Skeletal muscle oxidative capacity in patients ... - Wiley Online Library

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Exp Physiol 100.5 (2015) pp 545–552

Research Paper

Skeletal muscle oxidative capacity in patients with cystic fibrosis Melissa L. Erickson1 , Nichole Seigler2 , Kathleen T. McKie3 , Kevin K. McCully1 and Ryan A. Harris2,4 1

Department of Kinesiology, University of Georgia, Athens, GA, USA Division of Clinical Translational Science, Department of Pediatrics, Georgia Regents University, Augusta, GA, USA 3 Pediatric Pulmonology, Georgia Regents University, Augusta, GA, USA 4 Sport and Exercise Science Research Institute, University of Ulster, Jordanstown, County Antrim, UK

Experimental Physiology

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New Findings r What is the central question of this study? Do patients with cystic fibrosis have reduced skeletal muscle oxidative capacity, measured with near-infrared spectroscopy, compared with demographically matched control subjects? r What is the main finding and is its importance? Patients with cystic fibrosis have impairments in skeletal muscle oxidative capacity. This reduced skeletal muscle oxidative capacity not only appears to be accelerated by age, but it may also contribute to exercise intolerance in patients with cystic fibrosis.

Exercise intolerance predicts mortality in patients with cystic fibrosis (CF); however, the mechanisms have yet to be elucidated fully. Using near-infrared spectroscopy, in this study we compared skeletal muscle oxidative capacity in patients with CF versus healthy control subjects. Thirteen patients and 16 demographically matched control subjects participated in this study. Near-infrared spectroscopy was used to measure the recovery rate of oxygen consumption (musV˙ O2 max ) of the vastus lateralis muscle after 15 s of electrical stimulation (4 Hz) and subsequent repeated transient arterial occlusions. The musV˙ O2 max was reduced in patients with CF (1.82 ± 0.4 min−1 ) compared with control subjects (2.13 ± 0.5 min−1 , P = 0.04). A significant inverse relationship between age and musV˙ O2 max was observed in patients with CF (r = −0.676, P = 0.011) but not in control subjects (r = −0.291, P = 0.274). Patients with CF exhibit a reduction in skeletal muscle oxidative capacity compared with control subjects. It appears that the reduced skeletal muscle oxidative capacity is accelerated by age and could probably contribute to exercise intolerance in patients with CF. (Received 19 December 2014; accepted after revision 3 March 2015; first published online 11 March 2015) Corresponding author R. A. Harris: 1120 15th Street HS 1707, Georgia Regents University, Augusta, GA 30912, USA. Email: [email protected]

Introduction Cystic fibrosis (CF) is a genetic disease that affects multiple organ systems. There is currently no cure for CF, so increasing longevity and enhancing quality of life are important clinical goals (Williams et al. 2014). Exercise is a recommended tool that can be used to achieve these goals (Schneiderman et al. 2014). Exercise capacity has clinical appeal as a marker of health because peak oxygen

uptake (V˙ O2 peak ) has also been shown to predict mortality in patients with CF (Nixon et al. 1992). A common phenotype observed in CF is exercise intolerance (reduced V˙ O2 peak ; Pianosi et al. 2005), and this occurs even in patients with normal lung function (forced expiratory volume in 1 s; FEV1 ). Thus, there is a growing interest in understanding physiological responses to exercise in patients with CF.

