Key result
Electrophysiological simulations identify [K+]o, IKATP, ICaL, and INa as potential therapeutic targets in myocardial ischemia.
Why the study?
Few studies focus on antiarrhythmic drugs directly targeting ion channels for myocardial ischemia because the effective targets across different ischemic stages remain unclear.
Computational modeling of human ventricular cells identifies [K+]o, IKATP, ICaL, and INa as potential effective targets for treating myocardial ischemia across different pathological stages.
Should not change practice; leaves open experimental and clinical validation of these targets.
Previous studies have shown that coronary artery occlusion can cause myocardial ischemia, which can induce ventricular tachycardia or fibrillation. According to the time sequence, myocardial ischemia can be divided into different pathological stages: the ischemia 1a stage (0-15 minutes), the ischemia 1b stage (15-45 minutes), the short-term myocardial infarction (MI) (within a few days) and the long-term MI (within a few weeks). However, few studies give attention to antiarrhythmic drugs directly acting on ion channels for the treatment of myocardial ischemia. The main reason is that the effective targets in myocardial ischemia are unclear. Therefore, based on the technology of electrophysiological simulation, the paper modeled the human ventricular cell model in myocardial ischemia. On this basis, the parameter sensitivity of the model was analyzed and the effective drug targets are selected. Firstly, human ventricular cell models were modeled in ischemia 1a, ischemia 1b, short-term MI and long-term MI based on the experimental data. Then, the sensitivity analysis of output parameters (APA, APD and RP) of the cell model in ischemia was analyzed based on the Sobol method. The results of parameter sensitivity analysis in this paper showed that APD of cell models in ischemia 1a, ischemia 1b and short-term MI was the most sensitive to the change of I<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">KATP</inf>, and APA and RP of cells were the most sensitive to the change of [K+]<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">o</inf>. The parameter sensitivity analysis of the cell model in long-term MI showed that APD of cell models was sensitive to I<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Ks</inf> and I<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">CaL</inf>, and APA was most sensitive to I<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Na</inf>. Therefore, according to the results of parameter sensitivity analysis, the possible effective targets for the treatment of myocardial ischemia can be preliminarily selected: [K+]<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">o</inf>, I<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">KATP</inf>, I<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">CaL</inf> and I<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Na</inf>.
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Liu et al. (2023) studied Myocardial ischemia. Electrophysiological simulation of myocardial ischemia was evaluated on Parameter sensitivity of output parameters (APA, APD, and RP). Electrophysiological simulation of human ventricular cells in myocardial ischemia identified [K+]o, IKATP, ICaL, and INa as possible effective targets for treatment.
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