Details
| Original language | English |
|---|---|
| Pages (from-to) | 3016-3051 |
| Number of pages | 36 |
| Journal | Cardiovascular research |
| Volume | 118 |
| Issue number | 15 |
| Early online date | 6 Jan 2022 |
| Publication status | Published - Nov 2022 |
Abstract
Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept.
Keywords
- Big data, Bioinformatics, Cardiovascular disease, Comorbidities, iPSC, Multiomics, Network medicine, Tissue engineering
ASJC Scopus subject areas
Sustainable Development Goals
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In: Cardiovascular research, Vol. 118, No. 15, 11.2022, p. 3016-3051.
Research output: Contribution to journal › Review article › Research › peer review
}
TY - JOUR
T1 - Animal models and animal-free innovations for cardiovascular research
T2 - current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart
AU - van der Velden, Jolanda
AU - Asselbergs, Folkert W.
AU - Bakkers, Jeroen
AU - Batkai, Sandor
AU - Bertrand, Luc
AU - Bezzina, Connie R.
AU - Bot, Ilze
AU - Brundel, Bianca J.J.M.
AU - Carrier, Lucie
AU - Chamuleau, Steven
AU - Ciccarelli, Michele
AU - Dawson, Dana
AU - Davidson, Sean M.
AU - Dendorfer, Andreas
AU - Duncker, Dirk J.
AU - Eschenhagen, Thomas
AU - Fabritz, Larissa
AU - Falcão-Pires, Ines
AU - Ferdinandy, Péter
AU - Giacca, Mauro
AU - Girao, Henrique
AU - Gollmann-Tepeköylü, Can
AU - Gyongyosi, Mariann
AU - Guzik, Tomasz J.
AU - Hamdani, Nazha
AU - Heymans, Stephane
AU - Hilfiker, Andres
AU - Hilfiker-Kleiner, Denise
AU - Hoekstra, Alfons G.
AU - Hulot, Jean Sébastien
AU - Kuster, Diederik W.D.
AU - van Laake, Linda W.
AU - Lecour, Sandrine
AU - Leiner, Tim
AU - Linke, Wolfgang A.
AU - Lumens, Joost
AU - Lutgens, Esther
AU - Madonna, Rosalinda
AU - Maegdefessel, Lars
AU - Mayr, Manuel
AU - van der Meer, Peter
AU - Passier, Robert
AU - Perbellini, Filippo
AU - Perrino, Cinzia
AU - Pesce, Maurizio
AU - Priori, Silvia
AU - Remme, Carol Ann
AU - Rosenhahn, Bodo
AU - Schotten, Ulrich
AU - Schulz, Rainer
AU - Sipido, Karin R.
AU - Sluijter, Joost P.G.
AU - van Steenbeek, Frank
AU - Steffens, Sabine
AU - Terracciano, Cesare M.
AU - Tocchetti, Carlo Gabriele
AU - Vlasman, Patricia
AU - Yeung, Kak Khee
AU - Zacchigna, Serena
AU - Zwaagman, Dayenne
AU - Thum, Thomas
N1 - Funding Information: J.v.d.V. acknowledges support from NWO-ZonMW (91818602 VICI grant), ZonMW and Heart Foundation for the translational research program, project 95105003; the Dutch Cardiovascular Alliance (DCVA) grant Double Dose 2021; the Leducq Foundation grant number 20CVD01; and Proper Therapy project funded by the Dutch Research Council, domain Applied and Engineering Sciences (NWO-AES), the Association of Collaborating Health Foundations (SGF), and ZonMW within the Human models 2.0 call. F.A. is supported by UCL Hospitals NIHR Biomedical Research Centre, and the DCVA grant Double Dose 2021. J.B. is supported by the Netherlands CardioVascular Research Initiative CVON (CVON2014-18, CVON2018-30, and CVON2019-002), Stichting Hartekind and the Dutch Research Counsel (NWO) (OCENW.GROOT.2019.029). L.B. is supported by National Fund for Scientific Research, Belgium and Action de Recherche Concertee de la Communaute Wallonie-Bruxelles, Belgium. C.R.B. acknowledges support from NWO-ZonMW (016.150.610 VICI grant), the Netherlands CardioVascular Research Initiative CVON (PREDICT2 and CONCOR-genes projects), the Leducq Foundation (project 17CVD02), and ERA PerMed (PROCEED study). B.B. acknowledges support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON2014-40 DOSIS, CVON-STW2016-14728 and the Medical Delta. L.C. is supported by the German Centre of Cardiovascular Research (DZHH); and the Leducq Foundation grant number 20CVD01. D.D. is supported by the British Heart Foundation (FS/RTF/20/30009, NH/19/1/34595, PG/18/35/33786, CS/17/4/32960, PG/15/88/31780, and PG/17/64/33205), Chest Heart and Stroke Scotland (19/53), Tenovus Scotland (G.18.01), Friends of Anchor and Grampian NHS-Endowments. S.D. was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (BRC233/CM/SD/101320) from the British Heart Foundation (PG/18/44/33790). A.D. is supported by the German Centre for Cardiovascular Research (DZHK, 81X2600253 and 81X2600257). D.J.D. was supported by the Netherlands CardioVascular Research Initiative CVON (CVON2014 RECONNECT and CVON2016 ARENA-PRIME). The work of T.E. was supported by the European Research Council (ERC-AG IndivuHeart), the Deutsche Forschungsgemeinschaft (DFG Es 88/12-1), the European Union Horizon 2020 (REANIMA and TRAINHEART), the German Ministry of Education and Research (BMBF), and the Centre for Cardiovascular Research (DZHK). L.F. was supported by European Union Horizon 2020 [grant agreement No 633196 (CATCH ME) and 965286 (MAESTRIA)]; British Heart Foundation (FS/13/43/30324; PG/17/30/32961; PG/20/22/35093; and AA/18/2/34218); DFG FA413. The Institute of Cardiovascular Sciences, University of Birmingham is a recipient of a BHF Accelerator Award (AA/18/2/34218). P.F. was supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program-TKP; National Heart Program NVKP 16-1-2016-0017); by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic program of the Semmelweis University; and by the European Union Horizon 2020 (COVIRNA, CRYTAL). H.G. is supported by PAC 'NETDIAMOND' POCI-01-0145-FEDER-016385; HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323; POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-032179, CENTRO-01-0145-FEDER-032414, PO CI-01-0145-FEDER-022122, UID/NEU/04539/2019, UIDB/04539/2020, and UIDP/04539/2020. C.G.-T. was supported by the Austrian Science Fund (P 32821). S.H. acknowledges the European Union Commission's Seventh Framework programme under grant agreement N∘ 305507 [HOMAGE0, IMI2-CARDIATEAM (N∘ 821508)] and support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21, CVON Arena-PRIME, 2017-18, CVON Double Dosis, and support of FWO G091018N and FWO G0B5930N. A.G.H. acknowledges support from the INSIST project (www.insist-h2020.eu) and the CompBioMed2 project (https://www.compbiomed.eu) that both received funding from the European Union's Horizon 2020 research and innovation programme under respectively grant agreement No 777072 and No 823712. D.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, Hi 842/4-3; 842/10-2;) and the Leducq Foundation (transatlantic network of excellence: Targeted Approaches for Prevention and Treatment of Anthracycline-Induced Cardiotoxicity) and Volkswagenstiftung (A128871). A.H. was/is supported by the Deutsche Forschungsgemeinschaft (DFG) via the Cluster of Excellence 'From regenerative biology to reconstructive therapy' (REBIRTH), via the project C7 of TRR127 (Biology of xeno-geneic cell and organ transplantation-from bench to bedside), and via the Project HA 13 06/9-1, the BMBF Project 'AUREKA', the project B4 of R2N by the Federal State of Lower Saxony, the Fördergemeinschaft 'Deutsche Kinderherzzentren e.V.' and the 'Cortiss' foundation. J.-S.H. is supported by AP-HP, INSERM, the French National Research Agency (NADHeart ANR-17-CE17-0015-02, PACIFIC ANR-18-CE14-0032-01, CORRECT_LMNA ANR-19-CE17-0013-02), the ERA-Net-CVD (ANR-16-ECVD-0011-03, Clarify project), Federation Française de Cardiologie, the Fondation pour la Recherche Medicale (EQU201903007852), and by a grant from the Leducq Foundation (18CVD05) and is coordinating a French PIA Project (2018-PSPC-07, PACIFIC-preserved, BPIFrance) and a University Research Federation against heart failure (FHU2019, PREVENT Heart Failure). D.K. acknowledges the PPP Allowance made available by Health_Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. L.W.v.L. is supported by the Netherlands Heart Foundation [Dekker Senior Clinical Scientist (2019T056), Health Holland TKI-LSH (LSHM19035), and TUe/UMCU/UU Alliance Fund]. S.L. is supported by grants from the south African National Foundation, the Cancer Association of South Africa and Winetech. T.L. is supported by the Netherlands Heart Foundation/Applied & Engineering Sciences grant number 14741 and Institutional research grant by Dutch Technology Foundation (P15-26) with participation of Pie Medical Imaging and Philips Healthcare; Institutional research grant by Dutch Technology