C 2015 The Authors. Experimental Physiology C 2015 The Physiological Society

DOI: 10.1113/EP085037

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M. L. Erickson and others

Investigations of exercise intolerance have contributed to increase the interest in understanding the pathophysiology of the musculature. Patients with CF have been reported to have intrinsic skeletal muscle defects (Lamhonwah et al. 2010). Excessive muscle weakness is prevalent in patients with CF, thought to be caused by factors other than physical activity status (Troosters et al. 2009). Reductions in muscle force and strength, as well as differences in metabolism in female athletes have also been reported (Selvadurai et al. 2003). In addition, using culture studies, there has been a report of mitochondrial defects in patients with CF (Shapiro, 1989). Another study reported a reduction in mitochondrial function using the recovery rate of phosphocreatine measured by 31 P magnetic resonance spectroscopy (Wells et al. 2011). Near-infrared spectroscopy (NIRS) offers a novel way to assess skeletal muscle oxidative metabolism non-invasively. Near-infrared spectroscopy has several advantages over magnetic resonance spectroscopy and muscle biopsies due to greater accessibility, lower cost and the ability to conduct repeated measures with minimal burden to participants. Near-infrared spectroscopy has been used previously to measure skeletal muscle oxidative capacity in a variety of populations (Brizendine et al. 2013; Erickson et al. 2013; Ryan et al. 2014), and findings have been shown to be similar to those from magnetic resonance spectroscopy (Ryan et al. 2013). Accordingly, NIRS is a promising tool that can be applied to the CF population. The purpose of the present study was to evaluate skeletal muscle oxidative capacity using NIRS in patients with CF. It was hypothesized that patients with CF would have reduced skeletal muscle oxidative capacity when compared with demographically matched healthy control subjects. Methods Study design and participants

Employing a cross-sectional experimental design, skeletal muscle oxidative capacity was measured in 13 patients with CF (age range 7–42 years) and 16 demographically matched control subjects (age range 7–59 years). Data from seven matched control subjects have been published previously (Erickson et al. 2013). Patients with CF were instructed to adhere to the timing of their daily treatments and come to the laboratory following their morning airway clearance technique and inhaled medicines. Additionally, lung function and exercise capacity were determined only in patients with CF due to the experimental scope of this investigation. All NIRS testing and analyses were performed by the same investigator. Testing occurred in the Laboratory of Integrative Vascular and Exercise Physiology at Georgia Regents University and the Exercise Muscle Physiology Laboratory at the University of Georgia.

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Ethical approval

All study protocols conformed to the Declaration of Helsinki and were approved by the Human Assurance Committee at Georgia Regents University or by the Institutional Review Board at the University of Georgia. Written and verbal assent/consent was obtained from all subjects and parents prior to participation in this study. Experimental procedures Skeletal muscle oxidative capacity. Near-infrared spectroscopy was used to assess skeletal muscle oxidative capacity as described previously (Ryan et al. 2012). Both haemoglobin and myoglobin chromophores contribute to changes in the NIRS signals (Lutjemeier et al. 2008). Accordingly, the NIRS technique assumes that the signal changes are proportional to mitochondrial oxygen consumption due to relative changes in haemoglobin and myoglobin. Near-infrared spectroscopy testing was performed with the PORTAMON device (Artinis Medical Systems, The Netherlands), which is a portable, continuous-wave NIRS device. The PORTAMON consists of three channels with separation distances of 30, 35 and 40 mm. B-Mode ultrasound imaging (LOGIQ 7; GE HealthCare, USA) was used to measure adipose tissue thickness at the site of NIRS assessments to ensure that the NIRS penetration depth was deep enough to reach active skeletal muscle. Three consecutive recovery kinetics tests were conducted on the vastus lateralis with 15 s between each test. A rate constant (noted as the recovery rate of oxygen consumption; musV˙ O2 max ) was calculated and the mean of all three tests reported. For each recovery kinetics test, resting muscle metabolic rate was measured using three resting arterial occlusions (10 s in duration). The average of all three occlusions was reported. Figure 1 illustrates a representative trace of an oxygen recovery kinetics test in a patient with CF. The metabolic rate of the muscle was increased using 15 s of continuous electrical stimulation (4 Hz, highest tolerable current, pulse duration/interval = 200/50 μs), which has been used previously to activate mitochondrial oxygen consumption (Walter et al. 1997; McCully et al. 2011; Ryan et al. 2012). It is important to note that the musV˙ O2 max is not dependent on the frequency of electrical simulation (Ryan et al. 2012). Immediately after electrical stimulation, repeated short-duration arterial occlusions were used to assess changes in metabolic rate. The initial arterial occlusions (numbers one to four) were 5 s in duration followed by 5 s of rest. The subsequent occlusions (numbers five and six) were 10 s in duration followed by 10 s of rest, and the remaining occlusions (numbers seven to 15) were 10 s in duration followed by 20 s of rest. Near-infrared spectroscopy signals were corrected for blood volume C 2015 The Authors. Experimental Physiology C 2015 The Physiological Society

