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. Author manuscript; available in PMC: 2023 Jan 1.
Published in final edited form as: Nurs Res. 2022 Jan-Feb;71(1):75–82. doi: 10.1097/NNR.0000000000000554

Exercise Training and Cognitive Function in Kidney Disease: Protocol for a Pilot Randomized Controlled Trial

Ulf G Bronas 1, Mary Hannan 2, James P Lash 2, Olu Ajilore 2, Xiaohong Joe Zhou 2, Melissa Lamar 3
PMCID: PMC8732305  NIHMSID: NIHMS1739684  PMID: 34570042

Abstract

Background:

Chronic kidney disease (CKD) is extremely common in older adults and is associated with cognitive impairment. It is hypothesized that accelerated cognitive decline in CKD results from a vascular, dysfunction-induced reduction in the integrity of the brain white matter.

Objective:

To describe the protocol for a study to evaluate whether exercise training provides a cerebro-protective effect by improving cerebrovascular health.

Methods:

This is a randomized, controlled trial investigating feasibility and effect size.

Results:

Participants will be randomized to either a 24-week, home-based, walking program or a usual care group. Participants will undergo evaluation of cognitive function, brain structure via magnetic reasoning imaging, physical function, physical activity, and vascular function. The primary outcome is change in cognitive function.

Discussion:

The findings of this study will help determine whether exercise training influences cognitive function during a therapeutic window in the disease process of cognitive impairment in older adults with CKD.

Conclusion:

This protocol describes a study to evaluate cognition and brain structure following a home-based exercise program to an at-risk population.

Keywords: chronic renal insufficiency, cognition, exercise, protocol

Chronic kidney disease (CKD) affects more than 45% of individuals over 70 years of age; the prevalence is expected to increase due to the rising incidence of hypertension and diabetes in the general population (Coresh et al., 2007). Over 20% of individuals with moderate CKD have established cognitive impairment or overt dementia (Tollitt et al., 2020). Cognitive impairment in individuals with CKD can potentially lead to decreased ability to comply with medical care and loss of independence (Weiner & Seliger, 2014).

The etiology of accelerated cognitive decline in older adults with CKD is likely due in part to the CKD disease process itself, which creates a toxic vascular milieu that consists of chronic inflammation, oxidative stress, uremia, and systemic vascular endothelial dysfunction (Bronas et al., 2017a). This toxic internal environment is believed to result in impairment of the white matter, superimposed on age-related neurodegenerative damage (Bugnicourt et al., 2013). In fact, compromised white matter integrity appears to be a primary contributor to the cognitive decline found in patients with CKD (Sedaghat et al., 2015). Exercise and higher fitness levels in the general population have been associated with improved brain structure and function, suggesting a possible cerebro-protective effect (Erickson et al., 2011; Hayes et al., 2014); the effect of exercise training on cognitive function and white matter integrity in individuals with CKD is unknown.

There is no recommended treatment to prevent cognitive decline in patients with kidney disease, and the few medications available for cognitive impairment have only modest effects (Yiannopoulou et al., 2019). There is a critical need to evaluate therapies to forestall cognitive impairment and maintain or improve cognitive function in older adults with CKD. This paper aims to report the study protocol of a randomized controlled trial for feasibility and preliminary effect size of a 6-month exercise training program to maintain or improve cognitive function in older adults with subjective cognitive complaint and CKD.

Methods

Study Aims and Hypotheses

The specific aims and hypotheses of the study are to:

  • Aim 1: Determine the feasibility and preliminary efficacy of a 6-month, home-based exercise program to improve or maintain cognitive function in older adults with moderate to severe CKD and subjective cognitive complaint, compared to the usual care control group.

  • Hypotheses: Participants in the exercise group, compared to the usual care control group, at 6 months will:
    • H1a. Demonstrate a higher score on composite global cognitive functioning.
    • H1b. Demonstrate higher scores on executive functioning, learning and memory, and attention and information processing.

  • Aim 2: Determine the cerebro-protective effect of a 6-month exercise program compared to usual care on white matter integrity as quantified by Diffusion Tensor Imaging (DTI)-derived magnetic reasoning imaging (MRI) measures of mean diffusivity (MD) and fractional anisotropy (FA).

