title: Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve.
abstract: OBJECTIVE
  Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia.
  
  
  RESULTS
  A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase.
  
  
  CONCLUSIONS
  Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.
authors: Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors: Sara
authors: S
authors: Dutta
authors: Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
authors: Ana
authors: A
authors: Mincholé
authors: Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom.
authors: Ernesto
authors: E
authors: Zacur
authors: Department of Physiology and Biophysics, Dalhousie University, Canada.
authors: T Alexander
authors: TA
authors: Quinn
authors: Institute of Cardiovascular Science, University College London, Bars Heart Centre, United Kingdom.
authors: Peter
authors: P
authors: Taggart
authors: Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom. Electronic address: blanca.rodriguez@cs.ox.ac.uk.
authors: Blanca
authors: B
authors: Rodriguez
mesh_terms: D000208:Acute Disease; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008564:Membrane Potentials; D008953:Models, Anatomic; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D020746:Calcium Channels, L-Type
keywords: Computer-based model; Ischemic heart disease; Potassium channels; Repolarization; Ventricular arrhythmia