Using computational modelling to define the ideal characteristics of protective drugs in acute ischemia

Ander Loidi and Jose M Ferrero
Ci2B, Universitat Politecnica de Valencia


INTRODUCTION: It has been shown that increased [K+]o (hyperkalemia) and action potential (AP) alternans are highly proarrhythmic in acute ischemia. The aim of this work is to define the characteristics of an ”ideal” multi ion channel effect drug that would counteract these two proarrhythmic conditions using computational modelling.

METHODS: The O’Hara-Rudy model, modified by Gonzalez-Ferrero to account for acute ischemia, was used in the simulations. To define a population of 1000 candidate drugs, selected ionic currents were multiplied by random factors between 0 and 2 to mimic the inhibition/excitation effect of the drugs. Two different populations were considered: a more restrictive population (MRP), where only IKr, INaL, ICaL, INa and IKs were affected by the drug, and a less restrictive population (LRP) where three additional currents were altered (Ito, IKATP and IK1). Five minutes of normoxia followed by 30 minutes of progressive ischemia were simulated. For a drug model to be considered valid, it must modify the AP biomarkers only within predefined ranges in normoxia.

RESULTS: We identified those candidate drugs that improved two arhythmic biomarkers: time spent by [K+]o between 8 and 13 mM (BM1, 15.60 min in control) and duration of the alternating period of the AP (BM2, 1.70 min in control). Thirty-three candidate drugs in the LRP and two in the MRP were found to reduce BM2 to zero (no alternans). In the latter case, the drugs correspond to the following factors: 0.58-0.86-0.03-1.97-0.33 and 1.40-1.28-0.07-0.14-0.64 for IKr, INaL, ICaL, INa and IKs, respectively. In both cases, the drugs also reduce BM1 (10.43 min and 13.61 min, respectively).

CONCLUSION: Our results demonstrate the feasibility of using AP simulation to define an “ideal” drug that reduces the values of the two ischemic biomarkers (BM1 and BM2) and thus minimizes the arrhythmia vulnerability in acute myocardial ischemia.