Quantitative Comparison of Effects of Dofetilide, Sotalol, Quinidine, and Verapamil between Human Ex vivo Trabeculae and In silico Ventricular Models Incorporating Inter-Individual Action Potential Variability

Abstract

Background: In silico modeling could soon become a mainstream method of pro-arrhythmic risk assessment in drug development. However, a lack of human-specific data and appropriate modeling techniques has previously prevented quantitative comparison of drug effects between in silico models and recordings from human cardiac preparations. Here, we directly compare changes in repolarization biomarkers caused by dofetilide, dl-sotalol, quinidine, and verapamil, between in silico populations of human ventricular cell models and ex vivo human ventricular trabeculae.Methods and Results: Ex vivo recordings from human ventricular trabeculae in control conditions were used to develop populations of in silico human ventricular cell models that integrated intra- and inter-individual variability in action potential (AP) biomarker values. Models were based on the O'Hara-Rudy ventricular cardiomyocyte model, but integrated experimental AP variability through variation in underlying ionic conductances. Changes to AP duration, triangulation and early after-depolarization occurrence from application of the four drugs at multiple concentrations and pacing frequencies were compared between simulations and experiments. To assess the impact of variability in IC50 measurements, and the effects of including state-dependent drug binding dynamics, each drug simulation was repeated with two different IC50 datasets, and with both the original O'Hara-Rudy hERG model and a recently published state-dependent model of hERG and hERG block. For the selective hERG blockers dofetilide and sotalol, simulation predictions of AP prolongation and repolarization abnormality occurrence showed overall good agreement with experiments. However, for multichannel blockers quinidine and verapamil, simulations were not in agreement with experiments across all IC50 datasets and IKr block models tested. Quinidine simulations resulted in overprolonged APs and high incidence of repolarization abnormalities, which were not observed in experiments. Verapamil simulations showed substantial AP prolongation while experiments showed mild AP shortening.Conclusions: Results for dofetilide and sotalol show good agreement between experiments and simulations for selective compounds, however lack of agreement from simulations of quinidine and verapamil suggest further work is needed to understand the more complex electrophysiological effects of these multichannel blocking drugs.

Required G1 to Suppress Automaticity of iPSC-CMs Depends Strongly on I1 Model Structure

“…7 in (6)). Except for the models including the Bett I K1 formulation, all showed a median APD 90 value that was higher than the mean value reported by Britton et al (29) and O'Hara-Rudy et al (6). Therefore, upscaling relative to G K1, critical may be a strategy to make the repolarization faster and to close the gap between in silico and experimental data.…”

“…Simulations were run using G K1 values ranging from 0 (no I K1 ) to 10ÂG K1;critical and increase with 0.25ÂG K1;critical step. The experimental range for APD 50 and APD 90 refers to adult healthy cardiomyocytes from Britton et al(29). To see this figure in color, go online.…”

All-optical electrophysiology refines populations of in silico human iPS-CMs for drug evaluation

“…It must be noted that extensive experimental datasets from healthy adult human cardiomyocytes are non-existent due to unavailability of such cardiac tissue. Thus, inferences could only be made based on donor heart-derived human cells (34, 47, 48) or well-studied adult cardiomyocytes from other species. Nevertheless, different ion channel expressions can lead to underestimation (as for bepridil) or overestimation of the actual toxicity of a drug.…”

In Vitro and In Silico Risk Assessment in Acquired Long QT Syndrome: The Devil Is in the Details

“…However, each of the models is considerably different in relation to the conductance levels of individual cardiac ion channels. As a result, predictions around APD prolongation and emergence of proarrhythmic markers that each of the models make in response to drug block are significantly different (Mirams et al, 2014 ) and do not reproduce in vivo data (Britton et al, 2017 ). For example, Mann et al showed that 50% inhibition of Kv11.1 caused 113, 22, and 34 ms prolongation of APD 90 for ORD11, TT06 and GB10 respectively (Mann et al, 2016 ).…”