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Near-infrared spectroscopy in cystic fibrosis

shifts as described previously (Ryan et al. 2012). The rate of oxygen consumption during each arterial occlusion was calculated by linear regression, and the slope of this line was assumed to represent muscle oxygen consumption (mV˙ O2 ). Slopes from each measurement of mV˙ O2 were fitted to an exponential curve, and time constants were calculated using the following equation: y = End − × e−1/Tc For this equation, y represents relative mV˙ O2 during the arterial occlusion, End is the mV˙ O2 immediately after electrical stimulation, is the change in mV˙ O2 from rest to end exercise, and Tc is the fitting time constant. Matlab v. 7.13.0.564 (The Mathworks, Natick, MA, USA) was used to analyse all the NIRS signals. Once determined, time constants were converted to rate constants to represent skeletal muscle oxidative capacity using the following equation: k = 1 Tc × 60 For this equation, k represents rate constant, and Tc represents the time constant calculated from the exponential curve. A higher rate constant (k) is proportional to better muscle oxidative capacity and is reported here as musV˙ O2 max , analogous to Vmax reported for phosphocreatine rate constants (McCully et al. 2003). Conversely, a higher time constant (Tc) is inversely proportional to muscle oxidative capacity. Data are

reported as both musV˙ O2 max and time constants for convenience. For measurements of resting metabolic rate, a physiological calibration was used to normalize the NIRS signal for each subject’s complete NIRS test. This involved electrically stimulating the vastus lateralis for 15 s followed by a long (3–5 min) arterial cuff occlusion at 250–280 mmHg of pressure. The minimal oxygen levels during the long arterial cuff occlusion and maximal oxygen levels during reactive hyperaemia following cuff release were determined, and NIRS values obtained during each kinetics test were scaled within this range. Exercise testing. All patients with CF performed a maximal exercise test using the Godfrey protocol on an electronically braked cycle ergometer (Lode Corival or Lode Corival Pediatric, Groningen, The Netherlands), which maintains work rate (in watts) independent of the number of revolutions per minute. After a 1 min unloaded warm-up, exercise intensity started to increase 15–20 W depending on the height of the patient (Godfrey, 1974). Expired gases were analysed breath by breath by a TruOne 2400 metabolic cart (ParvoMedics, Sandy, UT, USA) and analysed as 30 s averages. In addition to reporting oxygen consumption controlling for body weight (in kilograms), oxygen uptake (V˙ O2 ) was normalized to fat-free mass (FFM), which helps to adjust for nutritional status in patients with CF (Gulmans et al. 1997). Peak oxygen consumption (V˙ O2 peak ) was verified using the American

Figure 1. Representative raw near-infrared spectroscopy (NIRS) data during a single recovery kinetics test conducted on a patient with cystic fibrosis Electrical stimulation (15 s, 4 Hz) was used to increase muscle metabolic rate, which was followed by a series of repeated arterial occlusions induced by a high-pressure cuff. The red signal represents oxyhaemoglobin (O2 Hb), the blue signal deoxyhaemoglobin (HHb) and the green signal total haemogloblin (tHb). Slopes of the NIRS signal during the repeated arterial occlusions were measured and fitted to an exponential curve. Rate constants, noted as musV˙ O2 max , were calculated to represent skeletal muscle oxidative capacity.


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College of Sports Medicine exercise testing criteria (ACSM, 2005), as follows: (i) volitional fatigue (>17 on the Borg rating of perceived exertion scale); (ii) a plateau in oxygen uptake; (iii) achieving 85% of predicted maximal heart rate; and (iv) a respiratory exchange ratio of > 1.1. A test was considered maximal effort if the patient met three of the four criteria. Tests that met fewer than three of the criteria were considered to be peak tests. Pulmonary function test. A pulmonary function test

using closed circuit spirometry (ParvoMedics, Sandy, UT) was performed in all patients with CF according to the American Thoracic Society standards (American Thoracic Society, 1995). Forced vital capacity (FVC), FEV1 and forced expiratory flow (FEF25–75 ) were determined. The National Health and Nutrition Examination Survey (NHANES) III spirometric reference standards were used to determine the percentage predicted data set. Statistical analysis

