In silico modelling
A population of n=500 human cardiac action potentials (AP) were
simulated using the endocardial configuration of the ToR-Ord model (17)
run in the Brain Dynamics Toolbox (18).To incorporate population
variability in expression levels of the ion channels and electrogenic
transporters that regulate cardiac excitability (i.e. the rhythmonome
genes), the maximum conductance for each current (L-type calcium
current, sodium current, transient outward current, late sodium current,
rapid delayed rectifier (hERG) potassium current, slow delayed rectifier
potassium current, inward rectifier potassium current, background
potassium current, sodium calcium exchanger, sodium potassium pump,
background sodium current, background calcium current, calcium pump,
chloride current through calcium channel, background chloride current,
calcium release from SR, calcium uptake to SR; Supplemental table 1) was
multiplied by a conductance scalar (G x) randomly
drawn from a log-normal distribution (19, 20) with unit mean and
variance of 0.05, which we previously demonstrated can account for the
range of QT intervals measured from normal and Long QT patient
populations (21). Hypokalemia was simulated by manipulating parameterko in the model. The pharmacology of hydroxychloroquine were
represented by an additional set of scaling factors, informed by the
IC50 measured in our hERG screen, as well as data
describing block of inward rectifier potassium current
(IK1), cardiac sodium current (INa), and
the cardiac L-type calcium current (ICaL) from the
literature (22) (Supplemental table 2). Simulated myocytes were paced at
1Hz and allowed to equilibrate for 300 beats prior to analysis. Source
code: https://git.victorchang.edu.au/projects/CC/repos/.