Li, Qince, Yan, Zheng, Wang, Zhen, Liang, Cuiping, Wang, Xiqian, Wu, Xianghu, Wang, Wei, Yuan, Yongfeng, and Wang, Kuanquan
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. Author summary: In acute coronary syndrome, the progression of ischemic, injury, and infarction conditions heightens the risk of ischemic cardiac arrhythmias. Despite the existence of various antiarrhythmic drugs, there remains a scarcity of medications specifically tailored for ischemic cardiac arrhythmias. Moreover, comprehending the diverse drug responses in tissues with multiple ischemic conditions (ischemia 1a, 1b, and infarction) remains incomplete. Therefore, in this study, mathematical models depicting the electrophysiological remodeling induced by different drugs such as amiodarone, telmisartan, E-4031, chromanol 293B, and glibenclamide, are constructed and integrated into multi-scale computational models to assess their antiarrhythmic effects. Simulation results demonstrate the potential of glibenclamide in mitigating ischemic cardiac arrhythmias. It can be attributed to its ability not only to improve the depolarization phase's membrane potential by inhibiting extracellular potassium accumulation during the ischemic stage, leading to an increased dV/dtmax, but also to extend the action potential duration (APD) by suppressing IKATP. Finally, the application of glibenclamide results in heightened conduction velocity and prolonged APD at the tissue level. Consequently, these effects enlarge the wavelength of excitation waves, ultimately reducing the vulnerable window for reentrant wave and exhibiting an anti-ischemic arrhythmic effect. More importantly, it's shown that glibenclamide's inhibition of [K+]o yields a more significant impact on antiarrhythmic effects compared to its prolongation of APD. This is partly due to the more pronounced enhancement in the wavelength of excitation waves resulting from CV elevation compared with APD prolongation. Additionally, in tissues with coexisting multiple ischemic conditions, suppressing [K+]o reduces the spatial dispersion of CV, especially at the boundaries of different ischemic tissues like ischemia 1b and infarction, facilitating a more uniform excitation wave propagation. This study offers insights into the anti-arrhythmic mechanisms of established agents during acute coronary syndrome and identifies potential targets for novel anti-arrhythmic drug development. [ABSTRACT FROM AUTHOR]