Factors Promoting Conduction Slowing as Substrates for Block and Reentry in Infarcted Hearts

Fernando O Campos,John Whitaker,Radhouene Neji,Sébastien Roujol,Mark O’Neill,Gernot Plank,Martin J Bishop

doi:10.1016/j.bpj.2019.08.008

Fernando O Campos, John Whitaker + Show 5 more

Open Access

https://doi.org/10.1016/j.bpj.2019.08.008

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Abstract

The development of effective and safe therapies for scar-related ventricular tachycardias requires a detailed understanding of the mechanisms underlying the conduction block that initiates electrical re-entries associated with these arrhythmias. Conduction block has been often associated with electrophysiological changes that prolong action potential duration (APD) within the border zone (BZ) of chronically infarcted hearts. However, experimental evidence suggests that remodeling processes promoting conduction slowing as opposed to APD prolongation mark the chronic phase. In this context, the substrate for the initial block at the mouth of an isthmus/diastolic channel leading to ventricular tachycardia is unclear. The goal of this study was to determine whether electrophysiological parameters associated with conduction slowing can cause block and re-entry in the BZ. In silico experiments were conducted on two-dimensional idealized infarct tissue as well as on a cohort of postinfarction porcine left ventricular models constructed from ex vivo magnetic resonance imaging scans. Functional conduction slowing in the BZ was modeled by reducing sodium current density, whereas structural conduction slowing was represented by decreasing tissue conductivity and including fibrosis. The arrhythmogenic potential of APD prolongation was also tested as a basis for comparison. Within all models, the combination of reduced sodium current with structural remodeling more often degenerated into re-entry and, if so, was more likely to be sustained for more cycles. Although re-entries were also detected in experiments with prolonged APD, they were often not sustained because of the subsequent block caused by long-lasting repolarization. Functional and structural conditions associated with slow conduction rather than APD prolongation form a potent substrate for arrhythmogenesis at the isthmus/BZ of chronically infarcted hearts. Reduced excitability led to block while slow conduction shortened the wavelength of propagation, facilitating the sustenance of re-entries. These findings provide important insights for models of patient-specific risk stratification and therapy planning.

Highlights

Ventricular tachycardias (VTs) are associated with an increased risk of sudden death in patients with myocardial infarction (MI) [1]
Experiments with a 2D model with prolonged action potential duration (APD) in the isthmus was carried out to serve as a basis for comparison
We have employed computational models with different complexities to investigate whether functional and structural remodeling promoting conduction slowing can lead to arrhythmia. This has not been robustly investigated in the literature so far and may have critical implications in the use of computational models to assess patient-specific arrhythmogenic risk and improve therapy planning

Summary

Introduction

Ventricular tachycardias (VTs) are associated with an increased risk of sudden death in patients with myocardial infarction (MI) [1]. Clinical scar-related VTs are characterized by continuous circulating electrical wavefronts that repetitively re-excite the ventricular myocardium around a re-entrant pathway, or diastolic isthmus, generated by the region of scar and surviving tissue [2,3]. In the chronic phase of MI, these diastolic isthmuses are comprised of a heterogeneous admixture of remodeled myocardium and patchy fibrosis [4]. Such tissue is often termed the infarct border zone (BZ) because it is found at peripheral scar boundaries and increased presence of which has been correlated strongly with arrhythmic risk [5,6]. A re-entry can only be sustained if the wavelength, given by the mathematical product of the conduction velocity (CV) and the effective refractory period (closely related to the action potential duration (APD)), is shorter than the conducting pathway within the heart [9]

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