All analyses were performed using SPSS, version 19.0 (IBM, Armonk, NY, USA). Data are presented as means ± SD unless otherwise noted. Values of musV˙ O2 max were compared between CF patients and healthy control subjects using Student’s unpaired t test. Regression and partial correlation analyses were performed to identify relationships among musV˙ O2 max , lung function and exercise capacity. Significance was accepted when P < 0.05. Results Subject characteristics

Characteristics of patients and control subjects are presented in Table 1. No differences in age (in years), sex (male/female ratio), height (in centimetres), weight (in kilograms) or body mass index (in kilograms per square metre) were observed between patients and control subjects (all P > 0.05). The range in age was similar between patients with CF (7–42 years) and control subjects (7–59 years). In addition, vastus lateralis adipose tissue thickness was similar (P = 0.528) between patients and control subjects.

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CF compared with control subjects (1.8 ± 0.4 versus 2.1 ± 0.5 min−1 , respectively, P = 0.04). The musV˙ O2 max is proportional to skeletal muscle oxidative capacity, and time constants are inversely proportional to oxidative capacity. For convenience, values expressed as time constants are as follows: CF, 35.2 ± 8.0 s versus control, 29.9 ± 7.7 s (P = 0.04). Pulmonary function and exercise testing

Pulmonary function and V˙ O2 peak were determined only in patients with CF. Values for spirometric lung function in patients are as follows: FVC, 3.27 ± 0.95 l; FEV1 , 2.40 ± 0.74 ; FEV1 , 84.6 ± 22.1% predicted (range 54–123% predicted); FEV1 /FVC, 73.5 ± 9.1%; and FEF25–75 , 2.03 ± 0.97 l s−1 . Given that only 12 of 13 patients achieved a true maximal test, values are expressed as V˙ O2 peak . Values for exercise testing in CF patients are as follows: absolute V˙ O2 peak , 1.57 ± 0.62 l min−1 ; relative V˙ O2 peak , 30.6 ± 6.5 ml kg−1 min−1 ; V˙ O2 peak normalized to FFM, 43.3 ± 6.6 ml (kg FFM) −1 min−1 ; V˙ O2 , 78.2 ± 15.6% predicted; maximal heart rate, 166 ± 14 beats min−1 ; and peak work rate, 115 ± 49 W. Relationship between skeletal muscle oxidative capacity and age

Combining patients and control subjects, musV˙ O2 max was significantly greater (P = 0.021) in young (2.22 ± 0.49 min−1 , ages 7–17 years; n = 13) compared with old participants (1.81 ± 0.42 min−1 , ages > 18 years; n = 16). Figure 3 illustrates the relationship between musV˙ O2 max and age in patients with CF (Fig. 3A) and control subjects (Fig. 3B) separately. A significant inverse relationship between musV˙ O2 max and age was observed

Skeletal muscle oxidative capacity measured with NIRS

Resting skeletal muscle oxygen consumption was similar between groups (CF, −0.60 ± 0.3 min−1 versus control, −0.57 ± 0.59 min−1 , P = 0.422). Figure 2 displays musV˙ O2 max calculated from the recovery of oxygen consumption for patients with CF and control subjects. The musV˙ O2 max was significantly lower in patients with

Figure 2. Individual data and mean difference in the rate constant (musV˙ O2 max ) between patients with cystic fibrosis and healthy control subjects. ∗ Significant (P = 0.021) difference between groups. C 2015 The Authors. Experimental Physiology C 2015 The Physiological Society

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Table 1. Characteristics of patients with cystic fibrosis and control subjects Characteristic n Age (years) Sex (male/ female) Height (cm) Body weight (kg) Body mass index (kg m−2 ) Adipose tissue thickness (cm)

Cystic fibrosis patients

Control subjects

13 20.2 ± 11.2 6/7 154.8 ± 15.5 51.3 ± 15.9 20.9 ± 3.3 0.72 ± 0.27

16 21.6± 13 7/9 160.4 ± 18.1 54.6 ± 21.1 20.4 ± 4.4 0.80 ± 0.30

P Value — 0.750 0.901 0.382 0.643 0.732 0.528

Values are means ± SD.

in patients with CF (r = −0.676, P = 0.011), but this relationship was absent in control subjects (r = −0.291, P = 0.274).

