Abstract
BackgroundOrgan-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.ObjectiveWe 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).MethodsWe 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.ResultsReducing 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.ConclusionOur 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.
Highlights
The effects of macroscopic structure on impulse propagation in cardiac tissue are well understood, having been characterized in tissue wedges and geometrically simple computer models [1,2,3,4]
Our new safety factor (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 premature ventricular contractions (PVCs) originating near regions of ventricular wall expansion, such as the RV outflow tract
The primary arrhythmogenesis mechanism in both cases was conduction block of wavefronts propagating from the thin RV into the thick left ventricular (LV) and septum; activation sequences and spatiotemporal Vm maps for two reentry-inducing PVCs (Figs. 3A–B) illustrate this point
Summary
The effects of macroscopic structure on impulse propagation in cardiac tissue are well understood, having been characterized in tissue wedges and geometrically simple computer models [1,2,3,4]. Wavefront propagation from thin to thick regions fails when source current emerging from the excited tissue is insufficient to elicit action potentials in non-excited downstream cells, which act as a current sink [5]. This source-sink mismatch at sites of structural expansion is exacerbated by conditions that impair tissue excitability, such as reduced depolarizing sodium current (INa) density [2]. Establishing mechanistic understanding of how decreased excitability diminishes propagation robustness and leads to arrhythmogenic conduction block is of major significance because many conditions that cause sudden cardiac death are associated with decreased INa, including ischemia [6] and Brugada syndrome (BrS) [7,8]. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
