Sensitivity of the Human Ventricular BPS2020 Action Potential Model to the In Silico Mechanisms of Ischemia

Mohamadamin Forouzandehmehr1, Chiara Bartolucci2, Jari Hyttinen1, Jussi Koivumäki1, Michelangelo Paci1
1Tampere University, 2University of Bologna


Myocardial ischemia is due to a reduced or suppressed blood supply to the heart, e.g. consequent to the occlusion of a blood vessel. Cardiomyocytes (CMs) experience a reduction of oxygen availability and metabolic alterations, that alter their electrical and mechanical functionality up to cell necrosis, also according to the severity and duration of the reduced perfusion.

We evaluate the effects of the three main consequences of acute ischemia (hypoxia, acidosis, and hyperkalemia) on the recent BPS2020 model of human adult ventricular CM, using literature data.

We run a sensitivity analysis considering different ischemia severity (mild and severe) and mechanisms. We simulate hyperkalemia by increasing the extracellular K+ concentration to 6.25 and 9 mM. Acidosis consists in the 12.5% and 25% inhibition of the fast and late Na+, and L-type Ca2+ current. Hypoxia involves several components: i) the ATP-sensitive K+ current IKatp, using the Ledezma2019 and Kazbanov2014 formulations, and the effects of metabolites on ii) the Na+/K+ pump (downscaling of MgATP, upscaling of MgADP ), and on iii) the ATP-sensitive sarcolemmal and sarcoplasmic reticulum Ca2+ pumps (both downscaled with the hypoxia/normoxia MgATP ratio).

In condition of severe acute ischemia, hyperkalemia showed the greatest impact on the maximum diastolic potential (MDP, +16%) and maximum upstroke velocity (dV/dtmax, -61%). Acidosis slightly shortened the action potential duration (APD90, -4%). Full ischemia (hyperkalemia, acidosis and hypoxia) resulted in an action potential that is shorter (APD90 -37% or -46% according to IKatp by Ledezma or Kazbanov), hyperpolarized (MDP +15%), with smaller peak (-38% or -46%), as well as elevated diastolic (+ 9% or 8%) and lower (-4% and -3%) intracellular Ca2+. Also, the full ischemia model produced alternans at fast pacing (cycle length 300ms).

Our sensitivity analysis demonstrates that the BPS2020 model correctly recapitulates the acute ischemia effects and it is suitable for more advanced simulations.