Cystic Fibrosis and Endothelial Function: At Rest and During Exercise

Study Overview
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Brief Summary
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Perhaps one of the most disturbing aspects of Cystic Fibrosis (CF) is the associated premature death. Oxidative stress has been observed in patients with CF and exercise intolerance has been shown to predict mortality in patients with CF, regardless of how healthy their lungs are. A critical barrier to improving the quality of life and longevity in patients with CF is our lack of knowledge regarding the different reasons why patients with CF cannot exercise to the level of their peers. We have collected preliminary data to support our central hypothesis that oxidative stress contributes to the impairment in blood vessel function at rest and during exercise which ultimately oxygen transport and delivery resulting in exercise intolerance. Exercise is therapeutic medicine for patients with CF and this investigation represents a major breakthrough in the approach to begin understanding the physiological mechanisms which contribute to exercise intolerance in these patients.

Detailed Description
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The overall goals of this proposal are to provide mechanistic evidence that oxidative stress contributes to 1) endothelial dysfunction and 2) exercise intolerance in patients with CF. This study consists of two separate sub-studies, or protocols. Protocol 1: AOC tested the effect of an antioxidant cocktail (AOC) on endothelial function at rest and during exercise in CF patients. Protocol 2: BH4 tested the effect of tetrahydrobiopterin (BH4) on endothelial function at rest and during exercise in CF patients.

Official Title
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Influence of Cystic Fibrosis on Vascular Endothelial Function at Rest and During Exercise

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: BH4 5mg
* Drug: BH4 20mg
* Dietary Supplement: Antioxidant Cocktail


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of CF and healthy controls Men and women (> 18 yrs. old) Boys and girls (7 -17 yrs. old) FEV1 percent predicted > 30% Resting oxygen saturation (room air) >90% Patients with or without CFRD Traditional CF-treatment medications Ability to perform reliable/reproducible PFTs Clinically stable for 2 weeks (no exacerbations or need for antibiotic treatment within 2 weeks of testing or major change in medical status) Exclusion Criteria: Children 6 yrs. old and younger FEV1 percent predicted < 30% Resting oxygen saturation (room air) < 90% Clinical diagnosis of heart disease Pulmonary artery hypertension Febrile illness within two weeks of visit Current smokers Currently pregnant or nursing Individuals on vaso-active medications (i.e. nitrates, beta blockers, ACE inhibitors, etc.) Inability to swallow pills Patients with B. Cepacia (only  3% of our CF center patient population)

Ages Eligible for Study
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Minimum Age: 7 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Protocol 1: AOC<br>measurements at baseline and 2 hours following the antioxidant cocktail that is comprised of over the counter vitamins (vitamin C 1000mg, vitamin E 600 IU, and alpha lipoic acid 600 mg) that will be given in two doses, 30 minutes apart. | Dietary Supplement: Antioxidant Cocktail<br>* Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID<br>|
| Experimental: Protocol 2: BH4 (5mg)<br>measurements at baseline and 3 hours following the single dose of 5mg/kg Kuvan® or sapropterin dihydrochloride which is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4).BH4 has been shown in past studies to increase NO bioavailability. | Drug: BH4 5mg<br>* Kuvan® or sapropterin dihydrochloride is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Subjects received an oral dose of 5 mg/kg of Kuvan® (Biomarin Pharmaceuticals Inc.)<br>* Other names: Kuvan;|
| Experimental: Protocol 2: BH4 (20mg)<br>measurements at baseline and 3 hours following the single dose of 20mg/kg Kuvan® or sapropterin dihydrochloride which is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4).BH4 has been shown in past studies to increase NO bioavailability. | Drug: BH4 20mg<br>* Kuvan® or sapropterin dihydrochloride is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Subjects received an oral dose of 20 mg/kg of Kuvan® (Biomarin Pharmaceuticals Inc.)<br>* Other names: Kuvan;|
| No Intervention: Healthy Controls<br>baseline measurements were done with no intervention | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Flow-Mediated Dilation (FMD) | Brachial artery FMD induced by reactive hyperemia assessed vascular endothelial function at baseline and several hours after treatment. | pre-treatment Baseline and 2-3 hours post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CF, cystic fibrosis, exercise