Drugs targeting atrial‐specific ion channels, K _v 1.5 or K _ir 3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non‐cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)‐derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial‐like (hESC‐atrial) and ventricular‐like (hESC‐ventricular) CMs. We found the expression of atrial‐specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding K _ir 3.1), in hESC‐atrial CMs and further demonstrated that these ion channel genes are regulated by COUP‐TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and K _v 1.5 blocker, XEN‐D0101, hESC‐atrial but not hESC‐ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC‐atrial CMs, XEN‐R0703, a novel K _ir 3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN‐R0703 had an effect on hESC‐ventricular CMs. In summary, we demonstrate that hESC‐atrial CMs are a robust model for pre‐clinical testing to assess atrial selectivity of novel antiarrhythmic drugs.

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This organ-on-a-chip device of the outer blood retinal barrier will allow future studies of complex disease mechanisms and treatments of visual disorders using clinically relevant endpoints in vitro.

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.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) generally have an immature fetal-like phenotype when directly compared to isolated CMs from human hearts, despite significant advance in differentiation of human pluripotent stem cells (hPSCs) to multiple cardiac lineages. Therefore, hPSC-CMs may not accurately mimic all facets of healthy and diseased human adult CMs. During embryonic development, the cardiac extracellular matrix (ECM) experiences a gradual assembly of matrix proteins that transits along the maturation of CMs. Mimicking these dynamic stages may contribute to hPSC-CMs maturation in vitro. Thus, in this review, we describe the progressive build-up of the cardiac ECM during embryonic development, the ECM of the adult human heart and the application of natural and synthetic biomaterials for cardiac tissue engineering with hPSC-CMs.