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      Myocardial fibrosis: biomedical research from bench to bedside

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          Abstract

          Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways. The European Commission funded the FIBROTARGETS consortium as a multinational academic and industrial consortium with the primary aim of performing a systematic and collaborative search of targets of myocardial fibrosis, and then translating these mechanisms into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. This review focuses on those methodological and technological aspects considered and developed by the consortium to facilitate the transfer of the new mechanistic knowledge on myocardial fibrosis into potential biomedical applications.

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          Swine as models in biomedical research and toxicology testing.

          M M Swindle, A. Makin, A J Herron … (2011)
          Swine are considered to be one of the major animal species used in translational research, surgical models, and procedural training and are increasingly being used as an alternative to the dog or monkey as the choice of nonrodent species in preclinical toxicologic testing of pharmaceuticals. There are unique advantages to the use of swine in this setting given that they share with humans similar anatomic and physiologic characteristics involving the cardiovascular, urinary, integumentary, and digestive systems. However, the investigator needs to be familiar with important anatomic, histopathologic, and clinicopathologic features of the laboratory pig and minipig in order to put background lesions or xenobiotically induced toxicologic changes in their proper perspective and also needs to consider specific anatomic differences when using the pig as a surgical model. Ethical considerations, as well as the existence of significant amounts of background data, from a regulatory perspective, provide further support for the use of this species in experimental or pharmaceutical research studies. It is likely that pigs and minipigs will become an increasingly important animal model for research and pharmaceutical development applications.
          Article 0 comments Cited 379 times – based on 0 reviews     Review now
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            Myofibroblast-mediated mechanisms of pathological remodelling of the heart.

            Karl T Weber, Yao Sun, Syamal K Bhattacharya … (2013)
            The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection.
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              Human iPSC-based Cardiac Microphysiological System For Drug Screening Applications

              Anurag Mathur, Peter Loskill, Kaifeng Shao … (2015)
              Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. A fundamental problem in this inefficient process is that non-human animal models cannot adequately represent human biology. Thus, there is an urgent need for high-content in vitro systems that can better predict drug-induced toxicity. Systems that predict cardiotoxicity are of uppermost significance, as approximately one third of safety-based pharmaceutical withdrawals are due to cardiotoxicty. Here, we present a cardiac microphysiological system (MPS) with the attributes required for an ideal in vitro system to predict cardiotoxicity: i) cells with a human genetic background; ii) physiologically relevant tissue structure (e.g. aligned cells); iii) computationally predictable perfusion mimicking human vasculature; and, iv) multiple modes of analysis (e.g. biological, electrophysiological, and physiological). Our MPS is able to keep human induced pluripotent stem cell derived cardiac tissue viable and functional over multiple weeks. Pharmacological studies using the cardiac MPS show half maximal inhibitory/effective concentration values (IC50/EC50) that are more consistent with the data on tissue scale references compared to cellular scale studies. We anticipate the widespread adoption of MPSs for drug screening and disease modeling.
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                Author and article information

                Contributors
                Mariann Gyöngyösi: mariann.gyongyosi@meduniwien.ac.at
                Journal
                Journal ID (nlm-ta): Eur J Heart Fail
                Journal ID (iso-abbrev): Eur. J. Heart Fail
                Journal ID (doi): 10.1002/(ISSN)1879-0844
                Journal ID (publisher-id): EJHF
                Title: European Journal of Heart Failure
                Publisher: John Wiley & Sons, Ltd (Oxford, UK )
                ISSN (Print): 1388-9842
                ISSN (Electronic): 1879-0844
                Publication date (Electronic): 03 February 2017
                Publication date (Print): February 2017
                Volume: 19
                Issue: 2 ( doiID: 10.1002/ejhf.2017.19.issue-2 )
                Pages: 177-191
                Affiliations
                [ 1 ] Department of CardiologyMedical University of Vienna Austria
                [ 2 ]Innovative Technologies in Biological Systems SL (INNOPROT) BizkaiaSpain
                [ 3 ]Greenpharma SAS OrléansFrance
                [ 4 ]Firalis S.A.S. HuningueFrance
                [ 5 ]University College Dublin Ireland
                [ 6 ] Program of Cardiovascular Diseases, Center for Applied Medical ResearchUniversity of Navarra PamplonaSpain
                [ 7 ] Institute of Molecular and Translational Therapeutic StrategiesHannover Medical School Germany
                [ 8 ] National Heart and Lung InstituteImperial College London UK
                [ 9 ] Department of Cardiology and Cardiac SurgeryUniversity of Navarra Clinic, University of Navarra PamplonaSpain
                [ 10 ] Centre de Recherche des Cordeliers, Inserm U1138Université Pierre et Marie Curie ParisFrance
                [ 11 ] UMRS U1116 Inserm, CIC 1433, Pierre DrouinCHU, Université de Lorraine NancyFrance
                Author notes
                [*] [* ]Corresponding author. Department of Cardiology, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria.Tel: +43 1 40400 46140, Fax: +43 1 40400 42160, Email: mariann.gyongyosi@ 123456meduniwien.ac.at
                Article
                Publisher ID: EJHF696
                DOI: 10.1002/ejhf.696
                PMC ID: 5299507
                PubMed ID: 28157267
                SO-VID: a6e35794-85e3-45cc-81fb-4e5ab649b680
                Copyright © © 2017 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 26 April 2016
                Date revision received : 07 September 2016
                Date accepted : 01 October 2016
                Page count
                Figures: 5, Tables: 8, Pages: 15, Words: 0
                Funding
                Funded by: European Commission FP7 Programme
                Award ID: FIBROTARGETS project grant HEALTH‐2013‐6029047
                Funded by: Institut National de la Santé et de la Recherche Médicale
                Funded by: National University of Ireland
                Funded by: Universiteit Maastricht
                Funded by: General Electric
                Categories
                Subject: Review
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                component-id ejhf696
                cover-date February 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.5 mode:remove_FC converted:09.02.2017

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: myocardial fibrosis,animal models,biomarkers,cardiac imaging
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: myocardial fibrosis, animal models, biomarkers, cardiac imaging

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