title: Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension: Relative Contribution of Fibrosis and Myofibril Stiffness.
abstract: The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction.
  
  
  
  By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction.
  
  
  
  RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness.
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Silvia
authors.initials: S
authors.lastname: Rain
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Stine
authors.initials: S
authors.lastname: Andersen
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Aref
authors.initials: A
authors.lastname: Najafi
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Jacob
authors.initials: J
authors.lastname: Gammelgaard Schultz
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Denielli
authors.initials: D
authors.lastname: da Silva Gonçalves Bós
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: M Louis
authors.initials: ML
authors.lastname: Handoko
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Bogaard
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Asger
authors.initials: A
authors.lastname: Andersen
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.).
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
authors.affiliation: From the Department of Pulmonology (S.R., D.d.S.G.B., H.-J.B., A.V.-N., F.S.d.M.), Department of Physiology (S.R., A.N., D.d.S.G.B., M.L.H., J.v.d.V., C.A.C.O., F.S.d.M.), and Department of Cardiology (M.L.H.), Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, the Netherlands (M.L.H.); Department of Cardiology, Aarhus University Hospital, Denmark (S. Anderson, A.N., J.G.S., A. Anderson); and Interuniversity Cardiology Institute of the Netherlands, The Netherlands Heart Institute, Utrecht (J.v.d.V.). fs.deman@vumc.nl.
authors.forename: Frances S
authors.initials: FS
authors.lastname: de Man
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D064211:Connectin / Q000378:metabolism; D003250:Constriction; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004548:Elasticity; D005355:Fibrosis; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009210:Myofibrils / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000503:physiopathology* / Q000601:surgery; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013997:Time Factors; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016278:Ventricular Function, Right
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D064211:Connectin; C577295:Ttn protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: collagen; fibrosis; heart failure; hypertension; right ventricular dysfunction