Foundation (12726) with participation of Pie Medical Imaging; institutional research grant by The Netherlands Organisation for Health Research and Development with participation of Pie Medical Imaging; Industrial research grant by Pie Medical Imaging. J.L. was supported by the Netherlands Organisation for Scientific Research (NWO-ZonMw, grant 016.176.340) and the Dutch Heart Foundation (ERA-CVD JTC2018 grant 2018T094, EMPATHY project; Dr. Dekker Program grant 2015T082). E.L. acknowledges the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences for the GENIUS-II project 'Generating the best evidence-based pharmaceutical targets for atherosclerosis' (CVON2017-20), the Deutsche Forschungsgemeinschaft (CRC 1123), the Netherlands Organization for Scientific Research (NWO) (VICI grant); the European Research Council (ERC consolidator grant 681493). R.M. is supported by grants from Incyte s.r.l. and from Ministero dell'Istruzione, Università e Ricerca Scientifica (549901_2020). L.M. is supported by the German Center for Cardiovascular Research (Junior Research Group & Translational Research Project), the European Research Council (ERC Starting Grant NORVAS), the SFB1123 and TRR267 of the German Research Council (DFG), the Swedish Heart-Lung-Foundation (20180680), the Swedish Research Council (Vetenkapsradet 2019-01577), the National Institutes of Health (NIH; 1R011HL150359-01), and the Bavarian State Ministry of Health and Care through the research project DigiMed Bayern. P.v.d.M. is supported by the ERC (StG 715732). R.P. is supported by ERA-CVD 2016T092, Health Holland TKI-LSH (LSHM19004), the Dutch Heart Foundation, ZonMw and by the NWO Gravitation project (024.003.001). C.P. was supported by Ministero dell'Istruzione, Università e Ricerca Scientifica grant (2015583WMX) and Programma STAR grant by Federico II University and Compagnia di San Paolo. M.P. is supported by grants of the Italian Ministry of Health (Ricerca Corrente, 5 per 1000) and from Regione Lombardia. C.A.R. is supported by the Netherlands CardioVascular Research Initiative CVON (CVON2018-30 and CVON2015-12) and the Netherlands Organisation for Health Research and Development (ZonMw 91714371). U.S. is supported by grants of the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodelling, and Vascular Destabilisation in the Progression of AF) and the European Union (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: a translational network, grant number 860974; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number 965286; REPAIR: Restoring cardiac mechanical function by polymeric artificial muscular tissue, grant number 952166). R.S. was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (Project number 268555672-SFB 1213, Project B05). J.S. was supported by European Union H2020 program to the project TECHNOBEAT (grant number 66724), EVICARE (grant number 725229) and BRAV3 (grant number 874827), and ZonMw program No. 116006102. S.S. is supported by the Deutsche Forschungsgemeinschaft (DFG CRC 1123) and the German Centre for Cardiovascular Research (DZHK). C.T. is supported by the British Heart Foundation Centre for Cardiac Regeneration RM/17/1/33377, British Heart Foundation studentship FS/18/37/33642, NC3Rs grant NC/T001488/1. S.Z. is supported by the Interreg ITA-AUS project InCARDIO (B56J19000210005) and by the Italian Association for Cancer Research (AIRC IG 2020 ID 24529). T.T. acknowledges funding from the Deutsche Forschungsgemeinschaft (KFO311, TRR267 and SFB1470).
PY - 2022/11
Y1 - 2022/11
N2 - Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept.
AB - Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept.
KW - Big data
KW - Bioinformatics
KW - Cardiovascular disease
KW - Comorbidities
KW - iPSC
KW - Multiomics
KW - Network medicine
KW - Tissue engineering
UR - http://www.scopus.com/inward/record.url?scp=85126467892&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvab370
DO - 10.1093/cvr/cvab370
M3 - Review article
C2 - 34999816
AN - SCOPUS:85126467892
VL - 118
SP - 3016
EP - 3051
JO - Cardiovascular research
JF - Cardiovascular research
SN - 0008-6363
IS - 15
ER -