  • Hypothesis 2. Participants in the exercise group will demonstrate an improvement in white matter integrity measured by DTI, i.e., higher FA, compared to the control group.

  • Aim 3: Determine the cerebro-protective effect of a 6-month exercise program compared to usual care on hippocampal volume and cerebral blood flow.

  • Hypothesis: Participants in the exercise group will have a larger hippocampal volume and improved cerebral blood flow post-6-month intervention, compared to the control group.

Design, Setting, and Sample

Our intervention is grounded in the Health Belief Model and Social Learning Theory, which posits that a health care intervention is more likely to influence behavior change if it includes the following components in its implementation: knowledge, self-efficacy, ability/skills, and environment (Rosenstock et al., 1988). We believe that our intervention program incorporates all of these elements and guides the study toward successful behavior change. The study is designed as a randomized, controlled trial investigating feasibility and effect size (Supplemental Digital content). There will be two groups; participants will be randomized to a 24-week walking program or a usual care group. Thirty-four older adults with moderate to severe CKD (defined as an estimated glomerular filtration rate [eGFR]) < 60ml/min/1.73m2-15 ml/min/1.73m2) will be enrolled in the 24-week program: 17 in the moderate-intensity walking exercise group and 17 in the usual care group. The study population is community-dwelling men and women with CKD, between 60 and 80 years of age, with preclinical cognitive impairment (Jessen et al., 2014). Subjective cognitive complaint will be defined as a participant answering affirmatively to the question, “Do you feel like your memory or thinking skills have gotten worse recently?” The inclusion and exclusion criteria for the study sample are detailed in Table 1. An eligibility checklist will be completed prior to any study participation during the initial phone screen and during the initial visit.

Table 1.

Inclusion and Exclusion Criteria

Inclusion Criteria (self-reported or ICD code) Exclusion Criteria (self-reported or ICD code)
 a) English speaking men and women  a) Current or past diagnosis of neurological or psychiatric disorders
 b) No history of major head trauma  b) Pregnancy
 c) 60–80 years of age  c) Diagnosed dementia or a score of ≤2 on the mini-cog assessment
 d) Subjective cognitive complaint (answering “yes” to the question: “Do you feel like your memory or thinking skills have gotten worse recently?”  d) Ischemic ulcerations or gangrene on the feet or legs
 e) Participating in a supervised exercise program with intent to increase fitness levels 3 days/week
 f) Requires assistive ambulation
 g) Limited exercise capacity due to:
  • unstable angina,
  • claudication
  • severe arthritis,
  • extreme dyspnea on exertion,
  • unstable coronary artery disease;
  • Class III-IV heart failure;
  • current uncontrolled sustained arrhythmias,
  • severe/symptomatic aortic or mitral stenosis,
  • hypertrophic obstructive cardiomyopathy,
  • severe pulmonary hypertension,
  • active myocarditis/pericarditis,
  • thrombophlebitis,
  • recent systemic/pulmonary embolus (within 3 months)
 h) Resting systolic blood pressure >200 mmHg or resting diastolic blood pressure >110 mmHg
 i) Revascularization procedures within the previous 6 months
 j) Any unforeseen illness or disability that would preclude exercise testing or training based on patient provider opinion
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Note. ICD = International Classification of Diseases

This is a pilot study to determine feasibility and preliminary effect size. It is expected that the data will be utilized to assess effect size and the necessary sample size to detect significant differences between groups. A sample size of 12/group is recommended for pilot studies estimating the mean and variability of continuous outcomes (Moore et al., 2011). The sample size is therefore based on a total sample of 24. We will oversample by 10 participants to ensure that we end the study with an n of 24 or greater. With this in mind, it is anticipated that 17 participants will be randomized to a 6-month, home-based exercise program and 17 participants randomized to the usual care control group. The study was reviewed and approved by the University of Illinois Chicago Institutional Review Board, and the study has been registered at Clinical Trials.gov (NCT# 03197038).

Intervention

The randomization will take place following all baseline testing procedures. Each participant will be assigned by chance to either intervention or control by a computer randomized numbers table with a 1:1 chance of being assigned to the walking group over the usual care group. Variable block randomization of 2 and 4 will be utilized. Participants cannot choose their group assignment. Allocation will be concealed from all investigators except for the statistician and the study research staff. The MRI technicians and the person analyzing imaging data will be blinded to group assignment.

