Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis

Jinhee Jeong, Nicole Lee, Matthew Tucker, Paula Rodriguez Miguelez, Jacob Looney, Jeffrey Thomas, Casandra Derella, Ahmed Elmarakby, Jacqueline Musall, Jennifer Sullivan, Kathleen McKie, Caralee Forseen, Gareth Davison, Ryan Harrie

Research output: Contribution to journalArticle

Abstract

Cystic fibrosis (CF) is a genetic disorder associated with a wide range of systemic complications, including 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. Methods: 29 patients with CF (18 ± 8 yrs old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received either 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 were retested following a placebo (PLC, n=9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function before and 3 h after treatment. Results: Baseline FMD was lower in patients compared to controls. No change in FMD was observed following either PLC or BH4-5 (∆FMD: -0.8 ± 0.0% and -0.5 ± 2.5%; p=0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in a significant improvement in FMD (∆FMD: 1.1 ± 1.4%) when compared to BH4-5 (p=0.023) and PLC (p=0.017). Conclusion: These data suggest that a single oral dose of BH4 at 20 mg/kg can improve vascular endothelial function in patients with CF. These findings support the hypothesis that BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF.
LanguageEnglish
JournalJournal of Applied Physiology
Publication statusAccepted/In press - 7 Nov 2018

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Cystic Fibrosis
Dilatation
Blood Vessels
Nitric Oxide
Inborn Genetic Diseases
Brachial Artery
sapropterin
Biological Availability
Oral Administration
Placebos
Therapeutics

Cite this

Jeong, J., Lee, N., Tucker, M., Rodriguez Miguelez, P., Looney, J., Thomas, J., ... Harrie, R. (Accepted/In press). Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis. Journal of Applied Physiology.
Jeong, Jinhee ; Lee, Nicole ; Tucker, Matthew ; Rodriguez Miguelez, Paula ; Looney, Jacob ; Thomas, Jeffrey ; Derella, Casandra ; Elmarakby, Ahmed ; Musall, Jacqueline ; Sullivan, Jennifer ; McKie, Kathleen ; Forseen, Caralee ; Davison, Gareth ; Harrie, Ryan. / Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis. In: Journal of Applied Physiology. 2018.
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title = "Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis",
abstract = "Cystic fibrosis (CF) is a genetic disorder associated with a wide range of systemic complications, including 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. Methods: 29 patients with CF (18 ± 8 yrs old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received either 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 were retested following a placebo (PLC, n=9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function before and 3 h after treatment. Results: Baseline FMD was lower in patients compared to controls. No change in FMD was observed following either PLC or BH4-5 (∆FMD: -0.8 ± 0.0{\%} and -0.5 ± 2.5{\%}; p=0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in a significant improvement in FMD (∆FMD: 1.1 ± 1.4{\%}) when compared to BH4-5 (p=0.023) and PLC (p=0.017). Conclusion: These data suggest that a single oral dose of BH4 at 20 mg/kg can improve vascular endothelial function in patients with CF. These findings support the hypothesis that BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF.",
author = "Jinhee Jeong and Nicole Lee and Matthew Tucker and {Rodriguez Miguelez}, Paula and Jacob Looney and Jeffrey Thomas and Casandra Derella and Ahmed Elmarakby and Jacqueline Musall and Jennifer Sullivan and Kathleen McKie and Caralee Forseen and Gareth Davison and Ryan Harrie",
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Jeong, J, Lee, N, Tucker, M, Rodriguez Miguelez, P, Looney, J, Thomas, J, Derella, C, Elmarakby, A, Musall, J, Sullivan, J, McKie, K, Forseen, C, Davison, G & Harrie, R 2018, 'Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis', Journal of Applied Physiology.

Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis. / Jeong, Jinhee; Lee, Nicole; Tucker, Matthew; Rodriguez Miguelez, Paula ; Looney, Jacob; Thomas, Jeffrey; Derella, Casandra; Elmarakby, Ahmed; Musall, Jacqueline; Sullivan, Jennifer; McKie, Kathleen; Forseen, Caralee; Davison, Gareth; Harrie, Ryan.

In: Journal of Applied Physiology, 07.11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis

AU - Jeong, Jinhee

AU - Lee, Nicole

AU - Tucker, Matthew

AU - Rodriguez Miguelez, Paula

AU - Looney, Jacob

AU - Thomas, Jeffrey

AU - Derella, Casandra

AU - Elmarakby, Ahmed

AU - Musall, Jacqueline

AU - Sullivan, Jennifer

AU - McKie, Kathleen

AU - Forseen, Caralee

AU - Davison, Gareth

AU - Harrie, Ryan

PY - 2018/11/7

Y1 - 2018/11/7

N2 - Cystic fibrosis (CF) is a genetic disorder associated with a wide range of systemic complications, including 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. Methods: 29 patients with CF (18 ± 8 yrs old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received either 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 were retested following a placebo (PLC, n=9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function before and 3 h after treatment. Results: Baseline FMD was lower in patients compared to controls. No change in FMD was observed following either PLC or BH4-5 (∆FMD: -0.8 ± 0.0% and -0.5 ± 2.5%; p=0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in a significant improvement in FMD (∆FMD: 1.1 ± 1.4%) when compared to BH4-5 (p=0.023) and PLC (p=0.017). Conclusion: These data suggest that a single oral dose of BH4 at 20 mg/kg can improve vascular endothelial function in patients with CF. These findings support the hypothesis that BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF.

AB - Cystic fibrosis (CF) is a genetic disorder associated with a wide range of systemic complications, including 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. Methods: 29 patients with CF (18 ± 8 yrs old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received either 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 were retested following a placebo (PLC, n=9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function before and 3 h after treatment. Results: Baseline FMD was lower in patients compared to controls. No change in FMD was observed following either PLC or BH4-5 (∆FMD: -0.8 ± 0.0% and -0.5 ± 2.5%; p=0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in a significant improvement in FMD (∆FMD: 1.1 ± 1.4%) when compared to BH4-5 (p=0.023) and PLC (p=0.017). Conclusion: These data suggest that a single oral dose of BH4 at 20 mg/kg can improve vascular endothelial function in patients with CF. These findings support the hypothesis that BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF.

M3 - Article

JO - Journal of Applied Physiology

T2 - Journal of Applied Physiology

JF - Journal of Applied Physiology

SN - 0021-8987

ER -

Jeong J, Lee N, Tucker M, Rodriguez Miguelez P, Looney J, Thomas J et al. Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis. Journal of Applied Physiology. 2018 Nov 7.