title: Stochastic spontaneous calcium release events trigger premature ventricular complexes by overcoming electrotonic load.
abstract: OBJECTIVE
  Premature ventricular complexes (PVCs) due to spontaneous calcium (Ca) release (SCR) events at the cell level can precipitate ventricular arrhythmias. However, the mechanistic link between SCRs and PVC formation remains incompletely understood. The aim of this study was to investigate the conditions under which delayed afterdepolarizations resulting from stochastic subcellular SCR events can overcome electrotonic source-sink mismatch, leading to PVC initiation.
  
  
  RESULTS
  A stochastic subcellular-scale mathematical model of SCR was incorporated in a realistic model of the rabbit ventricles and Purkinje system (PS). Elevated levels of diastolic sarcoplasmic reticulum Ca(2+) (CaSR) were imposed until triggered activity was observed, allowing us to compile statistics on probability, timing, and location of PVCs. At CaSR≥ 1500 µmol/L PVCs originated in the PS. When SCR was incapacitated in the PS, PVCs also emerged in the ventricles, but at a higher CaSR (≥1550 µmol/L) and with longer waiting times. For each model configuration tested, the probability of PVC occurrence increased from 0 to 100% within a well-defined critical CaSR range; this transition was much more abrupt in organ-scale models (∼50 µmol/L CaSR range) than in the tissue strand (∼100 µmol/L) or single-cell (∼450 µmol/L) models. Among PVCs originating in the PS, ∼68% were located near Purkinje-ventricular junctions (<1 mm).
  
  
  CONCLUSIONS
  SCR events overcome source-sink mismatch to trigger PVCs at a critical CaSR threshold. Above this threshold, PVCs emerge due to increased probability and reduced variability in timing of SCR events, leading to significant diastolic depolarization. Sites of lower electronic load, such as the PS, are preferential locations for triggering.
authors.affiliation: Institute of Biophysics, Medical University of Graz, Graz, Austria.
authors.forename: Fernando O
authors.initials: FO
authors.lastname: Campos
authors.affiliation: Department of Physics, California State University, Northridge, CA, USA.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Shiferaw
authors.affiliation: Institute of Biophysics, Medical University of Graz, Graz, Austria.
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Prassl
authors.affiliation: Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Boyle
authors.affiliation: LIRYC Institute, University of Bordeaux, Bordeaux, France Department of Electrical and Computer Engineering, University of Calgary, Calgary, Canada.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Vigmond
authors.affiliation: Institute of Biophysics, Medical University of Graz, Graz, Austria gernot.plank@medunigraz.at.
authors.forename: Gernot
authors.initials: G
authors.lastname: Plank
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002036:Bundle of His / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D003198:Computer Simulation; D006333:Heart Failure / Q000503:physiopathology; D006352:Heart Ventricles; D011817:Rabbits
chemical_list: D002118:Calcium
keywords: Arrhythmia; Computer-based model; Delayed afterdepolarization; Purkinje system; Triggered activity