Using a similar method previously conducted by the Claudication: Exercise vs Endoluminal Revascularization (CLEVER) study (Bronas et al., 2009), the exercise training group will participate in an educational session on walking exercise for CKD, receive a packet of information previously developed by the principal investigator (PI) with exercise prescription, and receive a heart rate monitor. The research team will work with the participant to: (a) set up a walking schedule that fits with their personal schedule; (b) identify timeslots for exercise; (c) work with the participants to assess their readiness to do exercise; (d) address perceived barriers to exercise; and (e) build a relationship with the participants to provide support and address concerns. Participants will be given an exercise prescription for walking at home at a moderate intensity (rating of perceived exertion scale of 11–13) at a dose of three times per week for 20–60 min for 24 weeks. Participants will be called biweekly or more frequently if they are not adhering to the exercise routine; they will meet with the research team monthly to provide encouragement, instruct them on the exercise program’s progression, and download the heart rate monitor. We elected a 6-month pilot study as we consider this the minimum to detect change in cognitive function (primary endpoint) as reported by Northey et al. (2018). The use of exercise three times or more per week was elected to achieve 150 min of exercise, which is in the middle of the range provided by Erikson et al. (2019; range 93–214 min per week) for improvement in cognitive function (primary endpoint). Participants will be allowed to exercise more. Therefore, we will be able to gauge a possible dose-response relationship, albeit the study is not designed to assess a dose-response relationship.

The usual care group will receive instructions on exercise for patients with CKD, per usual clinical care. Participants in the usual care group will be contacted via phone biweekly to answer any questions and assess for adverse events. Still, they will not meet with the research team monthly. To minimize feelings of disenfranchisement, participants in the control group will be offered the exercise training prescription following all post-test data collection. It is possible that the monthly meeting with the intervention group provides additional attention that could affect the outcomes. For this pilot study, it is not feasible to conduct monthly meetings for attention control. In future large-scale trials, it would be preferred to include an attention control group.

Study Procedure

Recruitment, Screening, and Enrollment

This study recruits in Midwestern states of the United States within a 100-mile radius of Chicago, Illinois. Subjects will be recruited through flyers and recruitment brochures in Chicago and surrounding communities, at outpatient clinics, and via invitation letters. The University of Illinois Chicago medical center’s electronic medical records database and the University of Illinois Chicago Clinical Research Data Warehouse (CRDW) will also be employed to identify potential patients who have a diagnosis of CKD, following HIPPA standards of authorization.

Patients who have a diagnosis code or meet criteria for CKD will be sent a letter mentioning that they might be eligible for a research study. Patients who have expressed an interest in the study to their provider at University of Illinois Chicago Hospital clinics will be approached. Media advertisements will be posted on media sites. Recruitment for the study also utilized ResearchMatch (https://www.researchmatch.org); it is a national health volunteer registry that was created by several academic institutions and supported by the U.S. National Institutes of Health as part of the Clinical Translational Science Award (CTSA) program. Respondents to the recruitment will be screened via phone interview. Following phone screening, interested participants will be scheduled for the first visit, where written informed consent will be obtained.

Data Collection

Enrolled participants will complete data collection of all measures at baseline and the 24-week study completion. The Charlson comorbidity index questionnaire will be administered to collect data on medical history. Participants will complete several questionnaires to assess cognitive function (Table 2). The California Verbal Learning Test Second Edition (CVLT–II) is a 16-item list learning and memory test that assesses free and cued recall and recognition (Delis et al., 2000). The Trails Making Test (TMT) Part A is a timed test of connecting a sequence in numerical order (Giovagnoli et al., 1996), while Part B is a timed test of completing an ascending number-letter sequence (Army Individual Test Battery, 1944). The Digit Symbol Substitution Test (DSST) evaluates the processing speed at which symbols are placed next to corresponding numbers (Wechsler, 1997). Fluency tests assess executive functions, including mental flexibility, maintenance of mental set, and self-monitoring by asking a participant to name words beginning with a particular letter or belonging to a specific category (Spreen & Strauss, 1998). The Digit Span (DSP) test evaluates the ability of a participant to repeat back number sequences (i.e., repeating numbers back in forward order and reverse order; Wechsler, 1997). The Montreal Cognitive Assessment (MoCA) is a test of global cognition (Nasreddine et al., 2005). The Wechsler test of adult reading (WTAR; Wechsler, 2001) evaluates correct word pronunciation and is often seen as a measure of educational quality as opposed to quantity/years (Manly et al., 2002).

