INTRODUCTION: Both heart failure (HF) and hypertrophic cardiomyopathy (HCM) may lead to potentially lethal arrhythmias. The aim of this work is to use computational simulation to study the potentially beneficial (i.e. anti-arrhythmic) effects of different drugs in HF and HCM-affected hearts.
METHODS: We used a modified version of the O'Hara et al. model of the human ventricular cardiac action potential (AP). The model includes the effects of HF and HCM on selected ionic currents. The data was taken from experimental patch-clamp data corresponding to human cardiomyocytes. Additionally, the effect of drugs has been implemented using the simple pore model on the basis of published IC50 values and Hill coefficients.
RESULTS: 126 control simulations were run in endo/mid/epicardial cells of both sexes and at different stimulation rates. 12 of them showed EADs, all belonging to the midmyocardium and with severe HF and HCM. In order to mitigate these effects, simulations were carried out using the same risk-promoting conditions but with the effect of 28 antiarrhythmic drugs individually. Also, different pre-clinical biomarkers (such as action potential duration) were measured in the simulations. Our results showed that 6 drugs (at normal therapeutical doses) were able to prevent the occurrence of EADs of which Diltiazem, Nifedipine and Nitrendipine are prescribed for cardiac symptomology. Moreover, there were 2 control conditions that provoked alternans, which were mitigated by the individual effect of 15 drugs at therapeutical doses, of which Nifedipine, Nitrendipine, Diltiazem and Verapamil are calcium channel blockers prescribed for cardiac pathologies. Drug effect simulations with healthy conditions were run as well, and results show that, at therapeutical doses, Ibutilide, Thioridazine and Quinidine, three drugs commonly used in clinical practice, increase the risk of EADs.
CONCLUSION: The risk of HF and HCM developing arrhythmias may be reduced with drugs as identified by our in-silico AP model.