Relationships between skeletal muscle oxidative capacity, lung function and V˙ O2 peak in CF

There was an inverse relationship between FVC (in litres) and musV˙ O2 max (r = −0.671, P = 0.012). The statistical value for the relationship between FEV1 (in litres) and musV˙ O2 max was r = −0.545, P = 0.054. There was no relationship between musV˙ O2 max and FEV1 as a percentage of predicted (r = 0.018, P = 0.953) observed in patients with CF. The partial correlation between musV˙ O2 max and V˙ O2 peak normalized for fat-free mass (expressed as millilitres per kilogram of FFM per minute) when controlling for age and sex was r = 0.602, P = 0.05. Discussion In this study, we identified that patients with CF exhibit an impairment in skeletal muscle oxidative capacity, measured with NIRS, in comparison to demographically matched control subjects. In addition, a significant inverse relationship between skeletal muscle oxidative capacity and age was observed in patients, but not in control subjects, indicating that muscle impairment may be accelerated by age in patients with CF. Exercise plays an important role in the assessment and treatment of patients with CF (Williams et al. 2014). The exercise intolerance that is observed in patients with CF has led to an increased interest in the pathophysiology of the musculature, and there are limited data to support skeletal muscle abnormalities in CF (Shapiro, 1989; Selvadurai et al. 2003; Lamhonwah et al. 2010). Skeletal muscle oxidative capacity in patients with CF

Figure 3. Association between musV˙ O2 max and age in patients with cystic fibrosis (CF; A) and healthy control subjects (HC; B) C 2015 The Authors. Experimental Physiology C 2015 The Physiological Society

Near-infrared spectroscopy is a non-invasive tool that has been used by our group and others to evaluate skeletal muscle oxidative capacity, an index of mitochondrial function, in different groups and patient cohorts (Brizendine et al. 2013; Erickson et al. 2013; Ryan et al. 2014). To our knowledge, this is the first study to document a deficit in skeletal muscle oxidative capacity, using NIRS, in patients with CF compared with control

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subjects (Fig. 2). The findings from the present study have identified a 15% reduction in skeletal muscle oxidative capacity in patients with CF compared with healthy demographically matched control subjects. The deficit we have observed using the NIRS methodology is similar to findings of a previous report of skeletal muscle metabolism in adolescents with CF (Wells et al. 2011). Using the rate of phosphocreatine resynthesis after exercise, Wells et al. (2011) documented a 19% lower mitochondrial capacity in patients with CF compared with control subjects. Although mean lung function appears to be preserved in patients with CF, the range in FEV1 was between 54 and 123% predicted. We did not observe a relationship between FEV1 (as a percentage of predicted) and musV˙ O2 max (r = 0.018, P = 0.953), which suggests that skeletal muscle oxidative capacity may be impaired even in patients with the highest lung function. Nonetheless, owing to the relatively small sample sizes of the two studies, additional investigations with larger patient cohorts are needed to classify further the magnitude of deficit of skeletal muscle oxidative exhibited in patients with CF. The present study identified a deficit in skeletal muscle oxidative capacity in patients with CF. Lung function was not assessed in control subjects; however, it is unlikely that any undiagnosed lung pathophysiology was present in our healthy comparator group. All control subjects reported to be apparently healthy and free of any overt cardiovascular, pulmonary or metabolic disease. The advantage of using the NIRS method for measuring skeletal muscle oxidative capacity, however, is that it does provide a quantifiable measure of in vivo muscle oxidative capacity that is not confounded by prior bouts of maximal exercise. In addition, the NIRS method compared with 31 P-magnetic resonance spectroscopy is inexpensive and non-invasive and can be repeated as often as necessary to investigate changes in muscle oxidative capacity over time (Wolf et al. 2007; Hamaoka et al. 2011; Ryan et al. 2013). It is important to accept that NIRS measurements of oxidative capacity cannot distinguish between a lower mitochondrial number and/or a decline in mitochondrial function. In addition, we have chosen to present the NIRS measurements as skeletal muscle oxidative capacity rather than skeletal muscle mitochondrial capacity to include the possibility that factors outside of mitochondria (such as intramuscular oxygen diffusion rates) may influence results. Thus, these data should be interpreted as an index of intact whole-tissue oxidative capacity. Further investigation of mitochondrial site-specific defects or impairments would require a more invasive technique. Use of the NIRS method is limited to investigation of limb muscles owing to the methodological involvement of arterial occlusion. Additionally, excessive adipose tissue thickness (>2 cm) will impede NIRS light penetration, which limits this

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method to non-obese populations. Nonetheless, it is reasonable to suspect that the presence of the cystic fibrosis transmembrane conductance regulator on the skeletal muscle (Fiedler et al. 1992) is contributing to impaired muscle oxidative capacity in CF, although future studies are warranted to investigate this phenomenon.