Table 2.

Cognitive Function Domains, Tests, and Associated Outcome Variables

Domain Tests Outcome variables
Learning & Memory CVLT-II (Delis et al., 2000) CVLT-II: Trials1–5 and learning slope; Long Delay Free Recall and Recognition Memory Discriminability
Attention/Information Processing TMT-A (Army Individual Test Battery, 1944); DSST (Wechsler, 1997) TMT-A time to completion and errors; DSST time to completion and errors
Executive Functioning Phonemic and Semantic Fluency (Spreen & Strauss, 1998); TMT-B; DSp (Wechsler, 1997) Total correct words produced for Phonemic and Semantic fluency separately; TMT-B time to completion and errors; DSp total score
Global Cognition MoCA (Nasreddine et al., 2005); WTAR (Wechsler, 2001) Total MOCA score; WTAR Estimated verbal IQ
*WTAR will only be given once as premorbid IQ is not anticipated to change with intervention
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Note. Abbreviations: CVLT-II = California Verbal Learning Test-II; DSp = Digit Span subtest; DSST = Digit Symbol Substitution Test; MoCA = Montreal Cognitive Assessment; TMT-A = Trail Making Test Part A; TMT-B = Trail Making Test Part B; WTAR = Wechsler Test of Adult Reading

After the cognitive function testing, a standard venipuncture will be done for a complete blood cell count and basic metabolic panel. The participants will then perform the short physical performance battery (SPPB) to assess physical function (Guralnik et al., 1994). The six-minute walk test (6–MWT), which is an indicator of functional capacity, following standard testing procedures for older adults, will also be assessed to determine total walking distance (ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories, 2002). The 6–MWT is considered sensitive to detect change in submaximal physical fitness in deconditioned older adults. Although a maximal treadmill test with respiratory gas exchange measures would have been a more rigorous assessment of fitness levels, the addition of a maximal treadmill test would place additional burden on the participants, which was deemed not necessary for this pilot study. Moreover, a clinically meaningful change in the 6-MWT has been defined for older people (Perera et al., 2006). It is correlated with peak oxygen consumption in patients with cognitive impairment (Bronas et al., 2017b). The test–retest reliability for the 6–MWT conducted 1 week apart is .96 with a coefficient of variation of 2.99% (Bronas et al., 2019). Upon completion of the baseline visit, the participant will wear a physical activity monitor (Actigraph GXT3) on their hip for 1 week to determine free-living physical activity (Byrom & Rowe, 2016). Three days of actigraphy measures are considered the minimum requirement for daily physical activity assessment in older adults (Hart et al., 2011). For this pilot study, we have elected to use a 7-day measure of actigraphy that includes weekdays and one weekend. We selected this time frame as the minimum number of days required to assess daily physical activity levels while minimizing participant burden. Participants will wear the sensor for 7 days at baseline, 6, 12, 18, and 24 weeks.

Participants will undergo MRI performed on a GE 3T MRI research dedicated scanner (Discovery MR 750) using a 32-channel, phased-array coil. After a brief scout image for localization, we will acquire whole-brain images using diffusion tensor imaging, diffusion tensor imaging (DTI); T1- and T2-weighted imaging for whole brain and specific white matter tracts; and arterial spin labeling (ASL), functional MRI (fMRI), and high-resolution 3D T1-weighted imaging to obtain indices of alterations of brain interconnections, structure, and function that are associated with cognitive function (Table 3). Change in MRI measures will be assessed as change at 6-months from baseline in global white matter integrity (fractional anisotropy and median diffusivity) averaged across 80 tracts, global connectivity averaged across 132 regions, left and right hippocampal volume adjusted for intracranial volume, and global cerebral blood flow in ml/100mg/min.

Table 3.

