Animal models and animal-free innovations for cardiovascular research: 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

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; Multiomics; Network medicine; Tissue engineering; iPSC.

Figure 1

(A) Models that are available for studies on cardiovascular disease, ranging from human and laboratory animals to stem cell-derived models. Aspects that can be measured currently in the different models are indicated with the white check mark. This overview shows that several models allow to reduce the number of studies in laboratory animals, as many initial steps in identification of pathomechansisms, testing drug toxicity and drug effectiveness can be studied in cell-based models. Clearly, studies in human itself offers multiple opportunities to reduce the work in laboratory animals. (B) Multiple tools have been developed in past years to refine and replace studies in the models used for cardiovascular research, and range from tools and expertise to characterize human tissue samples obtained during surgery to models derived from hiPSCs (human induced pluripotent stem cells). (C) Example of an experimental design making use of available complementary research models based on the 3R principles.

Figure 2

In situ valve engineering.

Figure 3

Aneurysm-on-a-chip manufactured with a 3D printing-based microfluidic channel patterned inside a polydimethylsiloxane (PDMS) block. The heatmap represents the distribution of the flow velocity reproducing the hemodynamic conditions occurring into aneurysms. Figure 3 is original and contains unpublished modelling and manufacturing images.