Age-associated changes in skeletal muscle oxidative capacity

A notable strength of the present study was the use of a cross-sectional approach to evaluate the impact that age has on skeletal muscle oxidative capacity in patients with CF. Age in CF is typically associated with disease severity and therefore represents another potential factor that may contribute to the skeletal muscle oxidative capacity deficit we observed in patients with CF. In the present study, no relationship between NIRS and FEV1 (as a percentage of predicted) was observed, probably due to relatively healthy cohort of patients and the preserved spirometric function. Additionally, the present study identified a significant inverse relationship between skeletal muscle oxidative capacity and age in the patients with CF that was not observed in the control subjects (Fig. 3). The control participants were selected to match the patients with CF, and therefore, it is plausible that a significant relationship in control subjects would have been observed in a cohort that included more older participants (i.e. between 50 and 70 years old). Moreover, it is likely that the significantly lower rate constant that was observed in older (1.81 ± 0.42 min−1 , ages > 18 years) compared with younger subjects (2.22 ± 0.49 min−1 , ages 7–17 years) overall was primarily driven by patients with CF. These data indicate that patients with CF experience an approximate 2.5% decline in skeletal muscle oxidative capacity per year that is not evident in healthy control subjects. To our knowledge, this is the first study to report an age-related decline in skeletal muscle oxidative capacity in CF. These data suggest that future investigations of skeletal muscle oxidative capacity should take age into account. The V˙ O2 peak reduces by 5–8% each year (Pianosi et al. 2005) in CF, so it is possible that the age-associated decline in muscle oxidative capacity in CF contributes to the accelerated decline in V˙ O2 peak . Controlling for age and sex, we observed an almost significant relationship (r = 0.602, P = 0.05) between V˙ O2 peak and skeletal muscle oxidative capacity (musV˙ O2 max ). However, the patient cohort tested in this study was relatively healthy, as evidenced by their lung function. It is possible that a stronger relationship between V˙ O2 peak and skeletal muscle oxidative capacity may be seen in CF patient cohorts with increased disease severity. Longitudinal studies will be needed to document patient-specific temporal changes further and determine what additional factors contribute C 2015 The Authors. Experimental Physiology C 2015 The Physiological Society

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to the age-related reductions in skeletal muscle oxidative capacity and V˙ O2 peak .

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In conclusion, this is the first study in which NIRS has been used to conduct a non-invasive recovery kinetics test for evaluation of skeletal muscle oxidative capacity in patients with CF. Findings from this study indicate that patients with CF exhibit a deficit in skeletal muscle oxidative capacity compared with demographically matched control subjects. Based on the present data, we propose that patients with CF experience an age-related reduction in skeletal muscle oxidative capacity. This may, in part, contribute to exercise intolerance in patients with CF. However, future research is needed to provide mechanistic insight into the impairment of skeletal muscle oxidative capacity and exercise capacity in CF.

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Additional information

Funding

Competing interests

This study was supported in part by the Georgia Regents University Child Health Discovery Institute (R.A.H.). R.A.H. is supported in part by the American Heart Association 10SDG3050006 and NIH/NIDDK (R21DK100783).

None declared. Author contributions M.L.E., K.K.M. and R.A.H. contributed to concept development and design; data analysis and interpretation; and drafting of the manuscript. N.S., R.A.H. and K.T.M. contributed to participant recruitment. M.L.E., N.S. and R.A.H. contributed to data collection. M.L.E., N.S., K.T.M., K.K.M. and R.A.H. reviewed and approved the final version of the manuscript.

Acknowledgements The authors thank all of the research participants for volunteering for this study. The authors would like to thank Valera Hudson, MD, Nicole Wimmer, RN, MSN, CPNP, Amy McKeen, RN, BSN and Dabney Edison, RRP for assistance in patient recruitment.