Imaging Parameters

Technique Purpose Parameters (TE=echo time; TR=repetition time; BW=bandwidth; FOV=field of view; TI=inversion time)
DTI White matter integrity (fractional anisotropy and mean diffusivity) quantification Single-shot EPI with parallel imaging using a 32- channel phased-array head coil; axial; TE/TR∼70/5525ms, b-values 0,1000s/mm2, 33 directions, FOV=20cm2, matrix = 160×160, NEX = 2, acceleration factor = 2, 6 B0 images, slice thickness = 3 mm
T1/BRAVO Hippocampal Volume Quantification Coronal; TE/TR = 5.2/12.8 ms, TI=450, Flip=13°, 1.5mm slice thickness, no gap, BW=±25kHz, FOV=22cm2
T2-FLAIR White matter hyperintensity quantification Coronal; TE/TR=104.5/9500ms, TI=2.5sec, FOV 22cm2
ASL Cerebrovascular perfusion
Cerebral blood flow		 axial; Spiral-FSE acquisition; post-label delay time = 1.8 sec, TE/TR=minimum, flip angle=90°, slice thickness = 3–5 mm, matrix size = 128×128, FOV 22cm2
Resting-state fMRI Resting state networks Subjects will be instructed to keep their eyes open, focus on a fixation point, and “not think of anything in particular”. Resting-state data will be acquired: total scan time = 8 minutes
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Note. ASL = arterial spin labeling; BW = bandwidth; DTI = diffusion tensor imaging; EPI = echo planar; fMRI = functional magnetic resonance imaging; FOV = field of view; FSE = fast spin echo; NEX = number of excitations; T1 = T1-weighted; T2 = T2-weighted; TE/TR = echo time/repetition time; TI = inversion time

Participants will also undergo assessment of vascular health indices, which will be done in the morning after an overnight fast. All measurements will be taken in the same dark, quiet, and stable temperature room after the participant rests for 15 min in a supine position (Townsend et al., 2015). Carotid femoral pulse wave velocity (cfPWV) will be measured using the Sphygmacor XCEL (AtCor Medical, West Ryde, Australia). Three measures will be obtained and averaged. Any measure will be removed if it differs by more than 0.5 m/s from the other measures (Townsend et al., 2015). Carotid compliance will be evaluated with Telemed ultrasound with a 10 MHz resolution HL9.0/40/128Z. We will take and average three measurements during the diastole of three different cardiac cycles at the carotid near wall (Laurent & Boutouyrie, 2015). The carotid intima-media thickness and artery diameter will be measured to calculate vascular compliance (Laurent & Boutouyrie, 2015; O’Rourke & Safar, 2005). Brachial artery flow-mediated dilation (FMD; Cohn et al., 2009) will be assessed with 10 MHz resolution Telemed (Telemed, Vilnius, LT-03154, Lithuania) ultrasound HL9.0/40/128Z at an insonation angle of 60 degrees with the cuff placed distal to the probe for an inflation time of 5 min (Thijssen et al., 2011). Artery diameter will be caliper measured three times and averaged at the exact location during systole of three cardiac cycles, and FMD will be calculated as relative change. All vascular measurements will be evaluated by a second researcher blinded to the group.

Follow-up testing will occur at 24 weeks. Participants will again perform cognitive function tests using alternative forms to reduce practice effects (Table 2), the 6–MWT, the SPPB, MRI procedures (Table 3), and the vascular health indices. Emerging health conditions or declining kidney function (complete blood cell count and basic metabolic panel) will be captured during the study period. Participants will also be queried using structured interviews and open-ended questions to assess study satisfaction. Free-living physical activity will again be measured via actigraphy (Actigraph GTX3) at 24-week follow-up.

