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. 2011 Sep 21;101(6):1307-15.
doi: 10.1016/j.bpj.2011.08.009. Epub 2011 Sep 20.

Susceptibility to arrhythmia in the infarcted heart depends on myofibroblast density

Kathleen S McDowell  1 , Hermenegild J Arevalo, Mary M Maleckar, Natalia A Trayanova
Affiliations

Susceptibility to arrhythmia in the infarcted heart depends on myofibroblast density

Kathleen S McDowell et al. Biophys J. .

Abstract

Fibroblasts are electrophysiologically quiescent in the healthy heart. Evidence suggests that remodeling following myocardial infarction may include coupling of myofibroblasts (Mfbs) among themselves and with myocytes via gap junctions. We use a magnetic resonance imaging-based, three-dimensional computational model of the chronically infarcted rabbit ventricles to characterize the arrhythmogenic substrate resulting from Mfb infiltration as a function of Mfb density. Mfbs forming gap junctions were incorporated into both infarct regions, the periinfarct zone (PZ) and the scar; six scenarios were modeled: 0%, 10%, and 30% Mfbs in the PZ, with either 80% or 0% Mfbs in the scar. Ionic current remodeling in PZ was also included. All preparations exhibited elevated resting membrane potential within and near the PZ and action potential duration shortening throughout the ventricles. The unique combination of PZ ionic current remodeling and different degrees of Mfb infiltration in the infarcted ventricles determines susceptibility to arrhythmia. At low densities, Mfbs do not alter arrhythmia propensity; the latter arises predominantly from ionic current remodeling in PZ. At intermediate densities, Mfbs cause additional action potential shortening and exacerbate arrhythmia propensity. At high densities, Mfbs protect against arrhythmia by causing resting depolarization and blocking propagation, thus overcoming the arrhythmogenic effects of PZ ionic current remodeling.

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Figures

Figure 1
Figure 1
Model generation. Representative MRI slice of the rabbit heart, segmentation of the slice, and whole heart mode.
Figure 2
Figure 2
(A) VREST maps in the models. 0% (top row) or 80% (bottom row) Mfbs in the scar region. 0% (left column), 10% (middle column), or 30% (right column) Mfbs in the PZ. Average PZ VREST values and standard deviations are listed below the respective preparations (B). Boxplots of VREST in PZ of each substrate. Whiskers represent minimum and maximum of all values in a given preparation.
Figure 3
Figure 3
APD maps in the models (A) and those when ionic current remodeling in the PZ is removed (B). 0% (top row) or 80% (bottom row) Mfbs in the scar region. 0% (left column), 10% (middle column), or 30% (right column) Mfbs in the PZ. The average APD and its standard deviation are listed below each preparation. Boxplots represent distribution of APD in the PZ (C) and healthy tissue (D) for both sets of models.
Figure 4
Figure 4
VREST and APD as a function of distance along the vertical line between points A (in the outer edge of the PZ) and B (10 mm removed from the outer edge of the PZ) in the Scar80PZ30 model.
Figure 5
Figure 5
Transmembrane potential maps of arrhythmia (top row) and termination of conduction (bottom row) at four time instants in two preparations. Cross-sectional views show endocardial surfaces for the right and left ventricles (RV and LV, respectively, marked at bottom right). Red arrows indicate the location of S3 on the endocardial apex. Line of unidirectional block is marked in black. Conduction direction is indicated by the black arrows.
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