A novel model of acute myocardial ischemia in human ventricular cardiomyocytes

Marta Girones-Sanguesa1, Claudia Esteban1, Ana González-Ascaso2, Jose F Rodriguez-Matas3, Jose M Ferrero1
1CI2B, Universitat Politecnica de Valencia, 2Universitat Politecnica de Valencia, 3Politecnico di Milano


INTRODUCTION: Acute myocardial ischemia (AMI) is a well-known pathological process that provokes more than 7 million deaths per year in the world. In the last decades, computational simulation has been used to study the electrophysiological effects of AMI. The aim of this work is to develop a new cellular model of AMI that goes beyond the state of the art by considering new effects of ischemic parameters in a variety of ionic currents.

METHODS: The model is based on the modified O’Hara-Rudy model of the human ventricular cardiac action potential (AP). Our AMI model includes new descriptions of the direct effects of [ATP]i, [ADP]i, pHi, pHo and [LPC]i on the INa, INaL, ICaL, IKr, IK(ATP), IK1, Ito, INaK, NCX, SERCA, RyR and IpCa currents. All the equations are based on patch-clamp data corresponding (or adapted) to human cardiomyocytes.

RESULTS: The model was tested by simulating the separate and combined effects of [ATP]i, [ADP]i, pHi, pHo and [LPC]i. Different pre-clinical biomarkers (such as action potential duration (APD90)) were measured in the simulations. Our results are in good agreement with experimental/clinical observations in human hearts. The behaviour of the IK(ATP) current is within the clinically inferred range (average increase of 0.03%/min in the faction of open channels). Separate intracellular and extracellular acidosis exert opposite effects in APD90 (32ms increase and 24ms decrease in APD90, respectively), which is in accordance with experimental data. In global ischemia, the average rates of APD90 reduction (-22ms/min), PRR increase (13ms/min) and [K+]o increase (0.9mM/min) were also in good agreement with clinical data. This level of agreement of our AMI model with human clinical data is thus higher than previously published models that include less ischemic effects in ionic currents.

CONCLUSION: The AMI developed in the present work is more accurate and comprehensive that previous AMI models.