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      Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension : Relative Contribution of Fibrosis and Myofibril Stiffness

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          Abstract

          Supplemental Digital Content is available in the text.

          Abstract

          Background—

          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.

          Methods and Results—

          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.

          Conclusions—

          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.

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          Most cited references33

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          Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.

          Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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            Cardiac interstitium in health and disease: the fibrillar collagen network.

            Composed of type I and III collagens, the valve leaflets, chordae tendineae and collagen matrix of the myocardium form a structural continuum. Synthesized by cardiac fibroblasts, these fibrillar collagens support and tether myocytes to maintain their alignment, whereas their respective tensile strength and resilience resist the deformation, maintain the shape and thickness, prevent the rupture and contribute to the passive and active stiffness of the myocardium. An acquired or congenital defect in this collagen network can lead to abnormalities in myocardial architecture, mechanics or valve function. In the hypertrophic process that accompanies a pressure overload, for example, increased collagen synthesis, fibroblast proliferation and a structural and biochemical remodeling of the matrix are seen. This includes distinctive patterns of reparative and reactive myocardial fibrosis, each of which alters diastolic and systolic myocardial stiffness and may lead to pathologic hypertrophy. Alternatively, a loss of collagen tethers or decline in matrix tensile strength can be responsible for regional or global transformations in myocardial architecture and function seen in the reperfused ("stunned") myocardium and in dilated (idiopathic) cardiopathy. Inherited disorders in the transcriptional and posttranslational processing of collagen can also alter the biophysical properties of the network. Future studies into collagen gene regulation, gene switching events and the control of collagen synthesis and degradation are needed to develop a more complete understanding of the relation between the collagen network and acquired and inherited forms of heart disease and to utilize therapeutics that will prevent, retard or regress abnormal collagen matrix remodeling.
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              Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure.

              The most important determinant of longevity in pulmonary arterial hypertension is right ventricular (RV) function, but in contrast to experimental work elucidating the pathobiology of left ventricular failure, there is a paucity of data on the cellular and molecular mechanisms of RV failure. A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure. Isolated RV pressure overload induced RV hypertrophy without failure, whereas in the context of angioproliferative pulmonary hypertension, RV failure developed that was associated with myocardial apoptosis, fibrosis, a decreased RV capillary density, and a decreased vascular endothelial growth factor mRNA and protein expression despite increased nuclear stabilization of hypoxia-induced factor-1alpha. Induction of myocardial nuclear factor E2-related factor 2 and heme-oxygenase 1 with a dietary supplement (Protandim) prevented fibrosis and capillary loss and preserved RV function despite continuing pressure overload. These data brought into question the commonly held concept that RV failure associated with pulmonary hypertension is due strictly to the increased RV afterload.
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                Author and article information

                Journal
                Circ Heart Fail
                Circ Heart Fail
                HHF
                Circulation. Heart Failure
                Lippincott Williams & Wilkins
                1941-3289
                1941-3297
                July 2016
                19 July 2016
                : 9
                : 7
                : e002636
                Affiliations
                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.).
                Author notes
                Correspondence to Frances S. de Man, PhD, Department of Pulmonology, Vrije Universiteit University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. E-mail fs.deman@ 123456vumc.nl
                Article
                00011
                10.1161/CIRCHEARTFAILURE.115.002636
                4956674
                27370069
                52cddafc-124a-4e08-9394-bcab72a03f3b
                © 2016 The Authors.

                Circulation: Heart Failure is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

                History
                : 19 March 2015
                : 12 May 2016
                Categories
                10017
                10094
                10101
                10113
                Original Articles
                Custom metadata
                TRUE

                collagen,fibrosis,heart failure,hypertension,right ventricular dysfunction

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