Ventricular endocardial tissue geometry affects stimulus threshold and effective refractory period

Connolly, A., Kelly, A., Campos, F. O., Myles, R. , Smith, G. and Bishop, M. J. (2018) Ventricular endocardial tissue geometry affects stimulus threshold and effective refractory period. Biophysical Journal, 115(12), pp. 2486-2498. (doi: 10.1016/j.bpj.2018.11.003) (PMID:30503533) (PMCID:PMC6301915)

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Background: Understanding the biophysical processes by which electrical stimuli applied to cardiac tissue may result in local activation is important in both the experimental and clinical electrophysiology laboratory environments, as well as for gaining a more in-depth knowledge of the mechanisms of focal-trigger-induced arrhythmias. Previous computational models have predicted that local myocardial tissue architecture alone may significantly modulate tissue excitability, affecting both the local stimulus current required to excite the tissue and the local effective refractory period (ERP). In this work, we present experimental validation of this structural modulation of local tissue excitability on the endocardial tissue surface, use computational models to provide mechanistic understanding of this phenomena in relation to localized changes in electrotonic loading, and demonstrate its implications for the capture of afterdepolarizations. Methods and Results: Experiments on rabbit ventricular wedge preparations showed that endocardial ridges (surfaces of negative mean curvature) had a stimulus capture threshold that was 0.21 ± 0.03 V less than endocardial grooves (surfaces of positive mean curvature) for pairwise comparison (24% reduction, corresponding to 56.2 ± 6.4% of the energy). When stimulated at the minimal stimulus strength for capture, ridge locations showed a shorter ERP than grooves (n = 6, mean pairwise difference 7.4 ± 4.2 ms). When each site was stimulated with identical-strength stimuli, the difference in ERP was further increased (mean pairwise difference 15.8 ± 5.3 ms). Computational bidomain models of highly idealized cylindrical endocardial structures qualitatively agreed with these findings, showing that such changes in excitability are driven by structural modulation in electrotonic loading, quantifying this relationship as a function of surface curvature. Simulations further showed that capture of delayed afterdepolarizations was more likely in trabecular ridges than grooves, driven by this difference in loading. Conclusions: We have demonstrated experimentally and explained mechanistically in computer simulations that the ability to capture tissue on the endocardial surface depends upon the local tissue architecture. These findings have important implications for deepening our understanding of excitability differences related to anatomical structure during stimulus application that may have important applications in the translation of novel experimental optogenetics pacing strategies. The uncovered preferential vulnerability to capture of afterdepolarizations of endocardial ridges, compared to grooves, provides important insight for understanding the mechanisms of focal-trigger-induced arrhythmias.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Myles, Dr Rachel and Kelly, Dr Allen
Authors: Connolly, A., Kelly, A., Campos, F. O., Myles, R., Smith, G., and Bishop, M. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Biophysical Journal
ISSN (Online):1542-0086
Published Online:09 November 2018
Copyright Holders:Copyright © 2018 Biophysical Society
First Published:First published in Biophysical Journal 115(12):2486-2498
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
665411Investigating the mechanisms of low-voltage defibrillation and its application to the human ventricle to facilitate its translation into the clinicGodfrey SmithBritish Heart Foundation (BHF)PG/14/66/30927RI CARDIOVASCULAR & MEDICAL SCIENCES