Myocardial Infarct Border Zone Structure and its Effects on Electrical Function of the Heart

Abstract

Heart disease is a leading cause of death in the developed world. Healed myocardial infarcts provide a substrate for potentially life-threatening reentrant arrhythmias. Slow non-uniform electrical propagation in the border zone of a healed infarct can give rise to such reentrant arrhythmia. The extent to which this is influenced by structural rather than cellular electrical remodelling is unclear. The objectives of this research were to characterise the structure of the infarct border zone at high resolution in a small animal model of structural heart disease, to describe the spread of activation through border zone using structure-based computer modelling, and to develop an experimental preparation that could be used to validate our structure-based computer modelling results. These methods combined are a strong tool to increase the understanding of how structural remodelling in the border zone alters electrical propagation, and predisposes hearts to reentrant arrhythmia. In this project, we have for the first time, acquired extensive volume images at high spatial resolution of the border zone and normal myocardium adjacent to healed rat infarcts and have reconstructed the 3D arrangement of myocytes, necrotic tissue, blood vessels and connective tissue throughout this region. We have simulated the spread of electrical activation using a structure-specific network model constructed from connected myocytes. In the final section of this study we developed an isolated Langendorff-supported rat heart preparation, in which electrical activation was mapped simultaneously on both the epicardial and endocardial surfaces of the left ventricle. To reduce artifact due to contraction in the optical datasets, a novel correction approach was developed in which variation in background fluorescence intensity was used to stabilise images and residual artifact was then extracted on a pixel-by-pixel basis. The key findings of the high resolution imaging and 3D reconstruction of the border zone were: 1) the infarct border zone was characterised by thin layers of surviving myocytes across the endocardial surface and in some regions of the epicardium near the edges of the infarct, 2) thin intramural tracts of preserved myocytes projected into the border zone and in some cases, formed continuous pathways across it from endocardium to epicardium, 3) lateral coupling between adjacent myocytes decreased abruptly across the interface between infarct and surrounding surviving myocardium, and 4) normal patterns of transmural myofibre rotation were disrupted in infarct border zone due to necrosis and infarct contraction. Computer modelling of the spread of activation through the network representation of the border zone structure demonstrated that the pathways described above exhibit direction and rate-dependent delay and block. Activation delays are not uniformly distributed along these pathways, but instead are associated with specific regions in which there are rapid changes in tract cross-section. This model demonstrates “zig-zag” conduction as described by de Bakker et al. [1]. It also describes the importance of source-to-sink electrical mismatch, which occurred as a result of abrupt changes in the dimensions of surviving myofibre tracts in the infarct border zone. These caused substantial local rate-dependent activation delay and unidirectional conduction block, on top of the tortuous activation pathways that cause slow global activation spread. We conclude that these mechanisms of local conduction velocity slowing and/or unidirectional conduction block, together with tortuous activation pathways causing global conduction velocity slowing, provide a dynamic substrate for reentry in the infarct border zone. We have demonstrated in a detailed image-based model of the infarct border zone that structural heterogeneity provides a dynamic substrate for electrical reentry. The novel experimental preparation that has been developed should allow us to validate these computer modelling results in the setting of infarct border zone and other forms of structural heart disease in the future.