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.
| 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 |
| DOIs | |
| Publication status | Published - 1 Nov 2022 |
Bibliographical note
Funding Information:Communauté 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-
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 Concertée de la
Data Availability Statement
No new data were generated or analysed in support of this consensus document.Keywords
- Big data
- Bioinformatics
- Cardiovascular disease
- Comorbidities
- iPSC
- Multiomics
- Network medicine
- Tissue engineering
