Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed reduction in recurrent arrhythmias through antiarrhythmic drug therapy, the precise mechanisms underlying their effectiveness in treating ischemic heart disease remain unclear. Moreover, there is a lack of specialized drugs designed explicitly for the treatment of myocardial ischemic arrhythmia. This study employs an electrophysiological simulation approach to investigate the potential antiarrhythmic effects and underlying mechanisms of various pharmacological agents in the context of ischemia and myocardial infarction (MI). Based on physiological experimental data, computational models are developed to simulate the effects of a series of pharmacological agents (amiodarone, telmisartan, E-4031, chromanol 293B, and glibenclamide) on cellular electrophysiology and utilized to further evaluate their antiarrhythmic effectiveness during ischemia. On 2D and 3D tissues with multiple pathological conditions, the simulation results indicate that the antiarrhythmic effect of glibenclamide is primarily attributed to the suppression of efflux of potassium ion to facilitate the restitution of [K+]o, as opposed to recovery of IKATP during myocardial ischemia. This discovery implies that, during acute cardiac ischemia, pro-arrhythmogenic alterations in cardiac tissue's excitability and conduction properties are more significantly influenced by electrophysiological changes in the depolarization rate, as opposed to variations in the action potential duration (APD). These findings offer specific insights into potentially effective targets for investigating ischemic arrhythmias, providing significant guidance for clinical interventions in acute coronary syndrome.

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 IKATP, and APA and RP of cells were the most sensitive to the change of [K+]o. The parameter sensitivity analysis of the cell model in long-term MI showed that APD of cell models was sensitive to IKsand ICaL, and APA was most sensitive to INa. Therefore, according to the results of parameter sensitivity analysis, the possible effective targets for the treatment of myocardial ischemia can be preliminarily selected: [K+]o, IKATP, ICaLand INa.

Myocardial ischemia, injury and infarction (MI) are the three stages of acute coronary syndrome (ACS). In the past two decades, a great number of studies focused on myocardial ischemia and MI individually, and showed that the occurrence of reentrant arrhythmias is often associated with myocardial ischemia or MI. However, arrhythmogenic mechanisms in the tissue with various degrees of remodeling in the ischemic heart have not been fully understood. In this study, biophysical detailed single-cell models of ischemia 1a, 1b, and MI were developed to mimic the electrophysiological remodeling at different stages of ACS. 2D tissue models with different distributions of ischemia and MI areas were constructed to investigate the mechanisms of the initiation of reentrant waves during the progression of ischemia. Simulation results in 2D tissues showed that the vulnerable windows (VWs) in simultaneous presence of multiple ischemic conditions were associated with the dynamics of wave propagation in the tissues with each single pathological condition. In the tissue with multiple pathological conditions, reentrant waves were mainly induced by two different mechanisms: one is the heterogeneity along the excitation wavefront, especially the abrupt variation in conduction velocity (CV) across the border of ischemia 1b and MI, and the other is the decreased safe factor (SF) for conduction at the edge of the tissue in MI region which is attributed to the increased excitation threshold of MI region. Finally, the reentrant wave was observed in a 3D model with a scar reconstructed from MRI images of a MI patient. These comprehensive findings provide novel insights for understanding the arrhythmic risk during the progression of myocardial ischemia and highlight the importance of the multiple pathological stages in designing medical therapies for arrhythmias in ischemia.

Cardiovascular obstruction could lead to myocardial ischemia and myocardial infarction (MI). MI can be further divided into short-term MI stage (several days) and long-term MI stage (several months) with the development of coronary artery obstruction, and the electrophysiological characteristics in these two MI stages vary greatly. At present, there are no relevant studies on the effects of different infarct areas (size and location) on the initialization and maintenance of reentrant waves in these two MI stages. Therefore, this study aims to investigate the differences in vulnerability to reentry between these two MI stages by computer modeling and simulation. Firstly, single cell models, based on the TP06 model were developed in two different MI stages. And simulation results on single-cells showed that the action potential duration (APD) significantly shortened and the resting potential (RP) elevated in the short-term MI stage, compared with that in the normal condition. However, APD prolonged and RP only changed little in the long-term MI stage. When MI areas in 2D annular ventricular tissues were designed with different lengths, widths and positions, the distribution of the vulnerable window (VW) in these two MI stages was investigated. The simulation results showed that the vulnerability of the two MI stages to the length and position of the infarct areas is the same. That is with the increase of the length, VW gradually increased and reached a constant value when the percentage of the length of the MI area reached 50%. And VW was the largest when the infarct area was close to the inner or outer wall. The vulnerability to the width of the infarct area in these two MI stages is different. In short-term MI, VW was the largest when the width of the infarct area was narrow or wide, while in long-term MI, VW was the largest when the width of the MI area reached half of the width of the ventricular wall. In this paper, the effect of the different infarct areas on the initialization and maintenance of reentrant waves in two different MI stages was investigated by computing simulation. This would improve the understanding of arrhythmogenicity in the MI stage and could provide new sights in arrhythmogenic mechanism of MI phases.

Myocardial ischemia and myocardial infarction (MI) are often accompanied by the occurrence of reentrant arrhythmias, which may lead to sudden cardiac death in severe cases. Previous studies show that electrical alternans can occur during myocardial ischemia and MI and may lead to arrhythmias. However, so far, the mechanism of alternans during myocardial ischemia and MI is unclear, so the related study on alternans is particularly important. Based on single-cell models previously modeled by us at three stages: ischemia 1a, 1b, and MI, the mechanism of alternans was revealed by comparing the changes in alternans at three levels: single cells, one-dimensional (1D) tissues, and two-dimensional (2D) tissues. In addition, the main factors inducing alternans were investigated, and the effect of antiarrhythmic drug glibenclamide on alternans was simulated. The simulation results on single cells of ischemia 1a, 1b and MI showed that the electrical alternans on the cell-levels were unstable electrical alternans. Simulation results in tissues showed that stable electrical alternans could occur in both 1D and 2D tissues. Simulation results showed that alternans in ischemia 1a were mainly caused by two factors: inhibition of $\mathrm{I}_{\mathrm{Na}}$ and elevation of $[\mathrm{K}^{+}]_{\mathrm{o}}$; alternans in ischemia 1b were mainly caused by two factors: inhibition of $\mathrm{I}_{\mathrm{NaK}}$ and elevation of $[\mathrm{K}^{+}]_{\mathrm{o}}$; alternans in MI were mainly caused by three factors: inhibition of $\mathrm{I}_{\mathrm{Kr}}$, inhibition of $\mathrm{I}_{\mathrm{Ks}}$, and elevation of $[\mathrm{K}^{+}]_{\mathrm{o}}$. And electrical alternans in the tissues result in a 2:1 conduction block. In addition, the simulation results showed that glibenclamide could inhibit electrical alternans in single cells and tissues. Electrical alternans during ischemia 1a, 1b and MI are caused by several currents that directly affect the action potential, and can lead to a 2:1 conduction block in tissues. Glibenclamide inhibits the occurrence of electrical alternans by inhibiting the efflux of potassium ions.