Mechanisms of ventricular arrhythmias elicited by coexistence of multiple electrophysiological remodeling in ischemia: a simulation study

Abstract

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 were constructed to investigate the mechanisms of initiation of reentrant waves during the progression of ischemia. Simulation results in 2D tissues showed that the vulnerable window (VW) in the tissue with multiple pathological conditions were determined by the VWs in the tissues with a single pathological condition. In different pathological conditions, action potential duration (APD) and the conduction velocity (CV) change differently. In the tissue with multiple pathological conditions, when the borders of different pathological conditions were perpendicular to the excitation wavefront, reentrant waves were mainly induced by the spatial heterogeneity of refractory periods due to the interaction of APD and CV along the wavefront. When the borders were parallel to the wavefront, the increased excitation threshold of MI region as well as the impaired excitability of ischemia region were the primary reason for the generation of reentry. 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 stage in designing medical therapies for arrhythmia in ischemia. Author summaryAbnormal initiation or conduction of electrical impulses may lead to cardiac arrhythmias, which are very important cause of sudden and early death in developed countries. In many cases, cardiac arrhythmias are accompanied by ventricular fibrillation sustained by re-entry. The occurrence of reentrant arrhythmias is often associated with acute coronary syndrome, including three phases of myocardial ischemia 1a, 1b, and infarction. Previous studies have made lots of efforts to unravel the mechanisms of the initiation and maintenance of reentry waves during myocardial ischemia or infarction. However, the mechanisms of initiation of reentrant waves in the tissue with multiple ischemic remodeling are not fully understood. Multi-scale computational models at the cellular, tissue, and organ levels were developed in this study. The main finding in this study is that reentrant waves in multiple pathological tissues were mainly induced by the spatial heterogeneity of refractory periods, when the borders of different pathological conditions were perpendicular to the wavefront of the excitation wave. In addition, the increased excitation threshold of MI region as well as the impaired excitability of ischemia region can induce the generation of reentry, when the borders were parallel to the excitation wavefront. This provides insights into mechanisms of ventricular arrhythmias elicited by coexistence of multiple electrophysiological remodeling in ischemia.