IL-6 at 3H (LO: 13.2 ± 2.7 vs. HI: 19.6 ± 4.0 pg·ml-1 ; p = 0.045) and 24H (LO: 4.2 ± 1.1 vs. HI: 12.5 ± 3.1 pg·ml-1 ; p = 0.016) was greater in the HI compared to the LO group. These findings indicate that low-amplitude WBV provides greater metabolic benefits compared to high-amplitude WBV.

Endothelial Dysfunction in Cystic Fibrosis: Role of Oxidative Stress.

Oxidative stress and vascular endothelial dysfunction are established characteristics of cystic fibrosis (CF). Oxidative stress may contribute to vascular dysfunction via inhibition of nitric oxide (NO) bioavailability. Purpose. To determine if ingestion of a single antioxidant cocktail (AOC) improves vascular endothelial function in patients with CF. Methods. In 18 patients with CF (age 8-39 y), brachial artery flow-mediated dilation (FMD) was assessed using a Doppler ultrasound prior to and two hours following either an AOC (n = 18; 1,000 mg vitamin C, 600 IU vitamin E, and 600 mg α-lipoic acid) or a placebo (n = 9). In a subgroup of patients (n = 9), changes in serum concentrations of α-tocopherol and lipid hydroperoxide (LOOH) were assessed following AOC and placebo. Results. A significant (p = 0.032) increase in FMD was observed following AOC (Δ1.9 ± 3.3%), compared to no change following placebo (Δ - 0.8 ± 1.9%). Moreover, compared with placebo, AOC prevented the decrease in α-tocopherol (Δ0.48 ± 2.91 vs. -1.98 ± 2.32 µM, p = 0.024) and tended to decrease LOOH (Δ - 0.2 ± 0.1 vs. 0.1 ± 0.1 µM, p = 0.063). Conclusions. These data demonstrate that ingestion of an antioxidant cocktail can improve vascular endothelial function and improve oxidative stress in patients with CF, providing evidence that oxidative stress is a key contributor to vascular endothelial dysfunction in CF.

Assessment of endothelial function is reproducible in patients with cystic fibrosis.

BACKGROUND: New treatments have improved life-expectancy in patients with cystic fibrosis (CF); however, cardiovascular health remains an area of concern in this population. Flow-mediated dilation (FMD), a non-invasive assessment of vascular endothelial function that predicts future cardiovascular disease and events, is attenuated in patients with CF compared to controls. The reproducibility of FMD in CF; however, has yet to be evaluated. Thus, this study sought to examine the within-day, between-day, and between-month reproducibility of FMD in patients with CF. METHODS: Pulmonary function, baseline diameter (cm), peak diameter (cm), and FMD(%) were assessed 5 times (sessions A-E) over four visits in 13 patients with CF (six males, seven females, age range: 13-43 years old; mean forced expiratory volume in 1 s = 71% predicted). Sessions A and B (within-day), C (between-day), and D and E (between-month) were separated by 3 h, at least 10 days, and ~3 months, respectively. Reproducibility was assessed by: (1) paired t-tests, (2) coefficients of variation (CV), (3) CV prime, (4) Pearson's correlation (r), (5) intra-class correlation coefficient, and (6) Bland-Altman plots. Five acceptable parameters were required to determine reproducibility. RESULTS: Pulmonary function was stable throughout all visits. FMD(%) and baseline diameter (cm) satisfied all six reproducibility criteria for within-day, while peak diameter (cm) met five of six criteria. All six reproducibility criteria were met for all between-day and between-month assessments. CONCLUSION: The present study provides evidence that endothelial function assessed by FMD is reproducible in patients with CF not only within-day, but also between-day and between-month.

Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis.

Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. Twenty-nine patients with CF (18 ± 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH4 (BH4-5; n = 17) or a 20 mg/kg dose of oral BH4 (BH4-20; n = 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n = 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 ± 3.4 vs. 8.4 ± 3.5%, respectively, P = 0.005). No change in FMD was observed following PLC or BH4-5 (∆FMD: -0.8 ± 1.9% and -0.5 ± 2.5%; P = 0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in significant improvements in FMD (∆FMD: 1.1 ± 1.4%) compared with BH4-5 ( P = 0.023) and PLC ( P = 0.017). Moreover, BH4-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH4 at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF. NEW & NOTEWORTHY For the first time, the present study documents that a single dose of oral BH4 can improve vascular endothelial function in patients with cystic fibrosis (CF), and our in vitro data suggest this is via decreasing uncoupled nitric oxide. These data provide insight into the important role of BH4 bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH4 treatment in patients with CF.

Exercise testing in patients with cystic fibrosis-importance of ventilatory parameters.

BACKGROUND: Ventilatory parameters obtained during exercise predict survival in several chronic diseases; however, long-term changes in exercise ventilatory parameters in patients with cystic fibrosis (CF) have yet to be examined and potential differences between sexes in CF are unknown. PURPOSE: We sought to examine the change in exercise ventilatory parameters over time in patients with CF and determine if the change is different between sexes. METHODS: Exercise capacity (VO2 peak) and exercise ventilatory parameters (VE/VO2 peak, VE/VCO2 peak, and VE/VCO2 slope) were determined from a maximal cardio-pulmonary test on a cycle ergometer on two visits separated by 39 ± 16 months in 20 patients with CF (10 female, 10 male). RESULTS: No differences between sexes were observed at visit 1 (all p > 0.05). Overall, exercise ventilatory parameters significantly (p < 0.05) deteriorated between visits, with no change (p > 0.05) in VO2 peak. Moreover, compared to males, female patients exhibited greater deteriorations in VE/VO2 peak (p = 0.001), VE/VCO2 peak (p = 0.002), and VE/VCO2 slope (p = 0.016) between visits. CONCLUSIONS: These data in patients with CF indicate that exercise ventilatory parameters decline over time despite no change in VO2 peak, and female patients exhibit a more rapid deterioration compared to males.