Thomas Radtke1, Helge Hebestreit2, Sabina Gallati3, Jane E Schneiderman4, Julia Braun5, Daniel Stevens6, Erik Hj Hulzebos7, Tim Takken8, Steven R Boas9, Don S Urquhart10, Larry C Lands11, Sergio Tejero12, Aleksandar Sovtic13, Tiffany Dwyer14, Milos Petrovic15, Ryan A Harris16, Chantal Karila17, Daniela Savi18, Jakob Usemann19, Meir Mei-Zahav20, Elpis Hatziagorou21, Felix Ratjen22, Susi Kriemler23. 1. University of Zurich, Epidemiology, Biostatistics and Prevention Institute , Hirschengraben84 , Zurich, Zurich, Switzerland ; thomas.radtke@uzh.ch. 2. University Hospitals Würzburg, Würzburg, Germany ; hebestreit@uni-wuerzburg.de. 3. Inselspital, University of Berne, Division of Human Genetics, Department of Pediatrics, and Department of Clinical Research, Berne, Switzerland ; Sabina.GallatiKraemer@insel.ch. 4. Hospital for Sick Children, 7979, Toronto, Ontario, Canada ; jane.schneiderman@sickkids.ca. 5. University of Zurich, Zurich, Switzerland ; julia.braun-gruebel@uzh.ch. 6. Dalhousie University, 3688, Halifax, Nova Scotia, Canada ; D.Stevens@Dal.Ca. 7. University Medical Center Utrecht, Utrecht, Netherlands ; H.Hulzebos@umcutrecht.nl. 8. UMC Utrecht, Utrecht, Netherlands ; t.takken@umcutrecht.nl. 9. Northwestern University Feinberg School of Medicine, 12244, Pediatric Pulmonology , 2401 Ravine Way, #302 , Glenview, Illinois, United States , 60025 ; sboas@wecare4lungs.com. 10. Royal Hospital for Sick Children, Edinburgh, United Kingdom of Great Britain and Northern Ireland ; don.urquhart@nhslothian.scot.nhs.uk. 11. Montreal Children's Hospital, Respiratory Medicine , Respiratory Medicine , Room D380, 2300 Tupper St. , Montreal, Quebec, Canada , H3H 1P3 ; larry.lands@muhc.mcgill.ca. 12. Virgen del Rocio University Hospital, Sevilla, Spain ; tejerogarciasergio@gmail.com. 13. University of Belgrade, Belgrade, Serbia ; asovtic@eunet.rs. 14. University of Sydney, Sydney, Australia ; tiffany.dwyer@sydney.edu.au. 15. Krankenhaus Hietzing mit Neurologischem Zentrum Rosenhugel Abteilung fur Atmungs- und Lungenerkrankungen, 422681, Wien, Wien, Austria ; milos.petrovic@wienkav.at. 16. Augusta University, 1421, Augusta, Georgia, United States ; RYHARRIS@augusta.edu. 17. Universite Paris Descartes Faculte de Medecine, 72790, Paris, Île-de-France, France ; chantal.karila@aphp.fr. 18. "Sapienza" University of Rome, Department of Pediatrics and Pediatric Neurology, Cystic Fibrosis Center , Viale Regina Elena, 324 , Rome, Italy , 00185 ; danielasavi1@virgilio.it. 19. University Children's Hospital (UKBB), University of Basel, Basel, Switzerland ; Jakob.Usemann@ukbb.ch. 20. Tel Aviv University, 26745, Tel Aviv, Israel ; mmeizahav@gmail.com. 21. Aristotle University of Thessaloniki, Thessaloniki, Greece ; elpcon@otenet.gr. 22. University of Toronto HSC, Division of Respiratory Medicine , Hospital for Sick Children , 555 University Avenue , Toronto, Ontario, Canada , M5G 1X8 ; felix.ratjen@sickkids.ca. 23. University of Zurich, Zurich, Switzerland ; susi.kriemlerwiget@uzh.ch.
