Electrophysiological and anatomical factors determine arrhythmic risk in acute myocardial ischaemia and its modulation by sodium current availability.

Hector Martinez-Navarro,Alfonso Bueno-Orovio,Xin Zhou,Blanca Rodriguez

doi:10.1098/rsfs.2019.0124

Abstract

Acute myocardial ischaemia caused by coronary artery disease is one of the main causes of sudden cardiac death. Even though sodium current blockers are used as anti-arrhythmic drugs, decreased sodium current availability, also caused by mutations, has been shown to increase arrhythmic risk in ischaemic patients. The mechanisms are still unclear. Our goal is to exploit perfect control and data transparency of over 300 high-performance computing simulations to investigate arrhythmia mechanisms in acute myocardial ischaemia with variable sodium current availability. The human anatomically based torso-biventricular electrophysiological model used includes representation of realistic ventricular anatomy and fibre architecture, as well as ionic to electrocardiographic properties. Simulations show that reduced sodium current availability increased arrhythmic risk in acute regional ischaemia due to both electrophysiological (increased dispersion of refractoriness across the ischaemic border zone) and anatomical factors (conduction block from the thin right ventricle to thick left ventricle). The asymmetric ventricular anatomy caused high arrhythmic risk specifically for ectopic stimuli originating from the right ventricle and ventricular base. Increased sodium current availability was ineffective in reducing arrhythmic risk for septo-basal ectopic excitation. Human-based multiscale modelling and simulations reveal key electrophysiological and anatomical factors determining arrhythmic risk in acute ischaemia with variable sodium current availability.

Highlights

Acute myocardial ischaemia is a leading cause of sudden cardiac death, produced by reduced blood flow in the coronary arteries
The authors identified the right-ventricular outflow tract (RVOT) and the posteroinferior septal region of the RV as the most pro-arrhythmic ectopic locations. These results are fully consistent with our findings: (i) the simulations of low INa availability presented in this study identified a higher occurrence of reentries than in [14], which can be explained by the presence of acute myocardial ischaemia in the anterior myocardial wall; (ii) our results identified royalsocietypublishing.org/journal/rsfs Interface Focus 11: 20190124
Multiscale simulations using a human biventricular ventricular model show that anatomical factors as well as electrophysiological properties explain increased arrhythmic risk in acute ischaemia caused by changes in INa availability

Summary

Introduction

Acute myocardial ischaemia is a leading cause of sudden cardiac death, produced by reduced blood flow in the coronary arteries. Its causes include blood clot formation, atherosclerosis or vasospasm and its electrophysiological consequences increase the risk of lethal arrhythmias such as ventricular fibrillation. The occurrence of ischaemia-induced arrhythmias is modulated by additional conditions, such as drug-induced effects and channelopathies. As reported in the clinical trial CAST (Cardiac Arrhythmia Suppression Trial), sodium channel blockers may increase arrhythmic risk in patients suffering from recurrent acute ischaemia episodes [2,3]. Studies have highlighted the genetic predisposition to ischaemia-induced arrhythmias of patients with sodium current (INa) channelopathies, such as Brugada syndrome or Lenègre’s disease [4,5]

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