Abstract
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) offer a new means to study and understand the human cardiac action potential, and can give key insight into how compounds may interact with important molecular pathways to destabilize the electrical function of the heart. Important features of the action potential can be readily measured using standard experimental techniques, such as the use of voltage sensitive dyes and fluorescent genetic reporters to estimate transmembrane potentials and cytosolic calcium concentrations. Using previously introduced computational procedures, such measurements can be used to estimate the current density of major ion channels present in hiPSC-CMs, and how compounds may alter their behavior. However, due to the limitations of optical recordings, resolving the sodium current remains difficult from these data. Here we show that if these optical measurements are complemented with observations of the extracellular potential using multi electrode arrays (MEAs), we can accurately estimate the current density of the sodium channels. This inversion of the sodium current relies on observation of the conduction velocity which turns out to be straightforwardly computed using measurements of extracellular waves across the electrodes. The combined data including the membrane potential, the cytosolic calcium concentration and the extracellular potential further opens up for the possibility of accurately estimating the effect of novel drugs applied to hiPSC-CMs.
Highlights
In recent reports (Tveito et al, 2018; Jæger et al, 2020a) we have demonstrated how microphysiological systems utilizing human induced pluripotent stem cell derived cardiomyocytes (Mathur et al, 2015; Mathur et al, 2016) can be used to estimate drug induced changes to the cardiac action potential using computational approaches
We show some examples of how bidomain-base model simulations are able to reproduce measured drug induced effects on the average conduction velocity, illustrating that including U data in the inversion procedure improves the identifiability of drug effects on INa
We observe that block of the IKr current results in increased action potential and calcium transient durations, whereas block of ICaL results in decreased action potential and calcium transient durations
Summary
In recent reports (Tveito et al, 2018; Jæger et al, 2020a) we have demonstrated how microphysiological systems utilizing human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) (Mathur et al, 2015; Mathur et al, 2016) can be used to estimate drug induced changes to the cardiac action potential using computational approaches. We have further shown how these estimates, at least in principle, carry over from immature cells to adult cardiomyocytes This methodology provides information on a number of the major ion channels and when compared to data presented in (Mohammad et al, 1997; Di Stilo et al, 1998; Zhang et al, 1999; Zhabyeyev et al, 2000; Mirams et al, 2011; Kramer et al, 2013; Crumb et al, 2016), the method is able to provide reasonable estimates of the IC50 values of well-known drugs like Nifedipine, Lidocaine, Cisapride, Flecainide and Verapamil; see Table 2 of (Jæger et al, 2020a). By combining imaging data for the membrane potential (V) and the cytosolic calcium concentration (Ca) with data for the extracellular potential (U), we are able to identify both the fast sodium current and other major currents characterizing the action potential of the hiPSC-CMs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
