Models of the human heart for biomedical research: Opportunities and challenges

Model systems that mimic human cardiac structure and function are essential for the development of novel diagnostics and effective treatments for cardiovascular diseases. While non-human vertebrate models, from zebrafish to pig, remain vital to cardiovascular research, the translatability of findings to human patients is often limited. Therefore, animal experiments should be supplemented with human model systems, including human induced pluripotent stem cell-derived cells, 3D engineered constructs, and last but not least, native tissue preparations and isolated primary cardiomyocytes. However, while human myocardium remains the gold standard, human heart tissue - and particularly tissue from control hearts-remains scarce, and its use in research is generally restricted to settings where tissue has been excised from diseased or failing hearts. While it is in principle possible to use tissue from rejected non-failing donor hearts that cannot be transplanted, legal hurdles (e.g., in Germany) can restrict the use of non-transplanted donor organs in research. Given the challenges associated with accessing and using human tissue in biomedical research, an integrated strategy towards combining non-human vertebrate models, in silico models, and human tissue-derived models is recommended, enhancing the chances of successful research and development, and helping bridge the gap between preclinical and clinical research.