Atrial fibrillation-associated electrical remodelling in human induced pluripotent stem cell-derived atrial cardiomyocytes: a novel pathway for antiarrhythmic therapy development.

AIMS: Atrial fibrillation (AF) is associated with tachycardia-induced cellular electrophysiology alterations which promote AF chronification and treatment resistance. Development of novel antiarrhythmic therapies is hampered by the absence of scalable experimental human models that reflect AF-associated electrical remodelling. Therefore, we aimed to assess if AF-associated remodelling of cellular electrophysiology can be simulated in human atrial-like cardiomyocytes derived from induced pluripotent stem cells in the presence of retinoic acid (iPSC-aCM), and atrial-engineered human myocardium (aEHM) under short term (24 h) and chronic (7 days) tachypacing (TP). METHODS AND RESULTS: First, 24-h electrical pacing at 3 Hz was used to investigate whether AF-associated remodelling in iPSC-aCM and aEHM would ensue. Compared to controls (24 h, 1 Hz pacing) TP-stimulated iPSC-aCM presented classical hallmarks of AF-associated remodelling: (i) decreased L-type Ca2+ current (ICa,L) and (ii) impaired activation of acetylcholine-activated inward-rectifier K+ current (IK,ACh). This resulted in action potential shortening and an absent response to the M-receptor agonist carbachol in both iPSC-aCM and aEHM subjected to TP. Accordingly, mRNA expression of the channel-subunit Kir3.4 was reduced. Selective IK,ACh blockade with tertiapin reduced basal inward-rectifier K+ current only in iPSC-aCM subjected to TP, thereby unmasking an agonist-independent constitutively active IK,ACh. To allow for long-term TP, we developed iPSC-aCM and aEHM expressing the light-gated ion-channel f-Chrimson. The same hallmarks of AF-associated remodelling were observed after optical-TP. In addition, continuous TP (7 days) led to (i) increased amplitude of inward-rectifier K+ current (IK1), (ii) hyperpolarization of the resting membrane potential, (iii) increased action potential-amplitude and upstroke velocity as well as (iv) reversibly impaired contractile function in aEHM. CONCLUSIONS: Classical hallmarks of AF-associated remodelling were mimicked through TP of iPSC-aCM and aEHM. The use of the ultrafast f-Chrimson depolarizing ion channel allowed us to model the time-dependence of AF-associated remodelling in vitro for the first time. The observation of electrical remodelling with associated reversible contractile dysfunction offers a novel platform for human-centric discovery of antiarrhythmic therapies.

Where Do Early Career Researchers Stand on Open Science Practices? A Survey Within the Max Planck Society.

Open science (OS) is of paramount importance for the improvement of science worldwide and across research fields. Recent years have witnessed a transition toward open and transparent scientific practices, but there is still a long way to go. Early career researchers (ECRs) are of crucial relevance in the process of steering toward the standardization of OS practices, as they will become the future decision makers of the institutional change that necessarily accompanies this transition. Thus, it is imperative to gain insight into where ECRs stand on OS practices. Under this premise, the Open Science group of the Max Planck PhDnet designed and conducted an online survey to assess the stance toward OS practices of doctoral candidates from the Max Planck Society. As one of the leading scientific institutions for basic research worldwide, the Max Planck Society provides a considerable population of researchers from multiple scientific fields, englobed into three sections: biomedical sciences, chemistry, physics and technology, and human and social sciences. From an approximate total population of 5,100 doctoral candidates affiliated with the Max Planck Society, the survey collected responses from 568 doctoral candidates. The survey assessed self-reported knowledge, attitudes, and implementation of different OS practices, namely, open access publications, open data, preregistrations, registered reports, and replication studies. ECRs seemed to hold a generally positive view toward these different practices and to be interested in learning more about them. Furthermore, we found that ECRs' knowledge and positive attitudes predicted the extent to which they implemented these OS practices, although levels of implementation were rather low in the past. We observed differences and similarities between scientific sections. We discuss these differences in terms of need and feasibility to apply these OS practices in specific scientific fields, but additionally in relation to the incentive systems that shape scientific communities. Lastly, we discuss the implications that these results can have for the training and career advancement of ECRs, and ultimately, for the consolidation of OS practices.