Cystic Fibrosis and Endothelial Function: At Rest and During Exercise

Phase 2

Completed

Interventions: Drug: BH4 20mg
Dietary Supplement: Antioxidant Cocktail
Drug: BH4 5mg

Brief Summary: 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: 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.

Recruitment & Eligibility

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)

Arm && Interventions

Group	Intervention	Description
Protocol 2: BH4 (20mg)	BH4 20mg	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.
Protocol 1: AOC	Antioxidant Cocktail	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.
Protocol 2: BH4 (5mg)	BH4 5mg	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.

Primary Outcome Measures

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

Secondary Outcome Measures