Abstract
RATIONALE: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTR dysfunction among patients with cystic fibrosis may be an important determinant of maximal exercise capacity in cystic fibrosis. Previous studies on the relationship between CFTR genotype and maximal exercise capacity are scarce and contradictory. OBJECTIVES: This study was designed to explore factors influencing maximal exercise capacity, expressed as peak oxygen uptake (V.O2peak), with a specific focus on CFTR genotype in children and adults with cystic fibrosis. METHODS: In an international, multicenter, cross-sectional study, we collected data on CFTR genotype and cardiopulmonary exercise tests in patients with cystic fibrosis who were ages 8 years and older. CFTR mutations were classified into functional classes I–V. RESULTS: The final analysis included 726 patients (45% females; age range, 8–61 yr; forced expiratory volume in 1 s, 16 to 123% predicted) from 17 cystic fibrosis centers in North America, Europe, Australia, and Asia, all of whom had both valid maximal cardiopulmonary exercise tests and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (V.O2peak, 77.3 ± 19.1% predicted), but values were comparable among different CFTR classes. We did not detect an association between CFTR genotype functional classes I–III and either V.O2peak (percent predicted) (adjusted β = −0.95; 95% CI, −4.18 to 2.29; P = 0.57) or maximum work rate (Wattmax) (adjusted β = −1.38; 95% CI, −5.04 to 2.27; P = 0.46) compared with classes IV–V. Those with at least one copy of a F508del-CFTR mutation and one copy of a class V mutation had a significantly lower V.O2peak (β = −8.24%; 95% CI, −14.53 to −2.99; P = 0.003) and lower Wattmax (adjusted β = −7.59%; 95% CI, −14.21 to −0.95; P = 0.025) than those with two copies of a class II mutation. On the basis of linear regression analysis adjusted for relevant confounders, lung function and body mass index were associated with V.O2peak. CONCLUSIONS: CFTR functional genotype class was not associated with maximal exercise capacity in patients with cystic fibrosis overall, but those with at least one copy of a F508del-CFTR mutation and a single class V mutation had lower maximal exercise capacity.
RATIONALE: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTRdysfunction among patients with cystic fibrosis may be an important determinant of maximal exercise capacity in cystic fibrosis. Previous studies on the relationship between CFTR genotype and maximal exercise capacity are scarce and contradictory. OBJECTIVES: This study was designed to explore factors influencing maximal exercise capacity, expressed as peak oxygen uptake (V.O2peak), with a specific focus on CFTR genotype in children and adults with cystic fibrosis. METHODS: In an international, multicenter, cross-sectional study, we collected data on CFTR genotype and cardiopulmonary exercise tests in patients with cystic fibrosis who were ages 8 years and older. CFTR mutations were classified into functional classes I–V. RESULTS: The final analysis included 726 patients (45% females; age range, 8–61 yr; forced expiratory volume in 1 s, 16 to 123% predicted) from 17 cystic fibrosis centers in North America, Europe, Australia, and Asia, all of whom had both valid maximal cardiopulmonary exercise tests and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (V.O2peak, 77.3 ± 19.1% predicted), but values were comparable among different CFTR classes. We did not detect an association between CFTR genotype functional classes I–III and either V.O2peak (percent predicted) (adjusted β = −0.95; 95% CI, −4.18 to 2.29; P = 0.57) or maximum work rate (Wattmax) (adjusted β = −1.38; 95% CI, −5.04 to 2.27; P = 0.46) compared with classes IV–V. Those with at least one copy of a F508del-CFTR mutation and one copy of a class V mutation had a significantly lower V.O2peak (β = −8.24%; 95% CI, −14.53 to −2.99; P = 0.003) and lower Wattmax (adjusted β = −7.59%; 95% CI, −14.21 to −0.95; P = 0.025) than those with two copies of a class II mutation. On the basis of linear regression analysis adjusted for relevant confounders, lung function and body mass index were associated with V.O2peak. CONCLUSIONS:CFTR functional genotype class was not associated with maximal exercise capacity in patients with cystic fibrosis overall, but those with at least one copy of a F508del-CFTR mutation and a single class V mutation had lower maximal exercise capacity.
Authors: Alexander L Bisch; Courtney M Wheatley; Sarah E Baker; Elizabeth R Peitzman; Erik H Van Iterson; Theresa A Laguna; Wayne J Morgan; Eric M Snyder Journal: Clin Med Insights Circ Respir Pulm Med Date: 2019-03-29
Authors: Marcella Burghard; Tim Takken; Merel M Nap-van der Vlist; Sanne L Nijhof; C Kors van der Ent; Harry G M Heijerman; H J Erik Hulzebos Journal: Ther Adv Respir Dis Date: 2022 Jan-Dec Impact factor: 4.031