Variables

Cognitive outcomes and the associated domains of functioning (Table 2) will be evaluated pre- and postintervention. At baseline and follow-up, participants will have MRI performed (Table 3) to obtain images using diffusion tensor imaging, DTI; T1- and T2-weighted imaging; and arterial spin labeling (ASL; Table 3). For the image analyses of DTI, we will quantify fractional anisotropy, axial (AD), radial (RD), and mean diffusion (MD) using DSI studio for whole brain and specific white matter tracts. For the T1/FSPGR, we will extract hippocampal volumes (right and left) and subfields of the hippocampus adjusted for intracranial volume using FreeSurfer 6.0. For the T2–FLAIR, we will quantify white matter hyperintensity volumes across the entire brain white matter using the FSL BIANCA package (Sundaresan et al., 2019). We will use a seed-based approach to measure resting-state networks of interest. Functional brain networks will be generated using the resting-state fMRI toolbox CONN (http://www.nitrc.org/projects/conn; Whitfield-Gabrieli & Nieto-Castanon, 2012). In brief, raw echo planar imaging (EPI )images are realigned, coregistered, normalized, and smoothed before analysis. Any confounding effects from motion artifact, white matter, and CSF are regressed out of the signal. Functional brain networks will be derived using pairwise blood oxygenation level dependent (BOLD) signal correlations using the same label maps as the structural brain networks. For the vascular indices, effective vascular compliance will be assessed via carotid-femoral pulse wave velocity, carotid compliance measurements, and flow-mediated dilation, following standard procedures. Possible covariates that will be captured and assessed for influence on outcomes include exercise adherence, education, premorbid IQ via WTAR, medical conditions via the Charlson comorbidity questionnaire, age, race, and sex. It is expected that randomization will minimize group differences. Covariates shown to not influence the outcomes will be excluded from analyses.

Statistical Analysis

The a priori analysis will be utilized to analyze this pilot study for feasibility and determination of effect size. Descriptive statistics will be used for these data, including means, standard deviations, interquartile ranges, frequencies, and percentages to demonstrate the feasibility of recruitment, adherence, and retention (Schoenfeld, 1980). The statistical approach for hypothesis testing and determination of effect size will be Generalized Linear Mixed Models (GLMM) with an identity link function for a continuous outcome or a logit link function for a binary outcome. GLMM is a more advanced version of repeated measures analysis of variance (ANOVA) that can account for potential correlation among multiple measurements over time while having flexibility in fitting outcomes with different distributions. One advantage of this approach over repeated measures ANOVA is that there is no assumption that participants are measured at every, or even the same, time points. Therefore, these models are very flexible in handling missing data. Participants who have a missing observation are not excluded; thus, this produces the intention to treat (ITT) full information maximum likelihood (FIML) model.

Discussion

This trial was designed with the consideration of many factors unique to individuals with CKD. We are focusing on patients with subjective cognitive complaints to capture a therapeutic window in the disease process. To date, there has been limited investigation of older adults with CKD and the role that exercise training may play in brain structure and function. Our study is also uniquely anticipating an enrollment of more than 50% Black individuals and more than 50% women. This will allow for discernment of trends in potential sex differences, and moderation analyses will be conducted to investigate differences related to age, sex, and race. We expect to find trends in these important aspects of research that will inform future larger trials. Although blinding of the research assistants would have been preferred, we will not be able to do this due to the nature of this pilot study. To minimize potential bias, we will use alternative forms for assessment of cognitive function at follow-up; we will use a single site design and utilize several strategies, including standardized protocols, operation manuals, case report forms, and training to achieve an acceptable test–retest reliability. We are further conducting consistency checks and treatment fidelity checks. Moreover, the MRI assessors and study statisticians are blinded to group assignment. We uniquely plan on investigating cognitive subdomains rather than multidomains, which will add significantly to what is known about cognitive function in older adults with CKD. We expect to see executive function to be primarily affected in the CKD population, so it is the primary focus of our analyses.

Conclusion

This study, if successful, will provide the initial step in providing an effective treatment designed to delay cognitive function-related loss of independence and curb the escalating costs of care for the growing CKD population that experiences accelerated brain aging and a high prevalence of cognitive impairment, providing potential clinical importance.

Supplementary Material

Supplemental Data File (doc, pdf, etc.)

Acknowledgments

Dr. Bronas and the parent study were supported by National Institutes of Health’s (NIH) National Institute on Aging (NIA) NIH–NIA, P30AG022849-15S1, and NIH–NIA P30AG022849. The project described was supported by the National Center for Advancing Translational Sciences, NIH, through Grant UL1TR002003. The content is solely the authors’ responsibility and does not necessarily represent the official views of the NIH.

Dr. Hannan reports grants from Robert Wood Johnson Foundation–Future of Nursing Scholar Postdoctoral Fellow and a grant from NHLBI T32 T32HL134634. The views expressed here do not necessarily reflect the views of the foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Institutional review board (IRB) approval was obtained at the University of Illinois of Chicago (IRB #2016-1217). Written informed consent is obtained from all participants of the study.

Footnotes

The authors have no conflicts of interest to report.

Clinical Trials registered (#NCT03197038).

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