  Current understanding of arrhythmia mechanisms and design of anti-arrhythmic
drug therapies hinges on the assumption that myocytes from the same region of a
single heart have similar, if not identical, action potential waveforms and
drug responses. On the contrary, recent experiments reveal significant
heterogeneity in uncoupled healthy myocytes both from different hearts as well
as from identical regions within a single heart. In this work, a methodology is
developed for quantifying the individual electrophysiological properties of
large numbers of uncoupled cardiomyocytes under ion channel block in terms of
the parameters values of a conceptual fast-slow model of electrical
excitability. The approach is applied to a population of nearly 500 rabbit
ventricular myocytes for which action potential duration (APD) before and after
the application of the drug nifedipine was experimentally measured (Lachaud et
al., 2022, Cardiovasc. Res.). To this end, drug action is represented by a
multiplicative factor to an effective ion conductance, a closed form asymptotic
expression for APD is derived and inverted to determine model parameters as
functions of APD and dAPD (drug-induced change in APD) for each myocyte. Two
free protocol-related quantities are calibrated to experiment using an
adaptive-domain procedure based on an original assumption of optimal
excitability. The explicit APD expression and the resulting set of model
parameter values allow (a) direct evaluation of conditions necessary to
maintain fixed APD or dAPD, (b) predictions of the proportion of cells
remaining excitable after drug application, (c) predictions of stimulus period
dependency and (d) predictions of dose-response curves, the latter being in
agreement with additional experimental data.
