Sodium current reduction unmasks a structure-dependent substrate for arrhythmogenesis in the normal ventricles.
BACKGROUND
Organ-scale arrhythmogenic consequences of source-sink mismatch caused by impaired excitability remain unknown, hindering the understanding of pathophysiology in disease states like Brugada syndrome and ischemia.


OBJECTIVE
We sought to determine whether sodium current (INa) reduction in the structurally normal heart unmasks a regionally heterogeneous substrate for the induction of sustained arrhythmia by premature ventricular contractions (PVCs).


METHODS
We conducted simulations in rabbit ventricular computer models with 930 unique combinations of PVC location (10 sites) and coupling interval (250-400 ms), INa reduction (30 or 40% of normal levels), and post-PVC sinus rhythm (arrested or persistent). Geometric characteristics and source-sink mismatch were quantitatively analyzed by calculating ventricular wall thickness and a newly formulated 3D safety factor (SF), respectively.


RESULTS
Reducing INa to 30% of its normal level created a substrate for sustained arrhythmia induction by establishing large regions of critical source-sink mismatch (SF<1) for ectopic wavefronts propagating from thin to thick tissue. In the same simulations but with 40% of normal INa, PVCs did not induce reentry because the volume of tissue with SF<1 was >95% smaller. Likewise, when post-PVC sinus activations were persistent instead of arrested, no ectopic excitations initiated sustained reentry because sinus activation breakthroughs engulfed the excitable gap.


CONCLUSIONS
Our new SF formulation can quantify ectopic wavefront propagation robustness in geometrically complex 3D tissue with impaired excitability. This novel methodology was applied to show that INa reduction precipitates source-sink mismatch, creating a potent substrate for sustained arrhythmia induction by PVCs originating near regions of ventricular wall expansion, such as the RV outflow tract.
Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.
Patrick M
PM
Boyle
Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.
Carolyn J
CJ
Park
Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.
Hermenegild J
HJ
Arevalo
Institut LIRYC, Université Bordeaux 1, Bordeaux, France.
Edward J
EJ
Vigmond
Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.
Natalia A
NA
Trayanova
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology* / Q000503:physiopathology*; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology*; D011817:Rabbits; D015222:Sodium Channels / Q000378:metabolism*; D018879:Ventricular Premature Complexes / Q000473:pathology / Q000503:physiopathology
D015222:Sodium Channels