INTRODUCTION: It is known that acute ischemia is highly proarrhythmic. Hyperkalemia and action potential alternans are among the most proarryhtmic features of this pathology. The aim of this work is to assess the effect of different drugs on the time-course of extracellular potassium concentration ([K+]o) and on the duration of the alternating period using computational simulation, and to identify new biomarkers that help to characterize the performance of a drug under ischemic conditions.
METHODS: The O’Hara-Rudy model, modified by Gonzalez and Ferrero to account for acute ischemia, was used in the simulations. The effect of 95 different drugs was modelled using their corresponding IC50s, Hill coefficients and therapeutic plasma concentrations (EFTPC). For each drug, different simulations were performed by modifying the drug concentration according to the EFTPC on an isolated cell stimulated for 5 minutes under control conditions followed by 30 minutes of progressive acute ischemia.
RESULTS: Two novel biomarkers were identified, which are the time spent by [K+]o between 8 and 13 mM (BM1) (15.6 min in control) and the duration of the alternating period of the action potential (BM2) (1.7 min in control), in addition to secondary biomarkers such as the [K+]o value in the potassium plateau. The best drugs for BM1 reduction are Ibutilide [2xEFTPC] (6.0 min) and [1xEFTPC] (12.7 min) and Nitrendipine [2xEFTPC] (13.5 min) and Nitrendipine [1xEFTPC] (13.6 min). The best drugs for BM2 reduction are Nitrendipine [1x and 2x EFTPC], that remove the alternating period (0 min), and Thioridazine [2xEFTPC] (0.1 min).
CONCLUSION: Nitrendipine may be a good candidate as a protective drug in acute ischemia. The results obtained show promising indications in terms of efficacy of drugs in acute ischemia, and serve as a preliminary identification step to model the effect of drugs in arrhythmia vulnerability using cardiac 3D models.