Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology
de Boer, Rudolf A; De Keulenaer, Gilles; Bauersachs, Johann; Brutsaert, Dirk; Cleland, John G; Diez, Javier; Du, Xiao-Jun; Ford, Paul; Heinzel, Frank R; Lipson, Kenneth E; McDonagh, Theresa; Lopez-Andres, Natalia; Lunde, Ida G; Lyon, Alexander R; Pollesello, Piero; Prasad, Sanjay K; Tocchetti, Carlo G; Mayr, Manuel; Sluijter, Joost P G; Thum, Thomas; Tschöpe, Carsten; Zannad, Faiez; Zimmermann, Wolfram-Hubertus; Ruschitzka, Frank; Filippatos, Gerasimos; Lindsey, Merry L; Maack, Christoph; Heymans, Stephane
(2019) European Journal of Heart Failure, volume 21, issue 3, pp. 272 - 285
(Article)
Abstract
Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and
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uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.
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Keywords: Biomarkers/blood, Cardiac Imaging Techniques/methods, Disease Management, Europe, Extracellular Matrix Proteins/blood, Fibrosis/classification, Heart Failure/diagnosis, Humans, Myocardium/metabolism, Prognosis, Research, Societies, Medical, Translational Medical Research, Heart failure, Matrix, Imaging, Fibrosis, Biomarkers, Fibroblast, Cardiology and Cardiovascular Medicine, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 1388-9842
Publisher: Oxford University Press
Note: Funding Information: R.A.d.B. is supported by the Netherlands Heart Foundation (CVON DOSIS, grant 2014-40, CVON SHE-PREDICTS-HF, grant 2017-21, and CVON RED-CVD, grant 2017-11); and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VIDI, grant 917.13.350). J.B. is supported is supported by the Deutsche Forschungsgemeinschaft (DFG), Clinical Research Group 311 (KFO 311) ‘(Pre)terminal heart and lung failure: unloading and repair’ (DFG; TP1, BA 1742/9-1) and ‘MR-Focus’‘ (DFG BA 1742/8-1). J.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (consolidator grant Evicare #725229) and by the Netherlands Heart Foundation (CVON-HUSTCARE). M.M. is a BHF Chair Holder (CH/16/3/32406), with BHF program grant support (RG/16/14/32397), and was awarded a BHF Special Project grant to participate in the ERA-CVD Translational Grant MacroERA. M.M. and T.T. are members of a network funded by the Foundation Leducq. C.G.T. is supported by a Federico II University/Ricerca di Ateneo grant. S.H. has received funding from the European Union Commission’s Seventh Framework programme under grant agreement n. 305507 (HOMAGE), n. 602904 (FIBROTARGETS) and FP7-Health-2013-Innovations-1 n. 602156 (HECATOS), CVON2016-Early HFPEF, 2015-10, and CVON SHE-PREDICTS-HF, grant 2017-21. C.M. is supported by the DFG (Ma 2528/7-1, SFB 894, TRR-219) and the Federal Ministry of Education and Science (BMBF; 01EO150, CF.3, RC2). Conflict of interest: The UMCG, which employs R.A.d.B., has received research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Roche, Trevena, and ThermoFisher GmbH. R.A.d.B. is a minority shareholder of scPharmaceuticals, Inc.; received personal fees from MandalMed Inc, Novartis, and Servier. J.B. received honoraria for lectures and/or consulting from Novartis, Pfizer, Vifor, Bayer, Servier, Orion, CVRx, Abiomed, Abbott, Medtronic, and research support from Zoll, CVRx, Bayer, Vifor, Abiomed, Medtronic. T.T. has filed and licensed patents in the field of noncoding RNAs; is founder of Cardior Pharmaceuticals GmbH. A.R.L. reports grants from Servier and Pfizer, and speaker fees, advisory board fees and/or consultancy fees from Servier, Pfizer, Novartis, Roche, Takeda, Boehringer Ingelheim, Amgen, Clinigen Group, Ferring Pharmaceuticals, Bristol Myers Squibb, Eli Lily and Janssens-Cilag Ltd. C.G.T. has a patent issued in the field of heart failure, and reports speaker fees from Alere. C.M. is a consultant to Servier and has received speaker honoraria from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Berlin Chemie, Daiichi Sankyo, Novartis, Pfizer and Servier. The other authors report no conflicts of interest. Funding Information: R.A.d.B. is supported by the Netherlands Heart Foundation (CVON DOSIS, grant 2014-40, CVON SHE-PREDICTS-HF, grant 2017-21, and CVON RED-CVD, grant 2017-11); and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VIDI, grant 917.13.350). J.B. is supported is supported by the Deutsche Forschungsgemeinschaft (DFG), Clinical Research Group 311 (KFO 311) ?(Pre)terminal heart and lung failure: unloading and repair? (DFG; TP1, BA 1742/9-1) and ?MR-Focus?? (DFG BA 1742/8-1). J.S. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (consolidator grant Evicare #725229) and by the Netherlands Heart Foundation (CVON-HUSTCARE). M.M. is a BHF Chair Holder (CH/16/3/32406), with BHF program grant support (RG/16/14/32397), and was awarded a BHF Special Project grant to participate in the ERA-CVD Translational Grant MacroERA. M.M. and T.T. are members of a network funded by the Foundation Leducq. C.G.T. is supported by a Federico II University/Ricerca di Ateneo grant. S.H. has received funding from the European Union Commission's Seventh Framework programme under grant agreement n. 305507 (HOMAGE), n. 602904 (FIBROTARGETS) and FP7-Health-2013-Innovations-1 n. 602156 (HECATOS), CVON2016-Early HFPEF, 2015-10, and CVON SHE-PREDICTS-HF, grant 2017-21. C.M. is supported by the DFG (Ma 2528/7-1, SFB 894, TRR-219) and the Federal Ministry of Education and Science (BMBF; 01EO150, CF.3, RC2). Conflict of interest: The UMCG, which employs R.A.d.B., has received research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Roche, Trevena, and ThermoFisher GmbH. R.A.d.B. is a minority shareholder of scPharmaceuticals, Inc.; received personal fees from MandalMed Inc, Novartis, and Servier. J.B. received honoraria for lectures and/or consulting from Novartis, Pfizer, Vifor, Bayer, Servier, Orion, CVRx, Abiomed, Abbott, Medtronic, and research support from Zoll, CVRx, Bayer, Vifor, Abiomed, Medtronic. T.T. has filed and licensed patents in the field of noncoding RNAs; is founder of Cardior Pharmaceuticals GmbH. A.R.L. reports grants from Servier and Pfizer, and speaker fees, advisory board fees and/or consultancy fees from Servier, Pfizer, Novartis, Roche, Takeda, Boehringer Ingelheim, Amgen, Clinigen Group, Ferring Pharmaceuticals, Bristol Myers Squibb, Eli Lily and Janssens-Cilag Ltd. C.G.T. has a patent issued in the field of heart failure, and reports speaker fees from Alere. C.M. is a consultant to Servier and has received speaker honoraria from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Berlin Chemie, Daiichi Sankyo, Novartis, Pfizer and Servier. The other authors report no conflicts of interest. Publisher Copyright: © 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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